Hydroxyamide derivatives and their use

Abstract

The present application provides a hydroxyamide derivative represented by formula (I), its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal. The compounds provided by the present application have an inhibitory effect on both HDAC and LSD1 and can be used for the treatment of diseases mediated by LSD1 and / or HDAC. 【Chemical 1】 JPEG2025516682000268.jpg3037

Description

[Technical Field]

[0001] The present disclosure belongs to the field of medicinal chemistry, and specifically discloses hydroxylamide derivatives and uses thereof, which have significant inhibitory effects on LSD1 and HDAC protein activity and can be used as LSD1 and / or HDAC protein inhibitors, and can be used to prepare therapeutic drugs for cancer and other diseases mediated by LSD1 and HDAC proteins, and have promising future applications. [Background technology]

[0002] The LSD1 protein (Lysine Specific Demethylase 1, also known as KDM1A, histone demethylase) was first discovered and reported by Shi Yang's team at Harvard University in 2004 (Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, JR, Cole, PA, Casero, RA, and Shi, Y. Histone demethylation mediated by the nucleoside Ar amine oxidase homolog LSD1. Cell 2004, 119, 941-953). As a histone demethylase involved in transcriptional regulation, LSD1 has various biological functions, including promoting tumor growth, suppressing energy metabolism, promoting lipid synthesis, inhibiting lipolysis, and controlling cell differentiation. Inhibition of LSD1 function enhances the expression of endogenous retroviral elements (ERVs) and inhibits the function of the RNA-induced silencing complex (RISC), leading to overexpression of double-stranded RNA (dsRNA) and activation of type I interferon (IFN) (Doll, S., Kriegmair, MC, Santos, A., Wierer, M., Coscia, F., Neil, HM, et al. Rapid proteomic analysis for solid tumors reveals LSD1 as a drug target in an end-stage cancer patient. Molecular Oncology, 2018, 12(8), 1296-1307.). Meanwhile, in a publicly available database of human cancers, researchers found a tendency for LSD1 overexpression in several cancer types. Patients with high LSD1 expression had significantly shorter survival times, suggesting that LSD1 overexpression is a poor prognostic factor. Other studies have also shown that LSD1 is highly expressed in various cancer tissues, and a growing number of reports indicate that LSD1 is involved as an epigenetic regulator in various tumor processes and embryonic development.Furthermore, the TCGA Cancer Database showed that LSD1 expression negatively correlated with the antiviral effect of IFN and CD8+ T cell infiltration, consistent with the results of mouse model studies. Therefore, LSD1 inhibition may enhance tumor immunogenicity, promote T cell infiltration, activate antitumor T cell immunity, and potentially target LSD1 for antitumor therapy in combination with anti-PD-1 immunotherapy. Related studies also suggest that DNA methylation inhibition alone or in combination with HDAC inhibitors leads to activation of the interferon (IFN) pathway, enhancing the efficacy of tumor immunotherapy.The PD-1 / PD-L1 cleavage of DNA fragments in a T cell Differential and structural properties of skeletal muscle (Chiappinelli,KB,Strissel,PL,D). esrichard , A. , Li , H. , Henke , C. , Akman , B. , Hein , A. , Rote , NS , Cope , LM , Snyder , A. , et al DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses.Cell 2015,162,974-986、Topper, MJ, Vaz, M., Chiappinelli, KB, DeStefanoShields, CE, Niknafs, N., Yen, RC, Wenzel, A., Hicks, J., Ballew, M., Stone, M., et al Cell 2017, 171, 1284-130 Ghoneim, HE, Fan, Y., Moustaki, A., Abdelsamed, HA, Dash, P., Dogra, P., Carter, R., Awad, W., NEAle, G., Thomas, PG, et al PD-1 blockade-mediated t cell rejuvenation.Cell 2017,70,142-157).

[0003] LSD1 consists of 852 amino acids and has a molecular weight of 93 kDa. Analysis of 27 tissue samples collected from 95 individuals showed that LSD1 is widely expressed in the body, with low secretion from the liver, pancreas, and salivary glands, but high expression levels in testicular tissue and similar levels in other tissues. In research, neuroblastoma, breast cancer (Wang, Y., Zhang, H., et al, Cell 2009, 138(4), 660-72.), anterior line adenocarcinoma (Zhao, L.-J., Fan, Q.-Q., etal., Pharmacol. Res. 2020, 159, 104991), pancreatic cancer (Sehrawat, A., Gao, L., etal., Proc. Nat. Acad. Sci. USA2018, 115(18), E4179-E4188.), colon cancer, glioma and hematological tumors (Hatzi, K., Geng, H., et al. al.,Nature Immunology 2019,20(1),86-96.), and it has been found that high expression of LSD1 is often associated with poor tumor prognosis and recurrence after treatment (Lynch, J., Harris, W., et al., Expert Opinion on Therapeutic Targets 2012,16(12),1239-1249.).

[0004] Previous studies have confirmed that LSD1 exerts its biological functions not only by demethylating histones but also by demethylating non-histone proteins such as p53 and Dnmt1. The biological roles of LSD1 are primarily seen in the regulation of sex hormone receptor-mediated gene transcription, tumor cell proliferation, apoptosis, and metastasis, as well as embryonic development (Ancelin, K., Syx, L., et al., eLife 2016, 5, e08851 / 1-e08851 / 24.) and mitosis. LSD1 has also been reported to be associated with osteoporosis (Sun, J., Ermann, J., et al., Bone Res. 2018, 6(1), 1-12). Furthermore, LSD1 inhibition studies have shown that it is associated with macrophage typing polarization (Tan, AHY, Tu, WJ, et al., Front. Immunol. 2019, 10, 1351.) and CD8+ T cell infiltration in the tumor microenvironment (Hatzi, K., Geng, H., et al., Nature Immunology 2019, 20(1), 86-96). Therefore, the development of LSD1 inhibitors is one of the hotspots in the field of oncology research.

[0005] Histone deacetylases (HDACs) regulate histone acetylation, bind to deacetylated proteins, and interact with nonhistone proteins. They have a wide range of biological functions, including neurodegeneration, inflammation, metabolic disorders, and cancer. HDAC1 is a potential prognostic marker for lung and breast cancer and is overexpressed in prostate, gastric, and colon cancers. HDAC2 is typically overexpressed in colorectal and gastric cancers, while HDAC3 expression is elevated in lung cancer and most solid tumors. HDAC6 is primarily overexpressed in breast cancers. In various human tumor cell lines, knockdown of HDAC8 inhibited tumor cell growth and proliferation. In cancer cells, overexpression of HDACs enhances deacetylation, adversely affecting the expression of certain genes, including some tumor suppressor genes. To date, five HDAC inhibitors (HDACis) have been approved for the treatment of various tumors, including malignant lymphoma, myeloma, hematological malignancies, and pancreatic cancer: vorinostat (SAHA), romidepsin (FK228), belinostat (PXD-101), panobinostat (LBH-589), and chidamide. Several HDAC inhibitor candidates are also in clinical trials. Both LSD1 and HDACs play important roles in the development and progression of some tumors. In various cancers, including bladder cancer, breast cancer, and lung cancer, reducing LSD1 expression or inhibiting LSD1 activity significantly enhances the sensitivity of cancer cells to HDAC inhibitors. reported that simultaneous inhibition of LSD1 and HDACs activity with small molecule inhibitors demonstrated synergistic antitumor effects (Duan, YC, et al., Eur J Med Chem. 2021, 220, 113453. doi:10.1016 / j.ejmech.2021.113453.). Research has also shown that dual-targeting agents have more predictable and less complex metabolic pathways, better PK / PD properties, and better bioavailability than multidrug combinations (Giulia S., et al., Current Opinion in Chemical Biology 2019, 50, 89-100).In contrast to drug combinations, dual-targeting agents can ensure that the dual pharmacodynamic sites act simultaneously and synchronously in the same cells (de Lera, AR, Ganesan, A., Clin Epigenetics 2016, 8:105). Dual-targeting monotherapy also offers advantages such as improved patient compliance and reduced medication costs (Fu, RG, Sun, Y., Sheng, WB, Liao, DF, Eur. J. Med. Chem. 2017, 136, 195-211). Recently, Cole et al. reported a class of LSD1 / HDAC1 dual-targeting inhibitors that showed superior in vivo activity in a mouse model of melanoma (Kalin, JH, et al., Nat. Commun. 2018, 9, 53). Other academic institutions, such as Xinxiang Medical University, have also recently disclosed several patents for LSD1 / HDAC dual inhibitors (CN111592487, CN113444038, CN113527195).

[0006] As dual-target inhibitors are not yet commercially available, there is an urgent need in this field to develop new dual-target inhibitors that have inhibitory effects on both HDAC and LSD1. Summary of the Invention

[0007] The present disclosure provides compounds represented by general formula (I) or tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts or co-crystals thereof: [ka] (In the formula, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 2~6 Alkynyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NR a -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 Aryl)-, -C 1~10 Alkyl-NH-6- to 10-membered heteroaryl-, -C 1~10 Alkyl-6 to 10-membered heteroaryl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10 Alkyl-OC 6~10 Aryl-, -C 1~10 Alkyl-6-10-membered heteroaryl-C 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered heteroaryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-SC 1~10 alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , COOH, -C(=O)NR a R b wherein said heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, and optionally one or more of said alkyls are optionally selected from -C(=O)-, -S(=O)2- or -NR a -, and Preferably, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 2~6 Alkynyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NR a -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 Aryl)-, -C 1~10 Alkyl-NH-6- to 10-membered heteroaryl-, -C 1~10 Alkyl-6 to 10-membered heteroaryl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10Alkyl-C 6~10 Aryl-C 3~6 Cycloalkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10 Alkyl-OC 6~10 Aryl-, -C 1~10 Alkyl-6-10-membered heteroaryl-OC 1~10 alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , COOH, -C(=O)NR a R b wherein said heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, and optionally one or more of said alkyls are optionally selected from -C(=O)-, -S(=O)2- or -NR a -, and Preferably, L 1 The leftmost group is connected to W, and the rightmost group is connected to a group shown in the formula: [ka] W is selected from the groups shown in the formula: [ka] L 2 is a bond, -O-, -C(=O)-, -NR a -, -CH2-NR a -, -NR a -C(O)-, -NR a -S(=O)2-, -S- or -S(=O)2-; Preferably, L 2 is a bond, -O-, -C(=O)-, -NR a -, -NR a -C(O)-, -NR a -S(=O)2-, -S- or -S(=O)2-; Ring A is a C containing N 3~10 Heteroaryl, C 3~10 Heterocycloalkyl, or C 3~10 heteroaryl, heterocycloalkyl, heterocycloalkenyl, and optionally one or more R 4 wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, and S; R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b Selected from the options, R 4 C 1~6 When selected from alkyl, R 4 any two of may be taken together with their connecting atom to form a 5- to 10-membered aliphatic heterocyclyl; R 1 , R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkyl-CN, C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b, -C(=O)NR a R b , -S(=O)2R a , -C 2~6 Alkenyl-C(=O)NR a R b is selected from Preferably, R 1 , R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b , -S(=O)2R a , -C 2~6 Alkenyl-C(=O)NR a R b is selected from R 2 , R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 are not both hydrogen, and wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy-substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, hydroxy substituted C 1~6Alkoxy-C 3~6 Cycloalkyl, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R b , -C 2~6 Alkenyl-C(=O)NR a R b , 3- to 6-membered heterocycloalkyl, and heterocycloalkenyl, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S; Preferably, R 2 , R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 and R and R are not both hydrogen, and wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R b , -C 2~6 Alkenyl-C(=O)NR a R b , 3- to 6-membered cycloheterocycloalkyl, and heterocycloalkenyl, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S; m is selected from 0, 1, 2, 3, 4 or 5; Q and T are each independently selected from N or C; X and Y are each independently selected from C and N; Z is selected from a bond, —CH—, —C(═O) or —S(═O)—; Preferably, R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, ═O, COOH, -NR a R b , -C(=O)NR a R b , C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from hydrogen, halogen, CN, NO, CF, CHF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -C(=O)-C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, and S; R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, ═O, COOH, -NR a R b , -C(=O)NR a R b , C 3~6Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from hydrogen, halogen, CN, NO, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, and S; As an option, R 5 , R 6 together with the atoms directly linked to them form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl optionally includes hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , -C(=O)NR a R b and is substituted with one or more substituents selected from R a , R b is independently selected from hydrogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, halogen-substituted C 1~6 Alkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl or C 6~10heteroaryl, heterocycloalkyl, containing 1 to 4 heteroatoms arbitrarily selected from N, O, or S; The following symbols indicate the absence or presence of a double bond, which may be present at any position within the ring: [ka]

[0008] The present disclosure provides compounds represented by general formula (I) or tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts or co-crystals thereof: (In the formula, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 2~6 Alkynyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NR a -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 aryl)-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , COOH, -C(=O)NR a R b wherein said heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, and optionally one or more of said alkyls are optionally selected from -C(=O)-, -S(=O)2- or -NR a -, and W is selected from the groups shown in the formula: [ka] L 2 is a bond, -O-, -C(=O)-, -NR a -, -S- or -S(=O)2-; Ring A is a C containing N 3~10 Heteroaryl, C 3~10 Heterocycloalkyl or C 3~10 heteroaryl, heterocycloalkyl, or heterocycloalkenyl, wherein said heteroaryl, heterocycloalkyl, or heterocycloalkenyl optionally comprises one or more R 4 wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, and S; R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b Selected from the options, R 4 C 1~6 When any two R are selected from alkyl, 4may be taken together with their connecting atoms to form a 5- to 10-membered aliphatic heterocyclyl; R 1 , R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, NR a R b , -C(=O)NR a R b , -S(=O)2R a , -C 2~6 Alkenyl-C(=O)NR a R b is selected from R 2 , R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 are not both hydrogen, and wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R b , -C 2~6 Alkenyl-C(=O)NR a R b , C 3~6substituted by one or more substituents selected from cycloalkyl, 3- to 6-membered heterocycloalkyl, or heterocycloalkenyl, wherein the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, or S; m is selected from 0, 1, 2, 3, 4 or 5; Q and T are each independently selected from N or C; X and Y each independently represent C, N, or -NR c -or-CR d - selected from Z is selected from a bond, —CH—, —C(═O) or —S(═O)—; R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, ═O, COOH, -NRaRb, -C(═O)NRaRb, C 3~6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, and S; As an option, R 5 , R 6together with the atoms directly linked to them form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl optionally includes hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , -C(=O)NR a R b and is substituted with one or more substituents selected from R a , R b is independently selected from hydrogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, halogen-substituted C 1~6 Alkyl, 3-6 membered heterocycloalkyl, C 6~10 Aryl or C 6~10 heteroaryl, heterocycloalkyl, containing 1 to 4 heteroatoms arbitrarily selected from N, O, or S; R c , R d are each independently a bond, H, C, 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl or C 3~6 cycloalkyl; The following symbols indicate the absence or presence of a double bond, which may be present at any position within the ring: [ka]

[0009] The present disclosure discloses a compound represented by general formula (I), or a tautomer, stereoisomer, solvate, metabolite, isotopically labeled compound, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is as represented by formula (II), (III), (IV), (V), or (VI): [ka] Here, the definition of each substituent in formula (II), (III), (IV), (V) or (VI) is as defined above.

[0010] The present disclosure provides a compound represented by formula (II-1). [ka] (In the formula, L 1 -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 alkenyl-, wherein said alkyl, alkenyl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy.

[0011] Preferably, L 1 -C 1~10 Alkyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 alkenyl-.

[0012] Preferably, L 1 -C 1~10 Alkyl-, -C 1~10Alkyl-(C 6~10 Aryl)-C 2~6 alkenyl-.

[0013] In some embodiments, L 1 -C 1~6 Alkyl-, -C 1~6 Alkyl-phenylene-C 2~6 alkenyl-.

[0014] In one embodiment of the present disclosure, ring A is an N-containing C 3~10 Heteroaryl or C 3~10 heterocycloalkyl, wherein said heteroaryl, heterocycloalkyl may optionally be selected from one or more R 4 is replaced by

[0015] Preferably, ring A is a C 3~10 heterocycloalkyl, wherein said heterocycloalkyl optionally comprises one or more R 4 is replaced by

[0016] Preferably, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 is substituted with a group, Preferably, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0017] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0018] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0019] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0020] In one embodiment of the present disclosure, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b is selected from.

[0021] Preferably, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b is selected from.

[0022] Preferably, R 4 is hydrogen, -NR a R b , C 1~6 alkyl.

[0023] Preferably, R4 is hydrogen, -NR a R b is selected from.

[0024] In one embodiment of the present disclosure, R 1 is hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 alkynyl.

[0025] Preferably, R 1 are hydrogen, halogen, CN, C 1~6 alkyl.

[0026] Preferably, R 1 is selected from hydrogen, halogen, and CN.

[0027] R 2 is hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -S(=O)2R a , -OC 1~6alkyl-OH, wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, or S; R 2 is hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -S(=O)2R a and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0028] In some embodiments, R 2 is hydrogen, C 6~10 Aryl or C 6~10 heteroaryl, wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b , -S(=O)2R a , -OC 1~6 alkyl-OH, wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, or S; Preferably, R 2 is hydrogen, C 6~10 Aryl or C 6~10heteroaryl, wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b , -S(=O)2R a and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0029] In some embodiments, R 2 is selected from hydrogen, a group represented by the formula: [ka] wherein the groups represented by the formula are optionally selected from hydrogen, halogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b , -S(=O)2-R a , -OC 1~6 alkyl-OH; Preferably, R 2 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally selected from hydrogen, halogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -NR a R b , -S(=O)2-R a is substituted with one or more substituents selected from:

[0030] Preferably, R 2 is selected from the group represented by the formula: [ka] wherein the groups represented by the formula are optionally selected from hydrogen, hydroxy, C 1~6 substituted with one or more substituents selected from alkoxy;

[0031] In one embodiment of the present disclosure, m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 or 2; more preferably, m is 2.

[0032] Each Q is independently selected from N or C; preferably, Q is selected from C.

[0033] In one embodiment of the present disclosure, R a , R b is independently selected from hydrogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, halogen-substituted C 1~6 alkyl.

[0034] Preferably, R a , R b is independently selected from hydrogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 cycloalkyl.

[0035] Preferably, R a , R b is independently selected from hydrogen and methyl at each occurrence.

[0036] Preferably, R a , R b are each independently selected from hydrogen.

[0037] The present disclosure provides a compound represented by general formula (III-1). [ka] (In the formula, X is selected from C and N; L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 aryl)-, -NRa-, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF3, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, -NR a R b , COOH; Optionally, one or more carbon atoms in said alkyl may be optionally substituted with one or more groups selected from -NH-.

[0038] Preferably, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 aryl)-, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R band is substituted with one or more substituents selected from Optionally, one or more carbon atoms in said alkyl may be optionally substituted with one or more groups selected from -NH-.

[0039] Preferably, L 1 -C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 aryl)-, wherein said alkyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy; Preferably, L 1 Ha-C 1~6 It is alkyl-.

[0040] In one embodiment of the present disclosure, L 2 is a bond, -O-, -C(=O)-, -NR a -, -NR a -C(O)- or -S(=O)2-; In some embodiments, L 2 is a bond, -O-, -C(=O)-, -NR a - or -S(=O)2-.

[0041] Preferably, L 2 is a bond, -O-, -NR a - is selected from.

[0042] Preferably, L 2 -O-, -NR a - is selected from.

[0043] In one embodiment of the present disclosure, ring A is an N-containing C 3~10 Heteroaryl or C 3~10heterocycloalkyl, wherein said heteroaryl, heterocycloalkyl may optionally be selected from one or more R 4 is replaced by

[0044] Preferably, ring A is a C 3~10 heterocycloalkyl, C 3~10 Heterocycloalkyl optionally includes one or more R 4 is replaced by

[0045] In some embodiments, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0046] Preferably, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0047] In some embodiments, ring A has the formula: [ka] or selected from the group represented by the following formula: [ka] The group represented by the formula: 4 The group is substituted. [ka]

[0048] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0049] In one embodiment of the present disclosure, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R b is selected from.

[0050] Preferably, R 4 is hydrogen, C 1~6 Alkyl, -NR a R b is selected from.

[0051] Preferably, R 4 is hydrogen and C 1~6 alkyl.

[0052] In one embodiment of the present disclosure, R 1 , R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, halogen-substituted C 1~6 Alkyl, halogen-substituted C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b is selected from.

[0053] Preferably, R 1 , R 6 is independently hydrogen, CN, hydroxy, C1~6 Alkoxy is selected from:

[0054] Preferably, R 1 , R 6 is independently selected at each occurrence from hydrogen, CN, and hydroxy.

[0055] Preferably, R 1 are each independently hydrogen, C 1~6 R is selected from alkoxy and hydroxy; 6 is independently selected from hydrogen and CN at each occurrence.

[0056] R 3 is hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl, wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0057] Preferably, R 3 is hydrogen, C 1~6 Alkyl, C 6~10 Aryl or C 6~10 Heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, and CN; and said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O, and S.

[0058] Preferably, R 3 is hydrogen, C 6~10 Aryl or C 6~10Heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, and CN; and said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O, and S.

[0059] Preferably, R 3 is selected from hydrogen, methyl, and a group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0060] Preferably, R 3 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0061] Preferably, R 3 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0062] In one embodiment of the present disclosure, R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 6~10 Aryl or C 6~10and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0063] As an option, R 5 , R 6 together with the atoms directly linked to them form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl optionally includes hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 alkynyl is substituted with one or more substituents selected from:

[0064] Preferably, R 5 are each independently hydroxy, C 1~6 alkoxy, selected from the group represented by the formula: [ka] wherein the alkyl, alkoxy, and groups represented by the formulae are optionally substituted with hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy;

[0065] As an option, R 5 , R 6 together with the atoms directly connected to them form a group of the formula: [ka] wherein the groups represented by the formula are optionally selected from hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more groups of alkoxy.

[0066] Preferably, R 5 is selected from the group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0067] As an option, R 5 , R 6 together with the atoms directly connected to them form a group of the formula: [ka]

[0068] In one embodiment of the present disclosure, m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 or 2.

[0069] Z is selected from a bond, -CH2- or -C(=O), preferably Z is selected from a bond.

[0070] In one embodiment of the present disclosure, R a , R b are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 alkynyl, COOH, wherein said alkyl, alkoxy, alkenyl, alkynyl are optionally selected from hydrogen, halogen, CN, CF3, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6alkynyl, substituted with one or more substituents selected from COOH.

[0071] Preferably, R a , R b are each independently hydrogen, C 1~6 alkyl,

[0072] Preferably, R a , R b is independently selected from hydrogen and methyl at each occurrence.

[0073] In some embodiments, the present disclosure provides a compound having formula (III-2): [ka] (wherein each substituent is defined as described in formula (III-1)).

[0074] The present disclosure provides compounds represented by general formula (IV-1a). [ka] (In the formula, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NRa -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 Aryl)-, -C 1~10 Alkyl-NH-6- to 10-membered heteroaryl-, -C 1~10 Alkyl-6 to 10-membered heteroaryl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10 Alkyl-OC 6~10 Aryl-, -C 1~10 Alkyl-6-10-membered heteroaryl-C 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered heteroaryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-SC 1~10 alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkenyl are substituted by one or more substituents selected from the group consisting of heteroaryl, heterocycloalkenyl, heteroaryl, heterocycloalkenyl, and heteroaryl containing 1 to 4 heteroatoms arbitrarily selected from N, O, and S; Preferably, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NR a -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 Aryl)-, -C 1~10 Alkyl-NH-6- to 10-membered heteroaryl-, -C 1~10 Alkyl-6 to 10-membered heteroaryl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10 Alkyl-OC 6~10 Aryl-, -C 1~10 Alkyl-6-10-membered heteroaryl-OC 1~10 alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6alkenyl, wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, or S; Optionally, one or more of said alkyls may optionally be —C(═O)—, —S(═O)—, or —NR a -, and may be substituted with one or more groups selected from

[0075] In some embodiments, in formula (IV-1a) provided herein, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -NR a -, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 aryl)-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6alkenyl, wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O, or S; Optionally, one or more of said alkyls may optionally be —C(═O)—, —S(═O)—, or —NR a -, optionally substituted with one or more groups selected from

[0076] In some embodiments, in formula (IV-1a) provided herein, L 1 -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 Aryl)-, -C 1~10 Alkyl-NH-6- to 10-membered heteroaryl-, -C 1~10 Alkyl-6 to 10-membered heteroaryl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10Alkyl-OC 6~10 Aryl-, -C 1~10 Alkyl-6-10-membered heteroaryl-C 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered heteroaryl-OC 1~10 Alkyl-, -C 1~10 Alkyl-6-10-membered aryl-SC 1~10 alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0077] In some embodiments, in formula (IV-1a) provided herein, L 1 -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl)-C 2~6 Alkenyl-, -C 6~10 Aryl-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10aryl)-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0078] Preferably, L 1 -C 1~10 Alkyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 aryl)-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0079] In some embodiments, in formula (IV-1a) provided herein, L 1 -C 1~10Alkyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(heteroaryl or heterocycloalkyl or heterocycloalkenyl)-C 2~6 Alkenyl--C 1~10 Alkyl-(C 6~10 (aryl)-(6- to 10-membered heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 Alkynyl-, -C 1~10 Alkyl-C 6~10 Cycloalkenyl-C 2~6 Alkenyl-, -C 1~10 Alkyl-C 6~10 Aryl-C 3~6 Cycloalkyl-, -C 1~10 Alkyl-OC 6~10 aryl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0080] Preferably, L 1 -C 1~10 Alkyl-, -C 1~10 Alkyl-C 2~6 Alkenyl-, -C 6~10 Heteroaryl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -C 1~10 Alkyl-(C6~10 Aryl)-, -C 1~10 Alkyl-(C 6~10 Aryl)-C 1~10 Alkyl-, -C 1~10 Alkyl-(C 6~10 Heterocycloalkyl)-(C 6~10 aryl)-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0081] Preferably, L 1 -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 alkenyl-, wherein said alkyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy;

[0082] Preferably, L 1 is selected from -CH2-, -CH2-(C=C)-, -(CH2)4-, -(CH2)6-, -(C=O)-phenyl-(C=C)-, -CH2-phenyl-, -(CH2)3-phenyl-, -CH2-phenyl-(CH2)2-, -(CH2)2-phenyl-CH2-, -CH2-phenyl-(C=C)-, -(CH2)2-phenyl-(C=C)-, -CH2-phenyl-(C≡C)-, -CH2-phenyl-(C=C)-CH2-, -phenyl-(C=C)-, pyrimidinyl, a group represented by the following formula: [ka]

[0083] Preferably, L 1 is selected from the group represented by the following formula: [ka]

[0084] In one embodiment of the present disclosure, L 2 is a bond, -O-, -C(=O)-, -S-, -NR a -, -CH2-NR a -, -NR a -C(=O) and -NR a -S(=O)2-, In some embodiments, L 2 is a bond, -O-, -C(=O)-, -S-, -NR a -, -NR a -C(=O) and -NR a -S(=O)2-.

[0085] In some embodiments, L 2 is a bond, -O-, -C(=O)-, -S- or -NR a - is selected from.

[0086] In some embodiments, L 2 is the bond, -NR a -, -CH2-NR a -, -NR a -C(=O) and -NR a -S(=O)2-.

[0087] In some embodiments, L 2 is the bond, -NR a -, -NR a -C(=O) and -NR a -S(=O)2-.

[0088] Preferably, L 2 is a bond, -C(=O)- or -NR a - is selected from.

[0089] Preferably, L 2 Ha-NR a - is selected from.

[0090] In one embodiment of the present disclosure, ring A is an N-containing C 3~10 Heteroaryl or C 3~10 heterocycloalkyl, wherein said heteroaryl, heterocycloalkyl may optionally be selected from one or more R 4 and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O and S.

[0091] Preferably, ring A is C 3~10 heterocycloalkyl, wherein said heterocycloalkyl optionally comprises one or more R 4 is replaced by

[0092] Preferably, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0093] In some embodiments, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0094] In some embodiments, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0095] In some embodiments, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0096] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0097] In one embodiment of the present disclosure, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R b is selected from.

[0098] Preferably, R 4 is hydrogen, C 1~6 Alkyl, -NR a R b is selected from.

[0099] Preferably, R 4 is hydrogen, C 1~6 alkyl.

[0100] In one embodiment of the present disclosure, R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkyl-CN, Halo-C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b is selected from.

[0101] Preferably, R 6 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, COOH, -NR a R b , -C(=O)NR a R b is selected from.

[0102] Preferably, R 6 are each independently hydrogen, halogen, CH2-CN, CN, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 alkyl.

[0103] Preferably, R 6 are each independently hydrogen, halogen, CN, C 1~6 alkyl.

[0104] Preferably, R 6 is independently selected from hydrogen and CN at each occurrence.

[0105] R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 are not both hydrogen, and wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy-substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkoxy-C 3~6 Cycloalkyl, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R b , 3- to 6-membered heterocycloalkyl, and heterocycloalkenyl, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0106] In some embodiments, R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 are not both hydrogen, and wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R band heterocycloalkenyl, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0107] In some embodiments, R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 and are not both hydrogen, wherein said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, HaloC 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, hydroxy substituted C 1~6 Alkoxy-C 3~6 Cycloalkyl, COOH, -NR a R b , -S(=O)2R a , -C(=O)NR a R b , 3- to 6-membered heterocycloalkyl, and heterocycloalkenyl, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0108] Preferably, R 3 , R 7 are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 Aryl or C 6~10 heteroaryl; R 3 and R 7 are not both hydrogen, and said aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, hydroxy, C1~6 Alkyl, C 1~6 It is substituted with one or more substituents selected from alkoxy and heterocycloalkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O and S.

[0109] Preferably, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally selected from hydrogen, halogen, CN, heterocycloalkenyl, hydroxy, CF, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, 3-6 membered heterocycloalkyl, hydroxy substituted C 1~6 Alkoxy-C 3~6 Cycloalkyl, hydroxy-substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, -NH2, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl).

[0110] Preferably, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally selected from hydrogen, halogen, CN, heterocycloalkenyl, CF, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, hydroxy substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 substituted with one or more substituents selected from alkoxy;

[0111] In some embodiments, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, and hydroxy.

[0112] In some embodiments, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The group represented by the formula: [ka] Optionally, hydrogen, halogen, CN, hydroxy, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, 3-6 membered heterocycloalkyl, hydroxy substituted C 1~6 Alkoxy-C 3~6 Cycloalkyl, hydroxy-substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, -NH2, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl).

[0113] Preferably, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally selected from hydrogen, halogen, CN, CF3, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, HaloC 1~6 Alkoxy, 3-6 membered heterocycloalkyl, hydroxy substituted C 1~6 Alkoxy-C 3~6 Cycloalkyl, hydroxy-substituted C 1~6 Alkyl, hydroxy-substituted C 1~6 Alkoxy, -NH2, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl).

[0114] Preferably, R 3 , R 7 is selected from hydrogen, a group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, and hydroxy.

[0115] In one embodiment of the present disclosure, R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, =O, C 2~6 Alkenyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, NO, CF, CHF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -C(=O)-C 1~6 Alkoxy, C 2~6 It is substituted with one or more substituents selected from alkenyl, -C(=O)-NH2, and said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms arbitrarily selected from N, O or S.

[0116] In some embodiments, R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, =O, C 2~6 Alkenyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, NO, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 and the heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0117] In some embodiments, R 5 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, =O, C 2~6 Alkenyl, C 6~10 Aryl or C 6~10 and heteroaryl, wherein said alkyl, alkoxy, alkenyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, NO, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, -C(=O)-C 1~6 Alkoxy, C 2~6 alkenyl, wherein said heteroarylheterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S.

[0118] In some embodiments, R 5 are each independently hydrogen, CN, or C 1~6 Alkoxy, =O, C 6~10 Aryl or C 6~10heteroaryl, wherein said alkoxy, aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, NO, CF, CHF, hydroxy, C 1~6 Alkyl, -C(=O)-C 1~6 The heteroaryl and heterocycloalkyl are substituted with one or more substituents selected from alkoxy and -C(=O)-NH2, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, and S.

[0119] As an option, R 5 , R 6 together with the atoms directly linked to them form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl optionally includes hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 alkynyl is substituted with one or more substituents selected from:

[0120] Preferably, R 5 are each independently CN, C 1~6 alkoxy, ═O, a group represented by the formula: [ka] The alkoxy group of formula may optionally be selected from the group consisting of hydrogen, halogen, CN, NO, CF, CHF, hydroxy, C 1~6 It is substituted with one or more substituents selected from alkyl, -C(O)OCH3, -C(=O)-NH2.

[0121] Preferably, R 5 are each independently selected from groups represented by the following formulae: [ka] The groups represented by the formula above are optionally selected from hydrogen, halogen, CN, NO, CF, CHF, hydroxy, C 1~6 It is substituted with one or more substituents selected from alkyl, -C(O)OCH3, -C(=O)-NH2.

[0122] Preferably, R 5 are each independently CN, C 1~6 alkoxy, ═O, a group represented by the formula: [ka] The alkoxy group of formula is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO2, and hydroxy.

[0123] In some embodiments, R 5 are each independently C 1~6 alkoxy, ═O, a group represented by the formula: [ka] The alkoxy group of formula is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, and hydroxy.

[0124] As an option, R 5 , R 6 together with the atoms directly connected to them form a group of the formula: [ka] wherein the groups represented by the formula are optionally selected from hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more groups of alkoxy.

[0125] Preferably, R 5 is C 1~6alkoxy, selected from the group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO2.

[0126] In some embodiments, R 5 is C 1~6 alkoxy, selected from the group represented by the formula: [ka] The groups represented by the formula above are optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0127] As an option, R 5 , R 6 together with the atoms directly connected to them form a group of the formula: [ka]

[0128] In one embodiment of the present disclosure, X and Y are each independently selected from C and N.

[0129] Z is selected from a bond, —CH 2 —, —C(═O) or —S(═O) 2 —.

[0130] Preferably, Z is selected from a bond, —CH 2 — or —C(═O).

[0131] Preferably, Z is selected from a bond.

[0132] In one embodiment of the present disclosure, R a , R b is independently selected from hydrogen, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, halogen-substituted C 1~6 alkyl, and said heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O or S.

[0133] Preferably, R a , R b are each independently hydrogen, C 1~6 alkyl.

[0134] Preferably, R a , R b is independently selected at each occurrence from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0135] Preferably, R a , R b is independently selected from hydrogen at each occurrence.

[0136] In some embodiments, the present disclosure provides compounds having the structure of formula (IV-2a), (IV-3a), or (IV-4a). [ka] (In the formula, the definition of each substituent is the same as that described in formula (IV-1a).)

[0137] The present disclosure provides compounds represented by general formula (V): [ka] (In the formula, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl-, -NR awherein said alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 alkenyl).

[0138] Preferably, L 1 -C 1~10 Alkyl-(C 6~10 aryl or heteroaryl)-C 2~6 alkenyl-, wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 alkenyl.

[0139] Preferably, L 1 -C 1~10 Alkyl-(C 6~10 Aryl)-C 2~6 alkenyl-, wherein said aryl or heteroaryl is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 alkenyl.

[0140] In one embodiment of the present disclosure, L 2 is a bond or -NR a - is selected from.

[0141] Preferably, L 2 Ha-NR a - is selected from.

[0142] In one embodiment of the present disclosure, ring A is an N-containing C 3~10 Heteroaryl or C 3~10 heterocycloalkyl, wherein said heteroaryl, heterocycloalkyl may optionally be selected from one or more R4 is replaced by

[0143] Preferably, ring A is C 3~10 heterocycloalkyl, wherein said heterocycloalkyl optionally comprises one or more R 4 is replaced by

[0144] Preferably, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0145] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0146] In one embodiment of the present disclosure, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 alkyl, wherein said alkyl, alkoxy is optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy;

[0147] Preferably, R 4 is selected from hydrogen.

[0148] In one embodiment of the present disclosure, R 1 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R b, C 6~10 Aryl or C 6~10 heteroaryl.

[0149] Preferably, R 1 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 alkyl.

[0150] R 3 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 alkenyl.

[0151] Preferably, R 3 is independently selected from hydrogen at each occurrence.

[0152] In one embodiment of the present disclosure, Z is selected from a bond, —CH 2 —, or —C(═O).

[0153] Preferably, Z is selected from -C(=O).

[0154] In one embodiment of the present disclosure, R a , R b are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 and alkoxy, wherein said alkyl, alkoxy is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF3, hydroxy.

[0155] Preferably, R a , R b is independently selected from hydrogen at each occurrence.

[0156] The present disclosure provides compounds represented by general formula (VI): [ka] (In the formula, L 1 is a bond, -C 1~10 Alkyl-, -C 2~6 Alkenyl-, -NR a wherein said alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl are optionally selected from hydrogen, halogen, CN, CF, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 alkenyl).

[0157] Preferably, L 1 Ha-C 1~10 alkyl-.

[0158] In one embodiment of the present disclosure, L 2 is a bond, -O- or -NR a - is selected from.

[0159] Preferably, L 2 is selected from —O—.

[0160] In one embodiment of the present disclosure, ring A is an N-containing C 3~10 Heteroaryl or C 3~10 heterocycloalkyl, wherein said heteroaryl, heterocycloalkyl may optionally be selected from one or more R 4 is replaced by

[0161] Preferably, ring A is C 3~10 heterocycloalkyl, wherein said heterocycloalkyl optionally comprises one or more R 4 is replaced by

[0162] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4is replaced by

[0163] In some embodiments, ring A is selected from the group represented by the following formula: [ka] wherein the group represented by the formula is optionally R 4 The group is substituted.

[0164] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 is replaced by

[0165] Preferably, ring A is selected from the group represented by the following formula: [ka] The group of the formula may optionally be R 4 The group is substituted.

[0166] In one embodiment of the present disclosure, R 4 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, -NR a R b wherein said alkyl, alkoxy is optionally selected from hydrogen, halogen, CN, CF3, hydroxy, C 1~6 Alkyl, C 1~6 substituted with one or more substituents selected from alkoxy;

[0167] Preferably, R 4 is hydrogen, C 1~6 Alkyl, -NR a R b is selected from.

[0168] In one embodiment of the present disclosure, R 1 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R b is selected from.

[0169] Preferably, R 1 is independently selected at each occurrence from hydrogen, halogen, CN, and hydroxy.

[0170] R 3 are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 Alkoxy, C 2~6 Alkenyl, -NR a R b is selected from.

[0171] Preferably, R 3 is independently selected from hydrogen at each occurrence.

[0172] In one embodiment of the present disclosure, Z is selected from a bond, —CH 2 —, or —C(═O).

[0173] Preferably, Z is selected from -C(=O).

[0174] In one embodiment of the present disclosure, R a , R b are each independently hydrogen, halogen, CN, hydroxy, C 1~6 Alkyl, C 1~6 and alkoxy, wherein said alkyl, alkoxy is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF3, hydroxy.

[0175] Preferably, R a , R b is independently selected from hydrogen at each occurrence.

[0176] The present disclosure provides the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0177] The present disclosure provides pharmaceutical compositions in which the active ingredient comprises one or a combination of two or more of the above-described compounds or their tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts, or co-crystals.

[0178] The present disclosure provides methods or uses of said compounds or their tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts or co-crystals in the prevention and treatment of diseases mediated by LSDs and / or HDACs, individually or synergistically.

[0179] The use or method comprises the step of administering to a patient in need thereof a therapeutically effective amount of the compound described above, or an inverted isomer, stereoisomer, solvate, metabolite, isotopically labeled compound, pharmaceutically acceptable salt, or co-crystal thereof.

[0180] In one embodiment of the present disclosure, the HDAC enzyme includes, but is not limited to, isoforms such as HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, and HDAC8, preferably HDAC1 and HDAC8 isoforms, and more preferably HDAC1 isoform.

[0181] The present disclosure provides the use of the compounds or their tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts, or co-crystals in the preparation of a medicament for use in the treatment of a disease mediated by LSD1 and / or HDAC.

[0182] In one aspect of the disclosure is the use of LSD1 in the preparation of a medicament for use in the treatment of a disease mediated by one or more of the HDACs.

[0183] In one aspect of the present disclosure, the disease is cancer or an autoimmune disease.

[0184] In one aspect of the present disclosure, the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic granulocytic leukemia, colorectal cancer, brain cancer, hepatocellular carcinoma, renal cancer, gastric cancer, breast cancer, triple-negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphoma, blood cancer, esophageal cancer, urethral cancer, and nasal cancer.

[0185] The present disclosure provides the use of the compounds or their tautomers, stereoisomers, solvates, metabolites, isotopically labeled compounds, pharmaceutically acceptable salts or co-crystals thereof in the prevention and treatment of diseases mediated or synergistically mediated by LSD1 protein and / or HDAC1 protein, LSD1 protein and / or HDAC8 protein, respectively.

[0186] In one aspect of the present disclosure, the disease is mediated by abnormal protein activity as described above. DETAILED DESCRIPTION OF THE INVENTION

[0187] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology as commonly understood in the art, including variations or substitutions of equivalent technology that are obvious to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are provided to better explain the present disclosure.

[0188] I. Definition The terms "comprise," "include," or "contain," and other variations thereof, used herein are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the above terms, such as "comprise," include the meaning "consisting of."

[0189] The term "one or more" or similar expressions such as "at least one" can refer to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0190] The term "aryl" means an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6~10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. An aryl may be optionally substituted with one or more suitable substituents, such as cyano (CN), halogen (F, Cl, Br), etc. When an aryl is substituted with one or more substituents, two adjacent substituents may be taken together with their connecting carbon atoms to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl, examples of which include, but are not limited to, groups represented by the following formulas: [ka]

[0191] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system containing at least one heteroatom, which may be the same or different, and which may be, for example, oxygen, nitrogen, or sulfur, and which, in any case, may be benzo-fused. As used herein, the term "C 6~10 "Heteroaryl" means a monocyclic, bicyclic, or tricyclic aromatic ring system having 6 to 10 ring atoms and containing at least one heteroatom, which may be the same or different, such as oxygen, nitrogen, or sulfur. Heteroaryl may optionally be substituted with one or more suitable substituents, such as cyano (CN), halogen (F, Cl, Br). Examples include, but are not limited to, groups represented by the following formulae: [ka]

[0192] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., or a bicyclic ring containing a spirocyclic, fused, or bridged system (e.g., bicyclo[2.2.1]heptyl, etc.)). As used herein, the term "C 3~6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). A cycloalkyl may be optionally substituted with one or more suitable substituents.

[0193] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more heteroatoms in the ring. The heterocycloalkyl may be connected to the remainder of the molecule by any of the carbon atoms or heteroatoms. As used herein, C 3~10 The term heterocycloalkyl refers to a saturated monocyclic or polycyclic (e.g., bicyclic) group having 3 to 10 ring-forming carbon atoms and at least one heteroatom, which may be the same or different, and which is, for example, oxygen, nitrogen, or sulfur. A heterocycloalkyl may be optionally substituted with one or more suitable substituents.

[0194] The term "heterocycloalkenyl" refers to a class of cycloalkenyl, as defined above, in which at least one ring-forming carbon atom is replaced with a heteroatom such as nitrogen, oxygen, or sulfur. Illustrative examples of C heterocycloalkenyl include, but are not limited to, tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, etc., and may be monocyclic or polycyclic (e.g., bicyclic) groups. Heterocycloalkenyl may be optionally substituted with one or more suitable substituents.

[0195] The term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0196] The term "hydroxy" means --OH.

[0197] The term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. As used herein, the term "C 1~6 "Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0198] The term "halogen-substituted alkyl" as used herein alone or in combination with other groups refers to an alkyl, as defined above, in which one or more hydrogen atoms are substituted with halogen. It will be understood by those skilled in the art that when more than one halogen substituent is present, the halogens may be the same or different and may be located on the same or different C atoms. As used herein, the term "halogen-substituted C 1~6 "Alkyl" refers to a C group in which one or more hydrogen atoms have been replaced by halogen. 1~6 Alkyl refers to, for example, trifluoromethyl.

[0199] The term "hydroxy-substituted alkyl" means an alkyl as defined above in which one or more hydrogen atoms have been replaced with hydroxy. As used herein, the term "hydroxy-substituted C 1~6 "Alkyl" refers to a C group in which one or more hydrogen atoms have been replaced with hydroxy. 1~6 Alkyl refers to groups such as those of the formula: [ka]

[0200] The term "alkoxy" refers to a linkage via an oxygen atom to an "alkyl" as defined above, i.e., an "alkoxy" group can be defined as -OR, where R is alkyl as defined above. As used herein, the term "C 1~6Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, and the like.

[0201] The term "halogen-substituted alkoxy" refers to the alkoxy as defined above, in which one or more hydrogen atoms are replaced with halogen. It is understood by those skilled in the art that when one or more halogen substituents are present, the halogens may be the same or different and may be located on the same or different C atoms. As used herein, the term "halogen-substituted C 1~6 "Alkoxy" refers to a C group in which one or more hydrogen atoms are replaced by halogens such as difluoromethoxy and trifluoromethoxy. 1~6 It refers to alkoxy.

[0202] The term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon group containing at least one carbon-carbon double bond. The double bond may be present as either an E or Z isomer. The double bond may be present in any possible position of the hydrocarbon chain. As used herein, the term "C 2~6 "Alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms, such as vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, etc. An alkenyl may be optionally substituted with one or more suitable substituents.

[0203] The term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon group containing at least one C≡C triple bond. The triple bond may be located at any available position on the hydrocarbon chain. As used herein, the term "C 2~6 "Alkynyl" means an alkynyl containing 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl may be optionally substituted with one or more suitable substituents.

[0204] The term "-(aryl or heteroaryl)-alkenyl-" refers to an aryl or heteroaryl linked to an alkenyl as defined above. As used herein, the term "-(C 6~10 aryl or heteroaryl)-C 2~6 Alkenyl- means an aryl or C 6~10 It refers to a group in which heteroaryl is bonded to alkenyl containing 2 to 6 carbon atoms, for example, a group represented by the following formula: [ka]

[0205] "Optionally, one or more of said alkyls may optionally be -C(=O)-, -S(=O)2-, or -NR a -" may be substituted with one or more groups selected from, for example, C 1~10 One or more of the alkyl or alkylene fragments of alkyl may optionally be —C(═O)—, —S(═O)—, or —NR a -. For example, L 1 Ga-C 10 Alkyl-C 6~10 Aryl-C 2~6 alkenyl-, C 10 When one alkylene fragment of an alkyl is replaced with -C(=O)-, it becomes -C3 alkyl-C(=O)-C6 alkyl-C 6~10 Aryl-C 2~6 Alkenyl- or -C9 alkyl-C(=O)-C 6~10 Aryl-C 2~6 Alkenyl- is obtained, including but not limited to, groups of the formula [ka] In the formula, one methylene is substituted with -NH-, and the like. [ka]

[0206] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the substitution does not exceed the normal atomic value of the designated atom and that such substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0207] The term "hydroxy-substituted C 1~6 Alkoxy-C 3~6 "Cycloalkyl" includes, but is not limited to, groups of the formula: [ka]

[0208] The term "optionally substituted" means optionally substituted with the specified groups, groups or moieties.

[0209] When a group is described as being "optionally substituted with one or more substituents," the group can be (1) unsubstituted or (2) substituted. When a carbon on a group is described as being optionally substituted with one or more substituents, one or more hydrogens on that carbon (up to the extent of any hydrogens present) can be either substituted or unsubstituted, singly and / or together, with independently selected substituents. When a nitrogen on a group is described as being optionally substituted with one or more substituents, one or more hydrogens on the nitrogen (up to the extent of any hydrogens present) can each be substituted or unsubstituted with independently selected substituents.

[0210] When a substituent bond is shown to be a bond connecting two atoms through a ring, then such substituent may be bonded to any of the ring-forming atoms of the substitutable ring.

[0211] The symbols shown below indicate the possibility of the presence or absence of a double bond at any position in the ring, and are intended to include various cases including saturated ring systems, unsaturated non-aromatic ring systems with double bonds, and aromatic ring systems. [ka]

[0212] Compounds of the present disclosure may also contain one or more (eg, one, two, three, or four) isotopic substitutions.

[0213] The term "stereoisomer" refers to an isomer formed by at least one asymmetric center. Compounds with one or more (e.g., one, two, three, or four) asymmetric centers can occur as racemates, racemic mixtures, single enantiomers, mixtures of diastereoisomers, and single diastereoisomers. Certain individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the present disclosure can exist in a mixture of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. The scope of this application covers all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0214] Pharmaceutically acceptable salts of the compounds of the present disclosure may include neutralization products and base salts of the acids and bases of the compounds. Suitable acid addition salts are formed from acids that form non-toxic salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0215] In some embodiments, pharmaceutically acceptable salts of compounds of the present disclosure are selected from hydrochloride salts, formate salts, trifluoroacetate salts, and the like.

[0216] The term "eutectic" refers to a crystal formed by the association of an active pharmaceutical ingredient with a co-crystal former (e.g., co-former) through the action of hydrogen bonds or other non-covalent bonds, and more specifically refers to a eutectic formed from a compound of formula (I) and a pharmaceutically acceptable co-former.

[0217] The term "therapeutically effective amount" refers to a nontoxic but sufficient amount of a drug or agent to achieve the desired effect. In embodiments of the present disclosure, when treating a patient according to the present disclosure, the amount of drug to be administered will depend on many factors, including the specific administration regimen, the type and severity of the disease or condition, and the specific characteristics (e.g., body weight) of the subject or host being treated. However, depending on the specific circumstances, including, for example, the specific drug employed, the route of administration, the disease or condition being treated, and the subject or host being treated, the dosage can be routinely determined by methods known in the art. Generally, for therapeutic use in adults, dosages typically range from 0.02 to 5000 mg / day, e.g., about 1 to 1500 mg / day. This desired dose can conveniently be expressed as a single dose, or as divided doses administered simultaneously (or shortly) or at appropriate intervals, e.g., two, three, four, or more times per day. While dosage ranges are provided above, those skilled in the art will understand that the specific effective amount can be appropriately adjusted depending on the patient's condition and in conjunction with the physician's diagnosis.

[0218] II. Working Examples The implementation process of the present disclosure and the beneficial effects of the present disclosure will be described in detail below through specific examples, which are intended to help readers better understand the substance and features of the present disclosure, but are not intended to limit the scope of the present disclosure.

[0219] The structures of the compounds of the present disclosure were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using an AVANCE NEO 400 MHz Bruker instrument. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CDOD), and the internal standard was tetramethylsilane (TMS). MS was measured using an ISQ-EC Thermo Fisher LC-MS instrument. The instrument used for preparative chromatograms was a Gilson GX-281 chromatograph. Separation methods were as follows: Separation Method 1: Sun Fire Prep C18 OBD™ 5μm, 30×150mm Column, 0.04% HCl aqueous solution / acetonitrile; Separation Method 2: Sun Fire Prep C18 OBD™ 5μm, 30×150mm Column, 0.02% TFA aqueous solution / acetonitrile; Separation Method 3: Sun Fire Prep C18 OBD™ 5μm, 30×150mm Column, 0.06% TFA aqueous solution / acetonitrile; Separation Method 4: Xbridge Prep C18 OBD™ 5μm, 30×150mm Column, 10mM NH4HCO3 aqueous solution / acetonitrile; Separation Method 5: Xbridge Prep C18 OBD™ 5μm, 30×150mm Column, 0.6% NH3.H2O aqueous solution / acetonitrile.

[0220] The solvents used in this disclosure are commercially available.

[0221] In the examples, unless otherwise specified, the solutions are aqueous solutions.

[0222] In the examples, the reaction temperature is room temperature, 20°C to 30°C, unless otherwise specified.

[0223] HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; DIPEA refers to diisopropylethylamine DMSO refers to dimethyl sulfoxide EA stands for ethyl acetate, Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium, DCE refers to dichloroethane, DCM refers to dichloromethane DMF refers to N,N-dimethylformamide. NMP refers to N-methylpyrrolidone. TFA refers to trifluoroacetic acid, NBS refers to N-bromosuccinimide TfOH refers to trifluoromethanesulfonic acid, DPPA refers to diphenylphosphoryl azide, The positive references are CC-90011 and SAHA (vorinostat), respectively.

[0224] Example 1 Preparation of 7-((6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride [ka]

[0225] Step a): Preparation of tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate 4-(Benzyloxy)-2,6-dichloropyridine (1.8 g, 7.1 mmol), tert-butyl piperidine-4-carbamate (1.4 g, 7.1 mmol), and DIPEA (415 mg, 14.2 mg) were dissolved in NMP (20 mL) and heated to 130 °C for 2 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate in 77.4% yield.

[0226] ESI-MS m / z=418.2[M+H] + .

[0227] Step b): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate (2.3 g, 5.5 mmol), (4-cyano-3-fluorophenyl)boronic acid (909 mg, 5.5 mmol), Cs2CO3 (3.5 g, 11.0 mmol), and Pd(dppf)Cl2 (77.2 mg, 0.11 mmol) were dissolved in dioxane (40 mL), water (4 mL) was added, and nitrogen substitution was performed three times. The reaction was heated to 100 °C and reacted for 2 hours. After that, the reaction was analyzed by LC-MS. Upon completion, the reaction was cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in 76.0% yield.

[0228] ESI-MS m / z=503.2[M+H] + .

[0229] Step c): Preparation of tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (1.8 g, 3.58 mmol) and NBS (687 mg, 2.41 mmol) were dissolved in DMF (30 mL) and reacted at room temperature for 2 hours. LC-MS showed the reaction was complete. Water (80 mL) was added and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in 81.0% yield.

[0230] ESI-MS m / z=581.2[M+H] + .

[0231] Step d): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (1.7 g, 2.9 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (498 mg, 2.9 mmol), CsCO (1.9 g, 5.8 mmol), and Pd(dppf)Cl (214 mg, 0.29 mmol) were dissolved in dioxane (30 mL). Water (6 mL) was added, and the mixture was purged with nitrogen three times. The reaction was heated to 100 °C and run for 2 hours. LC-MS showed the disappearance of the starting material, indicating completion of the reaction. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1:1) to give tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 43.8%.

[0232] ESI-MS m / z=625.3[M+H] + .

[0233] Step e): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 0.32 mmol) was dissolved in methanol (20 mL), 100 mg of 10% Pd(OH)2 was added, and the mixture was purged with hydrogen three times. The mixture was allowed to react at room temperature for 4 hours. The reaction mixture was sonicated for 15 minutes, then filtered, and the filtrate was concentrated in vacuo to obtain tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate, with a yield of 96.8%.

[0234] ESI-MS m / z=535.2[M+H] + .

[0235] Step f): Preparation of methyl 7-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)heptanoate tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (150 mg, 0.22 mmol) was dissolved in acetonitrile (3 mL), diisopropylethylamine (86 mg, 0.66 mmol) and methyl 7-bromoheptanoate (74 mg, 0.33 mmol) were added, and the mixture was reacted overnight at 60 °C. The system was concentrated in vacuo, and the residue was purified on a silica gel column (eluent: petroleum ether: ethyl acetate = 1:1) to give methyl 7-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)heptanoate in 87% yield.

[0236] ESI-MS m / z=677.3[M+H] + .

[0237] Step g): Preparation of 7-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)heptanoic acid Methyl 7-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)heptanoate (135 mg, 0.20 mmol) was dissolved in THF / HO=5:1 (3 mL) and reacted at room temperature overnight. The pH of the mixture was adjusted to 2-3 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed once with brine, dried, concentrated, and the residue was used directly in the next step.

[0238] ESI-MS m / z=663.3[M+H] + .

[0239] Step h): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate 7-((6-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)heptanoic acid (132 mg, 0.20 mmol) was dissolved in DMF (3 mL), HATU (114.1 mg, 0.3 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (47 mg, 0.4 mmol) were added, and the reaction was allowed to proceed at room temperature for 1 hour. Water was then added to the reaction mixture. The reaction mixture was quenched and extracted with ethyl acetate. The organic phase was washed twice with water, dried, and concentrated in vacuo. The residue was purified on a silica gel column (eluent: petroleum ether:ethyl acetate=1:1) to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate in an 85% yield.

[0240] ESI-MS m / z=762.4[M+H] + .

[0241] Step i): Preparation of 7-((6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate (130 mg, 0.17 mmol) was dissolved in HCl / EA (3 mL, 4 M) and reacted at room temperature for 1 hour. A solid formed in the reaction mixture, and LC-MS detection indicated completion of the reaction. The reaction mixture was filtered to obtain the solid, which was purified by prep-HPLC (Separation Method 1) to obtain 7-((6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride in a yield of 65.2%.

[0242] 1 H NMR(400MHz,DMSO-d6)δ10.41(d,J=27.2Hz,1H),8.39(s,3H),7.86(t,J=7.4Hz,1H),7.50(d,J=10.6Hz,1H),7.29(dd ,J=8.2,1.4Hz,1H),6.84(d,J=8.2Hz,1H),6.70(s,1H),6.59(d,J=2.0Hz,1H),6.45(dd,J=8.2,2.0Hz,1H),4.47(d,J= 13.3Hz,2H),4.17(t,J=6.3Hz,2H),3.79(s,3H),3.39(dq,J=11.5,5.5Hz,1H),3.13(t,J=12.9Hz,2H),2.13-2.04(m,2 H),1.98(t,J=7.4Hz,2H),1.68(tq,J=13.6,6.8,5.2Hz,4H),1.51(p,J=7.4Hz,2H),1.30(dq,J=19.9,6.6,5.3Hz,4H).

[0243] ESI-MS m / z=578.3[M+H] + .

[0244] The compounds of Examples 2 to 18 were prepared according to the synthesis method of Example 1 (compound isolation methods: hydrochloride, trifluoroacetate, formate and free base were prepared according to isolation methods 1, 2, 3 and 4, respectively), and their structures and property data are shown in the table below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0245] Example 19 Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride [ka]

[0246] Step a): Preparation of methyl 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate The product of step c) of Example 1: tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 345 μmol), methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (241 mg, 517 μmol), CsCO (225 mg, 690 μmol), Pd(dppf)Cl (26 mg, 35 μmol), 1,4-dioxane (10 mL), and HO (2.5 mL) were added to a reaction flask and the reaction was stirred at 120° C. for 1 hour. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 2) to obtain methyl 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate in a yield of 58.0%.

[0247] ESI-MS (m / z) = 843.4 [M+H] + .

[0248] Step b): Preparation of 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoic acid Methyl 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate (169 mg, 200 μmol), lithium hydroxide monohydrate (42 mg, 1.0 mmol), tetrahydrofuran (2 mL), isopropanol (2 mL) and water (1 mL) were added to a reaction flask and stirred at room temperature for 12 hours. While stirring in an ice bath, 1N concentrated hydrochloric acid was added dropwise to adjust the pH to 3-4, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried to give 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoic acid, which was used directly in the next step of the reaction.

[0249] ESI-MS (m / z) = 829.4 [M+H] + .

[0250] Step c: Preparation of tert-butyl (1-(4-(benzyloxy)-5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyloxy)phenyl)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate 7-(2-(benzyloxy)-4-(4-(benzyloxy)-6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoic acid (99 mg, 200 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (47 mg, 400 μmol), DIEA (52 mg, 400 μmol) and DMF (2 mL) were added to a reaction flask, and HATU (114 mg, 300 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed successively with saturated aqueous sodium bicarbonate (20 mL × 1) and saturated brine (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (1-(4-(benzyloxy)-5-(3-(benzyloxy)-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyloxy)phenyl)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, with a yield of 62.7%.

[0251] ESI-MS (m / z) = 928.5 [M+H] + .

[0252] Step d: Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4-(benzyloxy)-5-(3-(benzyloxy)-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyloxy)phenyl)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (117 mg, 126 μmol), palladium on carbon (25 mg, 5%), and ethanol (5 mL) were added sequentially to a reaction flask, dissolved with stirring, purged with hydrogen three times, and stirred under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 85.0%.

[0253] ESI-MS (m / z) = 748.4 [M+H] + .

[0254] Step e): Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate (80 mg, 107 μmol) was added to the reaction flask, followed by hydrogen chloride ethyl acetate solution (4 M, 2.5 mL), and the mixture was stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 1) to obtain 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride, with a yield of 35.8%.

[0255] 1 H NMR(400MHz,Methanol-d4)δ7.63(t,J=7.2Hz,1H),7.39(d,J=9.6Hz,1H),7.23(d,J=7.8Hz,1H) ,6.70(d,J=8.2Hz,1H),6.53(d,J=6.2Hz,2H),6.39(d,J=8.0Hz,1H),4.08(d,J=13.2Hz,2H),3.8 9(t,J=6.4Hz,2H),3.43(td,J=11.6,11.2,5.4Hz,1H),3.27(d,J=12.6Hz,2H),2.21-2.08(m,2H) ,2.03(t,J=7.4Hz,2H),1.72(dp,J=21.6,7.6,6.8Hz,4H),1.62-1.48(m,2H),1.38-1.28(m,4H).

[0256] ESI-MS (m / z) = 564.3 [M+H] + .

[0257] Example 20 Preparation of 7-(5-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)-N-hydroxyheptanamide hydrochloride [ka]

[0258] Step a): Preparation of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile 6-Chloro-2-methoxypyrimidin-4-amine (3.0 g, 0.03 mol), Na2CO3 (9.9 g, 0.09 mol), (4-cyano-3-fluorophenyl)boronic acid (7.8 g, 0.05 mol), and Pd(aphos)2Cl2 (4.3 g, 6 mmol) were dissolved in 1,4-dioxane:water (5:1) (150 mL). The solution was bubbled with nitrogen and protected with nitrogen. The reaction was heated to 95 °C in an oil bath. When LCMS showed the reaction was complete, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (20 mL), washed with water (20 mL), the aqueous phase was extracted with ethyl acetate (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 88.6%.

[0259] ESI-MS m / z: 245.1 [M+H] + .

[0260] Step b): Preparation of 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (2.0 g, 8 mmol) was dissolved in dry DMSO (10 mL) and anhydrous acetonitrile (50 mL). NBS (1.45 g, 8 mmol) was added to the reaction mixture in an ice-water bath under nitrogen protection for 2 h. Upon completion of the reaction as determined by LCMS, the mixture was quenched with water (40 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in 78.5% yield.

[0261] ESI-MS m / z: 323.0 [M+H] + .

[0262] Step c): Preparation of 4-(8-bromo-5-hydroxyimidazolopyrimidin-7-yl)-2-fluorobenzonitrile 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (500 mg, 1.55 mmol) was dissolved in isopropanol (13 mL), followed by the addition of chloroacetaldehyde (6.09 g, 31.06 mmol). The mixture was purged with nitrogen and reacted at 110 °C overnight. The reaction progress was monitored by TLC and LCMS. When LCMS showed the reaction was complete, the reaction mixture was concentrated in vacuo, dissolved in dichloromethane (5 mL), and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 4-(8-bromo-5-hydroxyimidazolopyrimidin-7-yl)-2-fluorobenzonitrile in 85.7% yield.

[0263] 1 H NMR(400MHz,DMSO-d6)δppm12.28(s,1H),8.14(dt,J=9.0,4.6Hz,1H),7.97(d,J=2.6Hz ,1H),7.84(dd,J=10.2,2.6Hz,1H),7.65(dd,J=7.8,2.4Hz,1H),7.50(d,J=2.4Hz,1H).

[0264] ESI-MS m / z: 333.0 [M+H] + .

[0265] Step d): Preparation of 4-(8-(3-(benzyloxy)-4-methoxyphenyl)-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile 4-(8-Bromo-5-hydroxyimidazolopyrimidin-7-yl)-2-fluorobenzonitrile (380 mg, 1.14 mmol), (3-(benzyloxy)-4-methoxyphenyl)boronic acid (292 mg, 1.72 mmol), Pd(dppf)Cl (167 mg, 0.21 mmol), and NaCO (243 mg, 2.29 mmol) were weighed and dissolved in 1,4-dioxane (15 mL), and water (3 mL) was added. The mixture was bubbled with N and protected with N, and reacted in a microwave reactor at 105 °C for 30 minutes. When the reaction was complete as determined by LCMS, it was extracted with ethyl acetate (10 mL × 3), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 4-(8-(3-(benzyloxy)-4-methoxyphenyl)-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in 89.7% yield.

[0266] ESI-MS m / z: 467.1 [M+H] + .

[0267] Step e): Preparation of tert-butyl (1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate 4-(8-(3-(benzyloxy)-4-methoxyphenyl)-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile (200 mg, 0.530 mmol), tert-butyl piperidine-4-carbamate (318 mg, 1.57 mmol), and Carter condensation agent (352 mg, 0.795 mmol) were dissolved in 16 mL of anhydrous acetonitrile, DIPEA (206 mg, 1.59 mmol) was added, the mixture was purged with nitrogen, and the mixture was heated to 60°C under nitrogen protection and reacted overnight. The reaction was monitored using TLC and LCMS. After completion of the reaction, the reaction mixture was cooled and concentrated in vacuo. The concentrate was directly purified by preparative thin-layer chromatography (methanol / dichloromethane=1 / 10) to give tert-butyl (1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate in a yield of 58.4%.

[0268] ESI-MS m / z: 649.3 [M+H] + .

[0269] Step f): Preparation of tert-butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate tert-Butyl (1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (200 mg, 309 μmol), palladium on carbon (50 mg, 5%), and ethanol (10 mL) were added sequentially to a reaction flask, and the mixture was purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate in 83.0% yield.

[0270] ESI-MS (m / z) = 559.2 [M+H] + .

[0271] Step g): Preparation of methyl 7-(5-(5-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoate tert-Butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (143 mg, 256 μmol), methyl 7-bromoheptanoate (114 mg, 512 μmol), KCO (72 mg, 512 μmol) and acetonitrile (5 mL) were added to a reaction flask, and the mixture was stirred at 75° C. for 12 hours. Concentrated under reduced pressure and dried, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=8 / 3) to obtain methyl 7-(5-(5-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoate in a yield of 57.0%.

[0272] ESI-MS (m / z) = 701.3 [M+H] + .

[0273] Step h): Preparation of 7-(5-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoic acid Methyl 7-(5-(5-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoate (102 mg, 146 μmol), lithium hydroxide monohydrate (31 mg, 730 μmol), tetrahydrofuran (2 mL), isopropanol (2 mL), and water (2 mL) were added to a reaction flask and stirred at room temperature for 8 hours. After completion of the reaction, 0.5 N aqueous hydrochloric acid solution (10 mL) was added. The resulting mixture was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (10 mL × 2), the organic phase was concentrated under reduced pressure, dried, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 8 / 3) to give 7-(5-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoic acid, the yield was 89.0%.

[0274] ESI-MS (m / z) = 687.3 [M+H] + .

[0275] Step i): Preparation of tert-butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(4-methoxy-3-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate 7-(5-(5-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)heptanoic acid (89 mg, 139 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (33 mg, 278 μmol), DIEA (36 mg, 278 μmol) and DMF (2 mL) were added to a reaction flask, and HATU (79 mg, 208 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed successively with saturated aqueous sodium bicarbonate (20 mL × 2) and saturated saline (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(4-methoxy-3-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate, the yield was 72.7%.

[0276] ESI-MS (m / z) = 786.4 [M+H] + .

[0277] Step j): Preparation of 7-(5-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)-N-hydroxyheptanamide hydrochloride tert-Butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(4-methoxy-3-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (79 mg, 101 umol) was added to the reaction flask, followed by hydrogen chloride in ethyl acetate (4 M, 2. 5 mL) was added, and the mixture was stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 1) to give 7-(5-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)-N-hydroxyheptanamide hydrochloride in a yield of 22.5%.

[0278] 1 H NMR(400MHz,DMSO-d6)δppm10.35(s,1H),8.24-8.19(m,3H),7.99(s,1H),7.87(dd,J= 8.2,6.8Hz,1H),7.55(dd,J=10.6,1.6Hz,1H),7.33(dd,J=8.2,1.6Hz,1H),7.03(d,J=8 .4Hz,1H),6.97-6.75(m,2H),4.08(s,2H),3.81(m,5H),3.41(s,1H),3.23(t,J=12.4Hz) ,2H),2.09(d,J=11.8Hz,2H),2.00-1.79(m,4H),1.70-1.39(m,4H),1.41-1.17(m,4H).

[0279] ESI-MS (m / z) = 602.3 [M+H] + .

[0280] The compounds of Examples 21 to 23 were prepared in the same manner as in Example 20 according to the synthesis method (compound isolation method 1), and their structures and property data are shown in the table below. [Table 2]

[0281] Example 24 Preparation of 7-(4-(5-cyano-4-(4-cyano-3-fluorophenyl)-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride [ka]

[0282] Step a): Preparation of 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile 2-Chloro-4-iodonicotinonitrile (1.0 g, 3.79 mmol), (4-cyano-3-fluorophenyl)boronic acid (688 mg, 4.17 mmol), CsCO (3.7 g, 11.37 mmol), Pd(dppf)Cl (275 mg, 0.38 mmol), 1,4-dioxane (10 mL), and HO (2.5 mL) were added to a reaction flask and stirred at 100 °C for 1 h. The mixture was concentrated under reduced pressure and dried. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile in 68.0% yield.

[0283] ESI-MS (m / z) = 258.1 [M+H] + .

[0284] Step b): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate 2-Chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile (660 mg, 2.58 mmol), tert-butyl piperidin-4-yl-carbamate (552 mg, 2.58 mmol), DIPEA (332 mg, 2.58 mmol), and NMP (10 mL) were added to a reaction flask and stirred at 130 ° C. for 1 hour. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 2). The organic phase was concentrated under reduced pressure and dried. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl) (methyl)carbamate, with a yield of 68.5%.

[0285] ESI-MS (m / z) = 436.2 [M+H] + .

[0286] Step c): Preparation of tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate tert-Butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (600 mg, 1.38 mmol) and DMF (10 mL) were added to a reaction flask, and NBS (270 mg, 1.5 mmol) was added in batches while stirring in an ice bath. The reaction was stirred at room temperature for 30 minutes. After completion of the reaction, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with saturated brine (40 mL × 2). The organic phase was concentrated under reduced pressure and dried. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate in 77.0% yield.

[0287] ESI-MS (m / z) = 514.1 [M+H]+ .

[0288] Step d): Preparation of methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate tert-Butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate (500 mg, 0.97 mmol), methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (501 mg, 1.07 mmol), CsCO (950.8 mg, 2.92 mmol), Pd(dppf)Cl (70.6 mg, 0.1 mmol), 1,4-dioxane (10 mL), and HO (2.5 mL) were added to a reaction flask, and the mixture was stirred at 100 °C for 1 hour. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=3 / 1) to obtain methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate in a yield of 68.0%.

[0289] ESI-MS (m / z) = 776.4 [M+H] + .

[0290] Step e): Preparation of 7-(2-(benzyloxy)-4-(6-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoic acid Methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoate (500 mg, 0.66 mmol) was dissolved in tetrahydrofuran (6 mL) and water (1 mL), and lithium hydroxide (95.3 mg, 3.97 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. The pH of the mixture was adjusted to 2-3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo, and the residue was used directly in the next step.

[0291] ESI-MS (m / z) = 762.4 [M+H] + .

[0292] Step f: Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate 7-(2-(benzyloxy)-4-(6-(4-((tert-butoxycarbonyl)(methyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenoxy)heptanoic acid (186 mg, 0.24 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (84.35 mg, 0.72 mmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (309.6 mg, 2.4 mmol) and HATU (118.63 mg, 0.31 mmol) were added. The mixture was reacted for 30 minutes and then quenched with water (60 mL). The mixture was thawed and extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated brine (45 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 7) to obtain tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate in a yield of 96%.

[0293] ESI-MS m / z=861.4[M+H] + .

[0294] Step g): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate tert-Butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate (200 mg, 0.23 mmol) was dissolved in ethyl acetate (10 mL), 10% palladium carbon (50 mg) was added, and the mixture was substituted with hydrogen. The mixture was reacted for 30 minutes, filtered, and the obtained filtrate was concentrated to give the crude product, which was used directly in the next step.

[0295] ESI-MS m / z=771.4[M+H] + .

[0296] Step h): Preparation of 7-(4-(5-cyano-4-(4-cyano-3-fluorophenyl)-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide tert-Butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)piperidin-2-yl)piperidin-4-yl)(methyl)carbamate (200 mg, 0.26 mmol) was dissolved in 4N HCl / EA (5 mL), reacted for 30 minutes, and concentrated. The resulting crude product was separated by Prep-HPLC (Separation Method 1) to give 7-(4-(5-cyano-4-(4-cyano-3-fluorophenyl)-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride, the yield was 24%.

[0297] 1H NMR(400MHz,Methanol-d4)δppm8.31(s,1H),7.67(t,J=7.2Hz,1H),7.31(d,J=9.6Hz,1 H),7.18(d,J=7.8Hz,1H),6.72(d,J=8.2Hz,1H),6.48-6.36(m,2H),4.35(d,J=13.2Hz, 2H),3.88(t,J=6.6Hz,2H),3.21(m,3H),2.67(s,3H),2.29-2.05(m,4H),1.73(ddt,J=1 6.8,13.2,7.4Hz,4H),1.55(dp,J=12.6,7.2Hz,2H),1.36(dp,J=12.2,8.2,7.2Hz,4H).

[0298] ESI-MS m / z=587.3[M+H] + .

[0299] Examples 25 and 26 were synthesized according to the method of Example 24 (separation method 1), and their structures and property data are shown in the table below. [Table 3]

[0300] Example 27 Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride [ka]

[0301] Step a): Preparation of 2,6-dichloro-4-methoxypyridine 4-(Benzyloxy)-2,6-dichloropyridine (2 g, 11.049 mmol) and MeOH (20 mL) were added to the reaction flask and stirred at room temperature for 16 hours. After completion of the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 2) and concentrated under reduced pressure until dry. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 2,6-dichloro-4-methoxypyridine in 60.5% yield.

[0302] 1 HNMR (400MHz, Chloroform-d) δppm 6.79 (s, 2H), 3.87 (s, 3H).

[0303] ESI-MS (m / z) = 178.0 [M+H] + .

[0304] Step b): Preparation of tert-butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate 2,6-Dichloro-4-methoxypyridine (1.2 g, 6.63 mmol), tert-butyl piperidin-4-yl carbamate (2.7 g, 13.26 mmol), and NMP (15 mL) were added to a microwave reactor and stirred at 130 ° C. for 2 hours. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), and concentrated under reduced pressure until dry. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 52.0%.

[0305] ESI-MS (m / z) = 342.5 [M+H] + .

[0306] Step c): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (1.2 g, 3.45 mmol), (4-cyano-3-fluorophenyl)boronic acid (853 mg, 5.17 mmol), CsCO (2.2 g, 6.9 mmol), Pd(dppf)Cl (253 mg, 0.35 mmol), 1,4-dioxane (10 mL), and HO (2.5 mL) were added to a reaction flask and stirred at 120 °C for 1 h. The mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3) to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in 73.0% yield.

[0307] 1 HNMR(400MHz,DMSO-d6)δ8.12(dd,J=15.4,9.8Hz,2H),7.02(d,J=1.8Hz,1H),6.83(d,J=7.8Hz,1H),6.40(s,1H) ,4.33(d,J=13.2Hz,2H),3.86(m,3H),3.31(s,3H),2.94(t,J=12.4Hz,2H),1.80(d,J=12.0Hz,2H),1.39(s,9H).

[0308] ESI-MS (m / z) = 427.2 [M+H] + .

[0309] Step d): Preparation of tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (1.1 g, 2.52 mmol) and DMF (20 mL) were added to a reaction flask, and NBS (448 mg, 2.516 mmol) was added in batches while stirring in an ice bath. The reaction was stirred at room temperature for 30 minutes. After the reaction was completed, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 2), and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3) to obtain tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in 72.0% yield.

[0310] ESI-MS (m / z) = 505.2 [M+H] + .

[0311] Step e): Preparation of methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoate tert-Butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 397 μmol), methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (279 mg, 596 μmol), CsCO (259 mg, 794 μmol), Pd(dppf)Cl (29 mg, 39.7 μmol), 1,4-dioxane (10 mL), and HO (2.5 mL) were added to a reaction flask, and the mixture was stirred at 120° C. for 1 hour. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 2) to obtain methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoate in a yield of 56.0%.

[0312] ESI-MS (m / z) = 767.4 [M+H] + .

[0313] Step f): Preparation of 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoic acid Methyl 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoate (171 mg, 222 μmol), lithium hydroxide monohydrate (43 mg, 1.1 mmol), tetrahydrofuran (2 mL), isopropanol (2 mL) and water (1 mL) were added to a reaction flask and the mixture was stirred at room temperature for 12 hours. The mixture was stirred in an ice bath and adjusted to pH 3-4 by slowly adding 1N hydrochloric acid dropwise. Water (10 mL) was added and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried to give 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoic acid, which was used directly in the next step.

[0314] ESI-MS (m / z) = 753.4 [M+H] + .

[0315] Step g: Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate 7-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)phenoxy)heptanoic acid (167 mg, 222 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (52 mg, 444 μmol), DIEA (53 mg, 444 μmol) and DMF (2 mL) were added to a reaction flask, and HATU (114 mg, 300 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate (20 mL × 1) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, with a yield of 64.7%.

[0316] ESI-MS (m / z) = 852.4 [M+H] + .

[0317] Step h): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(5-(3-(benzyloxy)-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (122 mg, 143 μmol), palladium on carbon (25 mg, 5%), and ethanol (5 mL) were added sequentially to a reaction flask, and the mixture was purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 87.0%.

[0318] ESI-MS (m / z) = 762.4 [M+H] + .

[0319] Step i): Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (95 mg, 124 μmol) was added to the reaction flask, followed by hydrogen chloride ethyl acetate solution (4 M, 2.5 mL), and the mixture was stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 1) to obtain 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride, with a yield of 34.0%.

[0320] 1 H NMR(400MHz,Methanol-d4)δ7.63(t,J=7.0Hz,1H),7.39(d,J=9.4Hz,1H),7.24(d,J=7. 8Hz,1H),6.79-6.57(m,2H),6.49(s,1H),6.36(d,J=7.8Hz,1H),4.26(d,J=13.0Hz,2H), 3.95(s,3H),3.88(t,J=6.4Hz,2H),3.46(s,1H),3.32(t,J=12.8Hz,2H),2.14(d,J=12.2 Hz,2H),2.03(t,J=7.4Hz,2H),1.84-1.62(m,4H),1.57-1.50(m,2H),1.44-1.26(m,4H).

[0321] ESI-MS (m / z) = 578.3 [M+H] + .

[0322] Examples 28 to 30 were synthesized in the same manner as in Example 27 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively), and their structures and property data are shown in the table below. [Table 4]

[0323] Example 31 Preparation of 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride [ka]

[0324] Step a): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate The product of step b) of Example 1: tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (600 mg, 1.2 mmol) was dissolved in dichloromethane (12 mL), the temperature was lowered to 0°C, a 1N solution of boron tribromide in dichloromethane (5 mL) was added dropwise, and the reaction was carried out while keeping the temperature for 1 hour. The reaction was quenched with water, and sodium bicarbonate was added to adjust the pH to alkaline. Tetrahydrofuran (10 mL) and BocO (523.38 mg, 2.4 mmol) were added, stirred for 30 minutes, and extracted with ethyl acetate (30 mL × 3). The organic phase was washed once with brine, dried, and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: petroleum ether: ethyl acetate = 1:1) to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate in 80% yield.

[0325] ESI-MS m / z=413.2[M+H] + .

[0326] Step b): Preparation of methyl 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoate hydrochloride tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate (400 mg, 0.97 mmol) was dissolved in acetonitrile (4 mL), and methyl 7-bromoheptanoate (1.3 g, 5.82 mmol) and N,N-diisopropylethanamine (752.2 mg, 5.82 mmol) were weighed and added at room temperature. The mixture was purged with nitrogen, heated to 90°C, and reacted overnight. Completion of the reaction of the raw materials was monitored by LCMS, and the reaction solution was cooled to room temperature. After heating, the mixture was quenched by adding water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain methyl 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoate in a yield of 77.0%.

[0327] ESI-MS m / z=555.3[M+H] + .

[0328] Step c): Preparation of 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoic acid Lithium hydroxide (129.6 mg, 5.4 mmol) was dissolved in tetrahydrofuran:water = 2:1 (11 mL), and then methyl 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoate (300 mg, 0.54 mmol) was added to the lithium hydroxide solution. The mixture was purged with nitrogen and stirred at room temperature overnight. Completion of the reaction of the raw materials was monitored by LCMS. (20 mL) was added, and the pH was adjusted to 3-4 with 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product 7-((2-(4-((tert-butoxycarbonyl))amino)))amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoic acid, which was used directly in the next step of the reaction.

[0329] ESI-MS m / z=541.3[M+H] + .

[0330] Step d): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoic acid (300 mg, 0.47 mmol) was dissolved in DMF (5 mL) and stirred at room temperature for 10 minutes. Then, ethyldiisopropylamine (179.8 mg, 1.41 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (65 mg, 0.56 mmol), and hexafluorophosphate (211.8 mg, 0.56 mmol) were added, the atmosphere was replaced with nitrogen, and the reaction was carried out at room temperature for 1 hour. Completion of the reaction of the raw materials was monitored by LCMS. After this, the reaction mixture was cooled to room temperature, quenched by adding water (5 mL), and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate, which was used directly in the next step of the reaction.

[0331] ESI-MS m / z=640.3[M+H] + .

[0332] Step e): Preparation of 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride tert-Butyl (1-(6-(4-cyano-3-fluorophenyl)-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 0.31 mmol) was added to ethyl acetate (10 mL), and then hydrochloric acid (11.47 mg, 0.31 mmol) was added and stirred at room temperature for 1 hour. The reaction of the raw material was monitored for completion by LCMS. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by Prep-HPLC (Separation Method 1) to obtain 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptanamide hydrochloride, with a yield of 31%.

[0333] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.34-7.90(m,2H),7.62(s,1H),7.08(d,J=10.0Hz,1H),6.45(s,2H),4.45( d,J=13.2Hz,2H),4.11(s,2H),3.29(s,1H),2.92(d,J=13.2Hz,2H),1.96(m,4H),1.72(s,2H),1.59-1.26(m,8H).

[0334] ESI-MS m / z=456.2[M+H] + .

[0335] Example 32 Preparation of 7-(4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-fluorophenyl)thiophen-2-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride [ka]

[0336] Step a): Preparation of methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate 2-(Benzyloxy)-4-bromophenol (2 g, 7.16 mmol), methyl 7-bromoheptanoate (2.39 g, 10.74 mmol), and DIEA (3.7 g, 28.64 mmol) were added to a reaction solution containing acetonitrile (20 mL) and stirred at 90° C. for 16 hours. Silica gel was added to the reaction solution, which was then concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate in a 70% yield.

[0337] ESI-MS m / z=421.1[M+H] + .

[0338] Step b): Preparation of methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate Methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate (2 g, 4.75 mmol), coupled boronic acid pinacol ester (2.41 g, 9.5 mmol), Pd(dppf)Cl (0.35 g, 0.48 mmol), and potassium acetate (0.93 g, 9.5 mmol) were added to a reaction flask containing 1,4-dioxane (20 mL), and the mixture was stirred at 110 °C for 3 h. The reaction mixture was concentrated over silica gel, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate in 72% yield.

[0339] ESI-MS m / z=469.3[M+H] + .

[0340] Step c): Preparation of tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate 4-Bromothiophene-2-carboxylic acid (3 g, 14.47 mmol), HATU (8.25 g, 21.71 mmol), DIEA (5.61 g, 43.41 mmol) and tert-butyl (8-azabicyclo[3.2.1]oct-3-yl)carbamate (3.27 g, 14.47 mmol) were added to a reaction flask containing DMF (30 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate in a 90% yield.

[0341] ESI-MS m / z=415.1[M+H] + .

[0342] Step d): Preparation of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-Butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate (5.5 g, 13.24 mmol), 4-cyano-3-fluorophenylboronic acid (3.28 g, 19.86 mmol), Pd(dppf)Cl (0.97 g, 1.32 mmol), and cesium carbonate (8.63 g, 26.48 mmol) were added to a microwave tube containing 1,4-dioxane (40 mL) and water (8 mL), and the mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated with silica gel and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate in a yield of 98%.

[0343] ESI-MS m / z=456.2[M+H] + .

[0344] Step e): Preparation of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-Butyl (8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate (4 g, 8.78 mmol) and NBS (1.72 g, 9.66 mmol) were added to a reaction flask containing DMF (40 mL), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate in a 51% yield.

[0345] ESI-MS m / z=534.1[M+H] + .

[0346] Step f): Preparation of methyl 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3)-fluorophenyl)thiophen-2-yl)phenoxy)heptanoate Methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate (200 mg, 0.43 mmol), tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (0.23 g, 0.43 mmol), Pd(dppf)Cl2 (63 mg, 0.086 mmol), and cesium carbonate (0.28 g, 0.86 mmol) were added to a reaction solution containing 1,4-dioxane (6 mL) and water (1.5 mL), and the mixture was stirred at 120 °C under microwave heating for 1 h. Silica gel was added to the reaction mixture, which was then concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3)-fluorophenyl)thiophen-2-yl)phenoxy)heptanoate in a 70% yield.

[0347] ESI-MS m / z=796.3[M+H] + .

[0348] Step g): Preparation of 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-fluorophenyl)thiophen-2-yl)phenoxy)heptanoic acid Methyl 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-)-fluorophenyl)thiophen-2-yl)phenoxy)heptanoate (300 mg, 0.38 mmol) and lithium hydroxide (0.16 g, 3.8 mmol) were added to a reaction solution containing THF (10 mL), MeOH (6 mL), and water (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 10 mL of ice-water mixture, adjusted to pH 3 with 2 M HCl, and extracted with DCM / MeOH (5:1) (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-fluorophenyl)thiophen-2-yl)phenoxy)heptanoic acid in a 62% yield.

[0349] ESI-MS m / z=782.3[M+H] + .

[0350] Step h): Preparation of tert-butyl (8-(5-(3-benzyloxy)-4-(7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)aminoheptyl)oxy)phenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate 7-(2-(benzyloxy)-4-(5-(3-((tert-butoxycarbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-)fluorophenyl)thiophen-2-yl)phenoxy)heptanoic acid (130 mg, 0.17 mmol), HATU (4.5 mg, 65 μmol), O-(tetrahydro-2H-pyran-2-yl)2-yl)hydroxyamine (97 mg, 0.26 mmol), and DIEA (66 mg, 0.51 mmol) were added to the reaction mixture containing DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (8-(5-(3-benzyloxy)-4-(7-oxo-7-(tetrahydro-2H-pyran-2-yl)oxy)aminoheptyl)oxy)phenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate in a yield of 67%.

[0351] ESI-MS m / z=881.4[M+H] + .

[0352] Step i: Preparation of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-Butyl (8-(5-(3-benzyloxy)-4-(7-oxo-7-((tetrahydro-2H-pyran-2-yl)oxy)aminoheptyl)oxy)phenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (100 mg, 0.11 mmol) and palladium on carbon (21 mg, 0.11 mmol) were added to a reaction flask containing ethyl acetate (5 mL), and the mixture was reacted under hydrogen protection at 40° C. for 36 hours. The reaction mixture was filtered through diatomaceous earth and concentrated to give tert-butyl (8-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)thiophene-2-carbonyloxy)-8-azabicyclo[3.2.1]oct-3-yl)carbamate in a 75% yield.

[0353] ESI-MS m / z=791.3[M+H] + .

[0354] Step j): Preparation of 7-(4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-fluorophenyl)thiophen-2-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride A 4.0 M solution of hydrochloric acid in EA (3 mL) was added to a reaction flask containing tert-butyl (8-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxo-7-(((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate (85 mg, 0.11 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by Prep-HPLC (Separation Method 1) to obtain 7-(4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(4-cyano-3-fluorophenyl)thiophen-2-yl)-2-hydroxyphenoxy)-N-hydroxyheptanamide hydrochloride in a yield of 16%.

[0355] 1 H NMR(400MHz,DMSO-d6)δppm10.32(s,1H),9.16(t,J=8.0Hz,1H),8.63(s,1H),7.88(t,J=7.6Hz,2 H),7.65(s,1H),7.57(dd,J=10.8,1.4Hz,1H),7.27(dd,J=8.0,1.6Hz,1H),6.92(d,J=8.6Hz,1H) ,6.70(d,J=6.8Hz,2H),4.77(s,2H),3.95(t,J=6.6Hz,2H),3.62(s,1H),2.12-1.89(m,6H),1.72 (dq,J=21.8,7.8,6.8Hz,6H),1.51(p,J=7.4Hz,2H),1.41(p,J=7.4Hz,2H),1.30(q,J=8.0Hz,2H).

[0356] ESI-MS m / z=607.2[M+H] + .

[0357] Example 33 Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride [ka]

[0358] Step a): Preparation of tert-butyl (1-(4-bromothiophene-2-carbonyl)piperidin-4-yl)carbamate 4-Bromothiophene-2-carboxylic acid (1 g, 4.82 mmol), tert-butyl piperidin-4-yl carbamate (1.16 g, 5.78 mmol), HATU (2.75 g, 7.23 mmol), and DIEA (1.87 g, 14.46 mmol) were added to a reaction flask containing DMF (20 mL), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(4-bromothiophene-2-carbonyl)piperidin-4-yl)carbamate in 91% yield.

[0359] ESI-MS m / z=389.1[M+H] + .

[0360] Step b): Preparation of tert-butyl (1-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate tert-Butyl (1-(4-bromothiophene-2-carbonyl)piperidin-4-yl)carbamate (1.6 g, 4.11 mmol), (4-cyano-3-fluorophenyl)boronic acid (0.81 g, 4.93 mmol), Pd(dppf)Cl (0.30 g, 0.41 mmol), and cesium carbonate (2.68 g, 8.22 mmol) were added to a microwave tube containing 1,4-dioxane (10 mL) and water (2 mL), and the mixture was stirred at 120 °C under microwave heating for 45 minutes. The reaction mixture was concentrated with silica gel, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate in 99% yield.

[0361] ESI-MS m / z=430.2[M+H] + .

[0362] Step c): Preparation of tert-butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate tert-Butyl (1-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate (1.7 g, 3.96 mmol) and NBS (1.06 g, 5.94 mmol) were added to a reaction flask containing DMF (15 mL), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate in 98% yield.

[0363] ESI-MS m / z=508.1[M+H] + .

[0364] Step d): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate tert-Butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate (1.7 g, 3.34 mmol), (3-(benzyloxy)-4-methoxyphenyl)boronic acid (1.29 g, 5.01 mmol), Pd(dppf)Cl (0.24 g, 0.33 mmol), and cesium carbonate (2.18 g, 6.68 mmol) were added to a microwave tube containing 1,4-dioxane (14 mL) and water (2 mL), and the mixture was stirred at 120 °C for 1 h. Silica gel was added to the reaction mixture, which was then concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate in a yield of 93%.

[0365] ESI-MS m / z=642.2[M+H] + .

[0366] Step e): Preparation of 4-(5-(4-aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile tert-Butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate (900 mg, 1.40 mmol) and a 2 M solution of hydrochloric acid in ethyl acetate (10 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give 4-(5-(4-aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile in a 92% yield.

[0367] ESI-MS m / z=542.2[M+H] + .

[0368] Step f): Preparation of methyl (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4)-yl)-amino)methyl)phenyl)acrylate 4-(5-(4-aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile (680 mg, 1.26 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (0.24 g, 1.26 mmol) were added to a reaction flask containing DCE (10 mL), and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction of the raw material by LC-MS, sodium cyanoborohydride (0.32 g, 5.04 mmol) was added under ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding an ice-water mixture of saturated sodium bicarbonate and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4)-yl)amino)methyl)phenyl)acrylate in a yield of 72%.

[0369] ESI-MS m / z=716.3[M+H] + .

[0370] Step g): Preparation of (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)acrylate (630 mg, 0.88 mmol) and lithium hydroxide (0.21 g, 8.8 mmol) were added to a reaction flask containing THF (5 mL), MeOH (3 mL) and water (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 4 by dropwise addition of 2 M aqueous hydrochloric acid, extracted with MeOH / DCM (1:5) (20 mL × 2), and the organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid in a yield of 97%.

[0371] ESI-MS m / z=702.2[M+H] + .

[0372] Step h: Preparation of (E)-3-(4-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (600 mg, 0.85 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (0.20 g, 1.71 mmol), HATU (0.39 g, 1.02 mmol), and DIEA (0.33 g, 2.55 mmol) were added to a reaction flask containing DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to give (E)-3-(4-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide in a 44% yield.

[0373] ESI-MS m / z=801.3[M+H] + .

[0374] Step i: Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide A 1 M solution of boron tribromide in DCM (0.78 g, 3.11 mmol) was added dropwise to a reaction flask containing (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (60 mg, 0.075 mmol) and DCM (5 mL) at −60° C., and the mixture was stirred at −60° C. for 20 minutes. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide in a yield of 75%.

[0375] ESI-MS m / z=711.3[M+H] + .

[0376] Step j): Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride A 4.0 M solution of EA hydrochloride (4 ml) was added to a reaction flask containing (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (40 mg, 0.056 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by Prep-HPLC (Separation Method 1) to give (E)-3-(4-(((1-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiophene-2-carbonyl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride in a yield of 7.44%.

[0377] 1 H NMR(400MHz,DMSO-d6)δppm10.82(s,1H),9.28(d,J=1.6Hz,1H),9.04(s,1H),7.88(t,J=7.6 Hz,1H),7.62(s,3H),7.57-7.43(m,2H),7.37-7.23(m,1H),7.13(d,J=12.6Hz,2H),6.94(d,J =8.4Hz,1H),6.76-6.65(m,2H),6.56-6.44(m,1H),4.45(d,J=13.2Hz,2H),4.19(s,2H),3.7 8(s,3H),2.74(d,J=2.4Hz,2H),2.47(s,1H),2.21(d,J=12.4Hz,2H),1.67(d,J=12.8Hz,2H).

[0378] ESI-MS m / z=627.2[M+H] + .

[0379] Example 34 Preparation of 7-(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-ylamino)-n-hydroxyheptanamide hydrochloride. The raw materials were prepared according to the synthesis method of Example 20. [ka]

[0380] Step a): Synthesis of tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate tert-Butyl (1-(8-bromo-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (350 mg, 0.68 mmol), cesium carbonate (664.6 mg, 2.04 mmol), (3-(benzyloxy)-4-methylphenyl)boronic acid (246.9 mg, 1.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.0 mg, 0.01 mmol) were weighed and dissolved in 1,4-dioxane (12.5 mL) and water (2.5 mL), and the mixture was protected with nitrogen. The mixture was heated to 110°C in a microwave oven and reacted for 35 minutes. The mixture was diluted with water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1:1) to obtain tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate, with a yield of 84.9%.

[0381] ESI-MS m / z: 633.3 [M+H] + .

[0382] Step b): Synthesis of 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile tert-Butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (230 mg, 0.36 mmol) was added to a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) and stirred under nitrogen protection for 30 minutes. When the reaction was complete by LCMS, the reaction mixture was concentrated to dryness to give 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in 95.1% yield.

[0383] ESI-MS m / z: 533.2 [M+H] + .

[0384] Step c): Synthesis of methyl 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)heptanoate 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile (182.2 mg, 0.34 mmol), methyl 7-bromoheptanoate (169.5 mg, 0.76 mmol), and potassium carbonate (234.9 mg, 1.7 mmol) were dissolved in dry DMSO (2 mL), protected with nitrogen, and the reaction was carried out at 50°C for 16 hours with stirring. After that, the reaction mixture was cooled to room temperature and di-tert-butyldicarbonate was added. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 2:1) to give methyl 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butyloxycarbonyl)amino)heptanoate in 17.8% yield.

[0385] ESI-MS m / z: 775.4 [M+H] + .

[0386] Step d): Synthesis of 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)heptanoic acid Methyl 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)heptanoate (80 mg, 0.10 mmol) was dissolved in tetrahydrofuran:water = 1:1 (2 mL), lithium hydroxide (43.9 mg, 1.0 mmol) was added, and the mixture was stirred for 30 minutes. Extraction with ethyl acetate (10 mL × 3) was carried out, and the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)heptanoic acid in a yield of 94.6%.

[0387] ESI-MS m / z: 761.4 [M+H] + .

[0388] Step e): Synthesis of tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(7-oxo-7-(((tetrahydropyran-2-yl)carbamoyl)amino)heptyl ester 7-(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)heptanoic acid (90 mg, 0.12 mmol), N,N-carbonyldiimidazole (97.3 mg, 0.60 mmol) was dissolved in dry tetrahydrofuran (3 mL), protected with nitrogen, heated to 40 ° C. and reacted for 1 hour, triethylamine (121.4 mg, 1.2 mmol) was added, followed by 4-(aminooxy)tetrahydropyran (70.3 mg, 0.6 mmol), and reacted under nitrogen protection. After completion of the reaction was detected by LCMS, the product was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane, 1:20) to give tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(7-oxo-7-(((tetrahydropyran-2-yl)carbamoyl)amino)heptyl ester, the yield was 98.8%.

[0389] ESI-MS m / z: 860.4 [M+H] + .

[0390] Step f): Synthesis of 7-(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-ylamino)-n-hydroxyheptanamide hydrochloride tert-Butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)(7-oxo-7-(((tetrahydropyran-2-yl)carbamoyl)amino)heptyl ester (97 mg, 0.11 mmol) was weighed and dissolved in dry dichloromethane (1 mL), protected with nitrogen, and cooled to 0°C in an ice-water bath with 1 M tribromide. Boron (1.5 mL) was added, and the reaction was stirred for 30 minutes to precipitate a solid. Water (3 mL) was added to quench the reaction, followed by filtration and concentration. The residue was purified by Pre-HPLC (Separation Method 1) to obtain 7-(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-ylamino)-n-hydroxyheptanamide hydrochloride in a yield of 22.9%.

[0391] 1 H NMR(400MHz,DMSO-d6)δppm10.39(s,1H),9.71(d,J=16.2Hz,1H),9.10(s,2H),8.23(s,1H),8.08(s,1H),7.88(d d,J=8.2,6.9Hz,1H),7.59(dd,J=10.6,1.5Hz,1H),7.35(dd,J=8.2,1.6Hz,1H),7.17(d,J=7.6Hz,1H),6.80(d,J= 1.8Hz,1H),6.64(dd,J=7.6,1.8Hz,1H),4.14(s,2H),3.40(s,1H),3.23(t,J=12.6Hz,2H),2.92(s,2H),2.18(s,5 H),1.94(dt,J=12.0,5.9Hz,4H),1.66(p,J=7.6Hz,2H),1.50(p,J=7.4Hz,2H),1.30(dq,J=12.6,8.0,7.0Hz,4H).

[0392] ESI-MS m / z: 586.3 [M+H] + .

[0393] Examples 35 and 36 were prepared according to the synthesis method of Example 34 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively), and their structures and property data are shown in the table below. [Table 5]

[0394] Example 37 Preparation of (E)-3-(4-(((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride [ka]

[0395] Step a): Preparation of 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile To 80 mL of 1,4-dioxane:HO = 5:1, 2-chloro-4-iodopyridine-3-carbonitrile (6.4 g, 24.20 mmol), (4-cyano-3-fluorophenyl)boronic acid (4.19 g, 25.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.77 g, 2.42 mmol), and cesium carbonate (14.19 g, 4.20 mmol) were added, and the mixture was purged with nitrogen. The mixture was heated to 100 °C and reacted for 1 hour. The solvent was concentrated, silica gel was added, and the mixture was purified using a normal phase column to obtain the product, 2-chloro-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile, in a yield of 93.02%.

[0396] ESI-MS m / z: 258.1 [M+H] + .

[0397] Step b): Preparation of tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate To NMP (100 mL), 2-chloro-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile (2.0 g, 7.76 mmol), tert-butyl piperidin-4-ylcarbamate (1.6 g, 8.15 mmol), ethyl bis(2-propyl)amine (1.2 g, 9.31 mmol) were added, and the temperature was raised to 120 ° C. and the reaction was continued overnight. After the disappearance of the raw materials was monitored by LCMS, water and EA were added for extraction. The organic phases were combined, washed with saturated brine, concentrated to remove the solvent, silica gel was added, mixed, and purified by normal phase column chromatography to obtain the product tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, the yield was 85.6%.

[0398] ESI-MS m / z: 422.2 [M+H] + .

[0399] Step c): tert-butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate To DMF (4 mL), tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (2.0 g, 4.7 mmol) and N-bromosuccinimide (3.3 g, 18.5 mmol) were added, and the mixture was allowed to react at room temperature for 1 hour. After monitoring the disappearance of the raw materials by LCMS, water was added to the system, extracted with EA, the organic phases were combined, concentrated, silica gel was added, mixed, and purified using a normal phase column to obtain the product tert-butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, with a yield of 93.5%.

[0400] ESI-MS m / z: 500.1 [M+H] + .

[0401] Step d): Preparation of 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-formonitrile tert-Butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (1.0 g, 2.0 mmol) was added to 4N HCl / EA (10 mL) and reacted at room temperature for 0.5 hours. After monitoring the disappearance of the raw materials by LCMS, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and EA was added to the reaction mixture. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and EA was added for extraction. The organic phase was washed with saturated brine and concentrated to remove the solvent, and the crude product, 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-formonitrile, was obtained in a yield of 91.2%.

[0402] ESI-MS m / z: 400.1 [M+H] + .

[0403] Step e): Preparation of methyl (E)-3-(4-((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)-amino)methyl)phenyl)acrylate To a 20 mL mixture of DCE:MeOH:AcOH (10:0.1:0.01), 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-formonitrile (600 mg, 1.50 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (381.55 mg, 1.50 mmol) were added. The mixture was stirred at room temperature for 0.5 hours, cooled in an ice bath, and then sodium cyanoborohydride (285.26 mg, 4.5 mmol) was added. The mixture was then allowed to react in an ice bath for 2 hours. LCMS showed that approximately 5% of the starting material remained, and the product was the main component. The reaction was stopped, quenched with aqueous sodium bicarbonate, and used directly in the next step.

[0404] ESI-MS m / z: 574.1 [M+H]+ .

[0405] Step f): Preparation of methyl (E)-3-(4-((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate Methyl (E)-3-(4-((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (200 mg, 0.35 mmol) was dissolved in THF / HO=5:1 (5 mL), di-tert-butyl dicarbonate (78 mg, 0.35 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The disappearance of the raw materials was monitored by LCMS. After filtration, EA was added for extraction, and the organic phase was washed with saturated brine and then concentrated to remove the solvent. Silica gel was added and the mixture was purified using a normal phase column to give methyl (E)-3-(4-(((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate in a yield of 84.71%.

[0406] ESI-MS m / z: 674.2 [M+H] + .

[0407] Step g): Preparation of (E)-3-(4-((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-(((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxy)carbonyl)amino)methyl)phenyl)acrylate (100 mg, 0.15 mmol) and lithium hydroxide (17.96 mg, 0.75 mmol) were added to THF / HO=5:1 (1 mL) and the reaction was allowed to proceed at room temperature overnight. LCMS showed that the starting materials had disappeared and the product remained as the main component. The reaction was then terminated. The system was adjusted to a weak acidity with dilute hydrochloric acid, and EA was added for extraction. The organic phase was washed with saturated brine and concentrated to remove the solvent, yielding a solid product, which was used directly in the next step of the reaction.

[0408] ESI-MS m / z: 660.2 [M+H] + .

[0409] Step h): Preparation of tert-butyl (E)-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate To 4 mL of DMF was added the crude material obtained in step g above (100 mg, 0.15 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (21.09 mg, 0.18 mmol), HATU (68.44 mg, 0.18 mmol), and ethyldiisopropylamine (58.16 mg, 0.45 mmol). The reaction was carried out at room temperature for 0.5 hours, and LCMS was used to monitor the disappearance of the starting materials and the remaining product. The system was then poured into water, EA was added for extraction, the organic phase was concentrated to remove the solvent, silica gel was added, and the mixture was stirred. The mixture was purified using a normal phase column to obtain the product, tert-butyl (E)-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate, with a yield of 71.96%.

[0410] ESI-MS m / z: 759.2 [M+H] + .

[0411] Step i): Preparation of tert-butyl (E)-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate To a dioxane / HO mixture (5 mL) at a ratio of 5:1, tert-butyl (E)-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (100 mg, 0.13 mmol), (3-hydroxy-4-methoxyphenyl)boronic acid (48.77 mg, 0.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.51 mg, 0.013 mmol), and cesium carbonate (84.71 mg, 0.26 mmol) were added. After replacing with nitrogen, the mixture was subjected to a microwave reaction at 110°C for 1 hour. LCMS showed that the raw materials had disappeared and the product remained as the main component. The mixture was then directly concentrated to remove the solvent, silica gel was added, and the mixture was stirred. The mixture was then purified using a normal phase column to obtain the product tert-butyl (E)-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate, with a yield of 82.39%.

[0412] ESI-MS m / z: 719.3 [M+H] + .

[0413] Step j): Preparation of (E)-3-(4-(((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride tert-Butyl (E)-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (60 mg, 75 μmol) was added to 4 N HCl (EA) (4 mL), and the mixture was reacted at room temperature for 0.5 hours. The reaction was monitored for the disappearance of the raw materials by LCMS. The reaction mixture was concentrated to remove the solvent, and the product, (E)-3-(4-(((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide hydrochloride, was obtained by Prep-HPLC (Separation Method 1) in a yield of 71.12%.

[0414] 1 H NMR(400MHz,DMSO-d6)δ10.41(d,J=18.6Hz,1H),8.39(s,3H),7.86(t,J=7.6Hz,1H),7.50(d,J=10.4Hz,1H),7.29(dd ,J=8.0,1.4Hz,1H),6.84(d,J=8.0Hz,1H),6.70(s,1H),6.59(d,J=2.2Hz,1H),6.45(dd,J=8.2,2.0Hz,1H),4.47(d,J= 13.2Hz,2H),4.17(t,J=6.2Hz,2H),3.79(s,3H),3.39(dq,J=11.4,5.6Hz,1H),3.13(t,J=12.8Hz,2H),2.13-2.04(m,2 H),1.98(t,J=7.4Hz,2H),1.68(tq,J=13.6,6.8,5.2Hz,4H),1.51(p,J=7.4Hz,2H),1.30(dq,J=16.8,6.6,5.4Hz,4H).

[0415] ESI-MS m / z: 619.2 [M+H] + .

[0416] Examples 39 to 53 were prepared according to the synthesis method of Example 37 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively), and their structures and property data are shown in the table below. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0417] Example 54 Preparation of (E)-3-(4-(((1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate [ka]

[0418] Step a): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-bromo-4-methoxypyridin-2-yl)-2-fluorobenzonitrile To HCl (EA) (4 mL), the product of step d) of Example 27, tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (600 mg, 1.20 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The solvent was concentrated to obtain the crude product, 4-(6-(4-aminopiperidin-1-yl)-3-bromo-4-methoxypyridin-2-yl)-2-fluorobenzonitrile, with a yield of 41.81%.

[0419] ESI-MS m / z: 405.1 [M+H] + .

[0420] Step b): Preparation of methyl (E)-3-(4-(((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)-amino)methyl)phenyl)acrylate To DCE / MeOH / CH3COOH = 20:1:0.1 (8 mL) were added 4-(6-(4-aminopiperidin-1-yl)-3-bromo-4-methoxypyridin-2-yl)-2-fluorobenzonitrile (420 mg, 1.04 mmol) and methyl 4-formylcinnamate (356.05 mg, 1.87 mmol), and the mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (326.77 mg, 5.2 mmol) was added while cooling in an ice bath, and the mixture was slowly returned to room temperature and reacted for 1 hour. The disappearance of the raw materials was monitored by LCMS and TLC (EA:PE = 1:2). The reaction mixture was poured into water and extracted with DCM. The combined organic phases were concentrated to remove the solvent, and the resulting mixture was stirred with silica gel and purified using a normal phase column to obtain the product, methyl (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino}methyl}phenyl)acrylate, in a yield of 79.65%.

[0421] ESI-MS m / z: 479.1 [M+H] + .

[0422] Step c): Preparation of (E)-3-(4-(((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)-amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-(((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (500 mg, 0.86 mmol) and lithium hydroxide (123.58 mg, 5.16 mmol) were added to THF / HO=4:1 (10 mL), and the mixture was allowed to react at room temperature overnight. After monitoring the disappearance of the raw material by LCMS, the pH was adjusted to 3 with dilute hydrochloric acid, extracted with EA, and the organic phases were combined and concentrated to remove the solvent to give crude (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino}methyl}phenyl)acrylic acid, which was used directly in the next step.

[0423] ESI-MS m / z: 565.1 [M+H] + .

[0424] Step d): Preparation of (E)-3-(4-((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)[(tert-butoxy)carbonyl)amino)methyl)phenyl)acrylic acid (E)-3-(4-(((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (300 mg, 0.53 mmol), di-tert-butyl dicarbonate (347.02 mg, 1.59 mmol), and sodium bicarbonate (222.63 mg, 2.65 mmol) were added to THF / HO=4:1 (4 mL), and the mixture was allowed to react at room temperature overnight. The disappearance of the raw materials was monitored by LCMS. The pH was adjusted to 7 with dilute hydrochloric acid, extracted with EA, the organic phases were combined and concentrated to remove the solvent, silica gel was added and stirred, and the mixture was purified by normal phase column to obtain the product (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)[(tert-butoxy)carbonyl]amino}methyl}phenyl)acrylic acid, the yield was 90.72%.

[0425] ESI-MS m / z: 664.2 [M+H] + .

[0426] Step e): Preparation of tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate To 4 mL of DMF was added (E)-3-(4-(((1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)((tert-butoxy)carbonyl)amino)methyl)phenyl)acrylic acid (50 mg, 75 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (10.54 mg, 0.09 mmol), HATU (34.22 mg, 90 μmol), and ethyldiisopropylamine (29.08 mg, 0.22 mmol). The reaction was carried out at room temperature for 0.5 hours, and after monitoring by LCMS that the starting materials had disappeared and the product mainly remained, the reaction was terminated. The system was poured into water, and EA was added for extraction. The organic phase was washed with saturated brine and concentrated to remove the solvent. Silica gel was added, and the mixture was stirred. The mixture was purified using a normal phase column to obtain tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 73.23%.

[0427] ESI-MS m / z: 764.2 [M+H] + .

[0428] Step f): tert-butyl (E)-(1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate In a 5:1 mixture of 1,4-dioxane and HO (4 mL), tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (50 mg, 65 μmol), 2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (19.51 mg, 0.78 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]diol were added. Chloropalladium (II) (4.76 mg, 6.5 μmol) and cesium carbonate (38.12 mg, 0.12 mmol) were added, and the mixture was purged with nitrogen. After that, silica gel was added and the mixture was stirred. The mixture was purified using a normal phase column to obtain the product tert-butyl (E)-(1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate, with a yield of 66.65%.

[0429] ESI-MS m / z: 808.4 [M+H] + .

[0430] Step g): Preparation of (E)-3-(4-(((1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate tert-Butyl (E)-(1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (150 mg, 0.19 mol) was added to HCl (EA) (4 M, 5 mL), and the mixture was stirred at room temperature for 0.5 hours. After the reaction was monitored for the disappearance of the raw materials by LCMS, the reaction mixture was concentrated to remove the solvent, and the residue was purified by Prep-HPLC (Separation Method 1) to obtain (E)-3-(4-(((1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate in a yield of 90%.

[0431] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),8.28(s,1H),7.73(dd,J=8.0,7.0Hz,1H),7.51(d,J=7.8Hz,2 H),7.48-7.36(m,3H),7.27(dd,J=11.0,1.6Hz,1H),7.19(dd,J=8.0,1.6Hz,1H),6.78(d,J=8.4Hz, 1H),6.54-6.44(m,2H),6.42(s,1H),6.37(dd,J=8.2,2.0Hz,1H),4.29(m,2H),3.81(s,2H),3.77(s ,3H),3.73(s,3H),3.04-2.83(m,2H),2.77-2.63(m,1H),2.02-1.86(m,2H),1.33(q,J=9.6Hz,2H).

[0432] ESI-MS m / z: 624.3 [M+H] + .

[0433] Example 56 N 1-(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 Preparation of α-hydroxyoctanediamide hydrochloride [ka]

[0434] Step a): Preparation of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile 6-Chloro-2-methoxypyrimidin-4-amine (24 g, 150.40 mmol), (4-cyano-3-fluorophenyl)boronic acid (29.77 g, 180.48 mmol), di-tert-butyl-(4-dimethylaminophenyl)phosphinepalladium(II) dichloride (5.32 g, 7.52 mmol) and sodium carbonate (47.82 g, 451.20 mmol) were added to a reaction solution containing 1,4-dioxane (350 mL) and water (70 mL), and the mixture was stirred at 95° C. for 2 hours. Water (150 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. The mixture was then filtered and the filter cake was placed in a 500 mL recovery flask. Isopropanol (250 mL) was added and the mixture was stirred at 50°C for 30 minutes. The mixture was then transferred to room temperature and stirred for 1 hour. The mixture was then filtered and the filter cake was dried to give 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 95%.

[0435] ESI-MS m / z=245.1[M+H] + .

[0436] Step b): Preparation of 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (24 g, 98.27 mmol) was added to a reaction mixture containing acetonitrile (240 mL) and DMSO (48 mL). NBS (18.36 g, 103.18 mmol) was added to this mixture in an ice bath, and the mixture was cooled to room temperature and stirred for 40 minutes. The reaction mixture and the reaction mixture from this experiment were combined and filtered. The filtrate was concentrated, EA (300 mL) was added, stirred thoroughly, and then filtered. The filter cake was washed with MTBE and dried to give 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in 92% yield.

[0437] ESI-MS m / z=322.0[M+H] + .

[0438] Step c): Preparation of 4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (34 g, 105.22 mmol) and 2-chloroacetaldehyde (103.25 g, 526.1 mmol) were added to a reaction solution containing IPA (300 mL), and the mixture was stirred at 100 °C for 24 hours. The reaction solution was transferred to room temperature and stirred for 2 hours, then filtered. The filter cake was washed with MTBE (50 mL). The filtrate was concentrated, and isopropanol (70 mL) was added. The mixture was stirred at 50 °C for 30 minutes. The mixture was transferred to room temperature and stirred for 2 hours. The filter cake was then filtered, washed with MTBE (70 mL), and the filter cake obtained after two filtrations was dried to give 4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in 75% yield.

[0439] ESI-MS m / z=333.0[M+H] + .

[0440] Step d): Preparation of tert-butyl (1-(8-bromo-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate 4-(8-Bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile (8 g, 24.02 mmol), BOP (21.25 g, 48.04 mmol), DIEA (12.42 g, 96.08 mmol), and tert-butyl piperidin-4-ylcarbamate (12.03 g, 60.05 mmol) were added to the reaction solution containing acetonitrile (80 mL), and the mixture was stirred at 60° C. for 16 hours. Silica gel was added to the reaction mixture, and the residue was purified by silica gel chromatography (eluent: DCM / MeOH=10 / 1) to obtain a crude product, which was further purified on a C18 column to obtain tert-butyl (1-(8-bromo-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5yl)piperidin-4-yl)carbamate in a yield of 31%.

[0441] ESI-MS m / z=515.1[M+H] + .

[0442] Step e): Preparation of tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate tert-Butyl (1-(8-bromo-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (400 mg, 0.78 mmol), Pd(dppf)Cl (57 mg, 78 μmol), cesium carbonate (0.51 g, 1.56 mmol), and (3-(benzyloxy)-4-methylphenyl)boronic acid (0.23 g, 0.94 mmol) were added to a reaction solution containing 1,4-dioxane (2 mL) and water (0.5 mL), and the mixture was stirred at 120 °C under microwave heating for 1 hour. Silica gel was added to the reaction solution, and the mixture was concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 1) to obtain tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate in an 84% yield.

[0443] ESI-MS m / z=633.3[M+H] + .

[0444] Step f): Preparation of 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile A solution of 4.0 M hydrochloric acid (25 mL) in EA was added to a reaction flask containing tert-butyl (1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (400 mg, 0.63 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in 93% yield.

[0445] ESI-MS m / z=533.2[M+H] + .

[0446] Step g): Preparation of methyl 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino) 8-oxooctanoate 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile (420 mg, 0.79 mmol) was added to a reaction flask containing DCM (20 mL). After cooling to 0°C, TEA (0.32 g, 3.16 mmol) and methyl 8-chloro-8-oxooctanoate (0.24 g, 1.19 mmol) were added sequentially and stirred for 10 minutes. After stirring for 10 minutes, the temperature was cooled to room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)-8-oxooctanoate in a 60% yield.

[0447] ESI-MS m / z=703.3[M+H] + .

[0448] Step h): Preparation of 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)-8-oxooctanoic acid Methyl 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)-8-oxooctanoate (500 mg, 0.71 mmol) and lithium hydroxide (29 mg, 0.71 mmol) were added to a reaction solution containing THF (10 mL), MeOH (6 mL), and water (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 4 with 2M HCl, quenched with water (20 mL), and extracted with DCM / MeOH (5:1) (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)-8-oxooctanoic acid in 84% yield.

[0449] ESI-MS m / z=689.3[M+H] + .

[0450] Step i):N 1 -(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 Preparation of -((tetrahydro-2H-pyran-2-yl)oxy)octanediamide 8-((1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)-8-oxooctanoic acid (520 mg, 0.75 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (130 mg, 1.13 mmol), HATU (430 mg, 1.13 mmol), and DIEA (480 mg, 3.75 mmol) were added to the reaction mixture containing DMF (15 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: DCM / MeOH = 8 / 1) and purified with N 1 -(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 -((tetrahydro-2H-pyran-2-yl)oxy)octanediamide was obtained in a yield of 48%.

[0451] ESI-MS m / z=788.4[M+H] + .

[0452] Step j):N 1 -(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 Preparation of α-hydroxyoctanediamide hydrochloride EA solution (6 mL) in 4.0 M hydrochloric acid was added to 1 -(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8The reaction mixture was added to a reaction flask containing 120 mg (0.15 mmol) of 2H-tetrahydropyran-2-yloxyoctanediamide, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by Prep-HPLC (Separation Method 1). 1 -(1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methylphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 -hydroxyoctanediamide hydrochloride was obtained in a yield of 22%.

[0453] 1 H NMR(400MHz,DMSO-d6)δppm10.36(s,1H),9.72(s,1H),8.24(d,J=2.2Hz,1H),8.14(s,1H),7.98- 7.85(m,2H),7.53(m,1H),7.42-7.31(m,1H),7.20(d,J=7.8Hz,1H),6.81(s,1H),6.70-6.59(m,1 H),4.02(d,J=13.2Hz,2H),3.93(d,J=8.6Hz,1H),3.32(t,J=12.2Hz,2H),2.19(s,3H),2.08(t,J =7.4Hz,2H),1.99-1.87(m,4H),1.69(q,J=11.2Hz,2H),1.47(p,J=7.6Hz,4H),1.32-1.16(m,4H).

[0454] ESI-MS m / z=614.3[M+H] + .

[0455] Example 57 N 1 -(4-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-hydroxyphenyl)-N 8 -hydroxyoctanediamine dicarboxylate was prepared according to the synthesis method of Example 56 (Separation Method 1), and the structure and properties are shown in the table below. [ka]

[0456] 1 H NMR(400MHz,Methanol-d4)δppm8.45(s,2H),7.73(d,J=1.6Hz,1H),7.67(d,J=8.2Hz,1H),7.56- 7.43(m,2H),7.40(dd,J=10.8,1.6Hz,1H),7.24(dd,J=8.2,1.6Hz,1H),6.78(d,J=1.2Hz,1H),6.6 6(dd,J=8.2,1.8Hz,1H),4.46(d,J=21.8Hz,1H),4.02(d,J=13.2Hz,2H),3.19-3.02(m,2H),2.37 (t,J=7.4Hz,2H),2.15-1.93(m,4H),1.91-1.75(m,2H),1.59(m,4H),1.32(dq,J=8.8,4.8Hz,4H).

[0457] ESI-MS m / z=615.3[M+H] +

[0458] Example 58 N 1 -(4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N 8 Preparation of α-hydroxyoctanediamide hydrochloride [ka]

[0459] Step a): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-nitrophenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate The product of step c) of Example 37: tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 401 μmol), 2-(3-(benzyloxy)-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (213 mg, 601 μmol), CsCO (261 mg, 802 μmol), Pd(dppf)Cl (29 mg, 40 μmol), 1,4-dioxane (4 mL), and HO (1 mL) were added to a reaction flask and the reaction was stirred at 120° C. for 1 hour. The mixture was concentrated under reduced pressure and dried, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 2) to obtain tert-butyl (1-(-5-(-3-(benzyloxy)-4-nitrophenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 78.5%.

[0460] ESI-MS (m / z) = 529.3 [M+H] + .

[0461] Step b): Preparation of tert-butyl (1-(5-(4-amino-3-(benzyloxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(5-(3-(benzyloxy)-4-nitrophenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (167 mg, 315 μmol), zinc powder (202 mg, 3.1 mmol), ammonium chloride (164 mg, 3.1 mmol), and THF (5 mL) were added to a reaction flask, heated to 65° C., and reacted for 12 hours. After the reaction was completed and the reaction mixture was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 2) to obtain tert-butyl (1-(-5-(4-amino-3-(benzyloxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 72.3%.

[0462] ESI-MS (m / z) = 619.3 [M+H] + .

[0463] Step c): Preparation of methyl 8-((2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino) 8-oxooctanoate tert-Butyl (1-(5-(4-amino-3-(benzyloxy)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (140 mg, 227 μmol), methyl 8-chloro-8-oxooctanoate (93 mg, 454 mmol), triethylamine (46 mg, 454 mmol) and DCM (5 mL) were added to a reaction flask and the reaction was stirred at room temperature for 2 hours. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=1 / 1) to obtain methyl 8-((2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino)-8-oxooctanoate in a yield of 58.0%.

[0464] ESI-MS (m / z) = 789.4 [M+H] + .

[0465] Step d): Preparation of 8-((2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino)-8-oxooctanoic acid Methyl 8-((2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino)-8-oxooctanoate (104 mg, 132 μmol), lithium hydroxide monohydrate (28 mg, 660 μmol), tetrahydrofuran (2 mL), isopropanol (2 mL) and water (1 mL) were added to a reaction flask and the mixture was stirred at room temperature for 12 hours. While stirring in an ice bath, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried to give 8-((2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino)-8-oxooctanoic acid, which was used directly in the next step of the reaction.

[0466] ESI-MS (m / z) = 775.4 [M+H] + .

[0467] Step e): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-(8-oxo-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate 8-(2-(benzyloxy)-4-(6-(4-(tert-butoxycarbonyl)amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)phenyl)amino)-8-oxooctanoic acid (102 mg, 132 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (31 mg, 264 μmol), DIEA (34 mg, 264 μmol) and DMF (2 mL) were added to a reaction flask, and HATU (62 mg, 158 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed successively with saturated aqueous sodium bicarbonate solution (20 mL × 1) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (1-(5-(3-(benzyloxy)-4-(8-oxo-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, the yield was 60.5%.

[0468] ESI-MS (m / z) = 874.4 [M+H] + .

[0469] Step f: Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((8-oxy-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(5-(3-(benzyloxy)-4-(8-oxy-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (70 mg, 80 μmol), palladium on carbon (15 mg, 5%), and ethanol (5 mL) were added sequentially to a reaction flask, dissolved with stirring, purged with hydrogen three times, and stirred under a hydrogen atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-(8-oxy-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 85.0%.

[0470] ESI-MS (m / z) = 784.4 [M+H] + .

[0471] Step g):N 1 -(4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N 8 Preparation of α-hydroxyoctanediamide hydrochloride tert-Butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((8-oxy-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate (53 mg, 68 μmol) was added to the reaction flask, followed by hydrogen chloride ethyl acetate solution (4 M, 2.5 mL), and stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 1) to obtain N1-(4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N8-hydroxyoctanediamide hydrochloride, with a yield of 21.5%.

[0472] 1 H NMR(400MHz,Methanol-d4)δ8.47(s,1H),7.77(dd,J=7.8,6.6Hz,1H),7.60(d,J=8 .2Hz,1H),7.41(dd,J=9.6,1.4Hz,1H),7.25(dd,J=8.0,1.4Hz,1H),6.65-6.43(m,2 H),4.44(d,J=13.6Hz,2H),3.45(ddt,J=11.4,8.6,4.4Hz,1H),3.23(s,2H),2.44( t,J=7.4Hz,2H),2.26-2.05(m,4H),1.94-1.55(m,6H),1.41(dd,J=7.6,4.0Hz,4H).

[0473] ESI-MS (m / z) = 500.3 [M+H] + .

[0474] Examples 59 and 60 were prepared according to the synthesis method of Example 58 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively), and their structures and property data are shown in the table below. [Table 7]

[0475] Example 61 Preparation of 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide hydrochloride [ka]

[0476] Step a): Preparation of methyl 4-(6-(4-{(tert-butoxy)carbonyl]amino}piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoate Product of Example 37, step c): tert-butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (100 mg, 0.20 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (53.99 mg, 0.30 mmol), CsCO (130.33 mg, 0.40 mmol), Pd(dppf)Cl (14.63 mg, 0.02 mmol) were dissolved in water (1 ml L), protected with nitrogen, and subjected to a microwave reaction at 120°C for 1 hour. After monitoring for complete reaction, the reaction mixture was concentrated to give a crude product, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give methyl 4-(6-(4-{(tert-butoxy)carbonyl)amino}piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoate in a yield of 94%.

[0477] ESI-MS m / z=556.2[M+H] +

[0478] Step b): Preparation of 4-(6-(4-{(tert-butoxy)carbonyl]amino)piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoic acid Methyl 4-(6-(4-{(tert-butoxy)carbonyl]amino}piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoate (105 mg, 0.19 mmol) and lithium hydroxide monohydrate (80 mg, 1.9 mmol) were dissolved in a reaction solution of tetrahydrofuran (2.5 mL) and water (1 mL) for 16 hours. Upon monitoring for complete reaction, water (20 mL) was added, and the organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was used directly in the next step.

[0479] ESI-MS m / z=542.2[M+H] +

[0480] Step c): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate 4-(6-(4-{(tert-butoxy)carbonyl)amino}piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoic acid (100 mg, 0.18 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (64 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (5 mL), DIPEA (120 mg, 0.93 mmol), HATU (210 mg, 0.55 mmol) were added, and the reaction was monitored for completeness. The mixture was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was used directly in the next step.

[0481] ESI-MS m / z=641.3[M+H] +

[0482] Step d): Preparation of 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide tert-Butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate (110 mg, 0.17 mmol) was dissolved in 4N HCl / EA (6 mL) and reacted for 30 minutes. After monitoring for complete reaction, the mixture was concentrated to obtain a crude product, which was then subjected to separation method 1 to obtain 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide hydrochloride in a yield of 62%.

[0483] 1 H NMR(400MHz,Methanol-d4)δppm8.49(s,1H),7.74(dd,J=7.8,6.6Hz,1H),7.66(d,J=7.8Hz,2H),7.47-7.34(m,1H),7.24(m,3H),4.49 (d,J=13.2Hz,2H),3.48(tt,J=11.0,4.0Hz,1H),3.25(d,J=11.2Hz,1H),3.00(s,1H),2.31-2.11(m,2H),1.83(qd,J=12.2,3.8Hz,2H).

[0484] ESI-MS m / z=457.2[M+H] +

[0485] Examples 62 to 64 were synthesized according to the method of Example 61 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively), and their structures and property data are shown in the table below. [Table 8]

[0486] Example 66 Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6)-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate [ka]

[0487] Step a): Synthesis of 2,5,6-trichloropyrimidin-4-ol Sodium hydroxide (1.19 g, 29.84 mmol) was weighed and dissolved in water (15 mL). 2,4,5,6-tetrachloropyrimidine (5 g, 22.95 mmol) was slowly added dropwise to tetrahydrofuran (40 mL) and stirred under nitrogen protection for 16 hours. When the reaction was complete as determined by LCMS, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pulping with ether to give 2,5,6-trichloropyrimidin-4-ol in 74.1% yield.

[0488] ESI-MS m / z: 199.0 [M+H] +

[0489] Step b): Synthesis of 2,5,6-trichloro-3-methylpyrimidin-4(3H)-one 2,5,6-Trichloropyrimidin-4-ol (3.3 g, 16.6 mmol) and potassium carbonate (3.43 g, 79.6 mmol) were dissolved in DMF (30 mL), and iodomethane (4.7 g, 33.1 mmol) was slowly added. The mixture was then allowed to react at room temperature for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 2,5,6-trichloro-3-methylpyrimidin-4(3H)-one in 82.5% yield.

[0490] ESI-MS m / z=213.0[M+H] +

[0491] Step c): Preparation of tert-butyl (1-(4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate 2,5,6-Trichloro-3-methylpyrimidin-4(3H)-one (2.5 g, 11.71 mmol), tert-butyl piperidin-4-ylcarbamate (2.35 g, 11.71 mmol), and DIPEA (3.03 g, 23.42 mg) were dissolved in NMP (20 mL) and heated to 130 °C for 2 h. After completion of the reaction was monitored by LC-MS, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give tert-butyl (1-(4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate in 67.4% yield.

[0492] ESI-MS m / z=213.0[M+H] +

[0493] Step d): Preparation of tert-butyl (1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate tert-Butyl (1-(4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate (1 g, 2.65 mmol), (4-cyano-3-fluorophenyl)boronic acid (570 mg, 3.44 mmol), cesium carbonate (1.73 g, 5.3 mmol), dppf palladium dichloride (190 mg, 0.27 mmol) were dissolved in 1,4-dioxane (15 mL), water (2 mL) was added, protected with nitrogen, and the reaction was heated to 120 °C in a microwave oven for 60 minutes. When the reaction was complete by LCMS, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography to give tert-butyl (1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate in a yield of 70.7%.

[0494] ESI-MS m / z: 462.2 [M+H] +

[0495] Step e): Preparation of 4-(2-(4-aminopiperidin-1-yl)-5-chloro-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile tert-Butyl (1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate (920 mg, 1.99 mmol) was added to 4N HCl / EA (10 mL) and reacted at room temperature for 0.5 hours. After monitoring the disappearance of the raw materials by LCMS, the reaction system was poured into saturated aqueous sodium bicarbonate solution, and EA was added for extraction. The organic phase was washed with saturated brine and concentrated to remove the solvent, and the crude product 4-(2-(4-aminopiperidin-1-yl)-5-chloro-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile was obtained in a yield of 91.2%.

[0496] ESI-MS m / z: 362.1 [M+H] +

[0497] Step f): Preparation of methyl (E)-3-(4-((1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate 4-(2-(4-aminopiperidin-1-yl)-5-chloro-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile (679 mg, 1.88 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (536.36 mg, 2.82 mmol) were added to DCE / MeOH / CH3COOH=20:1:0.1 (10 mL), the mixture was stirred at room temperature for 0.5 hours, and sodium cyanoborohydride (590.7 mg, 9.40 mmol) was added while cooling in an ice bath. The mixture was then slowly returned to room temperature and reacted for 1 hour. The disappearance of the raw materials was monitored by LCMS. The reaction mixture was poured into water, extracted with DCM, the organic phases were combined and concentrated to remove the solvent, silica gel was added, the mixture was stirred, and the mixture was purified using a normal phase column to obtain the product (E)-3-(4-((1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)methyl acrylate, with a yield of 76.5%.

[0498] ESI-MS m / z: 539.2 [M+H] + .

[0499] Step g): Synthesis of methyl (E)-3-(4-((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate Methyl (E)-3-(4-((1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (1.2 g, 2.24 mmol) was dissolved in THF:HO = 3:1 (12 ml) and stirred thoroughly. After that, (Boc)O (1.47 g, 6.72 mmol) and sodium bicarbonate (0.94 g, 11.20 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the solution was dissolved in 0.5 N aqueous hydrochloric acid. The resulting mixture was added with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried. The residue was purified by silica gel chromatography to give methyl (E)-3-(4-((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in a yield of 89.0%.

[0500] ESI-MS (m / z) = 636.2 [M+H] +

[0501] Step h): Synthesis of methyl (E)-3-(4-((tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate Methyl (E)-3-(4-((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (200 mg, 0.31 mmol), cesium carbonate (303.0 mg, 0.93 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (66.5 mg, 0.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21.8 mg, 0.031 mmol) were weighed and added to 1,4-dioxane (12.5 mL) and water (2.5 mL). The mixture was dissolved in 1 mL of methyl acrylate, protected with nitrogen, heated to 110°C in a microwave oven, and reacted for 35 minutes. The mixture was diluted with water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1:1) to obtain (E)-3-(4-((tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)methyl acrylate in a yield of 80.9%.

[0502] ESI-MS m / z: 726.3 [M+H] +

[0503] Step i): Synthesis of (E)-3-(4-(tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (E)-3-(4-((tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)methyl acrylate (225.1 mg, 0.31 mmol) was dissolved in tetrahydrofuran:water = 3:1 (4 mL), lithium hydroxide (74.3 mg, 3.1 mmol) was added, and the mixture was stirred for 30 minutes. Extraction with ethyl acetate (10 mL × 3) was carried out, and the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (E)-3-(4-(tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid in a yield of 93.1%.

[0504] ESI-MS m / z: 712.3 [M+H] + .

[0505] Step j): Synthesis of tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yloxy)amino)prop-1-en-1-yl)benzyl)carbamate (E)-3-(4-(tert-butoxycarbonyl)(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (200 mg, 0.28 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (39.4 mg, 0.34 mmol), HATU (127.8 mg, 0.34 mmol), and DIEA (108.6 mg, 0.84 mmol) were added to a reaction flask containing DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography to give tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yloxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 75.2%.

[0506] ESI-MS m / z=810.3[M+H] +

[0507] Step k): Synthesis of (E)-3-(4-((1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate A 4.0 M solution of hydrochloric acid in EA (6 mL) was added to a reaction flask containing tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-yloxy)amino)prop-1-en-1-yl)benzyl)carbamate (180 mg, 0.29 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by Prep-HPLC (Separation Method 3) to obtain (E)-3-(4-((1-(4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate in a yield of 25%.

[0508] ESI-MS m / z=627.3[M+H] + .

[0509] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.01(s,1H),8.21-8.16(m,1H),7.80(dd,J=8.1,6.9 Hz,1H),7.51(d,J=7.9Hz,2H),7.42-7.38(m,3H),7.20(dd,J=8.1,1.4Hz,1H),7.08-6.96( m,2H),6.78(dt,J=8.4,1.4Hz,1H),6.43(d,J=15.8Hz,1H),3.80(m,5H),3.62(d,J=13.0Hz ,2H),3.43(m,4H),2.93(t,J=11.9Hz,2H),1.95(d,J=12.6Hz,2H),1.48(q,J=11.0Hz,2H).

[0510] Example 67 was prepared according to the synthesis method of Example 66 (compound isolation method 3), and its structure and property data are shown in the table below. [Table 9]

[0511] Example 69 (E)-3-(4-(((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)methyl)phenyl)-N-hydroxyacrylamidoformic acid was synthesized according to the method of Example 31, and its structure and property data are shown below. [ka]

[0512] 1 H NMR(400MHz,DMSO+D2O-d6)δppm:8.41(s,1H),8.20-8.06(m,2H),7.99(t,J=7.6Hz,1H),7.60(d,J=8.0Hz,2H),7.55-7.40(m,3H),7.14(s,1 H),6.58-6.44(m,2H),5.28(s,2H),4.38(d,J=13.2Hz,2H),3.08(m,1H),3.02-2.89(m,2H),1.89(d,J=11.6Hz,2H),1.38(q,J=11.6Hz,2H).

[0513] ESI-MS m / z=488.2[M+H] + .

[0514] Example 70 (E)-3-(4-(((1-(7-(4-cyano-3-fluorophenyl)-8-(3-hydroxy-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was synthesized according to the method of Example 34, and its structure and property data are shown below. [ka]

[0515] 1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.04(s,1H),7.85(s,1H),7.80(t,J=7.6Hz,1H),7.64 (s,1H),7.57-7.39(m,6H),7.35-7.28(m,1H),6.89(d,J=8.4Hz,1H),6.83(d,J=2.0Hz,1H),6 .65(dd,J=8.2,2.0Hz,1H),6.44(d,J=15.8Hz,1H),3.90(d,J=12.0Hz,2H),3.84(s,2H),3.7 9(s,3H),3.08(t,J=11.2Hz,2H),2.78(s,1H),2.14-1.93(m,2H),1.62(q,J=5.0,5.6Hz,2H).

[0516] ESI-MS m / z=634.2[M+H] + .

[0517] Example 71 Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)-N-hydroxyacrylamide formate [ka]

[0518] Step a): Synthesis of 4-(2,5-dichloropyrimidin-4-yl)-2-fluorobenzonitrile 2,4,5-Trichloropyrimidine (4.0 g, 21.8 mmol), (4-cyano-3-fluorophenyl)boronic acid (3.59 g, 21.8 mmol), cesium carbonate (14.2 g, 43.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.8 g, 0.81 mmol) were weighed and dissolved in 1,4-dioxane (60 mL). Water (15 mL) was added, and the mixture was placed in a four-pot parallel setup, protected with nitrogen, and heated to 110°C in a microwave oven for 45 minutes. The mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain 4-(2,5-dichloropyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 53.5%.

[0519] ESI-MS m / z: 268.0 [M+H] + .

[0520] Step b): Synthesis of tert-butyl 1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)carbamate 4-(2,5-dichloropyrimidin-4-yl)-2-fluorobenzonitrile (3.5 g, 13.1 mmol), tert-butyl piperidin-4-yl-carbamate (2.62 g, 13.1 mmol) were weighed, dissolved in DMF (50 mL), protected with nitrogen, refluxed at 120 ° C for 2 hours, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 2: 1) to obtain tert-butyl ((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)carbamate, the yield was 96.2%.

[0521] 1 H NMR(400MHz,DMSO-d6)δppm8.55(s,1H),8.09(dd,J=8.2,6.8Hz,1H),7.89(dd,J=10.2,1.6Hz,1H),7.78(dd,J=8.2,1.6Hz,1H),6.8 6(d,J=7.8Hz,1H),4.57-4.41(m,2H),3.55(s,1H),3.15-2.99(m,2H),1.79(dd,J=13.4,3.9Hz,2H),1.38(s,9H),1.35-1.26(m,2H).

[0522] ESI-MS m / z: 432.2 [M+H] + .

[0523] Step c): Synthesis of 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile tert-Butyl ((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (2.1 g, 4.87 mmol) was weighed and dissolved in 4 M hydrochloric acid ethyl acetate solution (5 mL). The reaction was stirred at room temperature under nitrogen protection for 30 minutes, and the reaction completion was detected by LCMS. Concentration under reduced pressure gave 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile, with a yield of 95%.

[0524] ESI-MS m / z: 332.1 [M+H] + .

[0525] Step d): Synthesis of methyl (E)-3-(4-(((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile (1.7 g, 3.94 mmol), (E)-3-(4-formylphenyl)methyl acrylate (1.1 g, 5.91 mmol) were weighed and dissolved in 1,2-dichloroethane (20 mL), and acetic acid (2.4 g, 39.4 mmol) and methanol (6.3 g, 197 mmol) were added, and the mixture was stirred under nitrogen protection for 3 hours. Sodium cyanoborohydride (1.2 g, 19.7 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (eluent: dichloromethane:methanol=10:1) to obtain methyl (E)-3-(4-(((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in an 11.0% yield.

[0526] ESI-MS m / z: 506.2 [M+H] + .

[0527] Step e): Synthesis of methyl (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (E)-3-(4-(((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)methyl acrylate (250 mg, 0.49 mmol), di-tert-butyl dicarbonate (214 mg, 0.98 mmol), and triethylamine (150 mg, 1.44 mmol) were weighed and dissolved in dry dichloromethane (10 mL), and the mixture was allowed to react at room temperature with stirring. When the completion of the reaction was detected by LCMS, the mixture was concentrated under reduced pressure until dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:2) to obtain methyl (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in a yield of 90.9%.

[0528] 1 H NMR(400MHz,DMSO-d6)δppm8.53(s,1H),8.07(dd,J=8.2,6.8Hz,1H),7.85(dd ,J=10.2,1.6Hz,1H),7.76(dd,J=8.2,1.6Hz,1H),7.69-7.58(m,3H),7.25(d, J=7.8Hz,2H),6.58(d,J=16.0Hz,1H),4.67(d,J=13.2Hz,2H),4.37(s,2H),4. 17(s,1H),3.72(s,3H),2.90(s,2H),1.63(d,J=8.4Hz,4H),1.41-1.28(m,9H).

[0529] ESI-MS m / z: 592.2 [M+H] + .

[0530] Step f): Synthesis of (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (250 mg, 0.41 mmol) and lithium hydroxide monohydrate (168.2 mg, 4.1 mmol) were weighed and dissolved in tetrahydrofuran (3 mL), water (3 mL) was added, and the mixture was stirred at room temperature under nitrogen protection for 16 hours to give a diluted salt. Acid (0.5 mL) was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid in a yield of 90.0%.

[0531] ESI-MS m / z: 592.2 [M+H] + .

[0532] Step g): Synthesis of tert-butyl (E)-(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (E)-3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (260 mg, 0.44 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (206 mg, 1.76 mmol) were weighed and dissolved in DMF (5 mL). The mixture was stirred under nitrogen protection for 20 minutes, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (251 mg, 0.66 mmol) and DIPEA (284.3 mg, 2.2 mmol) were added. The mixture was stirred under nitrogen protection for 16 hours. The reaction was completed by LCMS, and the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give tert-butyl (E)-(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate, with a yield of 77.9%.

[0533] ESI-MS m / z: 691.3 [M+H] + .

[0534] Step h): Synthesis of tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate tert-Butyl (E)-(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (150 mg, 0.22 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Cesium carbonate (137.6 mg, 0.55 mmol), cesium carbonate (215 mg, 0.66 mmol), palladium acetate (9.8 mg, 0.04 mmol), and dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (31.2 mg, 0.04 mmol) were weighed, dissolved in 1,4-dioxane (5 mL) and water (1 mL), and heated to 120 °C in a microwave under nitrogen protection for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification on a preparative thin-layer chromatography plate (developing agent: dichloromethane:methanol=12:1) gave tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 42.8%.

[0535] ESI-MS m / z: 779.3 [M+H] + .

[0536] Step i): Synthesis of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)-N-hydroxyacrylamide formate Weigh out tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (64 mg, 0.08 mmol) and distill it over a 4 M solution of hydrochloric acid in ethyl acetate (2 mL). ) was added and dissolved, the reaction was stirred under nitrogen protection for 30 minutes, and the mixture was concentrated at low temperature to dryness. The residue was purified by Pre-HPLC (Separation Method 3) to obtain (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)-N-hydroxyacrylamide formate, the yield was 17.0%.

[0537] 1 H NMR(400MHz,Methanol-d4)δppm8.52(s,2H),8.38(s,1H),7.69-7.57(m,3H),7. 51-7.40(m,3H),7.35(dd,J=8.2,1.6Hz,1H),6.95-6.87(m,1H),6.62-6.55(m,2H ),6.50(d,J=15.8Hz,1H),4.94(d,J=13.6Hz,2H),4.09(s,2H),3.86(s,3H),3.18 (s,1H),3.09-2.98(m,2H),2.16(d,J=11.8Hz,2H),1.53(qd,J=12.0,4.2Hz,2H).

[0538] ESI-MS m / z: 595.2 [M+H] + .

[0539] Example 72 Preparation of (S,E)-3-(4-(((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4''-carbonylpyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide caprate [ka]

[0540] Step a): Preparation of tert-butyl (S)-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)carbamate 3-Bromo-4-iodobenzoic acid (500 mg, 1.5 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (335 mg, 1.8 mmol), DIEA (387 mg, 3.0 mmol), and DMF (5 mL) were added to a reaction flask, and HATU (684 mg, 1.8 mol) was added with stirring at room temperature. The reaction was allowed to proceed for 1 hour. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed sequentially with saturated aqueous sodium bicarbonate (20 mL × 1) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain tert-butyl (S)-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)carbamate in a yield of 60.5%.

[0541] ESI-MS (m / z) = 495.0 [M+H] + .

[0542] Step b): Preparation of (S)-(3-aminopyrrolidin-1-yl)(3-bromo-4-iodophenyl)methanone tert-Butyl (S)-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)carbamate (448 mg, 124 μmol) was added to the reaction flask, and then hydrogen chloride in ethyl acetate (4 M, 2.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and a large amount of solid precipitated. The mixture was concentrated under reduced pressure to give (S)-(3-aminopyrrolidin-1-yl)(3-bromo-4-iodophenyl)methanone hydrochloride in a yield of 95.5%.

[0543] ESI-MS (m / z) = 395.0 [M+H] + .

[0544] Step c): Preparation of methyl ((S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate (S)-(3-aminopyrrolidin-1-yl)(3-bromo-4-iodophenyl)methanone hydrochloride (343 mg, 867 mmol) and (E)-3-(4-formylphenyl)methyl acrylate (165 mg, 867 mmol) were added to a reaction flask containing DCE (10 mL), and the mixture was stirred at room temperature for 2 hours. After monitoring the reaction completion of the raw material by LC-MS, sodium cyanoborohydride (0.32 g, 5.04 mmol) was added under ice bath, and the mixture was subsequently stirred at room temperature for 2 hours. The reaction mixture was quenched by adding a mixture of saturated sodium bicarbonate in ice and water, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl ((S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate in a yield of 72%.

[0545] ESI-MS m / z=568.3[M+H] + .

[0546] Step d): Preparation of methyl (S,E)-3-(4-(((1-(3-bromo-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate Methyl (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate (355 mg, 624 μmol) and triethylamine (1 mL) were dissolved in DCM (5 mL), and di-tert-butyl dicarbonate (150 mg, 936 μmol) was added and reacted at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl (S,E)-3-(4-((1-(3-bromo-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate in 88% yield.

[0547] ESI-MS m / z = 669.1 [M+H] + .

[0548] Step e): Preparation of (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid Methyl (S,E)-3-(4-((1-(3-bromo-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate (367 mg, 549 μmol), lithium hydroxide monohydrate (109 mg, 2.6 mmol), tetrahydrofuran (2 mL), isopropanol (2 mL) and water (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 12 hours. While stirring in an ice bath, 1N concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 3-4, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried to give (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid, which was used directly in the next step of the reaction.

[0549] ESI-MS (m / z) = 655.2 [M+H] + .

[0550] Step f): Preparation of tert-butyl ((S)-1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid (359 mg, 549 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (96 mg, 824 μmol), DIEA (142 mg, 1.1 mmol) and DMF (4 mL) were added to a reaction flask, and HATU (250 mg, 659 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (20 mL × 1) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl ((S)-1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 60.5%.

[0551] ESI-MS (m / z) = 754.2 [M+H] + .

[0552] Step g): Preparation of tert-butyl (S,E)-(1-(2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-yl)(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)carbamate tert-Butyl ((S)-1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (250 mg, 332 μmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 398 μmol), CsCO (217 mg, 664 μmol), Pd(dppf)Cl (23 mg, 33 μmol), 1,4-dioxane (4 mL), and HO (1 mL) were added to a reaction flask and the mixture was stirred at 80° C. for 1 hour. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl (S,E)-(1-(2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-yl)(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)carbamate in a yield of 68.4%.

[0553] ESI-MS (m / z) = 666.2 [M+H] + .

[0554] Step h): Preparation of tert-butyl ((S)-1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate tert-Butyl (S,E)-(1-(2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidin-3-yl)(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)benzyl)carbamate (151 mg, 227 μmol), (4-cyano-3-fluorophenyl)boronic acid (45 mg, 272 μmol), CsCO (148 mg, 454 μmol), Pd(dppf)Cl (16 mg, 33 μmol), 1,4-dioxane (4 mL), and HO (1 mL) were added to a reaction flask and the reaction was carried out at 90°C for 1 hour with stirring. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain tert-butyl ((S)-1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate, the yield was 78.5%.

[0555] ESI-MS (m / z) = 791.1 [M+H] + .

[0556] Step i): Preparation of (S,E)-3-(4-((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1]:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate tert-Butyl ((S)-1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (141 mg, 178 μmol) was added to the reaction flask, followed by hydrogen chloride in ethyl acetate (4 M, 2 0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 3) to obtain (S,E)-3-(4-((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1]:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate, with a yield of 18.5%.

[0557] 1 H NMR(400MHz,DMSO-d6)δ7.77-7.40(m,8H),7.37(d,J=7.4Hz,1H),7.16(dd,J=4.8,8.8Hz,2H),6.90-6.79(m,1H),6.58(s,2H),6.46 (t,J=6.0Hz,1H),3.96(s,1H),3.88-3.80(m,6H),3.61(s,2H),3.40-3.31(m,1H),,2.54-2.48(m,1H),1.92(dd,J=7.2,6.2Hz,1H).

[0558] ESI-MS (m / z) = 607.2 [M+H] + .

[0559] Example 73 (S,E)-3-(4-(((1-(4''-cyano-3''-fluoro-4-hydroxy-3-methoxy-[1,1]:2',1''-terphenyl]-4'-carbonyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was synthesized according to the method of Example 72, and its structure and property data are shown in the table below. [ka]

[0560] 1 H NMR(400MHz,Methanol-d4)δ8.46(s,1H),7.70-7.40(m,8H),7.35(d,J=7.8Hz,1H),7.14(dt,J=11.2,8.8Hz,2H),6.85(dd,J=8.2,3.2Hz,1H), 6.62-6.53(m,2H),6.45(t,J=5.8Hz,1H),3.89(s,1H),3.84-3.79(m,4 H),3.79-3.36(m,5H),2.34-2.11(m,1H),1.93(dd,J=13.3,6.7Hz,1H).

[0561] ESI-MS m / z=607.3[M+H] + .

[0562] Example 74 Preparation of (S,E)-3-(4-(((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate [ka]

[0563] Step a): Preparation of (S)-1-(3-bromo-4-iodobenzyl)pyrrolidin-3-amine tert-Butyl (S)-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)carbamate (500 mg, 1.0 mmol) was added to the reaction flask, and then a solution of hydrogen chloride in ethyl acetate (4 M, 2.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and a large amount of solid precipitated. The mixture was concentrated under reduced pressure to give (S)-1-(3-bromo-4-iodobenzyl)pyrrolidin-3-amine hydrochloride in a yield of 95.5%.

[0564] ESI-MS (m / z) = 380.9 [M+H]+ .

[0565] Step b): Preparation of methyl (S,E)-3-(4-(((1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate (S)-1-(3-Bromo-4-iodobenzyl)pyrrolidin-3-amine hydrochloride (362 mg, 955 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (181 mg, 955 mmol) were added to a reaction flask containing DCE (10 mL), and the mixture was stirred at room temperature for 2 hours. After monitoring the reaction completion of the raw materials by LC-MS, sodium cyanoborohydride (0.32 g, 4.8 mmol) was added under ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding an ice-water mixture of saturated sodium bicarbonate and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl ((S,E)-3-(4-(((1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate in a yield of 68%.

[0566] ESI-MS m / z=555.0[M+H] + .

[0567] Step c): Preparation of methyl (S,E)-3-(4-(1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate Methyl (S,E)-3-(4-(((1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate (360 mg, 649 μmol) and triethylamine (1 mL) were dissolved in DCM (5 mL), and di-tert-butyl dicarbonate (150 mg, 936 μmol) was added and reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain methyl (S,E)-3-(4-(((1-(3-bromo-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate in 91% yield.

[0568] ESI-MS m / z=655.1[M+H] + .

[0569] Step d): Preparation of (S,E)-3-(4-(1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid Methyl (S,E)-3-(4-(((1-(3-bromo-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate (387 mg, 591 μmol), lithium hydroxide monohydrate (124 mg, 3.0 mmol), tetrahydrofuran (2 mL), isopropanol (2 mL) and water (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 12 hours. The mixture was adjusted to pH 3-4 by slowly adding 1N concentrated hydrochloric acid dropwise, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2). The organic phase was concentrated under reduced pressure and dried to give (S,E)-3-(4-(1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid, which was used directly in the next step of the reaction.

[0570] ESI-MS (m / z) = 641.1 [M+H] + .

[0571] Step e): Preparation of tert-butyl ((S)-1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (S,E)-3-(4-(1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid (379 mg, 591 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (104 mg, 887 μmol), DIEA (142 mg, 1.2 mmol) and DMF (4 mL) were added to a reaction flask, and HATU (270 mg, 709 μmol) was added with stirring at room temperature, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (20 mL × 1) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl ((S)-1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 63.1%.

[0572] ESI-MS (m / z) = 740.1 [M+H] + .

[0573] Step f): Preparation of tert-butyl ((S)-1-((2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate tert-Butyl ((S)-1-(3-bromo-4-iodobenzyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (275 mg, 372 μmol), (3-hydroxy-4-methoxyphenyl)boronic acid (112 mg, 446 μmol), CsCO (243 mg, 744 μmol), Pd(dppf)Cl (27 mg, 37 μmol), 1,4-dioxane (4 mL), and HO (1 mL) were added to a reaction flask and the reaction was carried out at 80° C. with stirring for 1 hour. After concentration under reduced pressure and drying, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain tert-butyl ((S)-1-((2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 70.4%.

[0574] ESI-MS (m / z) = 736.3 [M+H] + .

[0575] Step g): Preparation of tert-butyl ((S)-1-((4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate tert-Butyl ((S)-1-((2-bromo-3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (192 mg, 262 μmol), (4-cyano-3-fluorophenyl)boronic acid (52 mg, 314 μmol), CsCO (171 mg, 524 μmol), Pd(dppf)Cl (17 mg, 26 μmol), 1,4-dioxane (4 mL), and HO (1 mL) were added to a reaction flask and the reaction was carried out at 90°C for 1 hour with stirring. The mixture was concentrated under reduced pressure and dried, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain tert-butyl ((S)-1-((4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 70.5%.

[0576] ESI-MS (m / z) = 777.1 [M+H] + .

[0577] Step h): Preparation of (S,E)-3-(4-(((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate tert-Butyl ((S)-1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)(4-((E)-3-oxo-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (144 mg, 185 μmol) was added to the reaction flask, followed by hydrogen chloride in ethyl acetate (4 M, 2 0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour to precipitate a large amount of solid. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (Separation Method 3) to obtain (S,E)-3-(4-((1-(4''-cyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate, with a yield of 15.5%.

[0578] 1 H NMR(400MHz,Methanol-d4)δ8.48(s,1H),7.56(d,J=8.6Hz,4H),7.43-7.03(m,5H),7.13(s,2H),6.83(d,J=7.8Hz,1 H),6.61-6.42(m,3H),3.98(d,J=7.0Hz,4H),3.83(s,3H),3.69(s,1H),3.14-2.61(m,4H),2.33(s,1H),1.94(s,1H).

[0579] ESI-MS (m / z) = 593.3 [M+H] + .

[0580] Example 75 (S,E)-3-(4-(((1-(4''-cyano-3''-fluoro-4-hydroxy-3-methoxy-[1,1:2.1',1''-terphenyl]-4'-yl)methyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was synthesized according to the method of Example 74, and its structure and property data are shown in the table below. [ka]

[0581] 1 H NMR(400MHz,Methanol-d4)δ8.40(s,1H),7.74-7.57(m,4H),7.51(d,J=6.8Hz,5H),7.16(d,J=3.8Hz,2H),6.73(d,J=8.0Hz,1H),6.58(s,2H),6.50(d,J= 5.2Hz,1H),4.08(s,2H),3.96(s,2H),3.75(s,1H),3.63(s,3H),3.10(s,1H) ,2.95(s,2H),2.75(s,1H),2.38-2.30(m,4H),1.97(dd,J=10.2,8.0Hz,1H).

[0582] ESI-MS m / z=593.3[M+H] + .

[0583] Example 76 Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate [ka]

[0584] Step a): Preparation of 4-(2-chloro-3-fluoropyridin-4-yl)-2-fluorobenzonitrile 2-Chloro-3-fluoro-4-iodopyridine (2 g, 7.78 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.28 g, 7.78 mmol), CS2CO3 (5.07 g, 15.56 mmol), and Pd(dppf)Cl2 (0.57 g, 0.78 mmol) were dissolved in dioxane (3 mL) and water (1 mL), protected with nitrogen, and microwave-treated at 65 °C for 30 min. The mixture was concentrated to give the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give 4-(2-chloro-3-fluoropyridin-4-yl)-2-fluorobenzonitrile in 78% yield.

[0585] ESI-MS m / z=251.0[M+H] +

[0586] Step b): Preparation of tert-butyl N-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate 4-(2-chloro-3-fluoropyridin-4-yl)-2-fluorobenzonitrile (1.0 g, 3.99 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (186.19 mg, 0.40 mmol), tris(dibenzylidene-BASEacetone)dipalladium (182.69 mg, 0.20 mmol), and CS2CO3 (3.9 g, 11.97 mmol) were dissolved in toluene (15 mL) and subjected to a microwave reaction at 1100 °C for 4 hours under nitrogen protection. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to obtain tert-butyl N-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate in a yield of 42%.

[0587] ESI-MS m / z=415.2[M+H] +

[0588] Step c): Preparation of tert-butyl N-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate tert-Butyl N-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate (930 mg, 2.24 mmol) and N-bromosuccinimide (398.68 mg, 2.24 mmol) were dissolved in DMF (16 mL) and reacted for 30 minutes. Upon detecting complete reaction, the reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to obtain tert-butyl N-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate in an 87% yield.

[0589] ESI-MS m / z=493.1[M+H] +

[0590] Step d): Preparation of 4-(2-(4-aminopiperidin-1-yl)-5-bromo-3-fluoropyridin-4-yl)-2-fluorobenzonitrile tert-Butyl N-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate (970 mg, 1.97 mmol) was dissolved in a 4N HCl solution in ethyl acetate (20 mL), reacted for 30 minutes, and concentrated to give the crude product, which was used directly in the next step.

[0591] ESI-MS m / z=393.0[M+H] + .

[0592] Step e): Preparation of methyl (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate 4-(2-(4-aminopiperidin-1-yl)-5-bromo-3-fluoropyridin-4-yl)-2-fluorobenzonitrile (220 mg, 0.51 mmol) and methyl 4-formylcinnamate (97.00 mg, 0.51 mmol) were dissolved in 1,2-dichloroethane (6 mL), methanol (40 μL), and acetic acid (10 μL). The mixture was reacted for 30 minutes, and sodium cyanoborohydride (96.15 mg, 1.53 mmol) was added in an ice bath. The mixture was reacted overnight, quenched by adding water (5 mL), and concentrated to obtain the crude product. tert-Butoxycarbonyl anhydride (320.83 mg, 1.47 mmol) and Na2CO3 (155.82 mg, 1.47 mmol) were added. The resulting mixture was dissolved in THF (3 mL) and HO (2 mL), reacted for 30 minutes, and allowed to react completely. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to obtain methyl (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate in a yield of 91%.

[0593] ESI-MS m / z=666.2[M+H] + .

[0594] Step f): Preparation of (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate (300 mg, 0.45 mmol) and lithium hydroxide monohydrate (188.82 mg, 4.5 mmol) were dissolved in tetrahydrofuran (3 mL) and water (1 mL) and reacted for 36 hours. Water (10 mL) was added and the pH was adjusted to 3-4 with 1N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was used directly in the next step.

[0595] ESI-MS m / z=653.2[M+H] + .

[0596] Step g): Preparation of tert-butyl (E)-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid (280 mg, 0.43 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (151.12 mg, 1.29 mmol) were dissolved in DMF (30 mL), HATU (490.51 mg, 1.29 mmol), DIPEA (277.35 mg, 2.15 mmol) were added, and the reaction was carried out for 30 minutes. Water (20 mL) was added to quench the reaction, and the reaction mixture was added with ethyl acetate ( The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain tert-butyl (E)-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 92%.

[0597] ESI-MS m / z=752.2[M+H] + .

[0598] Step h: Preparation of tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate tert-Butyl (E)-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (300 mg, 0.40 mmol), (3-hydroxy-4-methoxyphenyl)boronic acid (100.77 mg, 0.60 mmol), CsCO (390.98 mg, 1.20 mmol), and Pd(dppf)Cl (58.54 mg, 0.080 mmol) were dissolved in dioxane (3 mL). The resulting mixture was dissolved in water (1 mL), protected with nitrogen, and reacted in a microwave at 900°C for 30 minutes. The mixture was concentrated to give a crude product, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to give tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in an 80% yield.

[0599] ESI-MS m / z=796.3[M+H] + .

[0600] Step i): Preparation of (E)-3-(4-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide Weigh out 0.7 g (0.88 mmol) of tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate and distillate at 40°C. The mixture was dissolved in HCl in ethyl acetate (15 mL), stirred for 30 minutes, concentrated under reduced pressure at low temperature, and the residue was purified by Pre-HPLC (Separation Method 3) to obtain (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate, with a yield of 5%.

[0601] 1 H NMR(400MHz,Methanol-d4)δppm8.52(s,1H),8.08(s,1H),7.72(t,J=7.4Hz,1H),7.6 5(t,J=8.6Hz,2H),7.62-7.45(m,3H),7.28(d,J=9.8Hz,1H),7.17(d,J=8.0Hz,1H),6 .84(d,J=8.8Hz,1H),6.58-6.45(m,3H),4.59(s,1H),4.24(s,1H),4.21(s,3H),3.84 (s,3H),3.05(t,J=12.6Hz,2H),2.24(d,J=12.2Hz,2H),1.77(dd,J=13.6,9.8Hz,2H).

[0602] ESI-MS m / z=612.2[M+H] + .

[0603] Example 77 (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(4-hydroxy-3-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was synthesized according to the method of Example 76, and its structure and property data are as follows: [ka]

[0604] 1 H NMR(400MHz,Methanol-d4)δppm8.52(s,2H),8.12(s,1H),7.73(dd,J=8.0,6.8Hz,1H), 7.63(t,J=10.2Hz,2H),7.55(t,J=8.0Hz,3H),7.30(d,J=9.8Hz,1H),7.19(d,J=8.0Hz,1 H),6.73(d,J=8.0Hz,1H),6.64-6.47(m,3H),4.23(s,1H),4.19(s,3H),3.65(s,3H),3. 26(s,1H),3.04(t,J=12.6Hz,2H),2.23(d,J=12.0Hz,2H),1.78(q,J=11.2,10.4Hz,2H).

[0605] ESI-MS m / z=612.2[M+H] + .

[0606] Example 80 Synthesis of (E)-3-(4-(((1-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate [ka]

[0607] Step a): Synthesis of 4-(5-bromo-2-chloropyridin-4-yl)-2-fluorobenzonitrile Dioxane: water = 5:1 (20 mL), 5-bromo-2-chloro-4-iodopyridine (3.0 g, 9.42 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.5 g, 9.42 mmol), 1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (689.26 mg, 0.94 mmol), cesium carbonate (6138.45 mg, 18.84 mmol) was added, and under nitrogen protection, the reaction was carried out in a microwave at 110 ° C for 1 hour, and the disappearance of the raw material was monitored by LCMS. The solvent was concentrated, silica gel was added, and the mixture was stirred. The mixture was purified by normal phase column chromatography to obtain the product 4- (5-bromo-2-chloropyridin-4-yl) -2-fluorobenzonitrile, and the yield was 82.46%.

[0608] ESI-MS (m / z) = 311.1 [M+H] + .

[0609] Step b): Synthesis of 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-2-chloropyridin-4-yl)-2-fluorobenzonitrile In a 5:1 mixture of dioxane and water (30 mL), 4-(5-bromo-2-chloropyridin-4-yl)-2-fluorobenzonitrile (1.5 g, 9.42 mmol), 2-(3-(benzyloxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 5.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (351.95 mg), , 0.48 mmol) and cesium carbonate (3.1 g, 9.62 mmol) were added and reacted at 80°C for 1 hour under nitrogen protection. After monitoring the disappearance of the raw materials by LCMS, the mixture was concentrated to remove the solvent, silica gel was added and stirred, and the mixture was purified using a normal phase column to obtain the product 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-2-chloropyridin-4-yl)-2-fluorobenzonitrile, with a yield of 88.32%.

[0610] ESI-MS (m / z) = 445.1 [M+H] + .

[0611] Step c): Synthesis of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate To toluene (50 mL), 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-2-chloropyridin-4-yl)-2-fluorobenzonitrile (1.5 g, 3.3 mmol), tert-butyl N-(piperidin-4-yl)carbamate (990.5 mg, 5.1 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (155 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (150.5 mg, 0.165 mmol), and cesium carbonate (3215.2 mg, 9.9 mmol) were added. After monitoring the disappearance of the raw materials by LCMS, the solvent was removed by concentration, silica gel was added, and the mixture was stirred and purified by normal phase column to obtain the product tert-butyl 4(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 51.98%.

[0612] ESI-MS (m / z) = 609.2 [M+H] + .

[0613] Step d): Synthesis of 4-(2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)pyridin-4-yl)-2-fluorobenzonitrile tert-Butyl 4(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (780 mg, 1.44 mmol) was added to 4 N hydrochloric acid EA (4 mL) and the reaction was allowed to proceed at room temperature for 0.5 hours. LCMS showed that the starting materials had disappeared and the product remained as the main component. The mixture was then concentrated to remove the solvent, adjusted to a weak acidity with saturated aqueous sodium bicarbonate, and extracted with EA. The organic phases were combined and concentrated to remove the solvent, giving a solid crude product, which was used directly in the next step.

[0614] ESI-MS (m / z) = 509.3 [M+H] + .

[0615] Step e): Synthesis of methyl (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate Dichloroethane (10 mL) was added with 4- (2- (4-aminopiperidin-1-yl) -5- (3- (benzyloxy) -4- methoxyphenyl) pyridin-4-yl) -2- fluorobenzonitrile (0.35 g, 0.68 mmol) methyl (E) -3- (4- formylphenyl) acrylate (0.16 g, 0.82 mmol), sodium cyanoborohydride (0.085 g, 1.36 mmol), and the mixture was allowed to react overnight at room temperature. After monitoring the disappearance of the raw material by LCMS, the mixture was concentrated to remove the solvent, and silica gel was added and stirred. The mixture was purified by normal phase column chromatography to obtain the product methyl (E) -3- (4- (((1- (5- (3- (benzyloxy) -4- methoxyphenyl) -4- (4- cyano-3-fluorophenyl) pyridin-2-yl) piperidin-4-yl) amino) methyl) phenyl) acrylate, and the yield was 75.38%.

[0616] ESI-MS (m / z) = 683.2 [M+H] + .

[0617] Step f): Synthesis of (E)-3-(4-(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidine-4-amino)methyl)phenyl)acrylic acid To tetrahydrofuran:water=4:1 (5 mL) were added methyl (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (254 mg, 0.37 mmol) and lithium hydroxide (44.31 mg, 1.85 mmol). The reaction was carried out at room temperature overnight, and the disappearance of the raw materials was monitored by LCMS. The system was then directly used in the next step.

[0618] ESI-MS (m / z) = 669.2 [M+H] + .

[0619] Step g): Synthesis of (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid Di-tert-butyl dicarbonate (170.5 mg, 0.78 mmol) and sodium bicarbonate were added to the reaction system of step f), and the mixture was stirred at room temperature overnight. The disappearance of the raw materials was monitored by LCMS. The pH was adjusted to weak acidity with dilute hydrochloric acid, water was added, and the mixture was extracted with EA. The organic phases were combined and concentrated to remove the solvent, and the mixture was added to silica gel and purified by normal phase column to obtain the product (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid, the yield was 80.64%.

[0620] ESI-MS (m / z) = 769.3 [M+H] + .

[0621] Step h): Synthesis of tert-butyl (E)-(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate To 4 mL of DMF was added (E)-3-(4-(((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid (215 mg, 0.28 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (40 mg, 0.33 mmol), 2-(7-azobenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (128 mg, 0.33 mmol), and ethyldiisopropylamine (109 mg, 0.84 mmol). The reaction was carried out at room temperature for 0.5 hours, and after monitoring by LCMS that the raw materials had disappeared and the product remained as the main component, the reaction mixture was poured into water, and acetic acid ester was added for extraction. The organic phase was washed with saturated saline and concentrated to remove the solvent. Silica gel was added, and the mixture was stirred. The mixture was purified using a normal phase column to obtain tert-butyl (E)-(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 65.83%.

[0622] ESI-MS (m / z) = 868.4 [M+H] + .

[0623] Step i): Synthesis of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate tert-Butyl (E)-(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (120 mg, 0.14 mmol) was added to DCM (8 mL), and boron tribromide (0.28 g, 1.12 mmol) was added at −78° C., followed by stirring on dry ice. The reaction was continued on the bath for 0.5 hours, and the disappearance of the raw materials was monitored by LCMS. Then, methanol was added to quench the reaction, and the mixture was concentrated to remove the solvent. The residue was purified by Prep-HPLC (Separation Method 3) to obtain (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate in a yield of 66.18%.

[0624] 1 H NMR(400MHz,Methanol-d4)δ8.53(s,1H),8.46(s,1H),8.14(s,1H),7.70-7.58(m,3H),7.53 (t,J=11.1Hz,2H),7.22(dd,J=10.2,1.5Hz,1H),7.15(dd,J=8.1,1.5Hz,1H),6.88-6.80(m,2 H),6.53(d,J=8.0Hz,1H),6.50(dt,J=4.4,2.4Hz,2H),4.52(d,J=13.6Hz,2H),4.21(s,2H), 3.83(s,3H),3.32(s,1H),2.99(t,J=12.7Hz,2H),2.27-2.14(m,2H),1.65(q,J=12.1Hz,2H).

[0625] ESI-MS (m / z) = 594.2 [M+H]+ .

[0626] Example 81 Preparation of (E)-3-(3-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)phenyl)-N-hydroxyacrylamide formate [ka]

[0627] Step a): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate The product of Step c of Example 51, tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (558.0 mg, 1.12 mmol), 2-(3-(benzyloxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280.1 mg, 1.12 mmol), CsCO (1.1 g, 3.36 mmol), and Pd(dppf)Cl (82.0 mg, 0.11 mmol) were dissolved in dioxane (40 mL), water (1 mL) was added, and the mixture was purged with nitrogen. The reaction was carried out three times, and the reaction was heated to 100°C. After reacting for 2 hours, mLC-MS showed that the reaction was complete. The reaction was cooled to room temperature, water (9 mL) was added, and extracted with ethyl acetate (8 mL x 3). The organic layers were combined, washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in 80.6% yield.

[0628] ESI-MS m / z=634.3[M+H] +.

[0629] Step b): Preparation of 2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)nicotinonitrile tert-Butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 0.36 mmol) and a 4 M solution of hydrochloric acid in ethyl acetate (5 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)nicotinonitrile in 92% yield.

[0630] ESI-MS m / z=534.2[M+H] + .

[0631] Step c): Preparation of methyl (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))piperidin-4)-yl)-amino)phenyl)acrylate 2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)nicotinonitrile (178 mg, 0.32 mmol) was dissolved in toluene (3 ml), and then the solution was treated with (E)-methyl 3-(3-bromophenyl)acrylate (77.2 mg, 0.32 mmol), cesium carbonate (208.6 mg, 0.64 mmol), tris(dibenzylidene-BASEacetone)dipalladium (58.6 mg, 0.06 mmol), 2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl (30.5 mg, 0.06 mmol) was added, protected with nitrogen, refluxed, heated to 100°C and reacted overnight. When the reaction was complete by LCMS, it was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography to obtain methyl (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))piperidin-4-yl)-amino)phenyl)acrylate, the yield was 73.3%.

[0632] ESI-MS m / z=694.3[M+H] + .

[0633] Step d): Preparation of (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin)-4-yl)amino)phenyl)acrylic acid Methyl (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))piperidin-4-yl)amino)phenyl)acrylate (135 mg, 0.20 mmol) was dissolved in THF / HO = 5:1 (3 mL), lithium hydroxide (48 mg, 2 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. The pH of the system was adjusted to 2-3 with 2N hydrochloric acid, and the system was extracted with ethyl acetate. The organic phase was washed once with brine, dried, concentrated, and the residue was used directly in the next step.

[0634] ESI-MS m / z=680.3[M+H] + .

[0635] Step e): Preparation of (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin)-4-yl)amino)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide Methyl (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))piperidin-4-yl)amino)phenyl)acrylate (80 mg, 0.12 mmol) was dissolved in DMF (2 mL), and HATU (54.75 mg, 0.14 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (16.9 mg, 0.14 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction was allowed to proceed for 1 hour, and water was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was washed twice with water, dried, and then concentrated in vacuo. The residue was purified using a silica gel column to give (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin)-4-yl)amino)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide in an 85% yield.

[0636] ESI-MS m / z=779.3[M+H] + .

[0637] Step f): Preparation of (E)-3-(3-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)phenyl)-N-hydroxyacrylamide formate (E)-3-(3-((1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin)-4-yl)amino)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (80 mg, 0.1 mmol) was dissolved in HCl / EA (3 mL, 2 M) and the mixture was allowed to react at room temperature for 1 hour. When a solid was formed in the reaction mixture and LC-MS detection showed the reaction was complete, the reaction mixture was filtered to obtain the solid, which was purified by Prep-HPLC (Separation Method 3) to obtain (E)-3-(3-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)phenyl)-N-hydroxyacrylamide formate in a yield of 55.2%.

[0638] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.40(s,1H),7.95-7.84(m,1H),7.61(dd,J=10.0,1.5Hz, 1H),7.34(d,J=15.8Hz,1H),7.26(dd,J=8.0,1.6Hz,1H),7.16(t,J=7.8Hz,1H),6.88-6.78(m, 3H),6.76-6.68(m,1H),6.51-6.43(m,2H),6.38(d,J=15.8Hz,1H),4.21(d,J=12.8Hz,2H),3.7 0(s,3H),3.60(s,1H),3.27(t,J=12.2Hz,2H),2.05(d,J=11.8Hz,2H),1.53(q,J=11.4Hz,2H).

[0639] ESI-MS m / z=605.2[M+H] + .

[0640] Example 82 (E)-3-(4-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-3-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino)phenyl)-N-hydroxyacrylamide formate was synthesized according to the method of Example 81, and its structure and property data are as follows: [ka]

[0641] 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.98(s,1H),8.43(s,1H),7.95(t,J=7.4Hz,1H) ,7.66(dd,J=10.0,1.4Hz,1H),7.36-7.23(m,4H),6.81(d,J=8.0Hz,1H),6.65(d,J=8. 2Hz,2H),6.48(d,J=8.4Hz,2H),6.14(d,J=12.0Hz,1H),4.22(d,J=13.2Hz,2H),3.72( s,3H),3.64(s,1H),3.31(t,J=11.8Hz,2H),2.07(d,J=11.8Hz,2H),1.63-1.46(m,2H).

[0642] ESI-MS m / z=605.2[M+H] + .

[0643] Example 83 2-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)amino-N-hydroxypyrimidine-5-amide formate was synthesized according to the method of Example 81, and its structure and property data are as follows: [ka]

[0644] 1H NMR(400MHz,Methanol-d4)δppm8.64(s,2H),8.52(s,1H),8.41(s,1H),7.74(dd ,J=8.0,6.6Hz,1H),7.37(dd,J=9.6,1.6Hz,1H),7.24(dd,J=8.0,1.6Hz,1H),6. 87-6.76(m,1H),6.56-6.46(m,2H),4.35(d,J=13.4Hz,2H),4.17(td,J=10.6,5. 4Hz,1H),3.81(s,3H),3.30-3.24(m,2H),2.21-2.11(m,2H),1.84-1.71(m,2H).

[0645] ESI-MS m / z=581.2[M+H] + .

[0646] Example 84 Preparation of (E)-3-(4-(((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide [ka]

[0647] Step a): Preparation of tert-butyl 1-(2-cyano-3-iodophenyl)piperidin-4-yl)carbamate 2-Chloro-6-iodobenzonitrile (2 g, 7.63 mmol), tert-butyl-piperidin-4-ylcarbamate (2.29 g, 11.45 mmol), and DIEA (3.94 g, 30.52 mmol) were added to a reaction flask containing NMP (20 mL), and the mixture was stirred at 100° C. for 24 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 1-(2-cyano-3-iodophenyl)piperidin-4-yl)carbamate in 37% yield.

[0648] ESI-MS m / z=428.1[M+H] + .

[0649] Step b): Preparation of tert-butyl (1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-yl)carbamate tert-Butyl 1-(2-cyano-3-iodophenyl)piperidin-4-ylcarbamate (1.3 g, 3.04 mmol), 4-cyano-3-fluorophenylboronic acid (0.60 g, 3.65 mmol), Pd(dppf)Cl (0.22 g, 0.30 mmol), and cesium carbonate (1.98 g, 6.08 mmol) were added to a microwave tube containing dioxane (2 mL) and water (0.4 mL), and the mixture was stirred at 80 °C for 45 min. The reaction mixture was concentrated with silica gel, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-yl)carbamate in 66% yield.

[0650] ESI-MS m / z=421.2[M+H] + .

[0651] Step c): Preparation of tert-butyl (1-(6-bromo-2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-yl)carbamate tert-Butyl (1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-yl)carbamate (840 mg, 2.00 mmol) and NBS (0.42 g, 2.36 mmol) were added to a reaction flask containing DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(6-bromo-2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-yl)carbamate in 67% yield.

[0652] ESI-MS m / z=499.1[M+H] + .

[0653] Step d): Preparation of tert-butyl (1-(3,4''-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-terphenyl]-4-yl)piperidin-4-yl)carbamate tert-Butyl 1-(6-bromo-2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate (620 mg, 1.24 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.31 g, 1.24 mmol), Pd(dppf)Cl2 (0.091 g, 0.12 mmol) and cesium carbonate (0.81 g, 2.48 mmol) were added to a microwave tube containing 1,4-dioxane (8 mL) and water (1.6 mL) and the mixture was stirred at 110 °C in a microwave for 45 min. The reaction mixture was concentrated with silica gel and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl (1-(3,4''-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-terphenyl]-4-yl)piperidin-4-yl)carbamate in a yield of 98%.

[0654] ESI-MS m / z=443.2[M+H] + .

[0655] Step e): Preparation of 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)benzonitrile tert-Butyl (1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-terphenyl]-4-yl)piperidin-4-yl)carbamate (620 mg, 1.18 mmol) was added to a reaction flask containing 4 M hydrochloric acid in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 7 by dropwise addition of saturated aqueous sodium bicarbonate solution, extracted with DCM:MeOH = 10:1 (20 mL × 2), and the combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-3-hydroxy-4-methoxyphenyl)benzonitrile in 16% yield.

[0656] ESI-MS m / z=443.2[M+H] + .

[0657] Step f): Preparation of methyl (E)-3-(4-(((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1'-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-3-hydroxy-4-methoxyphenyl)benzonitrile (240 mg, 0.54 mmol) and methyl 3-(4-formylphenyl)acrylate (0.30 g, 1.60 mmol) were added to a reaction flask containing DCE (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction system was cooled to 0°C, and sodium cyanoborohydride (0.17 g, 2.71 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl (E)-3-(4-(((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1'-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in a yield of 63%.

[0658] ESI-MS m / z=617.2[M+H] + .

[0659] Step g): Preparation of methyl (E)-3-(4-tert-butoxycarbonyl(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-1,1':2',1''-terphenyl]-4''-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate Methyl (E)-3-(4-(((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (150 mg, 0.24 mmol), di-tert-butyl dicarbonate (0.27 g, 1.22 mmol) and TEA (0.097 g, 0.96 mmol) were added to a reaction flask containing dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give methyl (E)-3-(4-tert-butoxycarbonyl(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in a yield of 93%.

[0660] ESI-MS m / z=717.3[M+H] + .

[0661] Step h): Preparation of (E)-3-(4-(tert-butoxycarbonyl)(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid Methyl (E)-3-(4-tert-butoxycarbonyl(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate (160 mg, 0.22 mmol) and lithium hydroxide (0.11 g, 4.42 mmol) were added to a reaction flask containing THF (3 mL), MeOH (1.8 mL) and water (1.2 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 4 by dropwise addition of 2 M aqueous HCl, extracted with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give (E)-3-(4-(tert-butoxycarbonyl)(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid in a yield of 91%.

[0662] ESI-MS m / z=703.2[M+H] + .

[0663] Step i): Preparation of tert-butyl (E)-(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (E)-3-(4-(tert-butoxycarbonyl)(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1:2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid (140 mg, 0.20 mmol), HATU (0.11 g, 0.30 mmol), DIEA (0.10 g, 0.80 mmol), and O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (0.047 g, 0.40 mmol) were added to a reaction flask containing DMF (5 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to give tert-butyl (E)-(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 93%.

[0664] ESI-MS m / z=802.3[M+H] + .

[0665] Step j): Preparation of ((E)-3-(4-((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide tert-Butyl (E)-(1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (140 mg, 0.17 mmol) and a 4 M solution of hydrochloric acid in acetate (12.00 g, 329.13 mmol) were added to the reaction flask and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, purified by Prep-HPLC (Separation Method 3), and then lyophilized to give ((E)-3-(4-((1-(3',4''-dicyano-3''-fluoro-3-hydroxy-4-methoxy-[1,1':2',1''-terphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate in a yield of 45%.

[0666] 1 H NMR(400MHz,DMSO-d6)δppm10.72(s,1H),8.97(s,1H),8.51(s,1H),8.19(s,1H),7.89(t,J= 7.4Hz,1H),7.63-7.49(m,4H),7.49-7.34(m,3H),7.27(d,J=8.6Hz,1H),7.21(dd,J=8.0,1. 4Hz,1H),6.77(d,J=8.3Hz,1H),6.49-6.34(m,3H),3.85(s,2H),3.70(s,3H),3.55(s,2H),2 .90(t,J=11.3Hz,2H),2.73-2.63(m,1H),2.06-1.95(m,2H),1.54(dq,J=106.2,9.9Hz,2H).

[0667] ESI-MS m / z=618.2[M+H] + .

[0668] Example 85 Synthesis of (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl))piperidin-4-yl)phenyl)-N-hydroxyacrylamide formate [ka]

[0669] Step a): Synthesis of tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate 2-(4-Bromophenyl)acetonitrile (5 g, 25.50 mmol) and tert-butyl N,N-bis(2-chloroethyl)carbamate (7.10 g, 29.32 mmol) were added to DMF (75 mL), and sodium hydroxide (1.84 g, 76.5 mmol) was added batchwise at 0 °C. After the addition was completed, the mixture was heated to 65 °C and reacted for 1.5 hours. The mixture was then cooled to room temperature and reacted for 1 hour. After monitoring the disappearance of the raw materials by TLC (petroleum ether: ethyl acetate = 3:1), water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, concentrated to remove the solvent, and purified using a normal phase column to obtain tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate in a yield of 83.74%.

[0670] ESI-MS (m / z) = 365.1 [M+H] + .

[0671] Step b): Synthesis of tert-butyl 4-(4-bromophenyl)-4-carbamoylpiperidine-1-carboxylate To DMSO (5 mL), tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate (5 g, 13.7 mmol) and potassium hydroxide (1537.4 mg, 27.4 mmol) were added, and hydrogen peroxide (465.9 mg, 13.7 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 1 hour. The disappearance of the starting material was monitored by TLC (petroleum ether:ethyl acetate = 3:1). The reaction was quenched by adding water, extracted with EA, and the combined organic phases were concentrated to remove the solvent. The solvent was then extracted with an oil pump and used directly in the next step.

[0672] ESI-MS (m / z) = 383.1 [M+H] + .

[0673] Step c): Synthesis of tert-butyl 4-amino-4-(4-bromophenyl)piperidine-1-carboxylate Potassium hydroxide (1641.2 mg, 29.3 mmol) was dissolved in ACN:HO = 1:4 (40 mL), and the crude product from step b, tert-butyl 4-(4-bromophenyl)-4-carbamoylpiperidine-1-carboxylate (2.5 g, 6.5 mmol), was added and stirred for 10 minutes. Then, 1,3-dibromo-5,5-dimethylethanediylurea (1022.2 mg, 3.6 mmol) was added in batches and the reaction was continued at room temperature for 1 hour. TL Monitoring the disappearance of the raw materials using C (ethyl acetate as a developer) revealed an increased polarity (Rf: 0.15) (ninhydrin color reaction). Sodium sulfite (0.082 g, 0.65 mmol) was added to the system and stirred for 15 minutes. Potassium triphosphate (1.7 g, 7.9 mmol) was added, followed by extraction with ethyl acetate. The organic phases were combined, washed with saline, and concentrated to remove the solvent. Silica gel was added and stirred, and the product was purified using a normal phase column to obtain tert-butyl 4-amino-4-(4-bromophenyl)piperidine-1-carboxylate in 77.95% yield.

[0674] ESI-MS (m / z) = 355.1 [M+H] + .

[0675] Step d): Synthesis of tert-butyl-(E)-4-amino-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)piperidine-1-carboxylate To tetrahydrofuran:water=5:1 (5 mL) were added tert-butyl 4-amino-4-(4-bromophenyl)piperidine-1-carboxylate (1400 mg, 3.9 mmol), methyl 2-enoate (430.5 mg, 5.0 mmol), tetrakis(triphenylphosphine)palladium (115.6 mg, 0.10 mmol), and triethylamine (202.4 mg, 2.0 mmol). The temperature was raised to 110°C and the reaction was continued for 4 hours. LCMS showed that the raw materials had disappeared and the product remained as the main component. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated to remove the solvent. Silica gel was added and the mixture was stirred. The mixture was purified by normal phase column chromatography to obtain the product tert-butyl-(E)-4-amino-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)piperidine-1-carboxylate, with a yield of 82.13%.

[0676] ESI-MS (m / z) = 361.1 [M+H] + .

[0677] Step e): Synthesis of tert-butyl-(E)-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-4-(((trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate To DMF (40 mL) was added tert-butyl-(E)-4-amino-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)piperidine-1-carboxylate (500 mg, 0.80 mmol), ethyl 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)carbonate (1415.9 mg, 5.5 mmol), and sodium bicarbonate (982.9 mg, 11.7 mmol). The reaction was allowed to proceed overnight at room temperature and monitored by TLC. The starting material disappeared and new traces appeared. Silicon gel was added, the mixture was stirred, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saline, and concentrated to remove the solvent. Silicon gel was added, the mixture was stirred, and the mixture was purified using a normal-phase column. tert-Butyl-(E)-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-4-(((trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate was obtained in a yield of 73.22%.

[0678] ESI-MS (m / z) = 491.2 [M+H] + .

[0679] Step f): Synthesis of methyl (E)-3-(4-(4-(((trimethylsilyl)ethoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate To a solution of 4N hydrochloric acid in ethyl acetate (5 mL) was added tert-butyl (E)-4-(4-(3-methoxy-3-oxoprop-1-enyl)phenyl)-4-(((trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate (180 mg, 0.37 mmol). The reaction was allowed to proceed at room temperature for 0.5 hours, and the mixture was concentrated to remove the solvent. An aqueous solution of sodium bicarbonate was added to make the mixture weakly alkaline, and EA was added for extraction. The organic phases were combined and concentrated to remove the solvent, yielding the crude product (E)-3-(4-(((trimethylsilyl)ethoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate in a yield of 83.04%.

[0680] ESI-MS (m / z) = 391.2 [M+H] + .

[0681] Step g): Synthesis of methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate In N-methylpyrrolidin-2-one (4 mL), methyl (E)-3-(4-(4-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidin-4-yl)phenyl)prop-2-enoate (100 mg, 0.24 mmol), 2-chloro-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile (86.86 mg, 0.34 mmol), ), ethylbis(prop-2-yl)amine (62.04 mg, 0.48 mmol) was added, the temperature was raised to 110 ° C., and the reaction was carried out overnight. The mixture was purified using a normal phase column to obtain the product, methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-((2-(trimethylsilyl)ethoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate.

[0682] ESI-MS (m / z) = 612.2 [M+H] + .

[0683] Step h): Synthesis of methyl (E)-3-(4-(4-amino-1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-{(2-(trimethylsilyl)ethoxy)carbonyl}amino}piperidin-4-yl)phenyl)acrylate Methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-{[(2-(trimethylsilyl)ethoxy)carbonyl]amino}piperidin-4-yl)phenyl)acrylate (100 mg, 0.160 mmol) and N-bromosuccinimide (34 mg, 0.2 mmol) were added to DMF (2 mL), and the mixture was reacted at room temperature for 2 hours. Water was added to quench the reaction, and the mixture was then quenched with ethyl acetate. The organic phases were combined and concentrated to remove the solvent, and the resulting mixture was stirred with silica gel and purified by normal phase column chromatography to obtain the product, methyl (E)-3-(4-(4-amino-1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-{(2-(trimethylsilyl)ethoxy)carbonyl]amino}piperidin-4-yl)phenyl)acrylate, in a yield of 49.67%.

[0684] ESI-MS (m / z) = 690.2 [M+H] + .

[0685] Step i): Synthesis of methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-4-{(2-(trimethylsilyl)ethoxy)carbonyl]amino}piperidin-4-yl)phenyl)acrylate Dioxane: water = 5: 1 (3 mL) methyl (E)-3- (4- (4-amino-1- (5-bromo-3-cyano-4- (4-cyano-3-fluorophenyl) pyridin-2-yl) -4- { (2- (trimethylsilyl) ethoxy) carbonyl] amino} piperidin-4-yl) phenyl) acrylate (49.25 mg, 0.071 mmol), 2-methoxy-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (23.08 mg, 0.092 mmol), 1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (10.39 mg, 0.014 mmol), cesium carbonate (41.64 mg, 0.13 mmol) was added. The reaction was carried out in a microwave at 105°C for 1 hour, and LCMS showed that the raw materials had disappeared and the product remained as the main component. The mixture was concentrated to remove the solvent, and the mixture was stirred with silica gel and purified using a normal phase column to obtain the product, methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-4-{(2-(trimethylsilyl)ethoxy)carbonyl]amino}piperidin-4-yl)phenyl)acrylate, with a yield of 72.63%.

[0686] ESI-MS (m / z) = 734.2 [M+H] + .

[0687] Step j): Synthesis of methyl (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate Methyl (E)-3-(4-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-4-{[(2-(trimethylsilyl)ethoxy)carbonyl]amino}piperidin-4-yl)phenyl)acrylate (30 mg, 0.041 mmol) and tetrabutylammonium fluoride (107.20 mg, 0.41 mmol) were added to DCM (5 mL), and the mixture was diluted with water. Add the extractant, extract with ethyl acetate, combine the organic phases, concentrate to remove the solvent, add silica gel and stir, purify with reverse phase column, then purify with silica gel column to obtain the product methyl (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate, the yield was 72.63%.

[0688] ESI-MS (m / z) = 604.2 [M+H] + .

[0689] Step k): Synthesis of methyl (E)-3-(4-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate To a mixture of THF:HO=4:1 (10 mL) were added methyl (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate (20 mg, 0.33 mmol), di-tert-butyl dicarbonate (360 mg, 1.7 mmol), and sodium bicarbonate (28.53 mg, 0.33 mmol). The reaction was carried out at room temperature overnight, and the mixture was concentrated to remove the solvent to obtain crude product methyl (E)-3-(4-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate, the yield was 79.06%.

[0690] ESI-MS (m / z) = 804.3 [M+H] + .

[0691] Step l): Synthesis of (E)-3-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylic acid Methyl (E)-3-(4-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylate (19 mg, 0.02 mmol) and lithium hydroxide (3 mg, 0.1 mmol) were added to THF:HO=4:1 (10 mL) and reacted at room temperature overnight. After that, the pH was adjusted to weak acidity with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phases were combined and concentrated to remove the solvent, and a crude product was obtained. (E)-3-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylic acid was obtained in a yield of 80.25%.

[0692] ESI-MS (m / z) = 790.3 [M+H] + .

[0693] Step m: Synthesis of tert-butyl (E)-(1-(5-(3-((tert-butoxycarbonyl)oxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))-4-(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)phenyl)piperidin-4-yl)carbamate To 8 mL of DMF was added (E)-3-(4-{[(tert-butoxy)carbonyl]amino}-1-(5-(3-{[(tert-butoxy)carbonyl]oxy}-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)phenyl)acrylic acid (15 mg, 0.02 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxyamine (3 mg, 0.02 mmol), 2-(7-azobenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.2 mg, 0.03 mmol), and ethyldiisopropylamine (90 mg, 0.7 mmol). The reaction was carried out at room temperature for 0.5 hours, and after monitoring by LCMS that the raw materials had disappeared and the product remained mainly, the reaction was terminated, the reaction solution was poured into water, EA was added for extraction, the organic phase was washed with saturated brine, concentrated to remove the solvent, silica gel was added, the mixture was stirred, and the mixture was purified by normal phase column chromatography to obtain tert-butyl (E)-(1-(5-(3-((tert-butoxycarbonyl)oxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl))-4-(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)phenyl)piperidin-4-yl)carbamate, the yield was 81.49%.

[0694] ESI-MS (m / z) = 889.5 [M+H] + .

[0695] Step n): Synthesis of (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl))piperidin-4-yl)phenyl)-N-hydroxyacrylamide formate salt To a 4N solution of hydrochloric acid in ethyl acetate (4 mL) was added tert-butyl (E)-(1-(5-(3-((tert-butoxycarbonyl)oxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)-4-(4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)phenyl)piperidin-4-yl)carbamate (15 mg, 0.01 mmol), the mixture was reacted at room temperature for 0.5 hours, concentrated to remove the solvent, and purified by preparative separation. (E)-3-(4-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl))piperidin-4-yl)phenyl)-N-hydroxyacrylamide was obtained in a yield of 65.61%.

[0696] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.00(s,1H),8.52(s,1H),8.43(s,1H),8.18(s,1H),7.96(t,J =7.4Hz,1H),7.67(dd,J=10.1,1.4Hz,1H),7.61(d,J=8.3Hz,2H),7.58-7.51(m,2H),7.45(d,J=15.8 Hz,1H),7.28(dd,J=8.0,1.4Hz,1H),6.81(d,J=8.1Hz,1H),6.52-6.39(m,3H),4.08-3.95(m,2H),3. 75(d,J=12.0Hz,2H),3.71(s,3H),3.44(q,J=6.9Hz,2H),2.22-2.05(m,2H),1.82(d,J=13.1Hz,2H).

[0697] ESI-MS (m / z) = 605.2 [M+H] + .

[0698] Example 86 was synthesized according to the method of Example 85 (Separation Method 3), and its structure and property data are shown in the table below.

[0699] Preparation of (E)-3-(4-(2-(4-amino-1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)ethyl)phenyl)-N-hydroxyacrylamide formate salt [ka]

[0700] 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),9.01(s,1H),8.44(s,1H),8.20(s,1H), 7.96(dd,J=8.0,6.9Hz,1H),7.67(dd,J=10.0,1.4Hz,1H),7.49(d,J=7.8Hz,2H ),7.42(d,J=15.8Hz,1H),7.34-7.24(m,3H),6.85-6.76(m,1H),6.53-6.37(m, 3H),3.78(d,J=5.2Hz,4H),3.72(s,3H),2.77-2.65(m,2H),1.93-1.71(m,6H).

[0701] ESI-MS (m / z) = 633.3 [M+H] + .

[0702] Example 88 Preparation of (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-3-methoxypyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide [ka]

[0703] Step a): Preparation of 2-fluoro-3-methoxypyridine 2-Fluoropyrimidin-3-ol (3.0 g, 26.5 mmol) and potassium carbonate (11.0 g, 79.6 mmol) were dissolved in DMF (30 mL), and iodomethane (7.6 g, 53.1 mmol) was slowly added. The mixture was then allowed to react at room temperature for 6 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give 2-fluoro-3-methoxypyridine in 75.5% yield.

[0704] ESI-MS m / z=128.1[M+H] + .

[0705] Step b): Preparation of 2-fluoro-4-iodo-3-methoxypyridine 2-Fluoro-3-methoxypyridine (1.2 g, 8.4 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL). The mixture was purged with nitrogen three times and cooled to -78 °C. n-Butyllithium (810 mg, 12.7 mmol) was slowly added dropwise to the reaction mixture and stirred at -78 °C for 30 minutes. Iodine (3.2 g, 12.5 mmol) was dissolved in ultra-dry tetrahydrofuran (20 mL) and slowly added to the reaction mixture. After addition, the mixture was allowed to react at room temperature for 1 hour. Saturated ammonium chloride (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined. The mixture was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to give 2-fluoro-4-iodo-3-methoxypyridine in 51.4% yield.

[0706] ESI-MS m / z=254.1[M+H] + .

[0707] Step c): Preparation of tert-butyl (1-(4-iodo-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate 2-Fluoro-4-iodo-3-methoxypyridine (1.1 g, 4.4 mmol) and 4-tert-butoxycarbonylaminopiperidine (1.3 g, 6.5 mmol) were dissolved in DMF (20 mL), N-methylmorpholine (2.2 g, 21.8 mmol) was added, and the mixture was heated to 80 °C and reacted overnight. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give tert-butyl (1-(4-iodo-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate in 48.8% yield.

[0708] ESI-MS m / z=434.0[M+H] + .

[0709] Step...

Claims

1. A compound represented by the general formula (I) or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof. 【Chemical 1】 (In the formula, L １ is a bond, -C １～１０ alkyl-, -C ２～６ alkenyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ２～６ alkynyl-, -C ６～１０ heteroaryl-, -C １～１０ alkyl-(C ６～１０ aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl)-C ２～６ alkenyl-, -(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -C １～１０ alkyl-(C ６～１０ aryl)-C １～１０ alkyl-, -NR ａ -, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ alkynyl-, -C １～１０ alkyl-(C ６～１０ heterocycloalkyl)-(C ６～１０ aryl)-, -C １～１０ alkyl-NH-6- to 10-membered heteroaryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-, -C １～１０ alkyl-C ６～１０ cycloalkenyl-C ２～６ alkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkyl-, -C １～１０ alkyl-O-C ６～１０ aryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered aryl-O-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-O-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered aryl-S-C １～１０ selected from alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, -NR ａ R ｂ , COOH, -C(=O)NR ａ R ｂ substituted with one or more substituents selected from, wherein said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, and optionally, one or more of said alkyl is optionally -C(=O)-, -S(=O) ２ - or -NR ａ - and may be substituted with one or more groups selected from, W is selected from the groups represented by the following formulas, [Chemical 2] L ２ is selected from a bond, -O-, -C(=O)-, -NR ａ -, -CH ２ -NR ａ -, -NR ａ -, -C(O)-, -NR ａ -S(=O) ２ -, -S- or -S(=O) ２ - and is selected from Ring A is C containing N ３～１０ heteroaryl, C ３～１０ heterocycloalkyl or C ３～１０ heterocycloalkenyl, where the heteroaryl, heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more R ４ and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S R ４ is, each time it appears, independently of one another, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , -C(=O)NR ａ R ｂ selected from, and as an option, when R ４ is selected from C １～６ alkyl, any two R ４ may, together with their linking atoms, form a 5- to 10-membered aliphatic heterocyclyl, R １ and R ６ are each independently, for each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkyl-CN, C １～６ alkoxy, hydroxy-substituted C １～６ alkyl, halogen-substituted C １～６ alkyl, halogen-substituted C １～６ alkoxy, C ３～６ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ 、 -C(=O)NR ａ R ｂ 、 -S(=O) ２ R ａ 、 -C ２～６ alkenyl-C(=O)NR ａ R ｂ selected from R ２ 、 R ３ 、 R ７ are each independently selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, C ６～１０ aryl or C ６～１０ heteroaryl, and R ３ and R ７ are not both hydrogen, where the aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ 3, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, halo C １～６ alkoxy, halo C1-6 alkyl, hydroxy-substituted C １～６ alkyl, hydroxy-substituted C １～６ alkoxy, hydroxy-substituted C １～６ alkoxy-C ３～６ cycloalkyl, COOH, -NR ａ R ｂ 、 -S(=O) ２ R ａ 、 -C(=O)NR ａ R ｂ 、 -C ２～６ alkenyl-C(=O)NR ａ R ｂ and are substituted with one or more substituents selected from 3-6 membered heterocycloalkyl and heterocycloalkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S. m is selected from 0, 1, 2, 3, 4 or 5, Q and T are each independently selected from N or C, X and Y are each independently selected from C and N, Z is a bond, -CH ２ -, -C(=O) or -S(=O) ２ - and is selected from R ５ is, for each occurrence, independently of one another, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, =O, COOH, -NR ａ R ｂ 、-C(=O)NR ａ R ｂ 、C ３～６ cycloalkyl, 3- to 6-membered heterocycloalkyl, C ６～１０ aryl or C ６～１０ heteroaryl, where the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO ２ 、CF ３ 、CHF ２ 、hydroxy, C １～６ alkyl, C １～６ alkoxy, -C(=O)-C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ 、-C(=O)NR ａ R ｂ and is substituted with one or more substituents selected from, and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, As an option, R ５ and R ６ together with the atoms directly linked to both form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, where the cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, -NR ａ R ｂ , -C(=O)NR ａ R ｂ substituted with one or more substituents selected from, R ａ and R ｂ are, each independently for each occurrence, hydrogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, halogen-substituted C １～６ alkyl, 3- to 6-membered heterocycloalkyl, C ６～１０ aryl or C ６～１０ heteroaryl, wherein said heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, The following symbols indicate a double bond or none that can exist at any position within the ring.) [Chemical Formula 3]

2. L １ The left-end group of is linked to W, and the right-end group is linked to the group represented by the following formula: 【Chemical Formula 4】 Preferably, the compound is represented by formula (II), (III), (IV), (V) or (VI), 【Chemical Formula 5】 The definition of each substituent is as defined in Claim 1, the compound according to Claim 1 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof.

3. The compound is represented by formula (II-1), the compound according to Claim 1 or Claim 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof. 【Chemical Formula 6】 (In the formula, L １ is selected from -C １～１０ alkyl-, -C ２～６ alkenyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ２～６ alkynyl-, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ alkenyl-, and the alkyl and alkenyl are optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, Preferably, L １ is selected from -C １～１０ alkyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ alkenyl- and is selected from Preferably, L １ is -C １～１０ alkyl-, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ is selected from alkenyl-, Preferably, L １ is -C １～６ alkyl-, -C １～６ alkyl-phenylene-C ２～６ alkenyl-. )

4. Ring A is C containing N ３～１０ heteroaryl or C ３～１０ heterocycloalkyl, where the heteroaryl and heterocycloalkyl are optionally substituted with one or more R ４ and Preferably, ring A is selected from C containing N ３～１０ heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one or more R ４ groups. Preferably, ring A is selected from the groups represented by the following formulas, 【Chemical Formula 7】 Here, the group represented by the above formula is optionally substituted with an R ４ group, Preferably, ring A is selected from the groups represented by the following formulas, 【Chemical Formula 8】 The group represented by the above formula is optionally R ４ The compound or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof according to any one of claims 1 to 3, which is substituted with a group.

5. R ４ is, each time it appears, independently of one another, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , -C(=O)NR ａ R ｂ selected from, Preferably, R ４ is, each time it appears, independently of one another, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, -NR ａ R ｂ selected from, Preferably, R ４ is selected from hydrogen, -NR ａ R ｂ , C １～６ alkyl, Preferably, R ４ is hydrogen, -NR ａ R ｂ selected from the group consisting of, a compound according to any one of claims 1 to 4 or a tautomer, stereoisomer, solvate, metabolite, isotopically labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

6. R １ is selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, hydroxy-substituted C １～６ alkyl, halogen-substituted C １～６ alkyl, halogen-substituted C １～６ alkoxy, C ３～６ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, and Preferably, R １ is selected from hydrogen, halogen, CN, C １～６ alkyl, Preferably, R １ is selected from hydrogen, halogen, CN, R ２ is selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , C ６～１０ aryl or C ６～１０ heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , -S(=O) ２ R ａ , -O-C １～６ alkyl-OH, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S. Preferably, R ２ is selected from hydrogen, C ６～１０ aryl or C ６～１０ heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, -NR ａ R ｂ , -S(=O) ２ R ａ , -O-C １～６ alkyl-OH, and said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S Preferably, R ２ is selected from hydrogen and a group represented by the following formula: 【Chemical Formula 9】 Here, the group represented by the above formula is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, -NR ａ R ｂ , -S(=O) ２ -R ａ , -O-C １～６ alkyl-OH Preferably, R ２ is selected from the groups represented by the following formulae, 【Chemical Formula 10】 Here, the group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, hydroxy, C １～６ The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, which is substituted with one or more substituents selected from alkoxy.

7. m is selected from 0, 1, 2 or 3, preferably, m is selected from 1 or 2, more preferably, m is 2, Q is each independently selected from N or C, preferably, Q is selected from C, the compound according to any one of Claims 1 to 6 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof.

8. R ａ 、 R ｂ is, each time it appears, independently of one another, hydrogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, halogen-substituted C １～６ alkyl, and is selected from Preferably, R ａ , R ｂ is, each time it appears, independently of one another, hydrogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ selected from cycloalkyl, Preferably, R ａ , R ｂ is, for each occurrence, independently selected from hydrogen and methyl, Preferably, R ａ , R ｂ is each independently selected from hydrogen, the compound according to any one of claims 1 to 7 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof.

9. The compound is represented by formula (III-1), the compound according to Claim 1 or Claim 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof. 【Chemical 11】 (In the formula, X is selected from C and N, L １ is selected from bonding, -C １～１０ alkyl-, -C ２～６ alkenyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ２～６ alkynyl-, -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -NRa-, and wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, -NR ａ R ｂ , COOH Optionally, one or more carbon atoms in the alkyl may be optionally substituted with one or more groups selected from -NH-, Preferably, L １ is a bond, -C １～１０ alkyl-, -C ２～６ alkenyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-selected from, said alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkoxy, C ２～６ alkenyl, -NR ａ R ｂ substituted with one or more substituents selected from, Optionally, one or more carbon atoms in the alkyl may be optionally substituted with one or more groups selected from -NH-, Preferably, L １ is selected from -C １～１０ alkyl-, -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, and the alkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy.

10. L ２ is selected from a bond, -O-, -C(=O)-, -NR ａ -, -NR ａ -C(O)- or -S(=O) ２ - and Preferably, L ２ is selected from a bond, -O-, -NR ａ -, and Preferably, L ２ is selected from -O-, -NR ａ -, the compound according to any one of claims 1 to 9 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

11. Ring A is C containing N ３～１０ heteroaryl or C ３～１０ heterocycloalkyl, where said heteroaryl, heterocycloalkyl is optionally substituted with one or more R ４ and is substituted with Preferably, ring A is selected from C containing N ３～１０ heterocycloalkyl, and C ３～１０ heterocycloalkyl is optionally substituted with one or more R ４ and Preferably, ring A is selected from the groups represented by the following formulas, 【Chemical 12】 The group represented by the formula is optionally substituted with R ４ and Preferably, ring A is the following formula 【Chemical 13】 Or selected from the following formulas, 【Chemical Formula 14】 The group represented by the following formula is, 【Chemical Formula 15】 Optionally, R ４ The compound according to any one of claims 1 to 10, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, which is replaced by

12. R ４ is, each independently at each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, -NR ａ R ｂ selected from, Preferably, R ４ is hydrogen, C １～６ alkyl, -NR ａ R ｂ selected from, Preferably, R ４ is hydrogen, -NR ａ R ｂ selected from, a compound according to any one of claims 1 to 11 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

13. R １ and R ６ are each independently, for each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, halogen-substituted C １～６ alkyl, halogen-substituted C １～６ alkoxy, C ３～６ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , -C(=O)NR ａ R ｂ and are selected from Preferably, R １ , R ６ is, each time of appearance, independently selected from hydrogen, CN, hydroxy, C １～６ alkoxy, Preferably, R １ , R ６ is, each time of appearance, independently selected from hydrogen, CN, and hydroxy, R ３ is selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, C ６～１０ aryl or C ６～１０ heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, and said heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S. Preferably, R ３ is selected from hydrogen, C １～６ alkyl, C ６～１０ aryl or C ６～１０ heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, and said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, R ３ is selected from hydrogen, methyl, and a group represented by the following formula: 【Chemical Formula 16】 The group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, halogen, and CN, Preferably, R ３ is selected from hydrogen and a group represented by the following formula: 【Chemical 17】 The group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, halogen, and CN, the compound according to any one of Claims 1 to 12 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

14. R ５ is, each time it appears, independently selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ６～１０ aryl or C ６～１０ heteroaryl, where the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, and the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S. As an option, R ５ , R ６ , together with the atoms directly linked to both, form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, where the cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, Preferably, R ５ is selected from hydroxy, C １～６ alkoxy, and a group represented by the following formula: 【Chemical 18】 Here, the alkoxy group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy. As an option, R ５ , R ６ together with the atoms directly linked to both form a group represented by the following formula: 【Chemical Formula 19】 Here, the group represented by the above formula is optionally substituted with one or more groups selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy. Preferably, R ５ is selected from the groups represented by the following formulae, 【Chemical 20】 The group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, halogen, and CN, As an option, R ５ , R ６ together with the atoms directly linked to both form a group represented by the following formula: 【Chemical Formula 21】 The compound according to any one of Claims 1 to 13 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

15. m is selected from 0, 1, 2 or 3, preferably, m is selected from 1 or 2, and Z is a bond, -CH ２ -, or -C(=O), preferably, Z is selected from a bond, the compound or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1 to 14.

16. R ａ and R ｂ are each independently selected, for each occurrence, from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH, where said alkyl, alkoxy, alkenyl, alkynyl are optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, COOH Preferably, R ａ , R ｂ is, each time of appearance, independently selected from hydrogen, C １～６ alkyl, Preferably, R ａ , R ｂ is, each independently at each occurrence, hydrogen or methyl, and the compound according to any one of claims 1 to 15 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

17. The compound is the compound according to Claim 1 or Claim 2 represented by formula (IV-1a) or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof. 【Chemical 22】 (In the formula, L １ is a bond, -C １～１０ alkyl-, -C ２～６ alkenyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ６～１０ heteroaryl-, -C １～１０ alkyl-(C ６～１０ aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl)-C ２～６ alkenyl-, -(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -C １～１０ alkyl-(C ６～１０ aryl)-C １～１０ alkyl-, -NR ａ -, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ alkynyl-, -C １～１０ alkyl-(C ６～１０ heterocycloalkyl)-(C ６～１０ aryl)-, -C １～１０ alkyl-NH-6- to 10-membered heteroaryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-, -C １～１０ alkyl-C ６～１０ cycloalkenyl-C ２～６ alkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkyl-, -C １～１０ alkyl-O-C ６～１０ aryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered aryl-O-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-O-C １～１０ alkyl-, -C １～１０ Alkyl-6- to 10-membered aryl-S-C １～１０ Selected from alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, and said heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S As an option, one or more of the alkyls may optionally be substituted with one or more groups selected from -C(=O)-, -S(=O) ２ -, or -NR ａ -, and may be substituted with one or more groups selected from Preferably, L １ is -C １～１０ alkyl-, -C ２～６ alkenyl-, -C ６～１０ heteroaryl-, -C １～１０ alkyl-(C ６～１０ aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl)-C ２～６ alkenyl-, -(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -C １～１０ alkyl-(C ６～１０ aryl)-C １～１０ alkyl-, -C １～１０ alkyl-(C ６～１０ aryl)-C ２～６ alkynyl-, -C １～１０ alkyl-(C ６～１０ heterocycloalkyl)-(C ６～１０ aryl)-, -C １～１０ alkyl-NH-6- to 10-membered heteroaryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-, -C １～１０ alkyl-C ６～１０ cycloalkenyl-C ２～６ alkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkenyl-, -C １～１０ alkyl-C ６～１０ aryl-C ３～６ cycloalkyl-, -C １～１０ alkyl-O-C ６～１０ aryl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered aryl-O-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered heteroaryl-O-C １～１０ alkyl-, -C １～１０ alkyl-6- to 10-membered aryl-S-C １～１０ Selected from alkyl-, wherein said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ substituted with one or more substituents selected from alkenyl, wherein said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, L １ is -C １～１０ alkyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ６～１０ heteroaryl-, -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -C １～１０ alkyl-(C ６～１０ aryl)-C １～１０ alkyl-, -C １～１０ alkyl-(C ６～１０ heterocycloalkyl)-(C ６～１０ aryl)-and is selected from, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl and is substituted with one or more substituents selected from, said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, L １ is -C １～１０ alkyl-, -C １～１０ alkyl-C ２～６ alkenyl-, -C ６～１０ heteroaryl-, -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, -C １～１０ alkyl-(C ６～１０ aryl)-, -C １～１０ alkyl-(C ６～１０ aryl)-C １～１０ alkyl-, -C １～１０ alkyl-(C ６～１０ heterocycloalkyl)-(C ６～１０ aryl)-, and is selected from the group consisting of, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, and is substituted with one or more substituents selected from the group consisting of, the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, L １ is selected from -C １～１０ alkyl-(C ６～１０ aryl or heteroaryl)-C ２～６ alkenyl-, and the alkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, Preferably, L １ is -CH ２ -, -CH ２ -(C=C)-, -(CH ２ ) ４ -, -(CH ２ ) ６ -, -(C=O)-phenyl-(C=C)-, -CH ２ -phenyl-, -(CH ２ ) ３ -phenyl-, -CH ２ -phenyl-(CH ２ ) ２ -, -(CH ２ ) ２ -phenyl-CH ２ -, -CH ２ -phenyl-(C=C)-, -(CH ２ ) ２ -phenyl-(C=C)-, -CH ２ -phenyl-(C≡C)-, -CH ２ -phenyl-(C=C)-CH ２ -, -phenyl-(C=C)-, pyrimidinyl, selected from the groups represented by the following formula 【Chemical 23】 Preferably, L １ is selected from the groups represented by the following formulas.) 【Chemical 24】

18. L ２ is selected from the group consisting of a bond, -O-, -C(=O)-, -S-, -NR ａ -, -CH ２ -NR ａ -, -NR ａ -, -C(=O) or -NR ａ -S(=O) ２ -, and is selected from the group consisting of: Preferably, L ２ is selected from bonding, -NR ａ -, -CH ２ -NR ａ -, -NR ａ -C(=O) or -NR ａ -S(=O) ２ -, and is selected from Preferably, L ２ is -NR ａ -, -NR ａ -C(=O) or -NR ａ -S(=O) ２ - and is selected from Preferably, L ２ is selected from a bond, -C(=O)- or -NR ａ -, Preferably, L ２ is selected from -NR ａ -, a compound according to any one of claims 1 to 17 or a tautomer, stereoisomer, solvate, metabolite, isotopically labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

19. Ring A is C containing N ３～１０ heteroaryl or C ３～１０ heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl are optionally substituted with one or more R ４ and said heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S Preferably, ring A is selected from C ３～１０ heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one or more R ４ groups Preferably, ring A is selected from groups represented by the following formulae, 【Chemical Formula 25】 Here, the group represented by the above formula is optionally substituted with an R ４ group, Preferably, ring A is selected from groups represented by the following formulae, 【Chemical 26】 Here, the group represented by the above formula is optionally substituted with an R ４ group, Preferably, ring A is selected from groups represented by the following formulae, 【Chemical 27】 Here, the group represented by the above formula is optionally substituted with an R ４ group, Preferably, ring A is selected from groups represented by the following formulae, 【Chemical formula 28】 The group represented by the above formula is optionally R ４ The compound according to any one of claims 1 to 18, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, which is substituted with a group.

20. R ４ is, each independently at each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, -NR ａ R ｂ selected from, Preferably, R ４ is hydrogen, C １～６ alkyl, -NR ａ R ｂ selected from, Preferably, R ４ is selected from hydrogen, C １～６ alkyl, and is the compound according to any one of claims 1 to 19 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

21. R ６ is, each independently at each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkyl-CN, halo C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, COOH, -NR ａ R ｂ , -C(=O)NR ａ R ｂ selected from, Preferably, R ６ is, each time it appears, independently of one another, hydrogen, halogen, CH ２ -CN, CN, C １～６ alkyl, C １～６ alkoxy, halo C １～６ alkyl, and is selected from Preferably, R ６ is, each time it appears, independently selected from hydrogen, halogen, CH ２ -CN, CN, C １～６ alkyl, Preferably, R ６ is, each time it appears, independently selected from hydrogen and CN, R ３ and R ７ are each independently selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, C ６～１０ aryl or C ６～１０ heteroaryl, and R ３ and R ７ are not both hydrogen, where the aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, halo C １～６ alkoxy, halo C １～６ alkyl, hydroxy-substituted C １～６ alkyl, hydroxy-substituted C １～６ alkoxy, COOH, -NR ａ R ｂ , -S(=O) ２ R ａ , -C(=O)NR ａ R ｂ , 3- to 6-membered heterocycloalkyl, hydroxy-substituted C １～６ alkoxy-C ３～６ cycloalkyl, heterocycloalkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O, or S Preferably, R ３ and R ７ are each independently selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, C ６～１０ aryl or C ６～１０ heteroaryl, and R ３ and R ７ are not both hydrogen, and the aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, heterocycloalkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S. Preferably, R ３ and R ７ are each independently selected from hydrogen, C １～６ alkyl, C １～６ alkoxy, C ６～１０ aryl or C ６～１０ heteroaryl, and R ３ and R ７ are not both hydrogen, where the aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, CF ３ , hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, halo C １～６ alkoxy, halo C １～６ alkyl, hydroxy-substituted C １～６ alkoxy, hydroxy-substituted C １～６ alkoxy-C ３～６ cycloalkyl, COOH, -NR ａ R ｂ , -S(=O) ２ R ａ , -C(=O)NR ａ R ｂ , 3- to 6-membered heterocycloalkyl, heterocycloalkenyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, R ３ , R ７ is selected from hydrogen and a group represented by the following formula: 【Chemical 29】 The group represented by the above formula is optionally hydrogen, halogen, CN, heterocycloalkenyl, hydroxy, CF ３ , C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, halo C １～６ alkoxy, 3- to 6-membered heterocycloalkyl, hydroxy-substituted C １～６ alkoxy-C ３～６ cycloalkyl, hydroxy-substituted C １～６ alkyl, hydroxy-substituted C １～６ alkoxy, -NH ２ , -N(C １～６ alkyl) ２ , -NH(C １～６ alkyl) and is substituted with one or more substituents selected from, Preferably, R ３ , R ７ is selected from hydrogen and a group represented by the following formula: 【Chemical 30】 The group represented by the following formula is 【Chemical 31】 Optionally, hydrogen, halogen, CN, hydroxy, CF ３ , C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, halo C １～６ alkoxy, 3- to 6-membered heterocycloalkyl, hydroxy-substituted C １～６ alkoxy-C ３～６ cycloalkyl, hydroxy-substituted C １～６ alkyl, hydroxy-substituted C １～６ alkoxy, -NH ２ , -N(C １～６ alkyl) ２ , -NH(C １～６ alkyl) and is substituted with one or more substituents selected from Preferably, R ３ , R ７ is selected from hydrogen and a group represented by the following formula: 【Chemical 32】 The group represented by the formula is optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, and hydroxy, The compound according to any one of Claims 1 to 20 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

22. R ５ is, each independently at each occurrence, hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, =O, C ２～６ alkenyl, C ６～１０ aryl or C ６～１０ heteroaryl, where the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO ２ , CF ３ , CHF ２ , hydroxy, C １～６ alkyl, C １～６ alkoxy, -C(=O)-C １～６ alkoxy, C ２～６ alkenyl, -C(=O)-NH ２ and the heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, Preferably, R ５ is, each time of appearance and independently of one another, hydrogen, CN, C １～６ alkoxy, =O, C ６～１０ aryl or C ６～１０ heteroaryl, where the alkoxy, aryl or heteroaryl is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO ２ , CF ３ , CHF ２ , hydroxy, C １～６ alkyl, -C(=O)-C １～６ alkoxy, -C(=O)-NH ２ and the heteroaryl, heterocycloalkyl contain 1 to 4 heteroatoms optionally selected from N, O or S, As an option, R ５ , R ６ together with the atoms directly linked to both form a cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl, where the cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl and are substituted with one or more substituents selected therefrom, Preferably, R ５ is, independently of each other, selected from CN, C １～６ alkoxy, =O, and a group represented by the following formula 【Chemical 33】 The alkoxy and the group represented by the formula are optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO ２ , CF ３ , CHF ２ , hydroxy, C １～６ alkyl, -C(=O)-NH ２ , -C(O)OCH ３ and are substituted with one or more substituents selected therefrom. As an option, R ５ , R ６ together with the atoms directly linked to both form a group represented by the following formula: 【Chemical 34】 Here, the group represented by the above formula is optionally substituted with one or more groups selected from hydrogen, halogen, CN, hydroxy, C １～６ alkyl, C １～６ alkoxy. Preferably, R ５ is selected from C １～６ alkoxy, and a group represented by the following formula: 【Chemical 35】 The group represented by the above formula is optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO ２ and is substituted with one or more substituents selected from As an option, R ５ , R ６ together with the atoms directly linked to both form a group represented by the following formula: 【Chemical 36】 The compound according to any one of Claims 1 to 21 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

23. X and Y are each independently selected from C and N, Z is a bond, -CH ２ -, -C(=O) or -S(=O) ２ - and is selected from Preferably, Z is selected from a bond, -CH ２ -, or -C(=O), Preferably, Z is selected from a bond, the compound according to any one of Claims 1 to 22 or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof.

24. R ａ 、R ｂ is, each time it appears, independently of one another, hydrogen, hydroxy, C １～６ alkyl, C １～６ alkoxy, C ２～６ alkenyl, C ２～６ alkynyl, C ３～６ cycloalkyl, halogen-substituted C １～６ alkyl, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms arbitrarily selected from N, O or S. Preferably, R ａ , R ｂ is, each time it appears, independently selected from hydrogen, C １～６ alkyl, Preferably, R ａ , R ｂ is, each time it appears, independently selected from hydrogen, A compound according to any one of claims 1 to 23, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof.

25. The following compound or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof. 【Chemical 37】 【Chemical 38】 【Chemical Formula 39】 【Chemical 40】 【Chemical 41】 【Chemical 42】 【Chemical 43】 【Chemical 44】 【Chemical 45】 【Chemical 46】 【Chemical 47】 【Chemical 48】 【Chemical 49】 【Chemical Formula 50】 【Chemical Formula 51】 【Chemical 52】 【Chemical 53】

26. A pharmaceutical composition, wherein the active ingredient comprises one or a combination of two or more of the compounds according to any one of claims 1 to 25, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof.

27. Use of a compound according to any one of claims 1 to 25, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof, in the prevention and treatment of diseases mediated by LSD and / or HDAC respectively or synergistically, furthermore, the HDAC enzyme includes, but is not limited to, isoforms such as HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, preferably the HDAC1 or HDAC8 isoform, more preferably the HDAC1 isoform.

28. Furthermore, it is the use in the preparation of a drug for use in the treatment of diseases mediated by one or more of LSD1, HDAC6, HDAC8, preferably, the disease is cancer or an autoimmune disease, preferably, the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic granulocytic leukemia, colorectal cancer, brain tumor, hepatocellular carcinoma, renal cancer, gastric cancer, breast cancer, triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphoma, blood cancer, esophageal cancer, urethral cancer, and nasal cancer. Use of a compound according to any one of claims 1 to 25, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof, in the preparation of a drug for use in the treatment of diseases mediated by LSD1 and / or HDAC.

29. Use of a compound according to any one of claims 1 to 25, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal thereof, in the prevention and treatment of diseases mediated by LSD1 protein and / or HDAC1 protein, LSD1 protein and / or HDAC8 protein, respectively or synergistically.

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