Hydroxyl amide derivative and application thereof

Abstract

The invention provides a hydroxyamide derivative as shown in a formula (I), and a tautomer, a stereoisomer, a solvate, a metabolite, an isotope labeled compound, a pharmaceutically acceptable salt or a eutectic thereof. The compound provided by the invention has an inhibition effect on HDAC and LSD1, and can be used for treating diseases mediated by the LSD1 and / or the HDAC. # imgabs0 #

Description

A hydroxyamide derivative and its application Technical Field

[0001] The present disclosure belongs to the field of medicinal chemistry and specifically discloses a hydroxyamide derivative and its use. The compound has a significant inhibitory effect on the activity of LSD1 and HDAC proteins, can be used as an LSD1 and / or HDAC protein inhibitor, and can be used to prepare drugs for treating diseases such as cancer mediated by LSD1 and HDAC proteins, and has broad application prospects. Background Art

[0002] LSD1 (Lysine Specific Demethylase 1, also known as KDM1A) 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 nuclear amine oxidase homolog LSD1. Cell 2004, 119, 941-953). As a histone demethylase involved in transcriptional regulation, LSD1 has multiple biological functions, including promoting tumor growth, inhibiting energy metabolism, promoting fat synthesis, inhibiting lipolysis, and regulating cell differentiation. Inhibiting the function of LSD1 can enhance the expression of endogenous retroviral elements (ERVs) and inhibit the function of RISC (RNA-induced silencing complex, RISC), thereby 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.). At the same time, based on public databases of human cancers, researchers found that LSD1 showed an overexpression trend in some cancer types. The survival time of patients with high LSD1 expression was significantly shortened, suggesting that overexpression of LSD1 is a poor prognostic factor. Furthermore, studies have found that LSD1 is highly expressed in various cancer tissues, and a growing number of reports indicate that LSD1, as an epigenetic regulator, is involved in various tumor progression and embryonic development. The TCGA cancer database also shows that LSD1 expression is negatively correlated with IFN antiviral effects and CD8 T cell infiltration, consistent with findings in mouse models. Therefore, LSD1 inhibition can enhance tumor immunogenicity and promote T cell infiltration, activating anti-tumor T cell immunity and potentially serving as a target for anti-PD-1 immunotherapy in tumor treatment.Related research results also show that inhibiting DNA methylation alone or in combination with HDAC inhibitors can lead to the activation of the tumor interferon (IFN) pathway and enhance the efficacy of tumor immunotherapy. At the same time, blocking DNA methylation in T cells can also enhance T cell activity and tumor suppression mediated by PD-1 / PD-L1 immunotherapy (Chiappinelli, KB, Strissel, PL, Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, NS, Cope, LM, Snyder, A., et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 2015, 162, 974-986; Topper, MJ, Vaz, M., Chiappinelli, KB, DeStefano Shields, CE, Niknafs, N., Yen, RC, Wenzel, A., Hicks, J., Ballew, M., Stone, M., et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. 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. De novo epigenetic programs inhibit PD-1 blockade-mediated t cell rejuvenation.Cell 2017, 170, 142-157).

[0003] LSD1 is composed of 852 amino acids and has a molecular weight of 93kDa. Analysis of 27 tissue samples from 95 individuals showed that LSD1 is widely expressed in the body, with lower secretion in the liver, pancreas, and salivary glands, while higher expression in testicular tissue, and similar expression levels in other tissues. Studies have found that the expression level of LSD1 is significantly increased in different tumor tissues, such as neuroblastoma, breast cancer (Wang, Y.; Zhang, H.; et al, Cell 2009, 138(4), 660-72.), prostate cancer (Zhao, L.-J.; Fan, Q.-Q.; et al., Pharmacol. Res. 2020, 159, 104991), pancreatic cancer (Sehrawat, A.; Gao, L.; et al., Proc. Nat. Acad. Sci. USA 2018, 115(18), E4179-E4188.), colon cancer and glioma and hematological tumors (Hatzi, K.; Geng, H.; et al., Nature Immunology 2019, 20(1), 86-96.), and 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] Studies have shown that LSD1 exerts its biological function not only by demethylating histones, but also by demethylating non-histone proteins p53 and Dnmt1. The biological effects of LSD1 are mainly manifested in the regulation of sex hormone receptor-mediated gene transcription, the regulation of tumor cell proliferation, apoptosis and metastasis, as well as the regulation of embryonic development (Ancelin, K.; Syx, L.; et al., eLife 2016, 5, e08851 / 1-e08851 / 24.), mitosis, etc. In addition, LSD1 has also been reported to be associated with osteoporosis (Sun, J.; Ermann, J.; et al., Bone Res. 2018, 6(1), 1-12); in addition, LSD1 inhibition studies have found that it is associated with macrophage polarization (Tan, AHY; Tu, WJ; et al., Front. Immunol. 2019, 10, 1351.) and the infiltration of CD8+ T cells 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 hot topics in the field of tumor research.

[0005] Histone deacetylases (HDACs) are involved in regulating histone acetylation, binding to deacetylated proteins and interacting with non-histone proteins. They have a wide range of biological functions, including neurodegeneration, inflammation, metabolic disorders, and cancer. HDAC1 is a possible prognostic marker for lung and breast cancer and is overexpressed in prostate, gastric, and colon cancers. HDAC2 is often overexpressed in colorectal and gastric cancers. HDAC3 expression is elevated in lung cancer and most solid tumors. HDAC6 is primarily overexpressed in breast cancer. In various human tumor cells, knocking down HDAC8 can inhibit tumor cell growth and proliferation. In cancer cells, overexpression of HDACs leads to enhanced deacetylation, which is detrimental to the expression of specific genes, including some tumor suppressor genes. To date, five HDAC inhibitors (HDACis) have been approved for marketing: Vorinostat (SAHA), Romidepsin (FK228), Belinostat (PXD-101), Panobinostat (LBH-589), and Chidamide. These are used to treat a variety of tumors, including malignant lymphoma, myeloma, blood cancers, and pancreatic cancer. 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 can significantly enhance cancer cells' sensitivity to HDAC inhibitors. Duan et al. reported that simultaneous inhibition of LSD1 and HDAC activity with small molecule inhibitors resulted in synergistic antitumor effects (Duan, YC; et al, Eur J Med Chem. 2021, 220, 113453. doi:10.1016 / j.ejmech.2021.113453.). Studies have also shown that dual-target drugs offer more predictable metabolic pathways, unlike complex multidrug combinations, better PK / PD properties, and improved bioavailability (Giulia S.; et al, Current Opinion in Chemical Biology 2019, 50, 89-100). Furthermore, compared to combination therapy, dual-target drugs ensure that both pharmacophores are activated simultaneously in the same cells (de Lera, AR; Ganesan, A., Clin Epigenetics 2016, 8:105). Additional advantages of dual-target single drugs include 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 and colleagues reported a class of LSD1 / HDAC1 dual-target inhibitors that showed promising in vivo activity in a melanoma mouse model (Kalin, JH; et al; Nat. Commun., 2018, 9, 53). Other academic institutions, such as Xinxiang Medical University, have also recently published several patents for LSD1 / HDAC dual inhibitors (CN111592487; CN113444038; CN113527195).

[0006] Given that there are still no dual-target drugs on the market, there is still an urgent need in this field to develop new dual-target inhibitors that have inhibitory effects on both HDAC and LSD1.

[0007] Summary of the Invention

[0008] The present disclosure provides a compound represented by general formula (I) or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or cocrystals,

[0009] in,

[0010] L 1 Selected from bonds, -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 or heteroaryl or 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-6-10 membered heteroaryl-, -C1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; alternatively, one or more alkyl groups in the alkyl group may be optionally substituted by one or more substituents selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group;

[0011] Preferably, L 1 Selected from bonds, -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 or heteroaryl or heterocycloalkyl or heterocycloalkenyl)-C 2-6 Alkenyl-, -(C 6-10 aryl or heteroaryl)-C 2-6 Alkenyl-, -C 1-10Alkyl-(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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; alternatively, one or more alkyl groups in the alkyl group may be optionally substituted by one or more substituents selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group;

[0012] Preferably, L 1 The left end group is connected to W, and the right end group is connected to connected;

[0013] W is selected from:

[0014] L 2Selected from bond, -O-, -C(=O)-, -NR a -、-CH2-NR a -、-NR a -C(O)-、-NR a -S(=O)2-, -S- or -S(=O)2-;

[0015] Preferably, L 2 Selected from bond, -O-, -C(=O)-, -NR a -、-NR a -C(O)-、-NR a -S(=O)2-, -S- or -S(=O)2-;

[0016] Ring A is selected from C containing N 3-10 Heteroaryl, C 3-10 Heterocycloalkyl or C 3-10 Heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl, heterocycloalkenyl is optionally substituted by one or more R 4 Substitution, the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S;

[0017] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 Alternatively, R 4 Selected from C 1-6 When alkyl, any two R 4 The atoms to which it is connected may together form a 5- to 10-membered aliphatic heterocyclic group;

[0018] R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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)NRa R b 、-S(=O)2R a 、-C 2-6 Alkenyl-C(=O)NR a R b ;

[0019] Preferably, R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 ;

[0020] R 2 、R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 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 Rb 、-C 2-6 Alkenyl-C(=O)NR a R b 、C 3-6 Substituted by a cycloalkyl, 3- to 6-membered heterocycloalkyl, or heterocycloalkenyl substituent, wherein the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O, or S;

[0021] Preferably, R 2 、R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 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 、C 3-6 Substituted by a cycloalkyl, 3- to 6-membered heterocycloalkyl, or heterocycloalkenyl substituent, wherein the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O, or S;

[0022] m is selected from 0, 1, 2, 3, 4 or 5;

[0023] Q and T are each independently selected from N or C;

[0024] X and Y are each independently selected from C and N;

[0025] Z is selected from a bond, -CH2-, -C(=O) or -S(=O)2-;

[0026] Preferably, R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6Alkoxy, 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, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, 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 Substituents are substituted, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S;

[0027] R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, hydroxyl, 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 Substituents are substituted, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S;

[0028] Alternatively, R 5、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 by a substituent;

[0029] R a 、R b Each occurrence 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, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S;

[0030] Indicates the presence or absence of a double bond at any position within the ring.

[0031] The present disclosure provides a compound represented by general formula (I) or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or cocrystals,

[0032] in,

[0033] L 1 Selected from bonds, -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 or heteroaryl or 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 1-10Alkyl-(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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; alternatively, one or more alkyl groups in the alkyl group may be optionally substituted by one or more substituents selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group;

[0034] W is selected from:

[0035] L 2 Selected from bond, -O-, -C(=O)-, -NR a -, -S- or -S(=O)2-;

[0036] Ring A is selected from C containing N 3-10 Heteroaryl, C 3-10 Heterocycloalkyl or C 3-10 Heterocycloalkenyl, wherein the heteroaryl, heterocycloalkyl, heterocycloalkenyl is optionally substituted by one or more R 4 Substitution, the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S;

[0037] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 Alternatively, R 4 Selected from C1-6 When alkyl, any two R 4 The atoms to which it is connected may together form a 5- to 10-membered aliphatic heterocyclic group;

[0038] R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 ;

[0039] R 2 、R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 3-6 Substituted by a cycloalkyl, 3- to 6-membered heterocycloalkyl, or heterocycloalkenyl substituent, wherein the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O, or S;

[0040] m is selected from 0, 1, 2, 3, 4 or 5;

[0041] Q and T are each independently selected from N or C;

[0042] X and Y are each independently selected from C, N, -NR c -or-CR d -;

[0043] Z is selected from a bond, -CH2-, -C(=O) or -S(=O)2-;

[0044] R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 Substituents are substituted, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S;

[0045] Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 by a substituent;

[0046] R a 、R bEach occurrence 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, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S;

[0047] R c 、R d Each occurrence is independently selected from a bond, H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0048] Indicates the presence or absence of a double bond at any position within the ring.

[0049] The present disclosure discloses a compound of general formula (I) or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is represented by formula (II), (III), (IV), (V) or (VI):

[0050] The definitions of the substituents in the general formula (II), (III), (IV), (V) or (VI) are consistent with the above definitions.

[0051] The present disclosure provides a compound represented by the general formula (II-1):

[0052] in,

[0053] L 1 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-, the alkyl, alkenyl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6substituted by an alkoxy substituent.

[0054] Preferably, L 1 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-.

[0055] Preferably, L 1 Selected from -C 1-10 Alkyl-, -C 1-10 Alkyl-(C 6-10 Aryl)-C 2-6 Alkenyl-.

[0056] In some embodiments, L 1 Selected from -C 1-6 Alkyl-, -C 1-6 Alkyl-phenylene-C 2-6 Alkenyl-.

[0057] In one aspect of the present disclosure, wherein,

[0058] Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace.

[0059] Preferably, ring A is selected from C containing N 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace.

[0060] Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group;

[0061] Preferably, Ring A is selected from: wherein Optionally R 4 group substituted.

[0062] Preferably, Ring A is selected from: described Optionally R 4 group substituted.

[0063] Preferably, Ring A is selected from: described Optionally R4 group substituted.

[0064] Preferably, Ring A is selected from: Optionally R 4 group substituted.

[0065] In one aspect of the present disclosure, wherein,

[0066] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 .

[0067] Preferably, R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b .

[0068] Preferably, R 4 Selected from hydrogen, -NR a R b 、C 1-6 alkyl.

[0069] Preferably, R 4 Selected from hydrogen, -NR a R b .

[0070] In one aspect of the present disclosure, wherein,

[0071] R 1 Selected from hydrogen, halogen, CN, hydroxyl, 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.

[0072] Preferably, R 1 Selected from hydrogen, halogen, CN, C 1-6 alkyl.

[0073] Preferably, R1 Selected from hydrogen, halogen, CN.

[0074] R 2 Selected from hydrogen, halogen, CN, hydroxyl, 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 by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 1-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S;

[0075] R 2 Selected from hydrogen, halogen, CN, hydroxyl, 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 by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 , substituted by a substituent, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms selected from N, O or S.

[0076] In some embodiments, R 2 Selected from hydrogen, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NRa R b 、-S(=O)2R a 、-OC 1-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S;

[0077] Preferably, R 2 Selected from hydrogen, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-S(=O)2R a , substituted by a substituent, wherein the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms selected from N, O or S.

[0078] In some embodiments, R 2 Selected from hydrogen, Among them, the Optionally, one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-S(=O)2-R a 、-OC 1-6 substituted by an alkyl-OH substituent;

[0079] Preferably, R 2 Selected from hydrogen, Among them, the Optionally, one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-S(=O)2-R a substituted by a substituent.

[0080] Preferably, R 2 Selected from Among them, the Optionally, one or more selected from hydrogen, hydroxy, C 1-6 substituted by an alkoxy substituent.

[0081] In one aspect of the present disclosure, wherein,

[0082] m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 and 2; more preferably, m is 2.

[0083] Each Q is independently selected from N or C; preferably, Q is selected from C.

[0084] In one aspect of the present disclosure, wherein,

[0085] R a 、R b Each occurrence 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, C 3-6 Cycloalkyl.

[0086] Preferably, R a 、R b Each occurrence 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.

[0087] Preferably, R a 、R b Each occurrence is independently selected from hydrogen and methyl.

[0088] Preferably, R a 、R b are each independently selected from hydrogen.

[0089] The present disclosure provides a compound represented by the general formula (III-1):

[0090] in,

[0091] X is selected from C and N;

[0092] L 1 Selected from bonds, -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)-, -NR a-, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , substituted by a substituent of COOH;

[0093] Alternatively, one or more carbon atoms in the alkyl group may be optionally replaced by one or more groups selected from -NH-.

[0094] Preferably, L 1 Selected from bonds, -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)-, the alkyl, alkoxy, alkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b 、-NR a R b substituted by a substituent;

[0095] Alternatively, one or more carbon atoms in the alkyl group may be optionally replaced by one or more groups selected from -NH-.

[0096] Preferably, L 1 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)-, the alkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0097] Preferably, L 1 -C 1-6 alkyl-.

[0098] In one aspect of the present disclosure, wherein,

[0099] L 2 Selected from bond, -O-, -C(=O)-, -NR a -、-NR a -C(O)- or -S(=O)2-;

[0100] In some embodiments, L 2 Selected from bond, -O-, -C(=O)-, -NR a -, or -S(=O)2-.

[0101] Preferably, L 2 Selected from bond, -O-, -NR a -.

[0102] Preferably, L 2 Selected from -O-, -NR a -.

[0103] In one aspect of the present disclosure, wherein,

[0104] Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace.

[0105] Preferably, ring A is selected from C containing N 3-10 Heterocycloalkyl, C 3-10 Heterocycloalkyl is optionally substituted with one or more R 4 replace.

[0106] In some embodiments, Ring A is selected from: wherein Optionally R 4 group substituted.

[0107] Preferably, Ring A is selected from: wherein Optionally R 4 group substituted.

[0108] In some embodiments, Ring A is selected from: described Optionally R 4 group substituted.

[0109] Preferably, Ring A is selected from: Optionally R 4 group substituted.

[0110] In one aspect of the present disclosure, wherein,

[0111] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b .

[0112] Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, -NR a R b .

[0113] Preferably, R 4 Selected from hydrogen, -NR a R b .

[0114] In one aspect of the present disclosure, wherein,

[0115] R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 .

[0116] Preferably, R 1 、R 6 Each occurrence is independently selected from hydrogen, CN, hydroxyl, C 1-6 Alkoxy.

[0117] Preferably, R 1 、R 6 Each occurrence is independently selected from hydrogen, CN, and hydroxy.

[0118] Preferably, R 1 Each occurrence is independently selected from hydrogen, C 1-6 Alkoxy and hydroxyl groups; R 6 Each occurrence is independently selected from hydrogen and CN.

[0119] R 3 Selected from hydrogen, C 1-6Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0120] Preferably, R 3 Selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from hydrogen, halogen, and CN, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms selected from N, O, or S.

[0121] Preferably, R 3 Selected from hydrogen, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from hydrogen, halogen, and CN, and the heteroaryl and heterocycloalkyl contain 1 to 4 heteroatoms selected from N, O, or S.

[0122] Preferably, R 3 Selected from hydrogen, methyl, described Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0123] Preferably, R 3 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0124] Preferably, R 3 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0125] In one aspect of the present disclosure, wherein,

[0126] R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0127] Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 substituted by an alkynyl substituent.

[0128] Preferably, R 5 Each independently selected from hydroxyl, C 1-6 Alkoxy, Wherein, the alkyl, alkoxy, Optionally, one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0129] Alternatively, R 5 、R 6 Together with the atoms directly connected to them, Among them, the Optionally substituted with one or more of the following groups: hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0130] Preferably, R 5 Selected from Among them, the Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0131] Alternatively, R 5 、R 6 Together with the atoms directly connected to them,

[0132] In one aspect of the present disclosure, wherein,

[0133] m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 and 2.

[0134] Z is selected from a bond, -CH2- or -C(=O); preferably, Z is selected from a bond.

[0135] In one aspect of the present disclosure, wherein,

[0136] R a 、R b Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, COOH, wherein the alkyl, alkoxy, alkenyl, alkynyl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or COOH substituents.

[0137] Preferably, R a 、R b Each occurrence is independently selected from hydrogen, C 1-6 alkyl;

[0138] Preferably, R a 、R b Each occurrence is independently selected from hydrogen and methyl.

[0139] In some embodiments, the present disclosure provides a compound having formula (III-2):

[0140] The definitions of the substituents are consistent with those in formula (III-1).

[0141] The present disclosure provides a compound represented by the general formula (IV-1a):

[0142] in,

[0143] L 1 Selected from bonds, -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 or heteroaryl or heterocycloalkyl or heterocycloalkenyl)-C 2-6 Alkenyl-, -(C 6-10 aryl or heteroaryl)-C2-6 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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S;

[0144] Preferably, L 1 Selected from bonds, -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 6-10aryl or heteroaryl or 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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S;

[0145] Alternatively, one or more of the alkyl groups may be optionally replaced by one or more groups selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group.

[0146] In some embodiments, in the formula (IV-1a) provided herein, L 1 Selected from bonds, -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -C 1-10 Alkyl-C 2-6 Alkenyl-, -C6-10 Heteroaryl-, -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl or 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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S;

[0147] Alternatively, one or more of the alkyl groups may be optionally replaced by one or more groups selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group.

[0148] In some embodiments, in the formula (IV-1a) provided herein, L 1 Selected from -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -C 6-10 Heteroaryl-, -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl or 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-(C6-10 Heterocycloalkyl)-(C 6-10 Aryl)-, -C 1-10 Alkyl-NH-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0149] In some embodiments, in the formula (IV-1a) provided herein, L 1 Selected from -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -C 6-10 Heteroaryl-, -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl or 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 2-6Alkynyl-, -C 1-10 Alkyl-(C 6-10 Heterocycloalkyl)-(C 6-10 aryl)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0150] Preferably, L 1 Selected from -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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0151] In some embodiments, in the formula (IV-1a) provided herein, L 1 Selected from -C 1-10 Alkyl-, -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)-vinyl-, -(6-10 membered heteroaryl)-C 2-6 Alkenyl-, -C 1-10 Alkyl-(C 6-10 Aryl)-C 1-10Alkyl-, -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 the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0152] Preferably, L 1 Selected from -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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0153] Preferably, L 1 Selected from -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl)-C 2-6Alkenyl-, the alkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0154] Preferably, L 1 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,

[0155] Preferably, L 1 Selected from

[0156] In one aspect of the present disclosure, wherein,

[0157] L 2 Selected from bond, -O-, -C(=O)-, -S-, -NR a -、-CH2-NR a -、-NR a -C(=O) and -NR a -S(=O)2-;

[0158] In some embodiments, L 2 Selected from bond, -O-, -C(=O)-, -S-, -NR a -、-NR a -C(=O) and -NR a -S(=O)2-.

[0159] In some embodiments, L 2 Selected from a bond, -O-, -C(=O)-, -S- or -NR a -.

[0160] In some embodiments, L 2 Selected from bond, -NR a -、-CH2-NR a -、-NR a -C(=O) and -NR a -S(=O)2-.

[0161] In some embodiments, L 2 Selected from bond, -NR a -、-NR a -C(=O) and -NR a -S(=O)2-.

[0162] Preferably, L 2 Selected from a bond, -C(=O)- or -NR a -.

[0163] Preferably, L 2 Selected from-NR a -.

[0164] In one aspect of the present disclosure, wherein,

[0165] Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 Substituted; the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0166] Preferably, ring A is selected from C 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace.

[0167] Preferably, Ring A is selected from: wherein Optionally R 4 group substituted.

[0168] In some embodiments, Ring A is selected from: wherein Optionally R 4 group substituted.

[0169] In some embodiments, Ring A is selected from: wherein Optionally R 4 group substituted.

[0170] In some embodiments, Ring A is selected from: wherein Optionally R 4 group substituted.

[0171] Preferably, Ring A is selected from: Optionally R4 group substituted.

[0172] In one aspect of the present disclosure, wherein,

[0173] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b .

[0174] Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, -NR a R b .

[0175] Preferably, R 4 Selected from hydrogen, C 1-6 alkyl.

[0176] In one aspect of the present disclosure, wherein,

[0177] R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-CN, halogenated 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 .

[0178] Preferably, R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, COOH, -NR a R b 、-C(=O)NR a R b .

[0179] Preferably, R 6 Each occurrence is independently selected from hydrogen, halogen, CH2-CN, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 alkyl.

[0180] Preferably, R 6 Each occurrence is independently selected from hydrogen, halogen, CN, C 1-6 alkyl.

[0181] Preferably, R 6 Each occurrence is independently selected from hydrogen, CN.

[0182] R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 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, hydroxy substituted C 1-6 Alkoxy-C 3-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0183] In some embodiments, R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 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 , substituted by a substituent of a heterocycloalkenyl group, wherein the heteroaryl group and the heterocycloalkyl group contain 1 to 4 heteroatoms selected from N, O or S.

[0184] In some embodiments, R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkoxy, halogenated 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, or heterocycloalkenyl substituents, wherein the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O, or S.

[0185] Preferably, R 3 、R 7 are 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 7are not hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0186] Preferably, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, CN, heterocycloalkenyl, hydroxy, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated 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, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) substituent.

[0187] Preferably, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, CN, heterocycloalkenyl, hydroxy, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, hydroxy substituted C 1-6 Alkyl, hydroxy substituted C 1-6 substituted by an alkoxy substituent.

[0188] In some embodiments, R 3 、R 7 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, hydroxyl,.

[0189] In some embodiments, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, CN, hydroxyl, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated 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, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) substituent.

[0190] Preferably, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, hydroxy, CN, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated 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, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl).

[0191] Preferably, R 3 、R 7 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, hydroxy.

[0192] In one aspect of the present disclosure, wherein,

[0193] R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =O, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0194] In some embodiments, R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =O, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0195] In some embodiments, R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =O, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkoxy, C 2-6 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S.

[0196] In some embodiments, R 5 Each occurrence is independently selected from hydrogen, CN, C 1-6 Alkoxy, =O, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkoxy, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 Alkyl, -C(=O)-C 1-6 Alkoxy, -C (= O) -NH2 substituents, said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S;

[0197] Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 substituted by an alkynyl substituent.

[0198] Preferably, R 5 Each independently selected from CN, C 1-6 Alkoxy, =O, wherein the alkoxy group, Optionally, one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 The alkyl group is substituted by a substituent such as -C(O)OCH3 or -C(=O)-NH2.

[0199] Preferably, R 5 Each independently selected Among them, the Optionally, one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 It is substituted by a substituent such as an alkyl group, -C(O)OCH3, or -C(=O)-NH2.

[0200] Preferably, R 5 Each independently selected from CN, C 1-6 Alkoxy, =O, wherein the alkoxy group, Optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO2, hydroxy.

[0201] In some embodiments, R 5 Each independently selected from C 1-6 Alkoxy, =O, wherein the alkoxy group, Optionally substituted with one or more substituents selected from hydrogen, halogen, CN, hydroxy.

[0202] Alternatively, R 5 、R 6 Together with the atoms directly connected to them, Among them, the Optionally substituted with one or more of the following groups: hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0203] Preferably, R 5 Selected from C 1-6 Alkoxy, Among them, the Optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO2.

[0204] In some embodiments, R 5 Selected from C 1-6 Alkoxy, Among them, the Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

[0205] Alternatively, R 5 、R 6 Together with the atoms directly connected to them,

[0206] In one aspect of the present disclosure, wherein,

[0207] X and Y are each independently selected from C and N.

[0208] Z is selected from a bond, -CH2-, -C(=O) or -S(=O)2-.

[0209] Preferably, Z is selected from a bond, -CH2- or -C(=O).

[0210] Preferably, Z is selected from a bond.

[0211] In one aspect of the present disclosure, wherein,

[0212] R a 、R b Each occurrence 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 The alkyl group, the heteroaryl group, and the heterocycloalkyl group contain 1 to 4 heteroatoms selected from N, O, or S.

[0213] Preferably, R a 、R b Each occurrence is independently selected from hydrogen, C 1-6 alkyl.

[0214] Preferably, R a 、R b Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl.

[0215] Preferably, R a 、R b Each occurrence is independently selected from hydrogen.

[0216] In some embodiments, the present disclosure provides compounds having structures shown in Formula (IV-2a), Formula (IV-3a), and Formula (IV-4a):

[0217] The definitions of the substituents are consistent with those in formula (IV-1a).

[0218] The present disclosure provides a compound having the general formula (V):

[0219] in,

[0220] L 1 Selected from bonds, -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl)-C 2-6 Alkenyl-, -NR a -, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Substituted with alkenyl.

[0221] Preferably, L 1 Selected from -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl)-C 2-6 Alkenyl-, the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Substituted with alkenyl.

[0222] Preferably, L 1 Selected from -C 1-10 Alkyl-(C 6-10 Aryl)-C 2-6 Alkenyl-, the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Substituted with alkenyl.

[0223] In one aspect of the present disclosure, wherein,

[0224] L 2 Selected from bond or -NR a -.

[0225] Preferably, L 2 Selected from-NR a -.

[0226] In one aspect of the present disclosure, wherein,

[0227] Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace.

[0228] Preferably, ring A is selected from C 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace.

[0229] Preferably, Ring A is selected from: wherein Optionally R 4 group substituted.

[0230] Preferably, Ring A is selected from: Optionally R 4 group substituted.

[0231] In one aspect of the present disclosure, wherein,

[0232] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, wherein the alkyl, alkoxy is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0233] Preferably, R 4 Selected from hydrogen.

[0234] In one aspect of the present disclosure, wherein,

[0235] R 1 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NRa R b 、C 6-10 Aryl or C 6-10 Heteroaryl.

[0236] Preferably, R 1 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkoxy.

[0237] R 3 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl.

[0238] Preferably, R 3 Each occurrence is independently selected from hydrogen.

[0239] In one aspect of the present disclosure, wherein,

[0240] Z is selected from a bond, -CH2- or -C(=O).

[0241] Preferably, Z is selected from -C(=O).

[0242] In one aspect of the present disclosure, wherein,

[0243] R a 、R b Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted by one or more substituents selected from hydrogen, halogen, CN, CF3, and hydroxyl.

[0244] Preferably, R a 、R b Each occurrence is independently selected from hydrogen.

[0245] The present disclosure provides a compound having the general formula (VI):

[0246] in,

[0247] L 1 Selected from bonds, -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -NR a -, wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Substituted with alkenyl.

[0248] Preferably, L 1 Selected from -C 1-10 alkyl-.

[0249] In one aspect of the present disclosure, wherein,

[0250] L 2 Selected from a bond, -O- or -NR a -.

[0251] Preferably, L 2 Selected from -O-.

[0252] In one aspect of the present disclosure, wherein,

[0253] Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace.

[0254] Preferably, ring A is selected from C 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace.

[0255] Preferably, Ring A is selected from: wherein Optionally R 4 group substituted.

[0256] In some embodiments, Ring A is selected from: wherein Optionally R 4 group substituted.

[0257] Preferably, Ring A is selected from: described Optionally R 4 group substituted.

[0258] Preferably, Ring A is selected from: Optionally R 4 group substituted.

[0259] In one aspect of the present disclosure, wherein,

[0260] R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, -NR a R b, wherein the alkyl and alkoxy groups are optionally replaced by one or more groups selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0261] Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, -NR a R b .

[0262] In one aspect of the present disclosure, wherein,

[0263] R 1 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b .

[0264] Preferably, R 1 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxy.

[0265] R 3 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b .

[0266] Preferably, R 3 Each occurrence is independently selected from hydrogen.

[0267] In one aspect of the present disclosure, wherein,

[0268] Z is selected from a bond, -CH2- or -C(=O).

[0269] Preferably, Z is selected from -C(=O).

[0270] In one aspect of the present disclosure, wherein,

[0271] R a 、R b Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted by one or more substituents selected from hydrogen, halogen, CN, CF3, and hydroxyl.

[0272] Preferably, R a 、Rb Each occurrence is independently selected from hydrogen.

[0273] The present disclosure provides the following compounds:

[0274] The present disclosure provides a pharmaceutical composition, characterized in that the active ingredient of the pharmaceutical composition is selected from one or a combination of two or more of the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or cocrystals.

[0275] The present disclosure provides uses or methods of the above-described compounds or their tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or co-crystals in preventing and treating LSD and / or HDAC-related diseases mediated separately or synergistically.

[0276] The use or method comprises the step of administering a therapeutically effective amount of the above-mentioned compound or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal to a patient in need thereof.

[0277] In one aspect of the present disclosure, the HDAC enzyme includes but is not limited to HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8 and other subtypes, preferably HDAC1 and HDAC8 subtypes, and further preferably HDAC1 subtype.

[0278] The present disclosure provides use of the above-described compound or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or co-crystal in the preparation of a medicament for treating diseases mediated by LSD1 and / or HDAC.

[0279] In one aspect of the present disclosure, is a use in the preparation of a medicament for treating a disease mediated by one or more of LSD1 and HDAC.

[0280] In one aspect of the disclosure, the disease is cancer or an autoimmune disease.

[0281] In one aspect of the present disclosure, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, stomach 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.

[0282] The present disclosure provides uses of the above-described compounds or their tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts, or co-crystals in preventing and treating diseases mediated separately or synergistically by LSD1 protein and / or HDAC1 protein, LSD1 protein, and / or HDAC8 protein.

[0283] In one aspect of the present disclosure, the disease is a disease mediated by abnormal activity of the above-mentioned protein. DETAILED DESCRIPTION

[0284] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain this disclosure.

[0285] I. Definition

[0286] The terms "include," "comprises," or "comprising" and their variations herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the terms "include" encompass the meaning of "consisting of."

[0287] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0288] The term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. As used herein, the term "C6-10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may optionally be substituted with one or more suitable substituents, for example, cyano (CN), halogen (F, Cl, Br). When the aryl group is substituted with multiple substituents, two adjacent substituents may form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group together with the carbon atom to which they are attached, examples of which include but are not limited to wait.

[0289] 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 (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may be benzo-fused. As used herein, the term "C6-10 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 (the heteroatom being, for example, oxygen, nitrogen or sulfur). Heteroaryl may be optionally substituted by one or more suitable substituents, for example by cyano (CN), halogen (F, Cl, Br). Examples include, but are not limited to wait.

[0290] 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, or a bicyclic ring including a spirocyclic, fused or bridged system (e.g., bicyclo[2.2.1]heptyl, etc.). As used herein, the term "C3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). Cycloalkyl groups may be optionally substituted with one or more suitable substituents.

[0291] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic (such as 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 rest of the molecule by any one of the carbon atoms or heteroatoms. As used herein, the term C3-10 heterocycloalkyl is a saturated monocyclic or polycyclic (such as bicyclic) group having 3-10 ring carbon atoms in the ring, and wherein at least one heteroatom (such as oxygen, nitrogen or sulfur) that may be the same or different is included. Heterocycloalkyl may optionally be substituted with one or more suitable substituents.

[0292] The term "heterocycloalkenyl" refers to a class of cycloalkenyl groups as defined above, and at least one of the carbon atoms of its ring is replaced by a heteroatom, such as nitrogen, oxygen or sulfur. Examples of C3-10 heterocycloalkenyl groups include, but are not limited to, tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, etc., and can be a monocyclic or polycyclic (such as bicyclic) group. Heterocycloalkenyl groups can optionally be substituted by one or more applicable substituents.

[0293] The term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0294] The term "hydroxy" refers to -OH.

[0295] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. As used herein, the term "C1-6 The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0296] The term "halogen-substituted alkyl", when used herein alone or in combination with other groups, refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. It will be understood by those skilled in the art that when there are more than one halogen substituent, 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 C1-6 alkyl group in which one or more hydrogen atoms are replaced by halogen, such as trifluoromethyl.

[0297] The term "hydroxy substituted alkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxy group. 1-6 "Alkyl" refers to C 1-6 One or more hydrogen atoms in an alkyl group are replaced by a hydroxyl group, e.g.

[0298] The term "alkoxy" refers to an "alkyl" group as defined above attached via an oxygen atom, i.e., an "alkoxy" group may be defined as -OR, wherein R is an alkyl group as defined above. As used herein, the term "C 1-6 Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like.

[0299] The term "halogen-substituted alkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. It will be understood by those skilled in the art that when there are more than one halogen substituent, 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 C 1-6 One or more hydrogen atoms in the alkoxy group are replaced by halogen, such as difluoromethoxy and trifluoromethoxy.

[0300] The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond. The double bond can exist as an E or Z isomer. The double bond can be located at any possible position of the hydrocarbon chain. As used herein, the term "C2-6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms, such as vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, etc. The alkenyl group can optionally be substituted with one or more suitable substituents.

[0301] The term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing at least one C≡C triple bond. The triple bond can be located at any possible position of the hydrocarbon chain. As used herein, the term "C 2-6 The term "alkynyl" refers to an alkynyl group containing 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl group may be optionally substituted with one or more suitable substituents.

[0302] The term "-(aryl or heteroaryl)-alkenyl-" refers to an aryl or heteroaryl group as defined above attached to an alkenyl group. As used herein, the term "-(C 6-10 aryl or heteroaryl)-C 2-6 "Alkenyl-" refers to an aromatic group containing 6 to 10 carbon atoms or a C6-10 heteroaryl group connected to an alkenyl group containing 2 to 6 carbon atoms, for example

[0303] "Alternatively, one or more of the alkyl groups in the alkyl group may be optionally replaced by one or more groups selected from -C(=O)-, -S(=O)2- or -NR a - group is replaced by", refers to an alkyl group such as C 1-10 One or more alkyl or alkylene fragments in the alkyl group are optionally replaced by one or more radicals selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group such as L 1 -C 10 Alkyl-C 6-10 Aryl-C 2-6 When alkenyl-, C 10 In the alkyl group, an alkylene fragment is replaced by -C(=O)- to give -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 groups include, but are not limited to One of the methylene groups in the wait.

[0304] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valency in the present context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0305] The term "hydroxy substituted C 1-6 Alkoxy-C 3-6"Cycloalkyl" includes but is not limited to

[0306] The term "optionally substituted" means optionally substituted with the specified groups, radicals or moieties.

[0307] When a group is described as "optionally substituted with one or more substituents," the group may be (1) unsubstituted or (2) substituted. If a carbon on a group is described as optionally substituted with one or more substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be substituted individually and / or together with independently selected substituents or may be unsubstituted. If a nitrogen on a group is described as optionally substituted with one or more substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be substituted with independently selected substituents or may be unsubstituted.

[0308] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0309] It indicates that a double bond may exist at any position in the ring or not, and includes various situations including saturated ring systems, unsaturated non-aromatic ring systems with double bonds, and aromatic ring systems.

[0310] Compounds of the present disclosure may also contain one or more (eg, one, two, three, or four) isotopic substitutions.

[0311] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. The scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0312] Pharmaceutically acceptable salts of the disclosed compounds may include acid addition salts and base salts 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).

[0313] In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure is selected from hydrochloride, formate, trifluoroacetate, and the like.

[0314] The term "co-crystal" refers to a crystal formed by the active pharmaceutical ingredient and a co-crystal former (e.g., a co-former) combined by hydrogen bonds or other non-covalent bonds, more specifically, a co-crystal formed by a compound of formula (I) and a pharmaceutically acceptable co-former.

[0315] The term "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that can achieve the desired effect. In embodiments of the present disclosure, when a patient is treated according to the present disclosure, the amount of a given drug depends on many factors, such as a specific dosing regimen, a disease or condition type and its severity, the uniqueness (e.g., body weight) of the subject or host to be treated, but, according to specific surrounding circumstances, including, for example, a specific drug, route of administration, the condition to be treated, and the subject or host to be treated, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose can be conveniently expressed as a single dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with a physician's diagnosis.

[0316] II. Examples

[0317] The following describes in detail the implementation process and beneficial effects of the present disclosure through specific embodiments, which is intended to help readers better understand the essence and characteristics of the present disclosure and is not intended to limit the scope of implementation of the present invention.

[0318] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE NEO 400 MHz Bruker instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ISQ-EC Thermo Fisher LC-MS instrument. The instrument used for preparative chromatography was a GX-281 Gilson chromatograph. The separation methods are: Separation Method 1: Sun Fire Prep C18 OBDTM 5μm, 30x 150mm Column, 0.04% HCl aqueous solution / acetonitrile; Separation Method 2: Sun Fire Prep C18 OBDTM 5μm, 30x 150mm Column, 0.02% TFA aqueous solution / acetonitrile; Separation Method 3: Sun Fire Prep C18 OBDTM 5μm, 30x 150mm Column, 0.06% formic acid aqueous solution / acetonitrile; Separation Method 4: Xbridge Prep C18 OBDTM 5μm, 30x 150mm Column, 10mM NH4HCO3 aqueous solution / acetonitrile; Separation Method 5: Xbridge Prep C18 OBDTM 5μm, 30x 150mm Column, 0.6% NH3.H2O aqueous solution / acetonitrile.

[0319] The solvents used in the present disclosure are commercially available.

[0320] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0321] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0322] HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;

[0323] DIPEA refers to diisopropylethylamine;

[0324] DMSO refers to dimethyl sulfoxide;

[0325] EA refers to ethyl acetate;

[0326] Pd2(dba)3 refers to tris(dibenzylideneacetone)dipalladium;

[0327] DCE refers to dichloroethane;

[0328] DCM refers to dichloromethane;

[0329] DMF refers to N,N-dimethylformamide;

[0330] NMP refers to N-methylpyrrolidone;

[0331] TFA refers to trifluoroacetic acid;

[0332] NBS refers to N-bromosuccinimide;

[0333] TfOH refers to trifluoromethanesulfonic acid;

[0334] DPPA refers to diphenylphosphoryl azide;

[0335] The positive reference substances were CC-90011 and SAHA (Vorinostat).

[0336] Example 1

[0337] Preparation of 7-((6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)pyridin-4-yl)oxy)-N-hydroxyheptylamide hydrochloride

[0338] Step a): Preparation of tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate

[0339] 4-(Benzyloxy)-2,6-dichloropyridine (1.8 g, 7.1 mmol), tert-butylpiperidin-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. When the reaction was complete as monitored by LC-MS, the reaction solution was cooled to room temperature, then 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 = 2:1) to provide tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate in a yield of 77.4%.

[0340] ESI-MS m / z=418.2[M+H] + .

[0341] Step b): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0342] 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), Pd(dppf)Cl2 (77.2 mg, 0.11 mmol) were dissolved in dioxane (40 mL), and water (4 mL) was added. The atmosphere was replaced with nitrogen three times and the reaction was heated to 100 °C. After 2 h of reaction, LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×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 a yield of 76.0%.

[0343] ESI-MS m / z=503.2[M+H] + .

[0344] Step c): Preparation of tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0345] 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 allowed to react at room temperature for 2 h. LC-MS indicated the reaction was complete. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (40 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 = 1:2) to provide tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 81.0%.

[0346] ESI-MS m / z=581.2[M+H] + .

[0347] 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

[0348] 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-dioxybenzaldehyde-2-yl)phenol (498 mg, 2.9 mmol), Cs2CO3 (1.9 g, 5.8 mmol), and Pd(dppf)Cl2 (214 mg, 0.29 mmol) were dissolved in dioxane (30 mL). Water (6 mL) was added and the atmosphere was replaced with nitrogen three times. The reaction was heated to 100°C. After 2 h of reaction, LC-MS showed the disappearance of the starting material, indicating the reaction was complete. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was performed 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%.

[0349] ESI-MS m / z = 625.3 [M+H] + .

[0350] 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

[0351] 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, the mixture was replaced with hydrogen three times, and the reaction was carried out at room temperature for 4 h. The reaction solution was ultrasonicated for 15 minutes and then filtered. The filtrate was concentrated in vacuo to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 96.8%.

[0352] ESI-MS m / z=535.2[M+H] + .

[0353] 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

[0354] 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), and diisopropylethylamine (86 mg, 0.66 mmol) and methyl 7-bromoheptanoate (74 mg, 0.33 mmol) were added. The mixture was reacted at 60°C overnight. The mixture was concentrated in vacuo, and the residue was purified on a silica gel column (eluent: petroleum ether:ethyl acetate = 1:1) to provide 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 an 87% yield.

[0355] ESI-MS m / z=677.3[M+H] + .

[0356] 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

[0357] 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 / H2O = 5:1 (3 mL) and reacted at room temperature overnight. The pH of the system was adjusted to 2-3 with 2N HCl, and the mixture was extracted with ethyl acetate. The organic phase was washed once with brine, dried, and concentrated, and the residue was used directly in the next step.

[0358] ESI-MS m / z = 663.3 [M+H] + .

[0359] Step h): Preparation of 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

[0360] 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)hydroxylamine (47 mg, 0.4 mmol) were added, and the mixture was reacted at room temperature for 1 minute. The reaction mixture was stirred for 3 hours, quenched with water, extracted with ethyl acetate, and the organic phase was washed twice with water, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-((7-oxyl-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 85%.

[0361] ESI-MS m / z=762.4[M+H] + .

[0362] 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-hydroxyheptylamide hydrochloride

[0363] 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 (130 mg, 0.17 mmol) was dissolved in HCl / EA (3 mL, 4 M) and reacted at room temperature for 1 h. Solids formed in the reaction solution, and LC-MS analysis showed that the reaction was complete. The reaction solution was filtered to obtain a solid, which was then purified by Prep-HPLC (Isolation 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-hydroxyheptylamide hydrochloride in a yield of 65.2%.

[0364] 1H 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).

[0365] ESI-MS m / z=578.3[M+H] + .

[0366] Compounds of Examples 2-18 were prepared according to the synthetic method of Example 1 (compound isolation methods: hydrochloride, trifluoroacetate, formate, and free base were isolated and prepared according to isolation methods 1, 2, 3, and 4, respectively). Their structures and characterization data are as follows:

[0367] Example 19

[0368] Preparation of 7-(5-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0369] 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

[0370] 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-dioxybenzaldehyde-2-yl)phenoxy)heptanoate (241 mg, 517 μmol), Cs2CO3 (225 mg, 690 μmol), Pd(dppf)Cl2 (26 mg, 35 μmol), 1.4-Dioxane (10 mL) and H2O (2.5 mL) were added to a reaction flask and stirred at 120°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 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%.

[0371] ESI-MS (m / z) = 843.4 [M+H] + .

[0372] Step b): Preparation of 2-chloro-6-methylpyrimidine-4-carboxylic acid

[0373] 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 the reaction flask and stirred at room temperature for 12 hours. 1N concentrated hydrochloric acid was slowly added dropwise with stirring in an ice bath 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 to dryness to obtain 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 directly used in the next reaction;

[0374] ESI-MS (m / z) = 829.4 [M+H] + .

[0375] Step c): Preparation of 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

[0376] 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)hydroxylamine (47 mg, 400 μmol), DIEA (52 mg, 400 μmol) and DMF (2 mL) were added to the reaction bottle, 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, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially 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-(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 in a yield of 62.7%;

[0377] ESI-MS (m / z) = 928.5 [M+H] + .

[0378] Step d): Preparation of 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

[0379] 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 the reaction flask, stirred to dissolve, replaced with hydrogen three times, and stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxy-5-(3-hydroxy-4-((7-oxyl-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 85.0%.

[0380] ESI-MS (m / z) = 748.4 [M+H] + .

[0381] Step e): Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0382] 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 a reaction flask, followed by addition of a 4M hydrogen chloride ethyl acetate solution (2.5 mL). The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of a large amount of solid. The mixture was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 1) to give 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride in a yield of 35.8%.

[0383] 1H 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),3.89(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).

[0384] ESI-MS (m / z) = 564.3 [M+H] + .

[0385] Example 20

[0386] Preparation of 7-(5-(5-(4-aminopiperidin-1-yl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-8-yl)-2-methoxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0387] Step a): Preparation of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0388] Dissolve 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) in 1,4-dioxane:water = 5:1 (150 mL), sparge with nitrogen, and heat in an oil bath to 95°C for the reaction. When LCMS showed completion of the reaction, the reaction solution was concentrated in vacuo, dissolved in ethyl acetate (20 mL), and 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. 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%.

[0389] ESI-MS m / z:245.1[M+H] + .

[0390] Step b): Preparation of 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0391] 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). Under nitrogen protection in an ice-water bath, NBS (1.45 g, 8 mmol) was added and the reaction continued for 2 hours. LCMS indicated the reaction was complete, and the mixture was quenched with water (40 mL). The mixture was then extracted with ethyl acetate (50 mL x 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 afford 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 78.5%.

[0392] ESI-MS m / z:323.0[M+H] + .

[0393] Step c): Preparation of 4-(8-bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile

[0394] 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (500 mg, 1.55 mmol) was dissolved in isopropanol (13 mL). Chloroacetaldehyde (6.09 g, 31.06 mmol) was then added. The atmosphere was purged with nitrogen and the reaction was allowed to react overnight at 110°C. The reaction progress was monitored by TLC and LCMS. When LCMS indicated completion of the reaction, the reaction solution was concentrated in vacuo and dissolved in 5 mL of dichloromethane. The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1 / 20) to afford 4-(8-bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile in an 85.7% yield.

[0395] 1 H NMR(400MHz,DMSO-d6)δppm 12.28(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).

[0396] ESI-MS m / z:333.0[M+H] + .

[0397] Step d): Preparation of 4-(8-(3-(benzyloxy)-4-methoxyphenyl)-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile

[0398] 4-(8-Bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile (380 mg, 1.14 mmol), (3-(benzyloxy)-4-methoxyphenyl)boronic acid (292 mg, 1.72 mmol), Pd(dppf)Cl2 (167 mg, 0.21 mmol), and Na2CO3 (243 mg, 2.29 mmol) were weighed and dissolved in 1,4-dioxane (15 mL). Water (3 mL) was added. The mixture was purged with N2 and protected with N2. The reaction was carried out in a microwave reactor at 105°C for 30 minutes. When LCMS indicated the reaction was complete, the mixture was extracted with ethyl acetate (10 mL x 3), washed with 10 mL of brine, 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 a yield of 89.7%.

[0399] ESI-MS m / z:467.1[M+H] + .

[0400] 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

[0401] 4-(8-(3-(Benzyloxy)-4-methoxyphenyl)-5-hydroxyimidazole[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile (200 mg, 0.530 mmol), tert-butylpiperidine-4-carbamate (318 mg, 1.57 mmol), and Carter condensation agent (352 mg, 0.795 mmol) were dissolved in 16 mL of anhydrous acetonitrile, and DIPEA (206 mg, 1.59 mmol) was added. The atmosphere was replaced with nitrogen and heated to 60°C under nitrogen protection for overnight reaction. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction solution 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%.

[0402] ESI-MS m / z:649.3[M+H] + .

[0403] 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

[0404] 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. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 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 a yield of 83.0%.

[0405] ESI-MS (m / z) = 559.2 [M+H] + .

[0406] Step g): Preparation of tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methyl-3-nitropyridin-2-yl)piperidin-4-yl)carbamate

[0407] 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), K2CO3 (72 mg, 512 μmol), and acetonitrile (5 mL) were added to a reaction flask and stirred at 75°C for 12 hours. The mixture was concentrated to dryness under reduced pressure, and 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%.

[0408] ESI-MS (m / z) = 701.3 [M+H] + .

[0409] Step h): Preparation of tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methyl-3-nitropyridin-2-yl)piperidin-4-yl)carbamate

[0410] 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 the reaction flask and stirred at room temperature for 8 hours. After the reaction, 0.5N aqueous hydrochloric acid solution (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 to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 8 / 3) to obtain 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 in a yield of 89.0%.

[0411] ESI-MS (m / z) = 687.3 [M+H] + .

[0412] Step i): Preparation of tert-butyl (1-(3-amino-5-bromo-6-(4-cyano-3-fluorophenyl)-4-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0413] 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)hydroxylamine (33 mg, 278 μmol), DIEA (36 mg, 278 μmol) and DMF (2 mL) were added to the reaction bottle, 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, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially with saturated aqueous sodium bicarbonate solution (20 mL × 2) 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-(7-(4-cyano-3-fluorophenyl)-8-(4-methoxy-3-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate in a yield of 72.7%;

[0414] ESI-MS (m / z) = 786.4 [M+H] + .

[0415] 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-hydroxyheptylamide hydrochloride

[0416] Tert-butyl (1-(7-(4-cyano-3-fluorophenyl)-8-(4-methoxy-3-((7-oxy-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 a reaction flask, and hydrogen chloride ethyl acetate solution (4M, 2.5 mL) was added. The mixture was stirred at room temperature for 1 hour, and a large amount of solid precipitated. The reaction mixture was concentrated under reduced pressure, and the 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-hydroxyheptylamide hydrochloride in a yield of 22.5%.

[0417] 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.35(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),6.9 7–6.75(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).

[0418] ESI-MS (m / z) = 602.3 [M+H] + .

[0419] Compounds of Examples 21-23 were prepared according to the synthetic method of Example 20 (Compound Isolation Method 1), and their structures and characterization data are as follows:

[0420] Example 24

[0421] Preparation of 7-(4-(5-cyano-4-(4-cyano-3-fluorophenyl)-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0422] Step a): Preparation of 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile

[0423] 2-Chloro-4-iodonicotinonitrile (1.0 g, 3.79 mmol), (4-cyano-3-fluorophenyl)boronic acid (688 mg, 4.17 mmol), Cs2CO3 (3.7 g, 11.37 mmol), Pd(dppf)Cl2 (275 mg, 0.38 mmol), 1.4-dioxane (10 mL), and H2O (2.5 mL) were added to a reaction flask and stirred at 100°C for 1 hour. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile in a yield of 68.0%.

[0424] ESI-MS (m / z) = 258.1 [M+H] + .

[0425] Step b): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate

[0426] 2-Chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile (660 mg, 2.58 mmol), tert-butyl piperidin-4-ylcarbamate (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 completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2) and concentrated to dryness under reduced pressure. 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 in a yield of 68.5%.

[0427] ESI-MS (m / z) = 436.2 [M+H] + .

[0428] Step c): Preparation of tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate

[0429] 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. NBS (270 mg, 1.5 mmol) was added portionwise with 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 phases were washed with saturated brine (40 mL × 2) and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate in a yield of 77.0%.

[0430] ESI-MS (m / z) = 514.1 [M+H] + .

[0431] 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

[0432] 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-dioxybenzaldehyde-2-yl)phenoxy)heptanoate (501 mg, 1.07 mmol), Cs2CO3 (950.8 mg, 2.92 mmol), Pd(dppf)Cl2 (70.6 mg, 0.1 mmol), 1.4-dioxane (10 mL) and H2O (2.5 mL) were added to the reaction flask and stirred at 100°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 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%.

[0433] ESI-MS (m / z) = 776.4 [M+H] + .

[0434] 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

[0435] 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 reaction was carried out at room temperature for 3 hours. The pH of the system was adjusted to 2-3 with 1N HCl, 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.

[0436] ESI-MS (m / z) = 762.4 [M+H] + .

[0437] Step f): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-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

[0438] 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)hydroxylamine (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 and reacted for 30 minutes. Water was added. The mixture was quenched with ethyl acetate (60 mL), 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 give a crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 7) to give tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-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, yield: 96%.

[0439] ESI-MS m / z=861.4[M+H] +

[0440] Step g): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate

[0441] Tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-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) and 10% palladium on carbon (50 mg) was added to replace the hydrogen atmosphere. The reaction was carried out for 30 minutes, and the filtrate was filtered to obtain a crude product, which was directly used in the next step.

[0442] ESI-MS m / z=771.4[M+H] +

[0443] 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-hydroxyheptylamide

[0444] Tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)(methyl)carbamate (200 mg, 0.26 mmol) was dissolved in 4N HCl / EA (5 mL) and reacted for 30 minutes. The crude product was concentrated and used to prepare 7-(4-(5-cyano-4-(4-cyano-3-fluorophenyl)-6-(4-(methylamino)piperidin-1-yl)pyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride with a yield of 24%.

[0445] 1H NMR(400MHz,Methanol-d4)δppm 8.31(s,1H),7.67(t,J=7.2Hz,1H),7.31(d,J=9.6Hz,1H),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=16.8,13 .2,7.4Hz,4H),1.55(dp,J=12.6,7.2Hz,2H),1.36(dp,J=12.2,8.2,7.2Hz,4H).

[0446] ESI-MS m / z=587.3[M+H] +

[0447] Examples 25-26 were synthesized according to the method of Example 24 (Isolation Method 1). Their structures and characterization data are shown in the following table:

[0448] Example 27

[0449] Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0450] Step a): Preparation of 2,6-dichloro-4-methoxypyridine

[0451] 4-(Benzyloxy)-2,6-dichloropyridine (2 g, 11.049 mmol) and MeOH (20 mL) were added to a reaction flask and stirred at room temperature for 16 hours. After the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 2). The organic phases were concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 2,6-dichloro-4-methoxypyridine in a yield of 60.5%.

[0452] 1 H NMR (400MHz, Chloroform-d) δppm 6.79 (s, 2H), 3.87 (s, 3H).

[0453] ESI-MS (m / z) = 178.0 [M+H] + .

[0454] Step b): Preparation of tert-butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0455] 2,6-Dichloro-4-methoxypyridine (1.2 g, 6.63 mmol), tert-butyl piperidin-4-ylcarbamate (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, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2). The organic phases were concentrated to dryness under reduced pressure, and 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%.

[0456] ESI-MS (m / z) = 342.5 [M+H] + .

[0457] Step c): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0458] 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 hour. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3) to obtain tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 73.0%.

[0459] 1 H NMR (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).

[0460] ESI-MS (m / z) = 427.2 [M+H] + .

[0461] Step d): Preparation of (tert-butyl(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0462] 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. NBS (448 mg, 2.516 mmol) was added portionwise with 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 organic phases were combined and washed with saturated brine (40 mL × 2). The organic phases were concentrated to dryness under reduced pressure, and 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 a yield of 72.0%.

[0463] ESI-MS (m / z) = 505.2 [M+H] + .

[0464] 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

[0465] Tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (200 mg, 397 μmol), 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenoxy)heptanoate (279 mg, 596 μmol), Cs2CO3 (259 mg, 794 μmol), Pd(dppf)Cl2 (29 mg, 39.7 μmol), 1.4-Dioxane (10 mL) and H2O (2.5 mL) were added to the reaction flask and stirred at 120°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 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%.

[0466] ESI-MS (m / z) = 767.4 [M+H] + .

[0467] 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

[0468] 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 the reaction flask and stirred at room temperature for 12 hours. 1N hydrochloric acid was slowly added dropwise with stirring in an ice bath 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 to dryness to obtain 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 directly used in the next reaction.

[0469] ESI-MS (m / z) = 753.4 [M+H] + .

[0470] Step g): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0471] 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)hydroxylamine (52 mg, 444 μmol), DIEA (53 mg, 444 μmol) and DMF (2 mL) were added to the reaction bottle, 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, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined and washed sequentially 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 give tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 64.7%.

[0472] ESI-MS (m / z) = 852.4 [M+H] + .

[0473] Step h): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxy-7-((tetrahydro-2H-pyran-2-yl)oxy)amino)heptyl)oxy)phenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0474] Tert-butyl (1-(5-(3-(benzyloxy)-4-((7-oxy-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 the reaction flask, replaced with hydrogen three times, and stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was completed, the reaction was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxyl-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%.

[0475] ESI-MS (m / z) = 762.4 [M+H] + .

[0476] Step i): Preparation of 7-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride

[0477] Tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-((7-oxy-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 a reaction flask, followed by addition of hydrogen chloride ethyl acetate solution (4 M, 2.5 mL). The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of 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-(4-(6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-4-methoxypyridin-3-yl)-2-hydroxyphenoxy)-N-hydroxyheptylamide hydrochloride in a yield of 34.0%.

[0478] 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).

[0479] ESI-MS (m / z) = 578.3 [M+H] + .

[0480] Examples 28-31 were synthesized according to the method of Example 27 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively). Their structures and characterization data are shown in the following table:

[0481] Example 31

[0482] Preparation of 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptylamide hydrochloride

[0483] Step a): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate

[0484] 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), cooled to 0°C, and a 1N dichloromethane solution (5 mL) of boron tribromide was added dropwise. The reaction was kept warm for 1 hour, quenched with water, and adjusted to an alkaline system with sodium bicarbonate. 10 mL of tetrahydrofuran and Boc2O (523.38 mg, 2.4 mmol) were added, and the mixture was stirred for 30 minutes. The mixture was 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 by silica gel column chromatography (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 a yield of 80%.

[0485] ESI-MS m / z=413.2[M+H] + .

[0486] 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

[0487] Dissolve tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate (400 mg, 0.97 mmol) in acetonitrile (4 mL), weigh and add methyl 7-bromoheptanoate (1.3 g, 5.82 mmol) and N,N-diisopropylethylamine (752.2 mg, 5.82 mmol) at room temperature, replace nitrogen, heat to 90°C, react overnight, and monitor the reaction until the reaction is complete. After the liquid was cooled to room temperature, water (5 mL) was added to quench the reaction mixture, and the mixture was 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 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%.

[0488] ESI-MS m / z=555.3[M+H] + .

[0489] Step c): Preparation of 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoic acid

[0490] Lithium hydroxide (129.6 mg, 5.4 mmol) was dissolved in tetrahydrofuran: water = 2:1 (11 mL), and 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 aqueous solution, the nitrogen atmosphere was replaced, and the mixture was stirred at room temperature overnight. After LCMS monitoring, the raw material had reacted completely, water (20 mL) was added, and the pH was adjusted to 3-4 with 1N HCl aqueous solution. The mixture was 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, 7-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)heptanoic acid, which was directly used in the next reaction.

[0491] ESI-MS m / z=541.3[M+H] + .

[0492] 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

[0493] 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 ten minutes. Ethyldiisopropylamine (179.8 mg, 1.41 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (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 one hour. LCMS monitored that the reaction was complete. After the reaction solution cooled to room temperature, water (5 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (5 mL×2). The organic phases were combined and washed with saturated brine (5 mL×4% HCl). 2) washed, 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 reaction.

[0494] ESI-MS m / z = 640.3 [M+H] + .

[0495] Step e): Preparation of 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptylamide hydrochloride

[0496] 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 hydrochloric acid (11.47 mg, 0.31 mmol) was added and stirred at room temperature for one hour. LCMS monitored that the raw material had reacted completely. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure and purified by Prep-HPLC (Isolation Method 1) to give 7-((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)-N-hydroxyheptylamide hydrochloride in a yield of 31%.

[0497] 1H 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).

[0498] ESI-MS m / z=456.2[M+H] + .

[0499] Example 32

[0500] 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-hydroxyheptylamide hydrochloride

[0501] Step a): Preparation of methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate

[0502] 2-(Benzyloxy)-4-bromophenol (2 g, 7.16 mmol), methyl 7-bromophenoxy)heptanoate (2.39 g, 10.74 mmol), and DIEA (3.7 g, 28.64 mmol) were added to a reaction mixture containing acetonitrile (20 mL), and the mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated on silica gel, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate in a 70% yield.

[0503] ESI-MS m / z=421.1[M+H] + .

[0504] Step b): Preparation of methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate

[0505] Methyl 7-(2-(benzyloxy)-4-bromophenoxy)heptanoate (2 g, 4.75 mmol), coupled boronate pinacol ester (2.41 g, 9.5 mmol), Pd(dppf)Cl2 (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). The mixture was stirred at 110°C for 3 hours. Silica gel was added to the reaction solution and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to provide methyl 7-(2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)heptanoate in a yield of 72%.

[0506] ESI-MS m / z=469.3[M+H] + .

[0507] Step c): Preparation of tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[0508] 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]octan-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 hours. Water (20 mL) was added to the reaction solution to quench it, and it was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, and filtered.

[0509] 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 yield of 90%.

[0510] ESI-MS m / z=415.1[M+H] + .

[0511] Step d): Preparation of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[0512] Tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (5.5 g, 13.24 mmol), 4-cyano-3-fluorophenylboronic acid (3.28 g, 19.86 mmol), Pd(dppf)Cl2 (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 hour. Silica gel was added to the reaction solution and concentrated. 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%.

[0513] ESI-MS m / z=456.2[M+H] + .

[0514] 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

[0515] 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 hours. The reaction solution was quenched with 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 provide tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate in a yield of 51%.

[0516] ESI-MS m / z=534.1[M+H] + .

[0517] 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

[0518] 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 the reaction solution containing 1,4-dioxane (6 mL) and water (1.5 mL), and the mixture was stirred under microwave heating at 120 °C for 1 hour. Silica gel was added to the reaction solution and 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 yield of 70%.

[0519] ESI-MS m / z=796.3[M+H] + .

[0520] 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

[0521] 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. To the reaction solution was added 10 ml of an ice-water mixture, the pH was adjusted to 3 with 2 M HCl, and the mixture was 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 yield of 62%.

[0522] ESI-MS m / z=782.3[M+H] + .

[0523] 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

[0524] 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)hydroxylamine (97 mg, 0.26 mmol) and DIEA (66 mg, 0.51 mmol) were added to the reaction solution containing DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and 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, 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%.

[0525] ESI-MS m / z=881.4[M+H] + .

[0526] 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]octyl-3-yl)carbamate

[0527] 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 bottle containing ethyl acetate (5 mL), and the mixture was reacted at 40 ° C under hydrogen protection for 36 hours. The reaction solution was filtered through celite 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-carbonyl)-8-azabicyclo[3.2.1]octyl-3-yl)carbamate in a yield of 75%.

[0528] ESI-MS m / z=791.3[M+H] + .

[0529] 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-hydroxyheptylamide hydrochloride

[0530] A 4.0 M EA solution (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]octyl-3-yl)carbamate (85 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution 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-hydroxyheptylamide hydrochloride in a yield of 16%.

[0531] 1H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),9.16(t,J=8.0Hz,1H),8.63(s,1H),7.88(t,J=7.6Hz,2H),7.65(s,1H),7.5 7(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).

[0532] ESI-MS m / z = 607.2 [M+H] + .

[0533] Example 33

[0534] 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

[0535] Step a): Preparation of tert-butyl (1-(4-bromothiophene-2-carbonyl)piperidin-4-yl)carbamate

[0536] 4-Bromothiophene-2-carboxylic acid (1 g, 4.82 mmol), tert-butyl piperidin-4-ylcarbamate (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 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl (1-(4-bromothiophene-2-carbonyl)piperidin-4-yl)carbamate in a yield of 91%.

[0537] ESI-MS m / z=389.1[M+H] + .

[0538] Step b): Preparation of tert-butyl (1-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate

[0539] 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)Cl2 (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). The mixture was stirred under microwave heating at 120°C for 45 minutes. Silica gel was added to the reaction solution and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl (1-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate in a yield of 99%. ESI-MS m / z = 430.2 [M+H] + .

[0540] Step c): Preparation of tert-butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate

[0541] Tert-butyl (1-(4-(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 solution 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, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate in a yield of 98%.

[0542] ESI-MS m / z=508.1[M+H] + .

[0543] Step d): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)piperidin-4-yl)carbamate

[0544] 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)Cl2 (0.24 g, 0.33 mmol) and cesium carbonate (2.18 g, 6.68 mmol) were added to a microwave tube charged with 1,4-dioxane (14 mL) and water (2 mL), and the mixture was stirred at 120 °C for 1 hour. Silica gel was added to the reaction solution and 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%.

[0545] ESI-MS m / z=642.2[M+H] + .

[0546] Step e): Preparation of 4-(5-(4-aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile

[0547] 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 2M hydrochloric acid solution 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 provide 4-(5-(4-aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile in a yield of 92%.

[0548] ESI-MS m / z=542.2[M+H] + .

[0549] 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

[0550] 4-(5-(4-Aminopiperidine-1-carbonyl)-2-(3-(benzyloxy)-4-methoxyphenyl)thiophen-3-yl)-2-fluorobenzonitrile (680 mg, 1.26 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (0.24 g, 1.26 mmol) were added to a reaction bottle containing DCE (10 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction of the raw materials was complete, sodium cyanoborohydride (0.32 g, 5.04 mmol) was added in an ice bath, and the mixture was stirred at room temperature for another 2 hours. The reaction solution was quenched by adding a mixture of saturated sodium bicarbonate and ice water, 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 filtered. 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%.

[0551] ESI-MS m / z=716.3[M+H] + .

[0552] 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

[0553] 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 bottle containing THF (5 mL), MeOH (3 mL) and water (2 mL), and the mixture was stirred at room temperature for 2 hours. 2M aqueous hydrochloric acid solution was added dropwise to the reaction solution to adjust the pH to 4. The mixture was extracted with MeOH / DCM (1:5) (20 mL×2). 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%.

[0554] ESI-MS m / z=702.2[M+H] + .

[0555] 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

[0556] (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)hydroxylamine (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 bottle containing DMF (10 mL), and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and 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, 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 yield of 44%.

[0557] ESI-MS m / z=801.3[M+H] + .

[0558] 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

[0559] 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. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was 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%.

[0560] ESI-MS m / z=711.3[M+H] + .

[0561] 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

[0562] A 4.0 M EA solution (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). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by Prep-HPLC (Separation Method 1) to obtain (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 in a yield of 7.44%.

[0563] 1H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),9.28(d,J=1.6Hz,1H),9.04(s,1H),7.88(t,J=7.6Hz,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),3.78(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).

[0564] ESI-MS m / z=627.2[M+H] + .

[0565] Example 34

[0566] For the 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-hydroxyheptylamide hydrochloride, the raw materials were prepared according to the synthesis method of Example 20.

[0567] 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

[0568] Tert-butyl (1-(3-amino-5-bromo-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-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), [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). L), nitrogen protection, microwave heating to 110 degrees Celsius, reaction for 35 minutes, diluted with water, extracted with ethyl acetate (15 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. 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 in a yield of 84.9%.

[0569] ESI-MS m / z:633.3[M+H] + .

[0570] Step b): Synthesis of 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile

[0571] 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 4M hydrochloric acid ethyl acetate solution (2 mL) and stirred under nitrogen for 30 minutes. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to dryness to provide 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile in a yield of 95.1%. ESI-MS m / z: 533.2 [M+H] + .

[0572] 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-butyloxycarbonyl)amino)heptanoate

[0573] 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), potassium carbonate (234.9 mg, 1.7 mmol) were dissolved in dry DMSO (2 mL) and stirred at 50 °C for 16 hours under nitrogen protection. After cooling to room temperature, di-tert-butyl dicarbonate (83 mg, 0.38 mmol) was added and the reaction continued for 30 minutes. The 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 afford 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 in a yield of 17.8%. ESI-MS m / z: 775.4 [M+H] + .

[0574] 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-butyloxycarbonyl)amino)heptanoic acid

[0575] 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 reaction was stirred for 30 minutes. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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%.

[0576] ESI-MS m / z:761.4[M+H] + .

[0577] 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)carbamate)amino)heptyl

[0578] 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) and N,N-carbonyldiimidazole (97.3 mg, 0.60 mmol) were dissolved in dry tetrahydrofuran (3 mL) and heated to 40 degrees Celsius for 1 hour under nitrogen protection. Triethylamine (121.4 mg, 1.2 mmol) was then added, followed by 4-(aminooxy)tetrahydropyran (70.3 mg, 0.6 mmol), and the mixture was reacted under nitrogen protection. After the reaction was completed, LCMS detected that the product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane, 1:20) 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)(7-oxo-7-(((tetrahydropyran-2-yl)carbamate)amino)heptyl ester in a yield of 98.8%.

[0579] ESI-MS m / z:860.4[M+H] + .

[0580] 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-hydroxyheptylamide hydrochloride

[0581] Weigh 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)carbamate)amino)heptyl ester (97 mg, 0.11 mmol) and dissolve it in dry dichloromethane (1 mL). Cool it to 0 degrees Celsius in an ice-water bath under nitrogen protection. Add 1 M trichloromethane. Boron bromide (1.5 mL) was stirred and reacted for 30 minutes to precipitate a solid. Water (3 mL) was added to quench the reaction, filtered, and concentrated. The residue was purified by Pre-HPLC (Isolation 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-hydroxyheptylamide hydrochloride in a yield of 22.9%.

[0582] 1H NMR(400MHz,DMSO-d6)δppm 10.39(s,1H),9.71(d,J=16.2Hz,1H),9.10(s,2H),8.23(s,1H),8.08(s,1H),7.88(dd,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,5H),1.9 4(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).

[0583] ESI-MS m / z:586.3[M+H] + .

[0584] Examples 35-36 were prepared according to the synthetic method of Example 34 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively). Their structures and characterization data are as follows:

[0585] Example 37

[0586] 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

[0587] Step a): Preparation of 2-chloro-4-(4-cyano-3-fluorophenyl)nicotinonitrile

[0588] 2-Chloro-4-iodopyridine-3-carbonitrile (6.4 g, 24.20 mmol), (4-cyano-3-fluorophenyl)boric 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, 43.56 mmol) were added to 1,4-Dioxane:H2O=5:1 (80 mL). After nitrogen substitution, the temperature was raised to 100 degrees Celsius for reaction for 1 hour. The solvent was concentrated, silica gel was added and the sample was mixed, and the product 2-chloro-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile was obtained by forward column purification in a yield of 93.02%.

[0589] ESI-MS m / z:258.1[M+H] + .

[0590] Step b): Preparation of tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0591] To NMP (100 mL) were added 2-chloro-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile (2.0 g, 7.76 mmol), tert-butyl N-(piperidin-4-yl)carbamate (1.6 g, 8.15 mmol), and ethylbis(2-propyl)amine (1.2 g, 9.31 mmol). The temperature was raised to 120 degrees Celsius and the reaction was carried out overnight. The disappearance of the starting material was monitored by LCMS. Water and EA were added for extraction. The organic phases were combined, washed with saturated brine, and the solvent was concentrated. Silica gel was added and the sample was stirred. The product tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate was obtained by normal phase column purification in a yield of 85.6%.

[0592] ESI-MS m / z:422.2[M+H] + .

[0593] Step c): tert-Butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0594] To DMF (4 mL) were added tert-butyl N-(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), and the reaction was carried out at room temperature for 1 hour. The starting material disappeared after monitoring by LCMS. Water was added to the system, and the mixture was extracted with EA. The organic phases were combined, concentrated, and silica gel was added to mix the sample. The product tert-butyl N-(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate was obtained by normal phase column purification in a yield of 93.5%.

[0595] ESI-MS m / z:500.1[M+H] + .

[0596] Step d): Preparation of 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile

[0597] To 4N HCl / EA (10 mL) was added 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) and the reaction was carried out at room temperature for 0.5 hour. After LCMS monitoring, the starting material disappeared. The reaction system was poured into saturated aqueous sodium bicarbonate solution and extracted with EA. The organic phase was washed with saturated brine and the solvent was concentrated to give the crude product 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile in a yield of 91.2%.

[0598] ESI-MS m / z:400.1[M+H] + .

[0599] 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

[0600] To DCE:MeOH:AcOH=10:0.1:0.01 (20 mL) were added 2-(4-aminopiperidin-1-yl)-5-bromo-4-(4-cyano-3-fluorophenyl)pyridine-3-carbonitrile (600 mg, 1.50 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (381.55 mg, 1.50 mmol). The mixture was stirred at room temperature for 0.5 hour. After cooling in an ice bath, sodium cyanoborohydride (285.26 mg, 4.5 mmol) was added and the reaction was maintained in an ice bath for 2 hours. LCMS monitoring showed that about 5% of the raw material remained, mainly the product. The reaction was stopped and sodium bicarbonate solution was added to quench the reaction. The mixture was directly used in the next reaction.

[0601] ESI-MS m / z:574.1[M+H] + .

[0602] 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-butyloxycarbonyl)amino)methyl)phenyl)acrylate

[0603] Methyl (E)-3-(4-{[(1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoate (200 mg, 0.35 mmol) was dissolved in THF / H2O=5:1 (5 mL), and di-tert-butyl dicarbonate (78 mg, 0.35 mmol) was added. The reaction was carried out at room temperature for 1 hour. LCMS monitoring showed that the starting material disappeared. EA was added for extraction. The organic phase was washed with saturated brine, the solvent was concentrated, and silica gel was added for sample mixing. The product was purified by normal phase column to obtain 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)prop-2-enoate in a yield of 84.71%.

[0604] ESI-MS m / z:674.2[M+H] + .

[0605] Step g): Preparation of (E)-3-(4-((1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)(tert-butyloxycarbonyl)amino)methyl)phenyl)acrylic acid

[0606] 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)prop-2-enoate (100 mg, 0.15 mmol) and lithium hydroxide (17.96 mg, 0.75 mmol) were added to THF / H2O=5:1 (1 mL) and the reaction was allowed to react at room temperature overnight. LCMS monitoring showed that the starting material disappeared and the main component was the product. The reaction was terminated and the system was adjusted to weak acidity with dilute hydrochloric acid. EA was added for extraction. The organic phase was washed with saturated brine and the solvent was concentrated to obtain a solid product, which was directly used in the next reaction.

[0607] ESI-MS m / z:660.2[M+H] + .

[0608] 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

[0609] To DMF (4 mL) was added (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)prop-2-enoic acid (100 mg, 0.15 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (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 h. LCMS monitoring showed that the starting material disappeared and the main product was obtained. The system was poured into water and extracted with EA. The organic phase was concentrated to remove the solvent, and silica gel was added to mix the sample. The product was purified by normal phase column to obtain 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 in a yield of 71.96%.

[0610] ESI-MS m / z:759.2[M+H] + .

[0611] 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-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate

[0612] To dioxane / H2O=5:1 (5 mL) were added 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), 2-methoxy-5-(tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenol (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). After nitrogen replacement, the mixture was reacted at 110 degrees Celsius in a microwave oven for 1 hour. LCMS monitoring showed that the starting material disappeared and the product was mainly the product. The solvent was directly concentrated, silica gel was added to mix the sample, and the product was purified by forward 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-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate in a yield of 82.39%.

[0613] ESI-MS m / z:719.3[M+H] + .

[0614] 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

[0615] To 4N HCl(EA) (4 mL) was added tert-butyl (E)-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)(4-(3-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate (60 mg, 75 μmol) and the reaction was carried out at room temperature for 0.5 h. The disappearance of the starting material was monitored by LCMS. The solvent was concentrated and the product was subjected to Prep-HPLC (separation method 1) to give 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 in a yield of 71.12%.

[0616] 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,2 H),2.13–2.04(m,2H),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).

[0617] ESI-MS m / z:619.2[M+H] + .

[0618] Examples 39-53 were prepared according to the synthetic method of Example 37 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively). Their structures and characterization data are as follows:

[0619] Example 54

[0620] 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

[0621] Step a): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-bromo-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0622] The product of Example 27, step d), 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 to HCl (EA) (4 mL) and reacted at room temperature for 1 h. The solvent was concentrated to give crude 4-(6-(4-aminopiperidin-1-yl)-3-bromo-4-methoxypyridin-2-yl)-2-fluorobenzonitrile in a yield of 41.81%.

[0623] ESI-MS m / z:405.1[M+H] + .

[0624] 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)prop-2-enoate

[0625] 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 hour. Sodium cyanoborohydride (326.77 mg, 5.2 mmol) was added under ice-cooling. The reaction mixture was slowly returned to room temperature and reacted for 1 hour. The starting material disappeared as monitored by LCMS (EA:PE=1:2). The reaction system was poured into water and extracted with DCM. The organic phases were combined and the solvent was concentrated. Silica gel was added and the sample was stirred. The product was purified by forward column chromatography 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)prop-2-enoate, in a yield of 79.65%.

[0626] ESI-MS m / z:479.1[M+H] + .

[0627] 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)prop-2-enoic acid

[0628] Methyl (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoate (500 mg, 0.86 mmol) and lithium hydroxide (123.58 mg, 5.16 mmol) were added to THF / H2O=4:1 (10 mL) and the reaction was allowed to proceed at room temperature overnight. After monitoring by LCMS, the starting material disappeared. The pH was adjusted to 3 with dilute hydrochloric acid, and the mixture was extracted with EA. The organic phases were combined and the solvent was concentrated to give crude (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoic acid, which was used directly in the next step.

[0629] ESI-MS m / z:565.1[M+H] + .

[0630] 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)prop-2-enoic acid

[0631] To THF / H2O=4:1 (4 mL) were added (E)-3-(4-{(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoic 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). The reaction was allowed to proceed overnight at room temperature. LCMS monitoring revealed the disappearance of the starting material. Dilute hydrochloric acid was added to adjust the pH to 7. The mixture was extracted with EA. The organic phases were combined and the solvent was concentrated. Silica gel was added and the sample was stirred. 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)prop-2-enoic acid was obtained in a yield of 90.72%.

[0632] ESI-MS m / z:664.2[M+H] + .

[0633] Step e): Preparation of tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate

[0634] To DMF (8 mL) 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)prop-2-enoic acid (50 mg, 75 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (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 h. LCMS monitoring showed that the starting material disappeared and the product was mainly obtained. The reaction was terminated and the system was poured into water. EA was added for extraction. The organic phase was washed with saturated brine and the solvent was concentrated. Silica gel was added and the sample was stirred. The product was purified by forward column to obtain tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 73.23%.

[0635] ESI-MS m / z:764.2[M+H] + .

[0636] 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-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate

[0637] To 1,4-Dioxane / H2O=5:1 (4 mL) were added tert-butyl (E)-(1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxy-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-dioxybenzaldehyde-2-yl)phenol (19.51 mg, 78 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4. The mixture was stirred for 1 h at 100°C. The mixture was purged with nitrogen and the reaction mixture was heated to 100°C for 1 h. LCMS showed that the starting material had disappeared and the main peak was the product. The solvent was concentrated, and the sample was added with silica gel for stirring. Purification with a normal flow column gave 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-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate, in a yield of 66.65%.

[0638] ESI-MS m / z:808.4[M+H] + .

[0639] 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

[0640] To HCl(EA) (4M, 5 mL) was added tert-butyl (E)-(1-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxyl-3-((tetrahydro-2H-pyran-2-yl)oxy)amino)propyl-1-en-1-yl)benzyl)carbamate (150 mg, 0.19 mol) and the reaction was carried out at room temperature for 0.5 h. After monitoring by LCMS, the starting material disappeared. The solvent residue was concentrated and the mixture was purified by Prep-HPLC (separation method 3) to give (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%.

[0641] 1H 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).

[0642] ESI-MS m / z:624.3[M+H] + .

[0643] Example 56

[0644] 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 -hydroxyoctanamide hydrochloride

[0645] Step a): Preparation of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0646] 6-Chloro-2-methoxypyrimidin-4-amine (24 g, 150.40 mmol), (4-cyano-3-fluorophenyl)boric acid (29.77 g, 180.48 mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (5.32 g, 7.52 mmol) and sodium carbonate (47.82 g, 451.20 mmol) were added to the 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 solution, and the mixture was stirred at room temperature for 30 minutes. After filtration, the filter cake was placed in a 500 mL eggplant-shaped flask, and isopropanol (250 mL) was added. The mixture was stirred at 50°C for 30 minutes, and the mixture was transferred to room temperature and continued to stir for 1 hour. After filtration, the filter cake was dried to obtain 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 95%.

[0647] ESI-MS m / z=245.1[M+H]+ .

[0648] Step b): Preparation of 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0649] 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 the mixture under ice-cooling, and the mixture was then brought 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 filtered again. The filter cake was washed with MTBE and dried to obtain 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 92%.

[0650] ESI-MS m / z=322.0[M+H] + .

[0651] Step c): Preparation of 4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile

[0652] 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. After filtration, the filter cake was washed with MTBE (50 mL). The filtrate was concentrated, isopropanol (70 mL) was added, and the mixture was stirred at 50°C for 30 minutes. After further stirring for 2 hours, the mixture was filtered and the filter cake was washed with MTBE (70 mL). The filtered cakes were dried to obtain 4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in a yield of 75%.

[0653] ESI-MS m / z=333.0[M+H] + .

[0654] 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

[0655] 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 a reaction solution containing acetonitrile (80 mL). The mixture was stirred at 60°C for 16 hours. Silica gel was added to the reaction solution, and the residue was purified by silica gel chromatography (eluent: DCM / MeOH = 10 / 1) to obtain the crude product, which was then purified on a C18 column to obtain tert-butyl (1-(8-bromo-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate in a yield of 31%.

[0656] ESI-MS m / z=515.1[M+H] + .

[0657] 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

[0658] 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)Cl2 (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). The mixture was stirred under microwave heating at 120°C for 1 hour. Silica gel was added to the reaction solution and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) 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)carbamate in a yield of 84%.

[0659] ESI-MS m / z = 633.3 [M+H] + .

[0660] Step f): Preparation of 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile

[0661] A 4.0 M hydrochloric acid solution in EA (25 mL) 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). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to provide 4-(5-(4-aminopiperidin-1-yl)-8-(3-(benzyloxy)-4-methylphenyl)imidazo[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile in a 93% yield.

[0662] ESI-MS m / z=533.2[M+H] + .

[0663] 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

[0664] 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 bottle 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 in sequence. After stirring for 10 minutes, the temperature was cooled to room temperature and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution to quench the reaction, and 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 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 yield of 60%.

[0665] ESI-MS m / z=703.3[M+H] + .

[0666] 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

[0667] 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. 2M HCl was added to the reaction solution to adjust the pH to 4, and then water (20 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with DCM / MeOH (5:1) (20 mL×2). The organic phases were combined, 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 a yield of 84%.

[0668] ESI-MS m / z=689.3[M+H] + .

[0669] 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) suberamide

[0670] 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)hydroxylamine (130 mg, 1.13 mmol), HATU (430 mg, 1.13 mmol) and DIEA (480 mg, 3.75 mmol) were added to the reaction solution containing DMF (15 mL), and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution to quench the mixture, and 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 the residue was purified by silica gel chromatography (eluent: DCM / MeOH = 8 / 1) to obtain 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, yield 48%.

[0671] ESI-MS m / z=788.4[M+H] + .

[0672] 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 -hydroxyoctanamide hydrochloride

[0673] 4.0 M EA solution (6 mL) was added to a 1 -(1-(8-(3-(benzyloxy)-4-methylphenyl)-7-(4-cyano-3-fluorophenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)-N 8 The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by Prep-HPLC (Separation Method 1) to afford (E)-3-(4-(6-(4-amino-4-methylpiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N-hydroxyacrylamide hydrochloride in a 22% yield.

[0674] 1H NMR(400MHz,DMSO-d6)δppm 10.36(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,1H),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).

[0675] ESI-MS m / z=614.3[M+H] + .

[0676] Example 57

[0677] 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 (Isolation Method 1), and its structure and characterization data are as follows:

[0678] 1 H NMR(400MHz,Methanol-d4)δppm 8.45(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),6.66(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).

[0679] ESI-MS m / z=615.3[M+H] +

[0680] Example 58

[0681] N 1 -(4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N 8 Preparation of -hydroxyoctanamide hydrochloride

[0682] 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

[0683] 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-dioxybenzaldehyde (213 mg, 601 μmol), Cs2CO3 (261 mg, 802 μmol), Pd(dppf)Cl2 (29 mg, 40 μmol), 1.4-Dioxane (4 mL) and H2O (1 mL) were added to a reaction flask and stirred at 120°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 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%.

[0684] ESI-MS (m / z) = 529.3 [M+H] + .

[0685] 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

[0686] 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 and heated to 65°C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature and 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%.

[0687] ESI-MS (m / z) = 619.3 [M+H] + .

[0688] 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

[0689] 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 stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to dryness, and 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%.

[0690] ESI-MS (m / z) = 789.4 [M+H] + .

[0691] 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

[0692] 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 the reaction flask and stirred at room temperature for 12 hours. 1N concentrated hydrochloric acid was slowly added dropwise with stirring in an ice bath 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 to dryness to obtain 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 directly used in the next reaction;

[0693] ESI-MS (m / z) = 775.4 [M+H] + .

[0694] Step e): Preparation of 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

[0695] 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)hydroxylamine (31 mg, 264 μmol), DIEA (34 mg, 264 μmol) and DMF (2 mL) were added to a reaction bottle, 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, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially 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-oxyl-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 60.5%;

[0696] ESI-MS (m / z) = 874.4 [M+H] + .

[0697] Step f): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-(8-oxyl-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0698] Tert-butyl (1-(5-(3-(benzyloxy)-4-(8-oxyl-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, stirred and dissolved, and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere 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-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-(8-oxyl-8-((tetrahydro-2H-pyran-2-yl)oxy)amino)octaamino)phenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 85.0%.

[0699] ESI-MS (m / z) = 784.4 [M+H]+ .

[0700] 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 -hydroxyoctanamide hydrochloride

[0701] Tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-(8-oxyl-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, and then hydrogen chloride ethyl acetate solution (4 M, 2.5 mL) was added. The mixture was stirred at room temperature for 1 hour. A large amount of solid precipitated. The mixture was concentrated under reduced pressure and the resulting crude product was purified by Prep-HPLC (separation method 1) to obtain N 1 -(4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-2-hydroxyphenyl)-N 8 -Hydroxyoctanamide hydrochloride, yield 21.5%.

[0702] 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).

[0703] ESI-MS (m / z) = 500.3 [M+H] + .

[0704] Examples 59-60 were prepared according to the method of Example 58 (compound isolation method: hydrochloride and formate were isolated and prepared according to isolation methods 1 and 3, respectively). Their structures and characterization data are shown in the following table:

[0705] Example 61

[0706] Preparation of 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide hydrochloride

[0707] Step a): Preparation of ethyl 4-(6-(4-{(tert-butoxy)carbonyl]amino}piperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)benzoate

[0708] The product of step c) of Example 37: 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), Cs2CO3 (130.33 mg, 0.40 mmol), Pd(dppf)Cl2 (14.63 mg, 0.02 mmol) was dissolved in water (1 mL) and dioxane (4 mL) under nitrogen protection and reacted in a microwave oven at 120°C for 1 hour. The reaction was monitored for completion and concentrated to obtain a crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to obtain ethyl 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%.

[0709] ESI-MS m / z=556.2[M+H] +

[0710] 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

[0711] Ethyl 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 tetrahydrofuran (2.5 mL) and water (1 mL) and reacted for 16 hours. After monitoring the completion of the reaction, water (20 mL) was added and the pH was adjusted to 3-4 with 1N HCl aqueous solution. 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 obtain a crude product, which was used directly in the next step.

[0712] ESI-MS m / z=542.2[M+H] +

[0713] Step c): Preparation of tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(4-[(oxepan-2-oxy)carbamoyl]phenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0714] 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)hydroxylamine (64 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (5 mL). DIPEA (120 mg, 0.93 mmol) and HATU (210 mg, 0.55 mmol) were added and reacted for 30 minutes. After monitoring the completion of the reaction, water (20 mL) was added to quench the reaction. 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 obtain a crude product, which was used directly in the next step.

[0715] ESI-MS m / z=641.3[M+H] +

[0716] Step d): Preparation of 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide

[0717] Tert-butyl N-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(4-[(oxepan-2-oxy)carbamoyl]phenyl)pyridin-2-yl)piperidin-4-yl)carbamate (110 mg, 0.17 mmol) was dissolved in 4N HCl (6 mL) and reacted for 30 minutes. The reaction was monitored for completion and concentrated to obtain the crude product. 4-(6-(4-aminopiperidin-1-yl)-5-cyano-4-(4-cyano-3-fluorophenyl)pyridin-3-yl)-N-hydroxybenzamide hydrochloride was prepared by method 1 in a yield of 62%.

[0718] 1H NMR(400MHz,Methanol-d4)δppm 8.49(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).ESI-MS m / z=457.2[M+H] +

[0719] Examples 62-64 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). Their structures and characterization data are shown in the following table:

[0720] Example 66

[0721] 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

[0722] Step a): Synthesis of 2,5,6-trichloropyrimidine-4-ol

[0723] Sodium hydroxide (1.19 g, 29.84 mmol) was dissolved in water (15 mL) and slowly added dropwise to 2,4,5,6-tetrachloropyrimidine (5 g, 22.95 mmol) in tetrahydrofuran (40 mL). Under nitrogen, the mixture was stirred for 16 hours. LCMS confirmed the reaction was complete. Dilute hydrochloric acid was added to acidify the mixture, followed by extraction 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 to dryness under reduced pressure. The residue was purified by slurrying with diethyl ether to obtain 2,5,6-trichloropyrimidin-4-ol in a yield of 74.1%.

[0724] ESI-MS m / z:199.0[M+H] + ;

[0725] Step b): Synthesis of 2,5,6-trichloro-3-methylpyrimidin-4(3H)-one

[0726] Dissolve 2,5,6-trichloropyrimidin-4-ol (3.3 g, 16.6 mmol) and potassium carbonate (3.43 g, 79.6 mmol) in DMF (30 mL). Slowly add iodomethane (4.7 g, 33.1 mmol). After addition, react at room temperature for 6 h. Add water (200 mL) and extract with ethyl acetate (50 mL x 3). The organic layer is washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography to obtain 2,5,6-trichloro-3-methylpyrimidin-4(3H)-one in a yield of 82.5%.

[0727] ESI-MS m / z=213.0[M+H] + ;

[0728] Step c): Synthesis of tert-butyl (1-(4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate

[0729] Dissolve 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 mmol) in NMP (20 mL) and heat to 130°C for 2 h. Once the reaction is complete as monitored by LC-MS, cool the reaction mixture to room temperature, add water (50 mL), and extract with ethyl acetate (30 mL x 3). The combined organic layers are washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography to obtain tert-butyl (1-(4,5-dichloro-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate in a yield of 67.4%.

[0730] ESI-MS m / z=213.0[M+H] + ;

[0731] Step d): Synthesis of tert-butyl (1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)carbamate

[0732] Weigh 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)boric acid (570 mg, 3.44 mmol), cesium carbonate (1.73 g, 5.3 mmol), and dppf palladium dichloride (190 mg, 0.27 mmol) and dissolve them in 1,4-dioxane (15 mL). Add water (2 mL), protect with nitrogen, and microwave heat to 120 ° C for 60 minutes. After LCMS detection, the reaction was completed, and water (10 mL) was added to dilute the mixture, and the mixture was 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 to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain 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%.

[0733] ESI-MS m / z:462.2[M+H] + ;

[0734] Step e): Synthesis of 4-(2-(4-aminopiperidin-1-yl)-5-chloro-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile

[0735] To 4N HCl (EA) (10 mL) was added 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) and the reaction was carried out at room temperature for 0.5 hour. After monitoring by LCMS, the starting material disappeared. The reaction system was poured into a saturated aqueous sodium bicarbonate solution and extracted with EA. The organic phase was washed with saturated brine and the solvent was concentrated to give the crude product 4-(2-(4-aminopiperidin-1-yl)-5-chloro-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 91.2%.

[0736] ESI-MS m / z:362.1[M+H] + ;

[0737] Step f): Synthesis of (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

[0738] To DCE:MeOH:CH3COOH=20:1:0.1 (10 mL) were added 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 (E)-methyl 3-(4-formylphenyl)acrylate (536.36 mg, 2.82 mmol), and the mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (59 mg, 2.82 mmol) was added under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the disappearance of the starting material by LCMS monitoring, the reaction system was poured into water and extracted with DCM. The organic phases were combined and the solvent was concentrated. Silica gel was added to mix the sample and the product was purified by normal flow 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)acrylate in a yield of 76.5%.

[0739] ESI-MS m / z:539.2[M+H] + .

[0740] Step g): Synthesis of methyl (E)-3-(4-((tert-butyloxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate

[0741] (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:H2O=3:1 (12 ml), stirred thoroughly, and then (Boc)2O (1.47 g, 6.72 mmol) and sodium bicarbonate (0.94 g, 11.20 mmol) were added. The mixture was stirred at room temperature for one hour and reacted. After the reaction was completed, 0.5N aqueous hydrochloric acid solution (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 to dryness under reduced pressure, and the residue was purified by silica gel chromatography to obtain E)-methyl 3-(4-((tert-butyloxycarbonyl)(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%;

[0742] ESI-MS (m / z) = 636.2 [M+H] + ;

[0743] Step h): Synthesis of methyl (E)-3-(4-((tert-butyloxycarbonyl)(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

[0744] E)-methyl 3-(4-((tert-butyloxycarbonyl)(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), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21.8 mg, 0.031 mmol) were weighed and dissolved in 1, 4-Dioxane (4 mL) and water (0.5 mL) were added under nitrogen protection and heated in a microwave oven at 110°C for 35 minutes. The mixture was diluted with water and extracted with ethyl acetate (15 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. The residue was purified by silica gel chromatography to obtain (E)-methyl 3-(4-((tert-butyloxycarbonyl)(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 in a yield of 80.9%.

[0745] ESI-MS m / z:726.3[M+H] + ;

[0746] Step i): Synthesis of (E)-3-(4-(tert-butyloxycarbonyl)(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

[0747] (E)-methyl 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 (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 reaction was stirred for 30 minutes. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (E)-3-(4-(tert-butyloxycarbonyl)(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%.

[0748] ESI-MS m / z:712.3[M+H] + ;

[0749] 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

[0750] (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)hydroxylamine (39.4 mg, 0.34 mmol), HATU (127.8 mg, 0.34 mmol) and DIEA (108.6 mg, 0.84 mmol) were added to the reaction solution containing DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and filtered. 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%.

[0751] ESI-MS m / z=810.3[M+H]+;

[0752] 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

[0753] 4.0 M EA hydrochloric acid solution (6 mL) was added to a reaction bottle 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 solution was concentrated and purified by Prep-HPLC (separation method 1) 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%;

[0754] ESI-MS m / z=627.3 [M+H]+.

[0755] 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).

[0756] Example 67 was prepared according to the synthetic method of Example 66 (Compound Isolation Method 3). Its structure and characterization data are as follows:

[0757] Example 69

[0758] (E)-3-(4-(((2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyridin-4-yl)oxy)methyl)phenyl)-N-hydroxyacrylamide formate was prepared according to the method of Example 31. Its structure and characterization data are as follows:

[0759] 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).

[0760] ESI-MS m / z=488.2[M+H] + .

[0761] Example 70

[0762] (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 prepared by the method of Example 34. Its structure and characterization data are as follows:

[0763] 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).

[0764] ESI-MS m / z=634.2[M+H] + .

[0765] Example 71

[0766] 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

[0767] Step a): Synthesis of 4-(2,5-dichloropyrimidin-4-yl)-2-fluorobenzonitrile

[0768] Weigh 2,4,5-trichloropyrimidine (4.0 g, 21.8 mmol), (4-cyano-3-fluorophenyl)boric 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) and dissolve them in 1,4-dioxane (60 mL). Add water (15 mL) and heat the mixture in four parallel pots under nitrogen protection to 110 degrees Celsius using a microwave for 45 minutes. After cooling to room temperature, the mixture was 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 to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give 4-(2,5-dichloropyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 53.5%.

[0769] ESI-MS m / z:268.0[M+H] + .

[0770] Step b): Synthesis of tert-butyl (1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)carbamate

[0771] 4-(2,5-Dichloropyrimidin-4-yl)-2-fluorobenzonitrile (3.5 g, 13.1 mmol) and tert-butyl piperidin-4-ylcarbamate (2.62 g, 13.1 mmol) were weighed and dissolved in DMF (50 mL). DIPEA (5.1 g, 39.6 mmol) was then added under nitrogen protection and refluxed at 120°C for 2 hours. After cooling to room temperature, water (50 mL) was added to dilute the mixture and 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 to dryness under reduced pressure. The residue was purified by silica gel column chromatography (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 in a yield of 96.2%.

[0772] 1 H NMR(400MHz,DMSO-d6)δppm 8.55(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),6.86(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).

[0773] ESI-MS m / z:432.2[M+H] + .

[0774] Step c): Synthesis of 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile

[0775] 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 in ethyl acetate (5 mL). The mixture was stirred at room temperature under nitrogen for 30 minutes. LCMS confirmed the reaction was complete. The mixture was concentrated under reduced pressure to give 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile in a yield of 95%.

[0776] ESI-MS m / z:332.1[M+H]+ .

[0777] 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

[0778] 4-(2-(4-aminopiperidin-1-yl)-5-chloropyrimidin-4-yl)-2-fluorobenzonitrile (1.7 g, 3.94 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (1.1 g, 5.91 mmol) were weighed and dissolved in 1,2-dichloroethane (20 mL). Acetic acid (2.4 g, 39.4 mmol) and methanol (6.3 g, 197 mmol) were added, and the mixture was stirred under nitrogen for 3 hours. Sodium cyanoborohydride (1.2 g, 19.7 mmol) was added, and the reaction was continued with stirring for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=10:1) to give (E)-methyl 3-(4-(((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate in a yield of 11.0%.

[0779] ESI-MS m / z:506.2[M+H] + .

[0780] Step e): Synthesis of (E)-methyl 3-(4-(((tert-butoxycarbonyl)(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate

[0781] (E)-methyl 3-(4-(((1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)amino)methyl)phenyl)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). The reaction was continued by stirring at room temperature. After the reaction was completed by LCMS, the product was concentrated to dryness under reduced pressure. 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%.

[0782] 1H NMR(400MHz,DMSO-d6)δppm 8.53(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,1 H), 3.72 (s, 3H), 2.90 (s, 2H), 1.63 (d, J = 8.4Hz, 4H), 1.41–1.28 (m, 9H).

[0783] ESI-MS m / z:592.2[M+H] + .

[0784] 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

[0785] Weigh tert-butyl (E)-(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-2-yl)piperidin-4-yl)(4-(3-methoxyprop-1-en-1-yl)benzyl)carbamate (250 mg, 0.41 mmol) and lithium hydroxide monohydrate (168.2 mg, 4.1 mmol) in tetrahydrofuran (3 mL). Add water (3 mL) and react at room temperature under nitrogen for 16 hours. To the reaction mixture, dilute hydrochloric acid (0.5 mL) was added for acidification, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, 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%.

[0786] ESI-MS m / z:592.2[M+H] + .

[0787] 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-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate

[0788] (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)hydroxylamine (206 mg, 1.76 mmol) were dissolved in DMF (5 mL) and stirred under nitrogen for 20 minutes. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (251 mg, 0.66 mmol) and DIPEA (284.3 mg, 2.2 mmol) were added and stirred under nitrogen for 16 hours. After the reaction was completed by LCMS, water (10 mL) was added for dilution and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL×3). 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. 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-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate in a yield of 77.9%.

[0789] ESI-MS m / z:691.3[M+H] + .

[0790] 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

[0791] Weigh tert-butyl (E)-(1-(5-chloro-4-(4-cyano-3-fluorophenyl)pyrimidin-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, 0.22 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Phenol (137.6 mg, 0.55 mmol), cesium carbonate (215 mg, 0.66 mmol), palladium acetate (9.8 mg, 0.04 mmol), and di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) dichloride (31.2 mg, 0.04 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL). The mixture was dissolved and heated in a microwave oven at 120°C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 12:1) afforded 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. Yield 42.8%.

[0792] ESI-MS m / z:779.3[M+H] + .

[0793] 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

[0794] 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) was added and dissolved in 4 M hydrochloric acid and ethyl acetate solution (2 mL). Under nitrogen protection, the mixture was stirred for 30 minutes, and concentrated to dryness at low temperature. The residue was purified by Pre-HPLC (separation method 3) to give (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 in a yield of 17.0%.

[0795] 1H NMR(400MHz,Methanol-d4)δppm 8.52(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).

[0796] ESI-MS m / z:595.2[M+H] + .

[0797] Example 72

[0798] 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 formate

[0799] Step a): Preparation of tert-butyl (S)-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)carbamate

[0800] 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. HATU (684 mg, 1.8 mol) was added with stirring at room temperature and the reaction was maintained at room temperature for 1 hour. After completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed sequentially with saturated sodium bicarbonate (20 mL x 1) and saturated brine (10 mL x 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%.

[0801] ESI-MS (m / z) = 495.0 [M+H] + .

[0802] Step b): Preparation of (S)-(3-aminopyrrolidin-1-yl)(3-bromo-4-iodophenyl)methanone

[0803] Tert-butyl (S)-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)carbamate (448 mg, 908 μmol) was added to a reaction flask, followed by addition of a 4M hydrogen chloride ethyl acetate solution (2.5 mL). The mixture was stirred at room temperature for 1 hour, during which 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%.

[0804] ESI-MS (m / z) = 395.0 [M+H] + .

[0805] Step c): Preparation of methyl (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate

[0806] (S)-(3-Aminopyrrolidin-1-yl)(3-bromo-4-iodophenyl)methanone hydrochloride (343 mg, 867 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (165 mg, 867 mmol) were added to a reaction flask containing DCE (10 mL). The mixture was stirred at room temperature for 2 hours. After the reaction of the raw materials was complete, sodium cyanoborohydride (0.32 g, 5.04 mmol) was added in an ice bath, and the mixture was stirred at room temperature for another 2 hours. The reaction solution was quenched by adding a mixture of saturated sodium bicarbonate and ice water, 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 filtered. 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%.

[0807] ESI-MS m / z=568.3[M+H] + .

[0808] Step d): Preparation of methyl (S, E)-3-(4-(((1-(3-bromo-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)aminomethyl)phenyl)acrylate

[0809] 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. The mixture was allowed to react 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 provide methyl (S,E)-3-(4-((1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate in an 88% yield.

[0810] ESI-MS m / z=669.1[M+H] + .

[0811] Step e): Preparation of (S,E)-3-(4-(1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid

[0812] Methyl (S,E)-3-(4-((1-(3-bromo-4-iodobenzoyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)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 stirred at room temperature for 12 hours. 1N concentrated hydrochloric acid was slowly added dropwise with stirring on ice 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 phases were concentrated under reduced pressure to dryness to obtain (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 reaction.

[0813] ESI-MS (m / z) = 655.2 [M+H] + .

[0814] 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

[0815] (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)hydroxylamine (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 completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined and washed sequentially 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 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%.

[0816] ESI-MS (m / z) = 754.2 [M+H] + .

[0817] 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

[0818] 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-dioxybenzaldehyde-2-yl)phenol (100 mg, 398 μmol), Cs2CO3 (217 mg, 664 μmol), Pd(dppf)Cl2 (23 mg, 33 μmol), 1.4-Dioxane (4 mL) and H2O (1 mL) were added to the reaction bottle and stirred at 80°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 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%.

[0819] ESI-MS (m / z) = 666.2 [M+H] + .

[0820] 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

[0821] 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), Cs2CO3 (148 mg, 454 μmol), Pd(dppf)Cl2 (16 mg,, 23 μmol), 1.4-Dioxane (4 mL) and H2O (1 mL) were added to the reaction bottle and stirred at 90°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 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 in a yield of 78.5%.

[0822] ESI-MS (m / z) = 791.1 [M+H] + .

[0823] 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

[0824] 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, and then hydrogen chloride ethyl acetate solution (4M) was added. , 2.5 mL), stirred at room temperature for 1 hour, a large amount of solid precipitated, concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (separation method 1) 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%.

[0825] 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).

[0826] ESI-MS (m / z) = 607.2 [M+H] + .

[0827] Example 73

[0828] (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 prepared according to the method of Example 72. Its structure and characterization data are as follows:

[0829] 1H 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).

[0830] ESI-MS m / z = 607.3 [M+H] + .

[0831] Example 74

[0832] 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

[0833] Step a): Preparation of (S)-1-(3-bromo-4-iodophenyl)pyrrolidin-3-amine

[0834] Tert-butyl (S)-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)carbamate (500 mg, 1.0 mmol) was added to a reaction flask, followed by addition of a 4M hydrogen chloride ethyl acetate solution (2.5 mL). The mixture was stirred at room temperature for 1 hour, during which a large amount of solid precipitated. The mixture was concentrated under reduced pressure to give (S)-1-(3-bromo-4-iodophenyl)pyrrolidin-3-amine hydrochloride in a yield of 95.5%.

[0835] ESI-MS (m / z) = 380.9 [M+H] + .

[0836] Step b): Preparation of methyl (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate

[0837] (S)-1-(3-Bromo-4-iodophenyl)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). The mixture was stirred at room temperature for 2 hours. After the reaction of the raw materials was complete, sodium cyanoborohydride (0.32 g, 4.8 mmol) was added in an ice bath, and the mixture was stirred at room temperature for another 2 hours. The reaction solution was quenched by adding a mixture of saturated sodium bicarbonate and ice water, 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 filtered. 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-iodophenyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate in a yield of 68%.

[0838] ESI-MS m / z=555.0[M+H] + .

[0839] Step c): Preparation of methyl (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butyloxycarbonyl)amino)methyl)phenyl)acrylate

[0840] Methyl (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)amino)methyl)phenyl)acrylate (360 mg, 649 umol) and triethylamine (1 mL) were dissolved in DCM (5 mL), and di-tert-butyl dicarbonate (150 mg, 936 umol) was added. The mixture was allowed to react 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 provide methyl (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylate in a yield of 91%.

[0841] ESI-MS m / z=655.1[M+H] + .

[0842] Step d): Preparation of (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid

[0843] Methyl (S, E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)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 the reaction flask and stirred at room temperature for 12 hours. 1N concentrated hydrochloric acid was slowly added dropwise while stirring on ice to adjust the pH to 3. ～ 4. Add water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), and concentrate the organic phase under reduced pressure to dryness to obtain (S, E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid, which is directly used in the next reaction.

[0844] ESI-MS (m / z) = 641.1 [M+H] + .

[0845] Step e): Preparation of tert-butyl ((S)-1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(4-(E)-3-oxo-3-(tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate

[0846] (S,E)-3-(4-(1-(3-bromo-4-iodophenyl)pyrrolidin-3-yl)(tert-butoxycarbonyl)amino)methyl)phenyl)acrylic acid (379 mg, 591 μmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (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, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed sequentially 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 give tert-butyl ((S)-1-(3-bromo-4-iodophenyl)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%.

[0847] ESI-MS (m / z) = 740.1 [M+H] + .

[0848] 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

[0849] Tert-butyl((S)-1-(3-bromo-4-iodophenyl)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), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenol (112 mg, 446 μmol), Cs2CO3 (243 mg, 744 μmol), Pd(dppf)Cl2 (27 mg, 37 μmol), 1.4-Dioxane (4 mL) and H2O (1 mL) were added to the reaction bottle and stirred at 80°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 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%.

[0850] ESI-MS (m / z) = 736.3 [M+H] + .

[0851] 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

[0852] 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), Cs2CO3 (171 mg, 524 μmol), Pd(dppf)Cl2 (17 mg, 26 μmol), 1.4-Dioxane (4 mL) and H2O (1 mL) were added to the reaction bottle and stirred at 90°C for 1 hour. The product was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 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%.

[0853] ESI-MS (m / z) = 777.1 [M+H] + .

[0854] 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

[0855] 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, and then hydrogen chloride ethyl acetate solution (4 M, 2.5 mL), stirred at room temperature for 1 hour, a large amount of solid precipitated, and concentrated under reduced pressure. 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 in a yield of 15.5%.

[0856] 1H 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).

[0857] ESI-MS (m / z) = 593.3 [M+H] + .

[0858] Example 75

[0859] (S,E)-3-(4-(((1-((4″-cyano-3″-fluoro-4-hydroxy-3-methoxy-[1,1:2,1″-terphenyl]-4′-yl)methyl)pyrrolidin-3-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was prepared by the method of Example 74. The structure and characterization data are as follows:

[0860] 1 H NMR(400MHz, Methanol-d4)δ8.40(s,1H),7.74–7.57(m,4H),7.51(d,J=6.8H z,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).

[0861] ESI-MS m / z=593.3[M+H] + .

[0862] Example 76

[0863] 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

[0864] Step a): Preparation of 4-(2-chloro-3-fluoropyridin-4-yl)-2-fluorobenzonitrile

[0865] 2-Chloro-3-fluoro-4-iodopyridine (2 g, 7.78 mmol), (4-cyano-3-fluorophenyl)boric 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) under nitrogen protection and microwave-treated at 65°C for 30 minutes. The product was concentrated to give a crude product, and 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 a yield of 78%.

[0866] ESI-MS m / z=251.0[M+H] +

[0867] Step b): Preparation of tert-butyl N-(1-(4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate

[0868] 4-(2-chloro-3-fluoropyridin-4-yl)-2-fluorobenzonitrile (1.0 g, 3.99 mmol) tert-butyl N-(piperidin-4-yl)carbamate (1.1 g, 5.99 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (186.19 mg, 0.40 mmol), tris(dibenzylidene-BASE acetone)dipalladium (182.69 mg, 0.20 mmol), CS2CO3 (3.9 g, 11.97 mmol) were dissolved in toluene ( The product was added into the reaction mixture of 4-nitrogen-1, 1,2-dimethyl-1-thiazolyl-1-ol (15 mL), protected by nitrogen, and microwaved at 110 ° C for 4 hours. The product was quenched with water (200 mL), extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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%.

[0869] ESI-MS m / z=415.2[M+H] +

[0870] Step c): Preparation of tert-butyl N-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)carbamate

[0871] 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. After the reaction was detected to be complete, water (20 mL) was added to quench the reaction and 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 obtain a 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 a yield of 87%.

[0872] ESI-MS m / z=493.1[M+H] +

[0873] Step d): Preparation of 4-(2-(4-aminopiperidin-1-yl)-5-bromo-3-fluoropyridin-4-yl)-2-fluorobenzonitrile

[0874] 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 4N HCl in ethyl acetate (20 mL) and reacted for 30 minutes. The crude product was concentrated and used directly in the next step.

[0875] ESI-MS m / z=393.0[M+H] +

[0876] Step e): Preparation of methyl (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butyloxycarbonyl)amino)methyl)phenyl)acrylate

[0877] 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) and reacted for 30 minutes. Sodium cyanoborohydride (96.15 mg, 1.53 mmol) was added under ice bath and reacted overnight. Water (5 mL) was added to quench the reaction and the crude product was obtained by concentration. Tert-butyloxycarbonyl anhydride (320.83 mg, 1.47 mmol) and Na2CO3 (155.82 mg) were added. , 1.47mmol) was dissolved in THF (3mL) and H2O (2mL) and reacted for 30 minutes until the reaction was complete. Water (20mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (20mL×2). The organic phases were combined, washed with saturated brine (15mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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, yield: 91%.

[0878] ESI-MS m / z=666.2[M+H] +

[0879] Step f): Preparation of (E)-3-(4-(1-(5-bromo-4-(4-cyano-3-fluorophenyl)-3-fluoropyridin-2-yl)piperidin-4-yl)(tert-butyloxycarbonyl)amino)methyl)phenyl)acrylic acid

[0880] 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). The mixture was reacted for 36 hours, and water (10 mL) was added. The pH was adjusted to 3-4 with 1N HCl aqueous solution, and 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 obtain a crude product, which was used directly in the next step.

[0881] ESI-MS m / z=653.2[M+H] +

[0882] 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

[0883] (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) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (151.12 mg, 1.29 mmol) were dissolved in DMF (30 mL), HATU (490.51 mg, 1.29 mmol) and DIPEA (277.35 mg, 2.15 mmol) were added, and the mixture was reacted for 30 minutes. Water (2 mL) was added to the mixture. The mixture was quenched with 1% paraformaldehyde (50 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 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, yield: 92%.

[0884] ESI-MS m / z=752.2[M+H] +

[0885] 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

[0886] 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), Cs2CO3 (390.98 mg, 1.20 mmol), Pd(dppf)Cl2 (58.54 mg, 0. The product was dissolved in dioxane (3 mL) and water (1 mL) under nitrogen protection and microwave-assisted reaction at 90° C. for 30 minutes. The product was concentrated to give a crude product. 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, yield: 80%.

[0887] ESI-MS m / z=796.3[M+H] +

[0888] 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

[0889] 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 (0.7 g, 0.88 mmol) was dissolved in 4N HCl in ethyl acetate (15 mL) and reacted for 30 minutes. The mixture was concentrated under reduced pressure at low temperature, and the residue was prepared by Prep-HPLC (separation method 3) to give (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 in a yield of 5%.

[0890] 1H NMR(400MHz,Methanol-d4)δppm 8.52(s,1H),8.08(s,1H),7.72(t,J=7.4Hz,1H),7.65(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).

[0891] ESI-MS m / z = 612.2 [M+H] +

[0892] Example 77

[0893] (E)-3-(4-(((1-(4-(4-cyano-3-fluorophenyl)-3-fluoro-5-(4-hydroxy-3-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide formate was prepared according to the method of Example 76. Its structure and characterization data are as follows:

[0894] 1 H NMR(400MHz,Methanol-d4)δppm 8.52(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,1H),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).

[0895] ESI-MS m / z = 612.2 [M+H] +

[0896] Example 80

[0897] 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-hydroxyprop-2-enamide formate

[0898] Step a) Synthesis of 4-(5-bromo-2-chloropyridin-4-yl)-2-fluorobenzonitrile

[0899] To dioxane:water = 5:1 (20 mL) were added 5-bromo-2-chloro-4-iodopyridine (3.0 g, 9.42 mmol), (4-cyano-3-fluorophenyl)boric acid (1.5 g, 9.42 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (689.26 mg, 0.94 mmol), and cesium carbonate (6138.45 mg, 18.84 mmol). The reaction was carried out in a microwave oven at 110°C under nitrogen protection for 1 hour. The disappearance of the starting material was monitored by LCMS. The solvent was directly concentrated, and the sample was added with silica gel and mixed. The product 4-(5-bromo-2-chloropyridin-4-yl)-2-fluorobenzonitrile was obtained by normal column purification in a yield of 82.46%.

[0900] ESI-MS (m / z) = 311.1 [M+H] + .

[0901] Step b) Synthesis of 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-2-chloropyridin-4-yl)-2-fluorobenzonitrile

[0902] To dioxane:water = 5:1 (30 mL) were added 4-(5-bromo-2-chloropyridin-4-yl)-2-fluorobenzonitrile (1.5 g, 4.81 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). The reaction was carried out at 80°C under nitrogen for 1 hour. The disappearance of the starting material was monitored by LCMS. The solvent was directly concentrated, and the sample was added with silica gel and mixed. The product 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-2-chloropyridin-4-yl)-2-fluorobenzonitrile was obtained by normal column purification in a yield of 88.32%.

[0903] ESI-MS (m / z) = 445.1 [M+H] + .

[0904] Step c) Synthesis of tert-butyl 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate

[0905] To toluene (50 mL) were added 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). LCMS monitoring showed that the starting material disappeared. The solvent was concentrated and silica gel was added to mix the sample. The product was purified by normal phase column to obtain tert-butyl 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate in a yield of 51.98%.

[0906] ESI-MS (m / z) = 609.2 [M+H] + .

[0907] Step d) Synthesis of 4-(2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)pyridin-4-yl)-2-fluorobenzonitrile

[0908] To 4N hydrochloric acid (EA) (4 mL) was added tert-butyl 4-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate (780 mg, 1.44 mmol). The mixture was allowed to react at room temperature for 0.5 h. LCMS monitoring revealed the disappearance of the starting material, with the product being the main component. The solvent was concentrated, and the mixture was adjusted to weak acidity with saturated sodium bicarbonate solution. The mixture was extracted with EA, and the organic phases were combined and the solvent was concentrated to obtain a crude solid. This was used directly in the next reaction.

[0909] ESI-MS (m / z) = 509.3 [M+H] + .

[0910] 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)prop-2-enoate

[0911] To dichloroethane (10 mL) were added 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)prop-2-enoate (0.16 g, 0.82 mmol), and sodium cyanoborohydride (0.085 g, 1.36 mmol). The mixture was reacted at room temperature overnight. After monitoring by LCMS, the starting material disappeared. The solvent was concentrated, and silica gel was added and the sample was stirred. The product was purified by normal phase column to obtain methyl (E)-3-(4-{[(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoate in a yield of 75.38%.

[0912] ESI-MS (m / z) = 683.2 [M+H] + .

[0913] Step f) Synthesis of (E)-3-(4-(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-amino)methyl)phenyl)acrylic acid

[0914] Methyl (E)-3-(4-{[(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)prop-2-enoate (254 mg, 0.37 mmol) and lithium hydroxide (44.31 mg, 1.85 mmol) were added to tetrahydrofuran:water (4:1) (5 mL). The reaction was allowed to proceed overnight at room temperature. LCMS monitoring revealed the disappearance of the starting material, and the system was used directly in the next reaction.

[0915] ESI-MS (m / z) = 669.2 [M+H] + .

[0916] 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-butoxy)carbonyl]amino]methyl}phenyl)prop-2-enoic acid

[0917] To the reaction system of step f, di-tert-butyl dicarbonate (170.5 mg, 0.78 mmol) and sodium bicarbonate were added, and the mixture was stirred at room temperature overnight. The starting material disappeared after monitoring by LCMS. The pH was adjusted to weak acidity with dilute hydrochloric acid, and water was added. The mixture was extracted with EA. The organic phases were combined, the solvent was concentrated, silica gel was added, and the product was purified by normal phase column chromatography to obtain (E)-3-(4-{[(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)[(tert-butoxy)carbonyl]amino]methyl}phenyl)prop-2-enoic acid in a yield of 80.64%.

[0918] ESI-MS (m / z) = 769.3 [M+H] + .

[0919] 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

[0920] To DMF (8 mL) was added (E)-3-(4-{[(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)[(tert-butoxy)carbonyl]amino]methyl}phenyl)prop-2-enoic acid (215 mg, 0.28 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (40 mg, 0.33 mmol), 2-(7-azobenzotriazole)-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 h. LCMS monitoring showed that the starting material disappeared and the main product was obtained. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine and the solvent was concentrated. Silica gel was added and the sample was stirred. The product was purified by forward column chromatography 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%.

[0921] ESI-MS (m / z) = 868.4 [M+H] + .

[0922] Step i) Synthesis of the formate salt 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-hydroxyprop-2-enamide

[0923] To DCM (8 mL) was added 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), and boron tribromide (0.28 g, 1.12 mmole) was added at -78°C. The reaction was continued in a dry ice bath for 0.5 hour. After monitoring the disappearance of the starting material by LCMS, methanol was added to quench the reaction. The solvent was concentrated and the residue was purified by Prep-HPLC (separation method 3) to give (E)-3-(4-{[(1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino]methyl}phenyl)-N-hydroxyprop-2-enamide formate in a yield of 66.18%.

[0924] 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).

[0925] ESI-MS (m / z) = 594.2 [M+H] + .

[0926] Example 81

[0927] 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

[0928] 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

[0929] 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), Cs2CO3 (1.1 g, 3.36 mmol), and Pd(dppf)Cl2 (82.0 mg, 0.11 mmol) were dissolved in dioxane (8 ml) L), and water (1 mL), and nitrogen was replaced three times. The reaction was heated to 100°C. After 2 h of reaction, LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, water (9 mL) was added, and extracted with ethyl acetate (8 mL×3). The combined organic layers were washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in a yield of 80.6%.

[0930] ESI-MS m / z=634.3 [M+H]+.

[0931] Step b): Preparation of 2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)nicotinonitrile

[0932] 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 4M 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 solution was concentrated to provide 2-(4-aminopiperidin-1-yl)-5-(3-(benzyloxy)-4-methoxyphenyl)-4-(4-cyano-3-fluorophenyl)nicotinonitrile in a yield of 92%.

[0933] ESI-MS m / z=534.2[M+H] + .

[0934] 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

[0935] 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 (E)-methyl 3-(3-bromophenyl)acrylate (77.2 mg, 0.32 mmol), cesium carbonate (208.6 mg, 0.64 mmol), tris(dibenzylidene-BASE acetone)dipalladium (58.6 mg, 0.06 mmol), 2-dicyclohexylphosphine were added. -2',6'-diisopropoxy-1,1'-biphenyl (30.5 mg, 0.06 mmol), nitrogen protection, reflux, heated to 100 ° C overnight, after the reaction was completed by LCMS, concentrated to dryness under reduced pressure, 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 in a yield of 73.3%.

[0936] ESI-MS m / z=694.3[M+H] + .

[0937] 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

[0938] 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 / H2O = 5:1 (3 mL), lithium hydroxide (48 mg, 2 mmol) was added and reacted at room temperature overnight. The pH of the system was adjusted to 2-3 with 2N HCl, and the mixture was extracted with ethyl acetate. The organic phase was washed once with brine, dried and concentrated, and the residue was used directly in the next step.

[0939] ESI-MS m / z=680.3[M+H] + .

[0940] 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

[0941] (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 (80 mg, 0.12 mmol) was dissolved in DMF (2 mL), HATU (54.75 mg, 0.14 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (16.9 mg, 0.1 The reaction mixture was stirred at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, and the organic phase was washed twice with water, dried, and concentrated in vacuo. The residue was purified by silica gel column to obtain (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 a yield of 85%.

[0942] ESI-MS m / z=779.3[M+H] + .

[0943] 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

[0944] (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 reacted at room temperature for 1 h. Solids formed in the reaction solution, and LC-MS analysis showed that the reaction was complete. The reaction solution was filtered to obtain a solid, which was then purified by Prep-HPLC (Isolation 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%.

[0945] 1H 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).

[0946] ESI-MS m / z=605.2[M+H] + .

[0947] Example 82

[0948] (E)-3-(4-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino)phenyl)-N-hydroxyacrylamide formate was prepared according to the method of Example 81. Its structure and characterization data are as follows:

[0949] 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).

[0950] ESI-MS m / z=605.2[M+H] + .

[0951] Example 83

[0952] 2-((1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)amino-N-hydroxypyrimidine-5-amide formate was prepared according to the method of Example 81. Its structure and characterization data are as follows:

[0953] 1 H NMR(400MHz,Methanol-d4)δppm 8.64(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).

[0954] ESI-MS m / z = 581.2 [M+H].

[0955] Example 84

[0956] Preparation of (E)-3-(4-[1-(2-cyano-3-(4-cyano-3-fluorophenyl)-4-(3-hydroxy-4-methoxyphenyl)phenyl)piperidin-4-yl)amino]methyl}phenyl)-N-propanol-2-enamide

[0957] Step a): Preparation of tert-butyl 1-(2-cyano-3-iodophenyl)piperidin-4-ylcarbamate

[0958] 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 mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl 1-(2-cyano-3-iodophenyl)piperidin-4-ylcarbamate in a yield of 37%.

[0959] ESI-MS m / z=428.1[M+H]+.

[0960] Step b): Preparation of tert-butyl 1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate

[0961] 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). The mixture was stirred at 80°C for 45 minutes. Silica gel was added to the reaction solution and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl 1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate in a yield of 66%.

[0962] ESI-MS m / z=421.2 [M+H]+.

[0963] Step c): Preparation of tert-butyl 1-(6-bromo-2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate

[0964] tert-Butyl 1-(2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate (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 x 2). The combined organic phases were washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to provide tert-butyl 1-(6-bromo-2,4'-dicyano-3'-fluoro-[1,1'-biphenyl]-3-yl)piperidin-4-ylcarbamate in a yield of 67%.

[0965] ESI-MS m / z=499.1[M+H]+.

[0966] Step d): Preparation of tert-butyl (1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-triphenyl]-4-yl)piperidin-4-yl)carbamate

[0967] 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), Pd2(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 under microwave at 110 °C for 45 minutes. Silica gel was added to the reaction solution and concentrated. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to give tert-butyl (1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-triphenyl]-4-yl)piperidin-4-yl)carbamate in a yield of 98%.

[0968] ESI-MS m / z=443.2 [M+H]+.

[0969] Step e): Preparation of 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(3-hydroxy-4-methoxyphenyl)benzonitrile

[0970] Tert-butyl (1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-[1,1:2,1:-triphenyl]-4-yl)piperidin-4-yl)carbamate (620 mg, 1.18 mmol) was added to a reaction flask containing 4M hydrochloric acid in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to 7, and the mixture was extracted with DCM:MeOH = 10:1 (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 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-hydroxy-4-methoxyphenyl)benzonitrile in a yield of 16%.

[0971] ESI-MS m / z=443.2 [M+H]+.

[0972] Step f): Preparation of methyl-(E)-3-(4-(((1-(3',4"-dicyano-3"-fluoro-3-hydroxy-4-methoxy-[1,1'2',1'-triphenyl]-4'-yl)piperidin-4-ylamino]methyl)phenyl)acrylate

[0973] 6-(4-Aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-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 bottle 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 solution was quenched by adding saturated aqueous sodium bicarbonate solution (5 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. 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'-triphenyl]-4'-yl)piperidin-4-ylamino]methyl)phenyl)acrylate in a yield of 63%.

[0974] ESI-MS m / z=617.2 [M+H]+.

[0975] Step g): Preparation of (E)-3-(4-tert-butoxycarbonylmethyl(1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-111'2',1"-terphenyl]-4"-yl)piperidin-4-yl)amino)methyl)phenyl)acrylate

[0976] 4-(1-Dicyano-3'-dicyano-3"-fluoro-3-hydroxy-4-methoxy-1,1'2',1'-triphenyl]-4'-yl)piperidin-4-ylaminomethyl)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 1 hour. The reaction solution was concentrated to obtain (E)-3-(4-tert-butoxycarbonylmethyl)(1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-1,1'2',1'-triphenyl]-4"-yl)piperidin-4-ylaminomethyl)phenyl)acrylate in a yield of 93%.

[0977] ESI-MS m / z=717.3 [M+H]+.

[0978] Step h): Preparation of (E)-3-(4-(tert-butyloxycarbonyl)(1-(3',4"-dicyano-3"-fluoro-3-hydroxy-4-methoxy-[1,1:2',1"-triphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid

[0979] 4-tert-Butyloxycarbonylmethyl (1-(3,4"-dicyano-3-fluoro-3-hydroxy-4-methoxy-111'2',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 bottle containing THF (3 mL), MeOH (1.8 mL) and water (1.2 mL), and the mixture was stirred at room temperature for 1 hour. 2M HCl aqueous solution was added dropwise to the reaction mixture to adjust the pH to 4, and the mixture was extracted with dichloromethane (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 (E)-3-(4-(tert-butyloxycarbonyl)(1-(3',4"-dicyano-3"-fluoro-3-hydroxy-4-methoxy-[1,1:2',1"-triphenyl]-4'-yl)piperidin-4-yl)amino)methyl)phenyl)acrylic acid in a yield of 91%.

[0980] ESI-MS m / z=703.2[M+H]+.

[0981] 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

[0982] 3-(tert-Butyloxycarbonyl)(1-(3,4-dicyano-3-fluoro-3-hydroxy-4-methoxy-1,1-diphenyl]-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)hydroxylamine (0.047 g, 0.40 mmol) were added to a reaction bottle containing DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution to quench the reaction, and 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, and filtered. 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%.

[0983] ESI-MS m / z=802.3[M+H]+.

[0984] Step j): Preparation of (E)-3-(4-[1-(2-cyano-3-fluorophenyl)-4-(3-hydroxy-4-methoxyphenyl)phenyl)piperidin-4-yl)amino]methyl}phenyl)-N-propylhydroxy-2-enamide

[0985] 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 4M hydrochloric acid in ethyl acetate (12.00 g) were added. , 329.13 mmol) was added to the reaction flask, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, purified by Prep-HPLC (Separation Method 3), and then lyophilized to obtain (E)-3-(4-[1-(2-cyano-3-(4-cyano-3-fluorophenyl)-4-(3-hydroxy-4-methoxyphenyl)phenyl)piperidin-4-yl)amino]methyl}phenyl)-N-hydroxypropyl-2-enamide formate in a yield of 45%.

[0986] 1H NMR(400MHz,DMSO-d6)δppm 10.72(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),6.7 7(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).

[0987] ESI-MS m / z=618.2 [M+H]+.

[0988] Example 85

[0989] Synthesis of the Formate Salt 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

[0990] Step a) Synthesis of tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate

[0991] 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). Sodium hydride (1.84 g, 76.5 mmol) was added in batches at 0 °C. After the addition, the temperature was raised to 65 °C for 1.5 hours, then cooled to room temperature for another hour. TLC monitoring (petroleum ether: ethyl acetate = 3:1) showed that the starting material disappeared. Water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, the solvent was concentrated, and the product 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester was obtained in a yield of 83.74%.

[0992] ESI-MS (m / z) = 365.1 [M+H] + .

[0993] Step b) Synthesis of tert-butyl 4-(4-bromophenyl)-4-carbamoylpiperidine-1-carboxylate

[0994] To DMSO (5 mL) was added tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate (5 g, 13.7 mmol) and potassium hydroxide (1537.4 mg, 27.4 mmol). Hydrogen peroxide (465.9 mg, 13.7 mmol) was slowly added and allowed to react at room temperature for 1 hour. TLC monitoring (petroleum ether:ethyl acetate = 3:1) indicated the disappearance of the starting material. The reaction was quenched by adding water and extracted with EA. The organic phases were combined, the solvent was concentrated, and the solvent was removed by oil pump and used directly in the next reaction.

[0995] ESI-MS (m / z) = 383.1 [M+H] + .

[0996] Step c) Synthesis of tert-butyl 4-amino-4-(4-bromophenyl)piperidine-1-carboxylate

[0997] Potassium hydroxide (1641.2 mg, 29.3 mmol) was dissolved in ACN:H2O = 1:4 (40 mL), and the crude product of step b was added. After stirring for 10 minutes, tert-butyl 4-(4-bromophenyl)-4-carbamoylpiperidine-1-carboxylate (2.5 g, 6.5 mmol) was added in batches. The reaction was carried out at room temperature for 1 hour. TLC (developing solvent ethyl acetate) was monitored. The starting material disappeared and a polarity-enhancing spot (Rf: 0.15) was produced (ninhydrin color development). Sodium sulfite (0.082 g, 0.65 mmol) was added to the system and stirred for 15 minutes. Potassium phosphate (1.7 g, 7.9 mmol) was added and extracted with ethyl acetate. The organic phases were combined, washed with brine, the solvent was concentrated, silica gel was added and the sample was mixed. The product was purified by normal phase column to obtain the product. tert-Butyl 4-amino-4-(4-bromophenyl)piperidine-1-carboxylate, yield 77.95%.

[0998] ESI-MS (m / z) = 355.1 [M+H] + .

[0999] Step d) Synthesis of tert-butyl-(E)-4-amino-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)piperidine-1-carboxylate

[1000] 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 reaction was heated to 110°C for 4 hours. LCMS monitoring revealed the disappearance of the starting material, with the product being the main product. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, the solvent was concentrated, and the sample was added with silica gel. The product was purified by forward 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, in a yield of 82.13%.

[1001] ESI-MS (m / z) = 361.1 [M+H] + .

[1002] Step e) Synthesis of tert-butyl-(E)-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-4-(((trimethylsilyl)methoxy)carbonyl)amino)piperidine-1-carboxylate

[1003] To DMF (40 mL) were 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. TLC monitoring revealed the disappearance of the starting material and the formation of a new spot. Silica gel was added and the sample was extracted with ethyl acetate. The organic phases were combined, the solvent was concentrated, and silica gel was added and the sample was added. Purification was performed on a normal flow column. tert-butyl-(E)-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-4-(((trimethylsilyl)methoxy)carbonyl)amino)piperidine-1-carboxylate was obtained in a yield of 73.22%.

[1004] ESI-MS (m / z) = 491.2 [M+H] + .

[1005] Step f) Synthesis of methyl (E)-3-(4-(((trimethylsilyl)methoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate

[1006] To 4N HCl in ethyl acetate (5 mL) was added tert-butyl (E)-4-(4-(3-methoxy-3-oxopropyl-1-enyl)phenyl)-4-(((trimethylsilyl)methoxy)carbonyl)amino)piperidine-1-carboxylate (180 mg, 0.37 mmol), and the reaction was carried out at room temperature for 0.5 hour. The solvent was concentrated, and the system was adjusted to a weak alkaline state by adding aqueous sodium bicarbonate. EA was added for extraction, and the organic phases were combined and the solvent was concentrated to give crude methyl (E)-3-(4-(((trimethylsilyl)methoxy)carbonyl)amino)piperidin-4-yl)phenyl)acrylate in a yield of 83.04%.

[1007] ESI-MS (m / z) = 391.2 [M+H] + .

[1008] 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

[1009] To N-methylpyrrolidin-2-one (4 mL) were added 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), and ethylbis(propan-2-yl)amine (62.04 mg, 0.48 mmol). The temperature was raised to 110 degrees Celsius for overnight reaction, and the product was purified by forward column to obtain 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

[1010] ESI-MS (m / z) = 612.2 [M+H] + .

[1011] 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

[1012] 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 reacted at room temperature for 2 hours. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, the solvent was concentrated, and silica gel was added to mix the sample. The product was purified by normal phase column to obtain 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%.

[1013] ESI-MS (m / z) = 690.2 [M+H] + .

[1014] 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

[1015] To dioxane:water=5:1 (3 mL) was added 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), and cesium carbonate (41.64 mg, 0.13 mmol). The reaction was carried out under microwave conditions at 105 degrees Celsius for 1 hour. LCMS monitoring showed that the starting material disappeared and the product was mainly obtained. The solvent was concentrated, silica gel was added to mix the sample, and the product was purified by forward 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 in a yield of 72.63%.

[1016] ESI-MS (m / z) = 734.2 [M+H] + .

[1017] 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

[1018] To DCM (5 mL) were added 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 tetra-n-butylammonium fluoride (107.20 mg, 0.41 mmol). Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, the solvent was concentrated, and the mixture was purified by reverse phase column chromatography and then by silica gel column chromatography to give 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 in a yield of 72.63%.

[1019] ESI-MS (m / z) = 604.2 [M+H] + .

[1020] 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

[1021] To THF:H2O=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 solvent was concentrated to give a 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, in a yield of 79.06%.

[1022] ESI-MS (m / z) = 804.3 [M+H] + .

[1023] Step 1) 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

[1024] To THF:H2O=4:1 (10 mL) were added 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). The reaction was allowed to react at room temperature overnight. 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 the solvent was concentrated to obtain a crude product. (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, yield 80.25%.

[1025] ESI-MS (m / z) = 790.3 [M+H] + .

[1026] 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

[1027] To DMF (8 mL) 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)hydroxylamine (3 mg, 0.02 mmol), 2-(7-azobenzotriazole)-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 h. LCMS monitoring showed that the starting material disappeared and the product was mainly obtained. The reaction was terminated and the system was poured into water. EA was added for extraction. The organic phase was washed with saturated brine, the solvent was concentrated, silica gel was added and the sample was mixed. The product was purified by forward column 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 in a yield of 81.49%.

[1028] ESI-MS (m / z) = 889.5 [M+H] + .

[1029] Step n) Synthesis of the formate salt 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

[1030] To a 4N hydrochloric acid solution 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 reaction was allowed to proceed at room temperature for 0.5 h. The solvent was concentrated and the product was sent for preparative purification. (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%.

[1031] 1H 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).

[1032] ESI-MS (m / z) = 605.2 [M+H] + .

[1033] Example 86 was synthesized according to the method of Example 85 (isolation method 3). Its structure and characterization data are shown in the following table:

[1034] Preparation of formate salt 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

[1035] 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).

[1036] ESI-MS (m / z) = 633.3 [M+H] + .

[1037] Example 88

[1038] 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

[1039] Step a): Preparation of 2-fluoro-3-methoxypyridine

[1040] Dissolve 2-fluoropyridin-3-ol (3.0 g, 26.5 mmol) and potassium carbonate (11.0 g, 79.6 mmol) in DMF (30 mL). Slowly add iodomethane (7.6 g, 53.1 mmol). After addition, react at room temperature for 6 h. Add water (200 mL) and extract with ethyl acetate (50 mL x 3). The organic layer is washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to provide 2-fluoro-3-methoxypyridine in a yield of 75.5%.

[1041] ESI-MS m / z=128.1[M+H] + .

[1042] Step b): Preparation of 2-fluoro-4-iodo-3-methoxypyridine

[1043] 2-Fluoro-3-methoxypyridine (1.2 g, 8.4 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL), the atmosphere was replaced with nitrogen three times, and the reaction mixture was cooled to -78°C. n-Butyl lithium (810 mg, 12.7 mmol) was slowly added dropwise to the reaction mixture, and the temperature was maintained at -78°C with stirring for 30 minutes. Elemental 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, 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 obtain 2-fluoro-4-iodo-3-methoxypyridine in a yield of 51.4%.

[1044] ESI-MS m / z=254.1[M+H] + .

[1045] Step c): Preparation of tert-butyl (1-(4-iodo-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[1046] Dissolve 2-fluoro-4-iodo-3-methoxypyridine (1.1 g, 4.4 mmol) and 4-tert-butoxycarbonylaminopiperidine (1.3 g, 6.5 mmol) in DMF (20 mL). Add N-methylmorpholine (2.2 g, 21.8 mmol) and warm to 80°C overnight. Add water (100 mL) and extract with ethyl acetate (40 mL x 3). Combine the organic layers, wash with brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. The residue is purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to provide tert-butyl (1-(4-iodo-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 48.8%.

[1047] ESI-MS m / z=434.0[M+H] + .

[1048] Step d): Preparation of tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[1049] Tert-butyl (1-(4-iodo-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate (1.0 g, 2.3 mmol), 4-cyano-3-fluorophenylboronic acid (400 mg, 2.4 mmol), sodium carbonate (730 mg, 6.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85 mg, 0.1 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5.0 mL). The reaction solution was heated to 100°C for 2 hours. The reaction solution was spin-dried, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-3-methoxypyridin-2-yl)piperidin-4-yl)carbamate in a yield of 63.8%.

[1050] ESI-MS m / z=427.4[M+H] + .

[1051] Synthesis steps e to l refer to steps c to i of Example 57.

[1052] Step m): 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 formate

[1053] Tert-butyl (E)-(1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-3-methoxypyridin-2-yl)piperidin-4-yl)(4-(3-oxo-3-((tetrahydro-2H-pyran-2-methyl)oxy)amino)prop-1-en-1-yl)benzyl)carbamate (80 mg, 0.19 mmol) was dissolved in 5 mL of 4M HCl and ethyl acetate (5 mL) and reacted at room temperature for 1 hour. The reaction was complete, the reaction solution was dried, and the residue was purified by Prep-HPLC (Separation Method 3) to give ((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 formate in a yield of 40.4%.

[1054] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.92(s,2H),7.98(s,1H),7.85(t,J=7.6Hz, 1H),7.52(d,J=8.0Hz,2H),7.48–7.37(m,4H),7.18–7.08(m,1H),6.77(d,J=8.8Hz, 1H),6.49–6.40(m,3H),3.99(d,J=12.8Hz,2H),3.84(s,2H),3.70(s,3H),3.46(s,3 H),2.86(t,J=11.6Hz,2H),2.68(s,1H),2.06–1.96(m,2H),1.48(q,J=10.8Hz,2H).

[1055] ESI-MS m / z:624.3[M+H] + .

[1056] Example 89

[1057] Preparation of (E)-3-(4-(2-(1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)ethyl)phenyl)-N-hydroxyacrylamide

[1058] Step a): Preparation of tert-butyl (E)-4-(4-bromostyryl)piperidine-1-carboxylate

[1059] (4-Bromobenzyl)triphenylphosphonium bromide (2.0 g, 3.8 mmol), NaHMDS (700 mg, 3.8 mmol), and ACN (20 mL) were added to a reaction flask, and the mixture was stirred at room temperature for 8 hours. 4-Formylpiperidine-1-carboxylic acid tert-butyl ester (808 mg, 3.8 mmol) was added, and the reaction was stirred overnight. After the reaction was complete, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain (E)-4-(4-bromostyryl)piperidine-1-carboxylic acid tert-butyl ester in a yield of 91%.

[1060] ESI-MS m / z=366.1[M+H] + .

[1061] Step b): Preparation of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate

[1062] (E)-tert-Butyl 4-(4-bromophenylvinyl)piperidine-1-carboxylate (1.3 g, 3.4 mmol), palladium on carbon (150 mg, 5%), and ethanol (5 mL) were added sequentially to a reaction flask, stirred to dissolve, and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate in a yield of 92.0%.

[1063] ESI-MS (m / z) = 368.1 [M+H] + .

[1064] Step c): Preparation of tert-butyl (E)-4-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenethyl)piperidine-1-carboxylate

[1065] tert-Butyl 4-(4-bromophenyl)piperidine-1-carboxylate (1.2 g, 3.2 mmol), methyl acrylate (535 mg, 6.4 mol), Cs2CO3 (2.1 g, 6.4 mmol), Pd(dppf)Cl2 (117 mg, 160 mmol), 1.4-Dioxane (12 mL), and H2O (4 mL) were added to a reaction flask and stirred at 100°C for 1 hour. The mixture ...

Claims

1. A compound represented by general formula (I) or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal, L 1 Selected from bonds, -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 or heteroaryl or 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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, 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 The heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; alternatively, one or more alkyl groups in the alkyl group may be optionally substituted by one or more substituents selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group; W is selected from: L 2 Selected from bond, -O-, -C(=O)-, -NR a -、-CH2-NR a -、-NR a -C(O)-、-NR a -S(=O)2-, -S- or -S(=O)2-; Ring A is selected from C containing N 3-10 Heteroaryl, C 3-10 Heterocycloalkyl or C 3-10 Heterocycloalkenyl, wherein The heteroaryl, heterocycloalkyl, heterocycloalkenyl are optionally substituted by one or more R 4 Substitution, the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S; R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 Alternatively, R 4 Selected from C 1-6 When alkyl, any two R 4 The atoms to which it is connected may together form a 5- to 10-membered aliphatic heterocyclic group; R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 ; R 2 、R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 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 、-C 2-6 Alkenyl-C(=O)NR a R b 、C 3-6 substituted by a cycloalkyl, 3- to 6-membered heterocycloalkyl, or heterocycloalkenyl substituent, wherein the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms 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 selected from a bond, -CH2-, -C(=O) or -S(=O)2-; R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, 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 Substituents are substituted, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 by a substituent; R a 、R b Each occurrence 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, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; Indicates the presence or absence of a double bond at any position within the ring.

2. The compound according to claim 1 or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal, wherein: L 1 The left end group is connected to W, and the right end group is connected to connected; Preferably, the compound is represented by formula (II), (III), (IV), (V) or (VI): The definitions of the substituents are consistent with those in claim 1.

3. The compound according to claim 1 or 2, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal, wherein: The compound is shown in formula (II-1): in, L 1 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-, the alkyl, alkenyl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Preferably, L 1 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-; Preferably, L 1 Selected from -C 1-10 Alkyl-, -C 1-10 Alkyl-(C 6-10 Aryl)-C 2-6 alkenyl-; Preferably, L 1 Selected from -C 1-6 Alkyl-, -C 1-6 Alkyl-phenylene-C 2-6 Alkenyl-.

4. The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace; Preferably, ring A is selected from C containing N 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace; Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group; Preferably, Ring A is selected from: described Optionally R 4 group substituted.

5. The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 ; Preferably, R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b ; Preferably, R 4 Selected from hydrogen, -NR a R b 、C 1-6 alkyl; Preferably, R 4 Selected from hydrogen, -NR a R b .

6. The compound according to claim 1 to 5, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal, wherein: R 1 Selected from hydrogen, halogen, CN, hydroxyl, 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; Preferably, R 1 Selected from hydrogen, halogen, CN, C 1-6 alkyl; Preferably, R 1 is selected from hydrogen, halogen, CN; R 2 Selected from hydrogen, halogen, CN, hydroxyl, 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 by one or more selected from hydrogen, halogen, CN, hydroxyl, 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 1-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 2 Selected from hydrogen, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-S(=O)2R a 、-OC 1-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 2 Selected from hydrogen, Among them, the Optionally, one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -NR a R b 、-S(=O)2-R a 、-OC 1-6 substituted by an alkyl-OH substituent; Preferably, R 2 Selected from Among them, the Optionally, one or more selected from hydrogen, hydroxy, C 1-6 substituted by an alkoxy substituent.

7. The compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 and 2; more preferably, m is 2; Each Q is independently selected from N or C; preferably, Q is selected from C.

8. The compound according to any one of claims 1 to 7, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: R a 、R b Each occurrence 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 Generation C 1-6 alkyl; Preferably, R a 、R b Each occurrence 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; Preferably, R a 、R b Each occurrence is independently selected from hydrogen and methyl; Preferably, R a 、R b are each independently selected from hydrogen.

9. The compound according to claim 1 or 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is shown in formula (III-1): in, X is selected from C and N; L 1 Selected from bonds, -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)-, -NR a -, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR a R b , substituted by a substituent of COOH; Alternatively, one or more carbon atoms in the alkyl group may be optionally replaced by one or more groups selected from -NH-; Preferably, L 1 Selected from bonds, -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)-, the alkyl, alkoxy, alkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b 、-NR a R b substituted by a substituent; Alternatively, one or more carbon atoms in the alkyl group may be optionally replaced by one or more groups selected from -NH-; Preferably, L 1 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)-, the alkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

10. 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, wherein: L 2 Selected from bond, -O-, -C(=O)-, -NR a -、-NR a -C(O)- or -S(=O)2-; Preferably, L 2 Selected from bond, -O-, -NR a -; Preferably, L 2 Selected from -O-, -NR a -.

11. 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, wherein: Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 replace; Preferably, ring A is selected from C containing N 3-10 Heterocycloalkyl, C 3-10 Heterocycloalkyl is optionally substituted with one or more R 4 replace; Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group; Preferably, Ring A is selected from: described Optionally R 4 group substituted.

12. The 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, wherein: R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b ; Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, -NR a R b ; Preferably, R 4 Selected from hydrogen, -NR a R b .

13. 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, wherein: R 1 、R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, 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 ; Preferably, R 1 、R 6 Each occurrence is independently selected from hydrogen, CN, hydroxyl, C 1-6 alkoxy; Preferably, R 1 、R 6 Each occurrence is independently selected from hydrogen, CN, hydroxyl; R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 3 Selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from hydrogen, halogen, and CN, and the heteroaryl or heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O, or S; Preferably, R 3 Selected from hydrogen, methyl, described Optionally substituted with one or more substituents selected from hydrogen, halogen, CN; Preferably, R 3 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, and CN.

14. 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, wherein: R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 substituted by a substituent of the alkynyl group; Preferably, R 5 Selected from hydroxyl, C 1-6 Alkoxy, wherein the alkoxy group, Optionally, one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Alternatively, R 5 、R 6 Together with the atoms directly connected to them, Among them, the Optionally substituted with one or more of the following groups: hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 alkoxy; Preferably, R 5 Selected from Among them, the Optionally substituted with one or more substituents selected from hydrogen, halogen, CN; Alternatively, R 5 、R 6 Together with the atoms directly connected to them, 15. The compound according to any one of claims 1 to 14, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: m is selected from 0, 1, 2 or 3; preferably, m is selected from 1 and 2; Z is selected from a bond, -CH2- or -C(=O); preferably, Z is selected from a bond.

16. 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, wherein: R a 、R b Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, COOH, wherein the alkyl, alkoxy, alkenyl, alkynyl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, COOH substituents; Preferably, R a 、R b Each occurrence is independently selected from hydrogen, C 1-6 alkyl; Preferably, R a 、R b Each occurrence is independently selected from hydrogen and methyl.

17. The compound according to claim 1 or 2, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is shown in formula (IV-1a): in, L 1 Selected from bonds, -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 or heteroaryl or 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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Alternatively, one or more of the alkyl groups may be optionally replaced by one or more groups selected from -C(=O)-, -S(=O)2- or -NR a - is replaced by a group; Preferably, L 1 Selected from -C 1-10 Alkyl-, -C 2-6 Alkenyl-, -C 6-10 Heteroaryl-, -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl or 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-6-10 membered heteroaryl-, -C 1-10 Alkyl-6-10 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-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, L 1 Selected from -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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, L 1 Selected from -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)-, the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl groups are optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, L 1 Selected from -C 1-10 Alkyl-(C 6-10 aryl or heteroaryl)-C 2-6 Alkenyl-, the alkyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Preferably, L 1 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, Preferably, L 1 Selected from 18. The compound according to any one of claims 1 to 17, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: L 2 Selected from bond, -O-, -C(=O)-, -S-, -NR a -、-CH2-NR a -、-NR a -C(=O) and -NR a -S(=O)2-; Preferably, L 2 Selected from bond, -NR a -、-CH2-NR a -、-NR a -C(=O) and -NR a -S(=O)2-; Preferably, L 2 Selected from-NR a -、-NR a -C(=O) and -NR a -S(=O)2-; Preferably, L 2 Selected from a bond, -C(=O)- or -NR a -; Preferably, L 2 Selected from-NR a -.

19. 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, wherein: Ring A is selected from C containing N 3-10 Heteroaryl or C 3-10 Heterocycloalkyl, wherein the heteroaryl, heterocycloalkyl is optionally replaced by one or more R 4 Substitution; the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; Preferably, ring A is selected from C 3-10 Heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by one or more R 4 replace; Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group; Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group; Preferably, Ring A is selected from: wherein Optionally R 4 substituted by a group; Preferably, Ring A is selected from: Optionally R 4 group substituted.

20. 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, wherein: R 4 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -NR a R b ; Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, -NR a R b ; Preferably, R 4 Selected from hydrogen, C 1-6 alkyl.

21. 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, wherein: R 6 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkyl-CN, halogenated 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 ; Preferably, R 6 Each occurrence is independently selected from hydrogen, halogen, CH2-CN, CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl; Preferably, R 6 Each occurrence is independently selected from hydrogen, halogen, CH2-CN, CN, C 1-6 alkyl; Preferably, R 6 Each occurrence is independently selected from hydrogen, CN; R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, 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 , 3 to 6 membered heterocycloalkyl, hydroxy substituted C 1-6 Alkoxy-C 3-6 Substituted by a cycloalkyl or heterocycloalkenyl substituent, wherein the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or heterocycloalkenyl substituents, wherein the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 3 、R 7 are 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 hydrogen at the same time, wherein the aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkoxy, halogenated 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, heterocycloalkenyl substituents, wherein the heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, CN, heterocycloalkenyl, hydroxy, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated 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, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) substituent; Preferably, R 3 、R 7 Selected from hydrogen, described Optionally, one or more selected from hydrogen, halogen, CN, hydroxyl, CF3, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated 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, -NH2, -N(C 1-6 Alkyl)2, -NH(C 1-6 alkyl) substituent; Preferably, R 3 、R 7 Selected from hydrogen, described Optionally substituted with one or more substituents selected from hydrogen, halogen, heterocycloalkenyl, hydroxy.

22. 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, wherein: R 5 Each occurrence is independently selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =O, C 2-6 Alkenyl, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkyl, alkoxy, alkenyl, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkoxy, C 2-6 The heteroaryl group or heterocycloalkyl group contains 1 to 4 heteroatoms selected from N, O or S; Preferably, R 5 Each occurrence is independently selected from hydrogen, CN, C 1-6 Alkoxy, =O, C 6-10 Aryl or C 6-10 Heteroaryl, wherein the alkoxy, aryl or heteroaryl is optionally substituted by one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 Alkyl, -C(=O)-C 1-6 Alkoxy, -C (= O) -NH2 substituents, said heteroaryl, heterocycloalkyl contains 1 to 4 heteroatoms selected from N, O or S; Alternatively, R 5 、R 6 Together with the atoms directly connected to the two, they form a cycloalkyl, alicyclic, aryl or heteroaryl group, wherein the cycloalkyl, alicyclic, aryl or heteroaryl group is optionally substituted by one or more selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 substituted by a substituent of the alkynyl group; Preferably, R 5 Each independently selected from CN, C 1-6 Alkoxy, =O, wherein the alkoxy group, Optionally, one or more selected from hydrogen, halogen, CN, NO2, CF3, CHF2, hydroxyl, C 1-6 Alkyl, -C(=O)-NH2, -C(O)OCH3; Alternatively, R 5 、R 6 Together with the atoms directly connected to them, Among them, the Optionally substituted with one or more of the following groups: hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 alkoxy; Preferably, R 5 Selected from C 1-6 Alkoxy, Among them, the Optionally substituted with one or more substituents selected from hydrogen, halogen, CN, NO2; Alternatively, R 5 、R 6 Together with the atoms directly connected to them, 23. 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, wherein: X and Y are each independently selected from C and N; Z is selected from a bond, -CH2-, -C(=O) or -S(=O)2-; Preferably, Z is selected from a bond, -CH2- or -C(=O); Preferably, Z is selected from a bond.

24. The compound according to any one of claims 1 to 23, or a tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal thereof, wherein: R a 、R b Each occurrence 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, wherein the heteroaryl and heterocycloalkyl groups contain 1 to 4 heteroatoms selected from N, O or S; Preferably, R a 、R b Each occurrence is independently selected from hydrogen, C 1-6 alkyl; Preferably, R a 、R b Each occurrence is independently selected from hydrogen.

25. The following compound or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or cocrystals:

26. A pharmaceutical composition, characterized in that The active ingredient of the pharmaceutical composition is selected from one or a combination of two or more of the compound according to any one of claims 1 to 25 or its tautomers, stereoisomers, solvates, metabolites, isotope-labeled compounds, pharmaceutically acceptable salts or cocrystals.

27. Use of the compound according to any one of claims 1 to 25, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt, or cocrystal thereof, in preventing and treating diseases mediated separately or synergistically by LSD1 and / or HDAC; Furthermore, the HDAC enzyme includes but is not limited to subtypes such as HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, and HDAC8, preferably HDAC1 or HDAC8 subtype, and more preferably HDAC1 subtype.

28. Use of the compound according to any one of claims 1 to 25, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt or cocrystal, in the preparation of a medicament for treating a disease mediated by LSD1 and / or HDAC; Furthermore, the invention relates to a use of the invention in the preparation of a medicament for treating a disease mediated by one or more of LSD1, HDAC6 and HDAC8; Preferably, the disease is cancer or an autoimmune disease; Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney 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, urethra cancer, and nasal cancer.

29. Use of the compound according to any one of claims 1 to 25, or its tautomer, stereoisomer, solvate, metabolite, isotope-labeled compound, pharmaceutically acceptable salt, or cocrystal thereof, in preventing and treating diseases mediated separately or synergistically by LSD1 protein and / or HDAC1 protein, LSD1 protein, and / or HDAC8 protein.

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