Polycyclic compounds and uses thereof

Abstract

Provided are a compound shown in general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, deuterium isotope derivative, pharmaceutically acceptable hydrate, solvate, salt or co-crystal thereof, a pharmaceutical composition thereof, and an application thereof in the preparation of a drug for a lysine-specific demethylase 1 inhibitor related disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a class of compounds that are inhibitors of lysine-specific demethylase 1 (LSD1), and their use in the preparation of drugs for treating LSD1-related diseases. Background Technology

[0002] LSD1 protein (Lysine Specific Demethylase 1, also known as KDM1A), is composed of 852 amino acids and has a molecular weight of 93 kDa. It was first discovered and reported in 2004 by a team led by Shi Yang at Harvard University (Shi,Y.,Lan,F.,Matson,C.,Mulligan,P.,Whetstine,JR.,Cole,PA.,Casero,RA.,andShi,Y..Histone demethylation mediated by the nuclear amine oxidase homologLSD1.Cell 2004,119,941-953). Studies have confirmed that LSD1 exerts its biological functions not only by demethylating histones but also by demethylating non-histone proteins p53 and Dnmt1. The biological functions of LSD1 are mainly manifested in the regulation of sex hormone receptor-mediated gene transcription, the regulation of tumor cell proliferation, apoptosis and metastasis, and 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). Furthermore, in the study of LSD1 inhibition, it was found to be associated with macrophage typing 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). LSD1 is widely expressed in the body, with lower secretion in the liver, pancreas and salivary glands, higher expression in the testes, and similar expression levels in other tissues.Studies have found that LSD1 expression levels are significantly elevated in various 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, glioma, and hematologic malignancies (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.). Researchers have also found an overexpression trend of LSD1 in some cancer types using public databases of human cancer. Patients with high LSD1 expression have significantly shorter survival times, suggesting that LSD1 overexpression is a poor prognostic factor. Other studies have also found high expression of LSD1 in various cancer tissues, and increasing reports indicate that LSD1, as an epigenetic regulator, participates in various tumor processes and embryonic development. The TCGA cancer database also shows that LSD1 expression is negatively correlated with the antiviral effect of IFN and the infiltration of CD8 T cells, which is consistent with the results in mouse models. Therefore, inhibition of LSD1 can enhance the immunogenicity of tumors and promote T cell infiltration, activate anti-tumor T cell immunity, and can be used as a target in conjunction with anti-PD-1 immunotherapy for tumor treatment.Inhibition of LSD1 function can enhance the expression of endogenous retroviral elements (ERVs) and inhibit the function of the RISC (RNA-induced silencing complex), 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.). Related studies have also shown that inhibition of DNA methylation alone or in combination with HDAC inhibitors can lead to activation of the tumor interferon (IFN) pathway and enhance the efficacy of tumor immunotherapy.Simultaneously, blocking DNA methylation in T cells can also enhance PD-1 / PD-L1 immunotherapy-mediated T cell activity and tumor suppression (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). Therefore, the development of LSD1 inhibitors is one of the hot topics in the field of cancer research.

[0003] Currently, there are no drugs targeting LSD1 on the market globally, and all compounds under investigation are in early clinical or preclinical research stages. Although many companies and research institutions have conducted research on LSD1 inhibitors and published related patents, such as GSK disclosing a class of cyclopropylamine compounds as LSD1 inhibitors for cancer treatment (Neil W. Johnson et al., US10,064,854; DECAPRIO, JA et al., WO2019075327), and Celgene disclosing a class of substituted heterocyclic compound LSD1 inhibitors for cancer treatment (YK Chen et al., US20180325900), some of the disclosed LSD1 inhibitors have narrow therapeutic windows due to poor activity, and others have less than ideal druggability. Therefore, there is still a great need in the field to develop new LSD1 inhibitors, especially those with high activity and superior druggability. Summary of the Invention

[0004] This invention provides a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, a deuterated isotope derivative, a pharmaceutically acceptable hydrate, a solvate, a salt, or a eutectic.

[0005]

[0006] in,

[0007] Ring A is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 3-10 Cycloalkenyl, C 2-10 Heterocyclic alkenyl, C 6-10 Aryl benzo[C] 3-10 cycloalkyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, C 6-10 Aryl benzo[C] 3-10 Cycloalkenyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkenyl, 5-10-membered heteroaryl benzo[C] 3-10 cycloalkyl, 5-10-membered heteroaryl benzo[C] 2-10 Heterocyclic alkyl, 5-10-membered heteroaryl benzo[C] 3-10 Cycloalkenyl, 5-10 heteroaryl benzo[C] 2-10 Heterocyclic alkenyl groups, wherein the above groups are optionally surrounded by 0 to 4 groups selected from halogens, -CN, hydroxyl groups, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C1-6 Alkoxy, C 6-10 aryl-substituted C 1-6 Alkoxy, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, -OC 1-6 Alkyl-(C 3-10 cycloalkyl), -O-(C 2-10 Heterocyclic alkyl), C 2-10 Heterocyclic alkyl, -OC 1-6 Alkyl-(C 2-10 Heterocyclic alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, =O, -NR c R d , The substituents are replaced by the non-aromatic ring substituents, and =O can only be substituents on non-aromatic rings, including heteroaryl, heterocyclic alkyl, heterocyclic alkenyl, and C. 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkenyl, 5-10-membered heteroaryl benzo[C] 3-10 cycloalkyl, 5-10-membered heteroaryl benzo[C] 2-10 Heterocyclic alkyl, 5-10-membered heteroaryl benzo[C] 3-10 Cycloalkenyl, 5-10 heteroaryl benzo[C] 2-10 The heterocyclic alkenyl group contains 1 to 4 heteroatoms, optionally selected from N, O, or S;

[0008] Preferably, ring A is selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 3-10 Cycloalkenyl, C 2-10 Heterocyclic alkenyl, C 6-10 Aryl benzo[C] 3-10 cycloalkyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, C 6-10 Aryl benzo[C] 3-10 Cycloalkenyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkenyl, 5-10-membered heteroaryl benzo[C] 3-10 cycloalkyl, 5-10-membered heteroaryl benzo[C] 2-10 Heterocyclic alkyl, 5-10-membered heteroaryl benzo[C] 3-10 Cycloalkenyl, 5-10 heteroaryl benzo[C] 2-10 Heterocyclic alkenyl groups, wherein the above groups are optionally surrounded by 0 to 4 groups selected from halogens, -CN, hydroxyl groups, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6alkoxy- or halogen-substituted C 1-6 Alkoxy, C 6-10 aryl-substituted C 1-6 Alkoxy, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =O, -NR c R d , The substituents are replaced by the non-aromatic ring substituents, and =O can only be substituents on non-aromatic rings, including heteroaryl, heterocyclic alkyl, heterocyclic alkenyl, and C. 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkenyl, 5-10-membered heteroaryl benzo[C] 3-10 cycloalkyl, 5-10-membered heteroaryl benzo[C] 2-10 Heterocyclic alkyl, 5-10-membered heteroaryl benzo[C] 3-10 Cycloalkenyl, 5-10 heteroaryl benzo[C] 2-10 Heterocyclic alkenyl groups contain 1 to 4 heteroatoms, chosen from N, O, or S.

[0009] Preferably, ring A is selected from C. 6-10 Aryl, C 3-10 heteroaryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally selected from 0 to 4 halogens, CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, =O or The heteroaryl or heterocycloalkyl group is replaced by a substituent and contains 1 to 4 heteroatoms optionally selected from N, O or S.

[0010] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally selected from 0 to 4 halogens, -CN, hydroxyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -NR c Rd The heteroaryl or heterocycloalkyl group is replaced by a substituent, and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms, optionally selected from N, O or S; provided that ring B is not a 9-membered spirocyclic ring.

[0011] Preferably, ring B is selected from C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally selected from 0 to 4 halogens, -CN, hydroxyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 acetylinyl or -NR c R d The heteroaryl or heterocycloalkyl group is replaced by a substituent, and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms, optionally selected from N, O or S; provided that ring B is not a 9-membered spirocyclic ring.

[0012] Preferably, ring B is selected from C. 6-10 Aryl, C 3-10 heteroaryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally selected from 0 to 4 halogens, -CN, CF3, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 acetylinyl or -NR c R d The heteroaryl or heterocycloalkyl group is replaced by a substituent, and the heteroaryl or heterocycloalkyl group contains 1 to 4 heteroatoms, optionally selected from N, O or S; provided that ring B is not a 9-membered spirocyclic ring.

[0013] W is selected from key, When W is selected as a key, ring A and ring B are directly connected by a key.

[0014] Preferably, W is selected from the bond, -CH2-, When W is selected from the key, ring A and ring B are directly connected by the key;

[0015] X1 is selected from -NR X -、-O- or -CHR X -

[0016] X2 is selected from -NH- or -O-.

[0017] Rw R X Each is independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further modified by 0 to 4 C groups selected from halogens or halogen-substituted C groups. 1-6 Alkyl, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl or C 1-4 The heterocyclic group is substituted by a substituent of an alkylthio group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0018] R1 and R2 are each independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 3-10 Cycloalkenyl, C 2-10 Heterocyclic alkenyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, -NR4R5, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl are optionally further divided by 0 to 4 halogens, -CN, -CH2CN, -NH2, hydroxyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 alkoxy- or hydroxy-substituted C 1-6 Alkoxy, =O, -C(=O)C 1-6 Alkyl group, -C(=O)OC1-6 Alkyl group, -COOH, C 2-6 C with alkynyl or hydroxyl substitution 2-6 alkynyl group, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, C 5-10 Heterocyclic aryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, -S(O)2R a The heteroaryl or heterocycloalkyl group is replaced by a substituent and contains 1 to 3 heteroatoms selected from N, O or S.

[0019] Preferably, R1 and R2 are each independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, -OC 6-10 Aryl, -O-(5-10 heteroaryl), C 6-10 Aryl, 5-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, -NR4R5, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclic alkyl may optionally be further divided by 0 to 4 halogens, -CN, -CH2CN, -NH2, hydroxyl, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 alkoxy- or hydroxy-substituted C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -COOH, C 2-6 C with alkynyl or hydroxyl substitution 2-6 alkynyl group, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, 5-10 heteroaryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 2-10 The heterocyclic alkyl group is substituted with a substituent of -S(O)2R6, wherein the heteroaryl group or heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O or S.

[0020] Preferably, R1 and R2 are each independently selected from hydrogen and C.1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 4-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further oxidized by 0 to 4 halogens, CF3, -CN, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl, -(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, C 5-10 Heterocyclic aryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, S(O)2R a The heterocyclic group is replaced by a substituent, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0021] R4 and R5 are each independently selected from hydrogen and C. 1-6 alkyl and amino substituted C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, R6 selected from C 1-6 Alkyl, amino.

[0022] R a R b Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 4-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 2-10Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further substituted with 0 to 4 halogens, or C groups substituted with halogens. 1-6 Alkyl, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, C 5-10 Heterocyclic aryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, -S(O)2R a The heterocyclic group is replaced by a substituent, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0023] R a R b Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 4-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further substituted with 0 to 4 halogens, or C groups substituted with halogens. 1-6 Alkyl, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, C 5-10 Heterocyclic aryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 2-10 The heterocyclic alkyl group is substituted with a -S(O)2R6 substituent, wherein the heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O or S, and R6 is selected from C. 1-6 Alkyl, amino.

[0024] R a R b Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN, C 2-6 alkenyl, C 2-6alkynyl group, -C(=O)C 1-6 Alkyl, -(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 4-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further oxidized by 0 to 4 halogens, CF3, CN, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy group, -C(=O)C 1-6 Alkyl, -(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 1-4 Alkylthio, C 5-10 Heterocyclic aryl, C 6-10 Aryl, C 4-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, S(O)2R a The heterocyclic group is replaced by a substituent, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0025] R c R d Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 4-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further denoted by 0 to 4 halogens, hydroxyl groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 Heterocyclic aryl, aryl, hydroxyl, -CN, -S(O)2R a The heterocyclic group is replaced by a substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, and R6 is selected from C. 1-6 Alkyl, amino; when ring A is selected from penta- or hexa-membered aromatic heterocycles, R c R d They are not both methyl groups.

[0026] Rc R d Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 4-10 cycloalkyl, C 2-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further denoted by 0 to 4 halogens, hydroxyl groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl, aryl, hydroxyl, -CN, or -S(O)2R6 substituents are used, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S, and R6 is selected from C. 1-6 Alkyl, amino; when ring A is selected from penta- or hexa-membered aromatic heterocycles, R c R d They are not both methyl groups.

[0027] R c R d Each is independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, CN, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)C 1-6 Alkyl, -(=O)C 1-6 Alkyl, -OC 3-6 cycloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 5-10 Heterocyclic aryl, C 4-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic alkyl group is optionally further surrounded by 0 to 4 halogens, amino, aminoalkyl, aminocycloalkyl, aminoheterocyclic, C 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 Heterocyclic aryl, aryl, hydroxyl, CN, S(O)2R a The heterocyclic group is replaced by a substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S; when ring A is selected from a penta- or hexa-membered aromatic heterocycle, R c R dThey are not both methyl groups; m and n are each independently selected from integers from 0 to 6. When m is selected from 0, R1 is directly connected to ring A.

[0028] Preferably, m and n are each independently selected from 0, 1, 2, 3, 4 or 5. When m is selected from 0, R1 is directly connected to ring A.

[0029] Preferably, m is selected from 0 or 1. When m is selected from 0, R1 is directly connected to ring A.

[0030] Preferably, m is selected from 0.

[0031] Preferably, n is selected from integers from 0 to 6. When n is selected from 0, It represents -NH-.

[0032] r is an integer selected from 1 to 6.

[0033] p is selected from 0 or 1. When p is selected from 0, it means that X2 does not exist.

[0034] q can be selected from 1, 2, 3 or 4.

[0035] This invention discloses a compound represented by general formula (I), wherein ring A in general formula (I) is selected from:

[0036]

[0037] Preferably, ring A is selected from:

[0038] Preferably, ring A is selected from:

[0039]

[0040] Z1, Z2, Z3, Z4, Z5, Z6, and Z7 are each independently selected from O, S, N, and -NR3-. =CR Z -、 -CRyR Z -

[0041] R3 is selected from hydrogen, C 1-6 alkyl.

[0042] Preferably, Z1, Z2, Z3, Z4, and Z5 are each independently selected from N, -NH-, or -CR. Z -

[0043] Preferably, Z6 is selected from -NH- or CR. Z .

[0044] Ry、R Z Each element is independently selected from hydrogen, halogen, -CN, hydroxyl, and C.1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 6-10 aryl-substituted C 1-6 Alkoxy, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, -OC 1-6 Alkyl-(C 3-10 cycloalkyl), -O-(C 2-10 Heterocyclic alkyl), C 2-10 Heterocyclic alkyl, -OC 1-6 Alkyl-(C 2-10 Heterocyclic alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -NR c R d ,

[0045] Preferably, Ry, R Z Each element is independently selected from hydrogen, halogen, -CN, hydroxyl, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 6-10 aryl-substituted C 1-6 Alkoxy, -OC 3-10 cycloalkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -NR c R d ,

[0046] Preferably, Ry, R Z Each is independently selected from hydrogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, C 6-10 aryl-substituted methoxy, -OC 3-10 cycloalkyl, R a R b Both are hydrogen.

[0047] More preferably, Ry, R Z Each is independently selected from hydrogen, -CN, hydroxyl, methyl, methoxy, ethoxy, propoxy, difluoromethoxy, benzyloxy, cyclopentyloxy, and -C(O)NH2.

[0048] Preferably, RZ Selected from hydrogen, halogen, CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, =O, NR c R d or

[0049] Y is selected from O or S.

[0050] This indicates whether a double bond may exist at any position within the ring or not.

[0051] Preferably, Represents the aromatic ring.

[0052] This disclosure provides compounds having the general formula (I-1):

[0053]

[0054] The definitions of each substituent in general formula (I-1) are consistent with the definitions above.

[0055] This disclosure provides compounds having the general formula (I-1a):

[0056]

[0057] Among them, Z1, Z3, Z4, Z5, and Z7 are each independently selected from N or = CR. Z -; W is the key.

[0058] In one aspect of this disclosure, Z3 is N, and Z1, Z4, Z5, and Z7 are each independently selected from N or = CR. Z -

[0059] In one aspect of this disclosure, ring A is selected from:

[0060] In one aspect of this disclosure, compounds having the general formula (I-1b) are provided:

[0061]

[0062] The definitions of each substituent are consistent with the definitions above.

[0063] In one aspect of this disclosure, wherein:

[0064] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally composed of 0 to 4 elements selected from F, CN, CF3, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is replaced by a substituent and contains 1 to 4 heteroatoms optionally selected from N, O or S.

[0065] R c R d Each is independently selected from hydrogen, F, CN, hydroxyl, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0066] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or -CR. Z -

[0067] R Z Selected from hydrogen, C 1-6 Alkyl or C 3-10 Cycloalkyl.

[0068] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 aryl, wherein the heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, C groups, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S.

[0069] m is selected from 0 or 1.

[0070] Preferably, ring B is selected from C. 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally composed of 0 to 4 elements selected from F, CN, CF3, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is replaced by a substituent and contains 1 to 4 heteroatoms optionally selected from N, O or S.

[0071] R c R d Each is independently selected from hydrogen, F, CN, hydroxyl, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0072] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or -CR. Z -

[0073] R Z Selected from hydrogen or C 1-6 alkyl.

[0074] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 aryl, wherein the heterocyclic alkyl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino, aminoalkyl, aminocycloalkyl, aminoheterocyclic, C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl, aryl, hydroxyl, or CN substituents are used, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S.

[0075] m is selected from 0.

[0076] Preferably, ring B is selected from The above The hydrogen atoms in the group are optionally replaced by 0 to 4 NH2, -NHCH3 or methyl groups.

[0077] R Z Selected from hydrogen.

[0078] R1 is selected from benzene rings or thiazoles, wherein the hydrogen on the benzene rings or thiazoles may optionally be further replaced by 0 to 3 CN or F substituents.

[0079] R2 is selected from benzene rings or thiophene, wherein the hydrogen on the benzene rings or thiophene is optionally further replaced by 0 to 3 methyl, methoxy, or F groups.

[0080] This disclosure provides compounds having the general formula (I-2),

[0081]

[0082] The definitions of each substituent are consistent with the definitions above.

[0083] This disclosure provides compounds having the general formula (I-2a),

[0084]

[0085] Where W is the key.

[0086] In one aspect of this disclosure, Z1 and Z5 are each independently selected from N or = CR Z -, Z3 is N, Z4 is -NR3-.

[0087] In one aspect of this disclosure, R Z It is hydrogen.

[0088] In one aspect of this disclosure, ring A is

[0089] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-2b).

[0090]

[0091] The definitions of each substituent are consistent with the definitions above.

[0092] In one aspect of this disclosure, wherein:

[0093] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally replaced by hydrogen, halogen, CN, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S;

[0094] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0095] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N, -NH-, or -CR. Z -;

[0096] R Z Selected from hydrogen or C 1-6 alkyl;

[0097] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S;

[0098] m is selected from 0;

[0099] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by 0 to 2 NH2, -NHCH3, or methyl groups;

[0100] R Z Selected from H or methyl;

[0101] R1 is selected from benzene rings and thiazoles, wherein the hydrogen on the benzene rings and thiazoles is optionally replaced by 0 to 2 CN or F groups;

[0102] R2 is selected from a benzene ring, wherein the hydrogen on the benzene ring is optionally replaced by one or more methyl, methoxy, or F groups.

[0103] This disclosure provides compounds having the general formula (I-3),

[0104]

[0105] The definitions of each substituent are consistent with the definitions above.

[0106] This disclosure provides compounds having the general formula (I-3a),

[0107]

[0108] Among them, Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or = CR. Z -; W is the key.

[0109] In one aspect of this disclosure, Z2 is N, and Z1, Z3, Z4, and Z5 are each independently selected from N or = CR. Z -

[0110] In one aspect of this disclosure, R Z Selected from hydrogen, C 1-6 alkyl.

[0111] In one aspect of this disclosure, ring A is selected from:

[0112] This disclosure provides compounds having the general formula (I-3b),

[0113]

[0114] Among them, Z1, Z4, and Z5 are each independently selected from N or = CR Z -,Z3 is selected from O, S, -NR3- or -CRyR Z -; W is the key.

[0115] In one aspect of this disclosure, Z1 is N, Z3 is selected from O or -NR3-, and Z4 and Z5 are each independently selected from N or =CR. Z -; W is the key.

[0116] In one aspect of this disclosure, R Z It is hydrogen.

[0117] In one aspect of this disclosure, ring A is selected from:

[0118] This disclosure provides compounds having the general formula (I-3c),

[0119]

[0120] Among them, Z1, Z3, and Z4 are each independently selected from N or = CR Z -,Z5 is selected from O, S, -NR3- or -CRyR Z -; W is the key.

[0121] In one aspect of this disclosure, Z1 is N, and Z3 and Z4 are each independently selected from N or = CR. Z -, Z5 is -NR3-; W is a bond.

[0122] In one aspect of this disclosure, R Z It is hydrogen.

[0123] In one aspect of this disclosure, ring A is selected from:

[0124] This disclosure provides compounds having the general formula (I-3d):

[0125]

[0126] Z1 is selected from N or = CR Z -, Z3, Z4, and Z5 are each independently selected from O, S, -NR3-, or -CRyR Z -; W is the key.

[0127] In one aspect of this disclosure, Z1 is N, and Z3, Z4, and Z5 are each independently selected from O or -CRyR. Z -; W is the key.

[0128] In one aspect of this disclosure, Ry, R Z Both are hydrogen.

[0129] In one aspect of this disclosure, ring A is

[0130] In one aspect of this disclosure, the compound is selected from compounds represented by general formulas (I-3e).

[0131]

[0132] The definitions of each substituent are consistent with the definitions above.

[0133] In one aspect of this disclosure, ring B is selected from C. 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by 0 to 4 halogens, C, N, hydroxyl groups, C, N, C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S.

[0134] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group; R c R d They are not both methyl groups.

[0135] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or CR. Z .

[0136] R Z Selected from hydrogen or C 1-6 alkyl.

[0137] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S.

[0138] m is selected from 0.

[0139] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by one or more -NH2, -NHCH3 or methyl groups.

[0140] R Z Selected from hydrogen.

[0141] R1 is selected from benzene rings or thiazoles, wherein the hydrogen atoms on the benzene rings or thiazoles are optionally replaced by 0 to 2 CN or F groups.

[0142] R2 is selected from a benzene ring, wherein the hydrogen on the benzene ring is optionally replaced by 0 to 2 methyl, methoxy, or F groups.

[0143] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-4).

[0144]

[0145] The definitions of each substituent are consistent with the definitions above.

[0146] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-4a).

[0147]

[0148] Among them, Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or = CR. Z -; W is the key.

[0149] In one aspect of this disclosure, R Z It is hydrogen.

[0150] In one aspect of this disclosure, ring A is

[0151] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-4b).

[0152]

[0153] The definitions of each substituent are consistent with the definitions above.

[0154] In one aspect of this disclosure, wherein:

[0155] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally replaced by hydrogen, halogen, CN, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R dThe heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S;

[0156] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0157] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N, -NH-, or CR. Z ;

[0158] R Z Selected from hydrogen or C 1-6 alkyl;

[0159] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S;

[0160] m is selected from 0;

[0161] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by 0 to 2 -NH2, -NHCH3 or methyl groups;

[0162] R Z Selected from hydrogen;

[0163] R1 is selected from benzene rings and thiazoles, wherein the hydrogen on the benzene rings and thiazoles is optionally replaced by 0 to 2 CN or F groups;

[0164] R2 is selected from a benzene ring, wherein the hydrogen on the benzene ring is optionally replaced by 0 to 2 methyl, methoxy, or F groups.

[0165] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-5).

[0166]

[0167] The definitions of each substituent are consistent with the definitions above.

[0168] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-5a).

[0169]

[0170] Z1 is selected from N or = CR Z -, Z3, Z4, and Z5 are each independently selected from O, S, -NR3-, or -CRyR Z -; W is the key.

[0171] In one aspect of this disclosure, Z1 is N, and Z3, Z4, and Z5 are each independently selected from O, -NR3-, or -CRyR. Z -; W is the key.

[0172] In one aspect of this disclosure, Ry, R Z Both are hydrogen.

[0173] In one aspect of this disclosure, ring A is

[0174] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-6).

[0175]

[0176] The definitions of each substituent are consistent with the definitions above.

[0177] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-6a).

[0178]

[0179] Among them, Z1, Z2, and Z3 are each independently selected from N or = CR Z -

[0180] In one aspect of this disclosure, W is selected from key, n is selected from 0 or 1.

[0181] In one aspect of this disclosure, ring A is selected from:

[0182]

[0183] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-6b).

[0184]

[0185] Z1 is selected from N or = CR Z-,Z3 is selected from -NR3- or -CRyR Z -

[0186] In one aspect of this disclosure, Z1 is N and Z3 is -NR3-.

[0187] In one aspect of this disclosure, W is -NH-.

[0188] In one aspect of this disclosure, ring A is

[0189] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-6c).

[0190]

[0191] The definitions of each substituent are consistent with the definitions above.

[0192] In one aspect of this disclosure, wherein:

[0193] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by 0 to 4 F, CN, hydroxyl, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S;

[0194] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0195] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N, -NH-, or CR. Z ;

[0196] R Z Selected from hydrogen;

[0197] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 2 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6Alkoxy, C 5-10 The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S;

[0198] m is selected from 0;

[0199] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by one or more -NH2, hydroxyl, -NHCH3 or methyl groups;

[0200] R1 is selected from benzene rings and thiazoles, wherein the hydrogen on the benzene rings and thiazoles is optionally replaced by 0 to 2 CN or F groups;

[0201] R2 is selected from a benzene ring, wherein the hydrogen on the benzene ring is optionally replaced by 0 to 2 methyl, methoxy, or F groups.

[0202] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-6d).

[0203]

[0204] The definitions of each substituent are consistent with the definitions above.

[0205] In one aspect of this disclosure, wherein:

[0206] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by 0 to 4 F, CN, hydroxyl, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S;

[0207] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0208] Z1, Z2, Z3, Z4, and Z5 are each independently selected from N or CR. Z ;

[0209] R Z Selected from hydrogen, hydroxyl, C 1-6 alkoxy or

[0210] R a R b Selected from H;

[0211] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 The heterocyclic aryl, aryl, hydroxyl, or CN substituents are used to replace the heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, or S;

[0212] m is selected from 0;

[0213] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by one or more -NH2, hydroxyl, -NHCH3 or methyl groups;

[0214] R Z Selected from hydrogen, hydroxyl, methoxy or

[0215] R1 is selected from benzene rings and thiazoles, wherein the hydrogen on the benzene rings and thiazoles is optionally replaced by 0 to 2 CN or F groups;

[0216] R2 is selected from a benzene ring, wherein the hydrogen on the benzene ring is optionally replaced by 0 to 2 methyl, methoxy, or F groups.

[0217] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-7).

[0218]

[0219] The definitions of each substituent are consistent with the definitions above.

[0220] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-7a).

[0221]

[0222] Z1 is selected from N or = CR Z -

[0223] In one aspect of this disclosure, R Z It is hydrogen.

[0224] In one aspect of this disclosure, W is selected from key, r is 1.

[0225] In one aspect of this disclosure, ring A is selected from:

[0226] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-7b).

[0227]

[0228] The definitions of each substituent are consistent with the definitions above.

[0229] In one aspect of this disclosure, ring B is selected from C. 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by 0 to 4 F, CN, hydroxyl, or C atoms. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S.

[0230] R c R d Each element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0231] W is selected from -CH2-.

[0232] Z1 is selected from N or CR Z ;

[0233] R Z Selected from hydrogen or C 1-6 alkyl;

[0234] Y is selected from O or S;

[0235] R1 and R2 are each independently selected from C. 1-6 Alkyl, C 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10The heterocyclic aryl group is substituted with a substituent of heterocyclic aryl, aryl, hydroxyl, or CN, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O, or S;

[0236] m is selected from 0;

[0237] Preferably, ring B is selected from The above The hydrogen atoms are optionally replaced by one or more -NH2, hydroxyl, -NHCH3 or methyl groups;

[0238] Z1 is selected from CR Z ;

[0239] R Z Selected from hydrogen;

[0240] R1 is selected from methyl, benzene ring, pyrimidine, pyridine, and thiazole, wherein the hydrogen on the methyl, benzene ring, and thiazole is optionally replaced by 0 to 2 CN or F groups;

[0241] R2 is selected from methyl, benzene ring, pyridine, pyrimidine, Among them, methyl, benzene ring, pyridine, pyrimidine, The hydrogen atoms are optionally replaced by 0 to 2 methyl, methoxy, or F groups.

[0242] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-8).

[0243]

[0244] The definitions of each substituent are consistent with those above.

[0245] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-8a).

[0246]

[0247] Among them, Z1, Z2, and Z3 are each independently selected from N or = CR Z -

[0248] In one aspect of this disclosure, R Z Selected from hydrogen, C 1-6 Alkyl group.

[0249] In one aspect of this disclosure, W is selected from key,

[0250] In one aspect of this disclosure, X2 is -O-, p is selected from 0 or 1, q is selected from 1, 2, 3, 4, X1 is -NH-, R w For H.

[0251] In one aspect of this disclosure, ring A is selected from:

[0252] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-8b).

[0253]

[0254] Among them, Z1 and Z3 are each independently selected from N or = CR Z -, Z6 is selected from N or

[0255] In one aspect of this disclosure, R Z Selected from hydrogen, C 1-6 alkyl.

[0256] In one aspect of this disclosure, W is

[0257] In one aspect of this disclosure, p is 0, q is 3, X1 is -NH-, R w For H.

[0258] In one aspect of this disclosure, ring A is

[0259] In one aspect of this disclosure, ring B is selected from C. 6-10 Aryl, C 3-10 cycloalkyl, C 2-10 The heterocyclic alkyl group contains 1 to 2 N heteroatoms, and the cycloalkyl group or heterocyclic alkyl group is monocyclic, bicyclic, or polycyclic, wherein the bicyclic or polycyclic group is a bridged ring or a fused ring; and...

[0260] The hydrogen atoms on the aryl, cycloalkyl, or heterocycloalkyl ring are optionally selected from 0 to 2 halogens, -CN, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-10 Heterocyclic alkyl or -NR c R d The substituent is replaced by the C group, where C is the substituent. 2-10 Heterocyclic alkyl groups contain one to two heteroatoms selected from N and O, R c R d Each is independently selected from H and C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 alkyl.

[0261] In one aspect of this disclosure, ring B is selected from: R 11 Selected from H, C 1-6 Alkyl group, wherein the hydrogen on the ring is optionally selected from 0 to 2 hydrogens selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 6-membered heterocyclic alkyl or -NR c R d The substituent is replaced by a 6-membered heterocyclic alkyl group, wherein the 6-membered heterocyclic alkyl group containing 1 to 2 heteroatoms selected from N and O, R c R d Each is independently selected from H and C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-3 alkoxy-substituted C 1-3 alkyl.

[0262] In one aspect of this disclosure, R c R d Each is independently selected from H, methyl,

[0263] In one aspect of this disclosure, the hydrogen atoms on the ring are optionally selected from 0 to 2 atoms selected from -F, -CN, hydroxyl, methyl, methoxy, -NH2, -NHCH3, -N(CH3)2, ... The substituents are replaced by the substituents.

[0264] In one aspect of this disclosure, the compound is selected from compounds represented by general formula (I-8c).

[0265]

[0266] The definitions of each substituent are consistent with the definitions above.

[0267] In one aspect of this disclosure, wherein:

[0268] Ring B is selected from C 6-10 Aryl, C 3-10 heteroaryl, C 3-10 Heterocyclic alkyl groups, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally replaced by hydrogen, halogen, CN, hydroxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy or NR c R d The heteroaryl or heterocycloalkyl group is substituted with 1 to 3 heteroatoms, optionally selected from N, O or S;

[0269] R c R dEach element is independently selected from hydrogen, halogen, CN, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0270] W selected

[0271] X is selected from -NR X -;

[0272] R w R X Each is independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl group;

[0273] Z1, Z2, and Z3 are each independently selected from N or CR. Z ;

[0274] R Z Selected from hydrogen or C 1-6 alkyl;

[0275] R1 and R2 are each independently selected from C. 5-10 Heterocyclic aryl, C 6-10 Aryl, of which C 5-10 Heterocyclic aryl and aryl groups are each optionally surrounded by 0 to 4 F groups, amino groups, aminoalkyl groups, aminocycloalkyl groups, aminoheterocyclic groups, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 5-10 Heterocyclic aryl, aryl, hydroxyl, CN, S(O)2R a The heterocyclic aryl group is substituted with a substituent, wherein the heterocyclic aryl group contains 1 to 3 heteroatoms selected from N, O or S;

[0276] R a Selected from C 1-6 alkyl;

[0277] m is selected from 1;

[0278] q is selected from 1, 2, 3, or 4;

[0279] Preferably, ring B is selected from benzene rings, The benzene ring, The hydrogen atoms are optionally replaced by 0 to 4 -NH2, CN, F or methyl groups;

[0280] X is selected from -NH-;

[0281] R w Selected from H, C1-6 Alkyl, C 1-6 Alkyl or halogen;

[0282] R Z Selected from hydrogen;

[0283] R1 is selected from benzene ring, in which The hydrogen atoms on the benzene ring are optionally replaced by 0 to 2 methyl groups. Substituted with methoxy groups;

[0284] R2 is selected from benzene rings, Among them, benzene ring, The hydrogen atom is optionally replaced by 0 to 2 methyl, methoxy, F, What it replaced.

[0285] In one aspect of this disclosure, ring B is selected from:

[0286] Preferably, ring B is selected from:

[0287]

[0288] In one aspect of this disclosure, ring B is selected from... Preferably, R c R d Each is independently selected from H and C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl; more preferably, R c R d Both are hydrogen.

[0289] In one aspect of this disclosure, one of R1 and R2 is hydrogen.

[0290] In one aspect of this disclosure, one of R1 and R2 is optionally selected from 0 to 1 C. 6-10 Aryl, 5-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 The C substituents of heterocyclic alkyl groups 1-6 Alkyl, the C 6-10 Aryl, 5-10 heteroaryl, C 3-10 cycloalkyl, C 2-10 The heterocyclic alkyl group is further optionally selected from 0 to 2 ions chosen from halogens, C 1-6The alkoxy group is replaced by a substituent, and the 5-10 membered heteroaryl group, C 2-10 Heterocyclic alkyl groups contain 1 to 3 heteroatoms selected from N, O, or S;

[0291] Preferably, one of R1 and R2 is a methyl group optionally substituted with 0 to 1 substituent selected from phenyl or 6-membered heterocyclic alkyl groups, wherein the phenyl or 6-membered heterocyclic alkyl group is further optionally substituted with 0 to 2 substituents selected from halogen or C. 1-6 The 6-membered heterocyclic alkyl group is substituted by an alkoxy group and contains one or two heteroatoms selected from N or O;

[0292] More preferably, one of R1 and R2 is selected from methyl,

[0293] In one aspect of this disclosure, one of R1 and R2 is optionally selected from 0 to 1 C. 6-10 C substituted by aryl or 5-10 heteroaryl substituents 2-6 alkynyl group, the C 6-10 Aryl, 5-10 heteroaryl groups are further optionally selected by 0 to 2 halogens, C 1-6 The 5-10 membered heteroaryl group is substituted by an alkoxy group and contains 1 to 3 heteroatoms selected from N, O or S;

[0294] Preferably, one of R1 and R2 is an acetylene group optionally substituted with 0 to 1 phenyl group, wherein the phenyl group is further optionally substituted with 0 to 2 hydroxyl groups selected from halogens, C 1-6 Substituents of alkoxy groups;

[0295] More preferably, one of R1 and R2 is

[0296] In one aspect of this disclosure, R1 and / or R2 are C 2-10 Heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally composed of 0 to 2 C-membered molecules. 1-6 Alkyl groups, -S(O)2R6, halogens, -COOH, -C(=O)OC 1-6 The alkyl group is substituted, and R6 is selected from C6. 1-6 Alkyl group, -NH2, wherein the heterocyclic alkyl group contains 1 to 2 heteroatoms selected from N or O; preferably, the heterocyclic alkyl group is a 6-membered heterocyclic alkyl group; more preferably, R1 and / or R2 are selected from...

[0297] In one aspect of this disclosure, R1 and / or R2 are selected from C. 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 Aryl, -O (5-10 heteroaryl), C6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl, the C 6-10 Aryl, 5-10 heteroaryl, -OC 6-10 Aryl, -O (5-10 heteroaryl), C 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl groups are optionally surrounded by 0 to 4 groups selected from -CN, -CH2CN, halogens, -S(O)2R6, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl, C 1-6 alkoxy- or halogen-substituted C 1-6 C-substituted with alkoxy, -NH2, or hydroxyl groups 1-6 Alkyl, hydroxyl substituted C 2-6 C with alkynyl or hydroxyl substitution 1-6 Alkoxy, 5-10 membered heteroaryl, C 2-10 The C is replaced by a substituent of a heterocyclic alkyl group. 6-10 Aryl benzo[C] 2-10 Heterocyclic alkyl groups can also be substituted with =O, wherein the heteroaryl or heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O, or S, and R6 is selected from C. 1-6 Alkyl group, -NH2;

[0298] Preferably, R1 and / or R2 are selected from phenyl, 5-10-membered heteroaryl, phenoxy, and benzo5-membered heterocyclic alkyl, wherein the phenyl, 5-10-membered heteroaryl, phenoxy, and benzo5-membered heterocyclic alkyl are optionally replaced by 0 to 4 elements selected from -CN, -CH2CN, halogen, -S(O)2R6, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, hydroxyl, C 1-6 alkoxy- or halogen-substituted C 1-6 C-substituted with alkoxy, -NH2, or hydroxyl groups 1-6 Alkyl, hydroxyl substituted C 2-6 C with alkynyl or hydroxyl substitution 1-6 The benzo[5] 5-membered heterocyclic alkyl group is substituted with an alkoxy group, a 5-6-membered heteroaryl group, or a 5-6-membered heterocyclic alkyl group. The benzo[5] 5-membered heterocyclic alkyl group may also be substituted with =O. The heteroaryl group or heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O, or S, and R6 is selected from C. 1-6 Alkyl group, -NH2;

[0299] Preferably, R1 and / or R2 are selected from phenyl, 5-10-membered heteroaryl, phenoxy, benzo5-membered heterocyclic alkyl, wherein the phenyl, 5-10-membered heteroaryl, phenoxy, benzo5-membered heterocyclic alkyl are optionally replaced by 0 to 4 elements selected from -CN, -CH2CN, -F, -Cl, -S(O)2R6, methyl, pentyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, -NH2, The benzo5-membered heterocyclic alkyl group is replaced by a substituent, and can also be replaced by =O. The heteroaryl or heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, O or S, and R6 is selected from methyl or -NH2.

[0300] More preferably, R1 and / or R2 are selected from:

[0301]

[0302]

[0303]

[0304] More preferably, R1 and / or R2 are selected from:

[0305]

[0306]

[0307] In one aspect of this disclosure, one of R1 and R2 is -NR4R5, and R4 and R5 are each independently selected from H and C. 1-6 Alkyl, -NH2-substituted C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 6-10 Aryl, 5-10 heteroaryl, said C 6-10 Aryl, 5-10 aryl groups, 0 to 4 of which are selected from halogens, C 1-6 The C is replaced by an alkoxy substituent. 2-10 Heterocyclic alkyl groups and 5-10-membered heteroaryl groups contain 1 to 3 heteroatoms selected from N, O or S;

[0308] Preferably, R4 and R5 are each independently selected from H and C. 1-6 Alkyl, -NH2-substituted C 1-6 Alkyl, 6-membered heterocyclic alkyl, phenyl, wherein the phenyl is optionally surrounded by 0 to 2 elements selected from halogens, C 1-6 The 6-membered heterocyclic alkyl group is substituted by an alkoxy group and contains one or two heteroatoms selected from N or O;

[0309] More preferably, one of R1 and R2 is selected from...

[0310] In one aspect of this disclosure, one of R1 and R2 is selected from C. 3-10 cycloalkyl, C 2-10 Heterocyclic alkyl, C 3-10 Cycloalkenyl, C 2-10Heterocyclic alkenyl groups, wherein the above groups are optionally surrounded by 0 to 4 groups selected from halogens, -CN, hydroxyl groups, C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Substituents include alkoxy groups and =O groups;

[0311] Preferably, one of R1 and R2 is selected from C. 3-10 cycloalkyl, C 2-10 Heterocyclic alkenyl groups, wherein the above groups are optionally surrounded by 0 to 4 groups selected from -CN, C 1-6 Alkyl groups and =O substituents are used;

[0312] Preferably, one of R1 and R2 is selected from... The above groups are optionally replaced by 0 to 2 elements selected from -CN, C 1-6 Alkyl groups and =O substituents are used;

[0313] More preferably, one of R1 and R2 is selected from...

[0314] This disclosure provides the following compounds:

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] This disclosure provides a pharmaceutical composition comprising a therapeutically effective dose of the compound described above or in the form of its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, deuterated isotope derivatives, pharmaceutically acceptable hydrates, solvates, salts, or cocrystals, and pharmaceutically acceptable carriers, diluents, adjuvants, mediators, or excipients; the composition may further comprise one or more other therapeutic agents.

[0332] This disclosure provides the use of the compounds described above, or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, deuterated isotope derivatives, pharmaceutically acceptable hydrates, solvates, salts, or cocrystals, and the compositions described above, in the preparation of LSD1 inhibitor-related pharmaceuticals.

[0333] In one aspect of this disclosure, the LSD1 inhibitor-related drug is a drug for treating tumors; preferably, the LSD1 inhibitor-related drug is a drug for treating lung cancer; more preferably, the LSD1 inhibitor-related drug is a drug for treating small cell lung cancer.

[0334] In one aspect of this disclosure, wherein,

[0335] Ring A is selected from

[0336] Ring B is selected from The above The hydrogen atoms in the group may optionally be replaced by 0 to 4 halogens, NH2, -NHCH3 or methyl groups;

[0337] Preferably, ring B is selected from

[0338] W is selected from the bond, -CH2-,

[0339] R1 and / or R2 are selected from:

[0340]

[0341] Detailed Implementation

[0342] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0343] I. Definition

[0344] The terms “comprising,” “including,” or “containing,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing terms such as “comprising” encompass the meaning of “consisting of.”

[0345] The term "one or more" or similar expression "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0346] The term "aryl" refers to a monocyclic or fused-ring aromatic group with a conjugated π-electron system. As used herein, the term "C" refers to a carbon-based monocyclic or fused-ring aromatic group. 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl groups can be optionally substituted with one or more suitable substituents, such as cyano (CN), halogens (F, Cl, Br).

[0347] 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 benzofused. As used herein, the term "5-10-membered heteroaryl" means a monocyclic, bicyclic, or tricyclic aromatic ring system having 5-10 ring atoms, and containing at least one heteroatom, which may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur). The heteroaryl group may optionally be substituted with one or more suitable substituents, such as cyano (CN) or halogens (F, Cl, Br).

[0348] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [2.2.1]heptyl, etc.). As used herein, the term "C" refers to a saturated monocyclic or polycyclic (e.g., bicyclic [2.2.1]heptyl, etc.). 3-10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) having 3 to 10 cyclic carbon atoms. Cycloalkyl groups may optionally be substituted with one or more suitable substituents.

[0349] The term "heterocyclic alkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more heteroatoms in the ring; the heterocyclic alkyl group may be attached to the remainder of the molecule through any one of the carbon atoms or the heteroatom. As used herein, the term C 2-10 Heterocyclic alkyl groups are saturated monocyclic or polycyclic (e.g., bicyclic) groups having 2-10 cyclic carbon atoms in a ring, and containing at least one heteroatom that may be the same or different (the heteroatom is, for example, oxygen, nitrogen, or sulfur). Heterocyclic alkyl groups may optionally be substituted with one or more suitable substituents.

[0350] The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring containing at least one carbon-carbon double bond (i.e., C=C). As used herein, the term C... 3-10 Cycloalkenyl refers to unsaturated non-aromatic alicyclic hydrocarbons having 3 to 10 cyclic carbon atoms, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. The cycloalkenyl group may optionally be substituted by one or more suitable substituents.

[0351] The term "heterocyclic alkenyl" refers to a class of cyclic alkenyl groups as defined above, wherein at least one carbon atom in the cyclic group is replaced by a heteroatom, such as nitrogen, oxygen, or sulfur. 2-10 Examples of heterocyclic alkenyl groups include, but are not limited to, tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, etc., and can be monocyclic or polycyclic (e.g., bicyclic) groups. The heterocyclic alkenyl group may optionally be substituted with one or more suitable substituents.

[0352] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0353] The term "amino" refers to -NH2.

[0354] The term "hydroxyl group" refers to -OH.

[0355] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. As used herein, the term "C" refers to... 1-6 "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0356] 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. Those skilled in the art will understand that when there are more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. As used herein, the term "halogen-substituted C 1-6 "alkyl" refers to C 1-6 One or more hydrogen atoms in an alkyl group are replaced by halogens, such as trifluoromethyl.

[0357] The term "hydroxyl-substituted alkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group. As used herein, the term "hydroxyl-substituted C" refers to... 1-6 "alkyl" refers to C 1-6 One or more hydrogen atoms in an alkyl group are replaced by a hydroxyl group, for example...

[0358] The term "amino (-NH2)-substituted alkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by an amino group (-NH2). As used herein, the term "amino (-NH2)-substituted C 1-6 "alkyl" refers to C 1-6 One or more hydrogen atoms in an alkyl group are replaced by an amino group (-NH2), for example...

[0359] The term "alkoxy-substituted alkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by an alkoxy group. As used herein, the term "C 1-6 alkoxy-substituted C 1-6 "alkyl" refers to C 1-6 One or more hydrogen atoms in an alkyl group are C 1-6 Alkoxy substitution, term "C" 1-3 alkoxy-substituted C 1-3 "alkyl" refers to C 1-3 One or more hydrogen atoms in an alkyl group are C 1-3 Alkoxy substitution, for example

[0360] The term "alkoxy" refers to an alkyl group connected to an oxygen atom as defined above; that is, an "alkoxy" group can be defined as -OR, where 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, and n-hexoxy.

[0361] The term "halogen-substituted alkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. Those skilled in the art will understand that when there are more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different carbon atoms. As used herein, the term "halogen-substituted carbon" refers to... 1-6 "Alkoxy" refers to C 1-6 One or more hydrogen atoms in an alkoxy group are replaced by halogens, such as difluoromethoxy and trifluoromethoxy.

[0362] The term "aryl-substituted alkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by an aryl group. As used herein, the term "C 6-10 aryl-substituted C 1-6 "Alkoxy" refers to C 1-6 One or more hydrogen atoms in the alkoxy group are C 6-10 Aryl substitution, such as benzyloxy

[0363] The term "hydroxyl-substituted alkoxy" refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group. As used herein, the term "hydroxyl-substituted C" refers to... 1-6 "Alkoxy" refers to C 1-6 In an alkoxy group, one or more hydrogen atoms are replaced by a hydroxyl group, for example...

[0364] The term "-O cycloalkyl" refers to a cycloalkyl group linked by an oxygen atom to a cycloalkyl group as defined above; that is, a "-O cycloalkyl" group can be defined as -OR, where R is a cycloalkyl group as defined above. As used herein, the term "-OC"... 3-10 Examples of "cycloalkyl" can be, for example, cyclopentoxy.

[0365] The term "-O aryl" refers to an aryl group linked to an oxygen atom as defined above; that is, a "-O aryl" group can be defined as -OR, where R is an aryl group as defined above. As used herein, the term "-OC"... 6-10 Examples of "aryl" can be, for example, phenoxy.

[0366] The term "-O heteroaryl" refers to a heteroaryl group that is attached to an oxygen atom as defined above. That is, the "-O heteroaryl" group can be defined as -OR, where R is a heteroaryl group as defined above.

[0367] The term "alkenyl" refers to a straight-chain 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 on the hydrocarbon chain. As used herein, the term "C" refers to... 2-6"Alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms, such as vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, etc. Alkenyl groups can be optionally substituted by one or more suitable substituents.

[0368] The term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group containing at least one C≡C triple bond. The triple bond can be located in any possible position on the hydrocarbon chain. As used herein, the term "C" refers to... 2-6 "Alynyl" refers to an alkynyl group containing 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl group can be optionally substituted by one or more suitable substituents.

[0369] The term "hydroxylated alkynyl" refers to an alkynyl group as defined above, wherein one or more hydrogen atoms are replaced by a hydroxyl group. As used herein, the term "hydroxylated C" refers to... 2-6 "Alkyne group" refers to C 2-6 In an alkynyl group, one or more hydrogen atoms are replaced by a hydroxyl group, for example...

[0370] The term "aminoalkyl", when used alone or in combination with other groups in this document, refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by amino groups.

[0371] The term "aminocycloalkyl", when used alone or in combination with other groups herein, refers to the cycloalkyl group described above, wherein one or more hydrogen atoms are replaced by amino groups.

[0372] The term "aminoheterocyclic alkyl", when used alone or in combination with other groups in this document, refers to the heterocyclic alkyl group described above, wherein one or more hydrogen atoms are replaced by amino groups.

[0373] The term "substituted" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0374] The term "optional substitution" refers to the optional substitution by a specific group, radical, or part thereof.

[0375] 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 atom in a group is described as being optionally substituted with one or more substituents, one or more hydrogen atoms on the carbon atom (to the extent that any hydrogen atoms are present) may be substituted individually and / or together with independently selected substituents or be unsubstituted. If a nitrogen atom in a group is described as being optionally substituted with one or more substituents, one or more hydrogen atoms on the nitrogen atom (to the extent that any hydrogen atoms are present) may each be substituted with independently selected substituents or be unsubstituted.

[0376] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0377] This indicates the presence or absence of double bonds at any position within the ring, implying a range of possibilities including saturated ring systems, unsaturated non-aromatic ring systems with double bonds, and aromatic ring systems.

[0378] The compounds of the present invention may also contain one or more (e.g., one, two, three or four) isotope substitutions.

[0379] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention 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-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. The scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0380] Pharmaceutically acceptable salts of the compounds disclosed herein may include acid addition salts and base salts of the compounds. Suitable acid addition salts are formed by acids that form non-toxic salts. Examples include acetates, aspartate salts, benzoates, benzenesulfonates, bicarbonates / carbonates, hydrogen sulfates / sulfates, borates, camphorsulfonates, citrates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hymenates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethanesulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthates, 1,5-naphthalenedisulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, glycosides, stearates, succinates, tartrates, toluenesulfonates, and trifluoroacetates. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzylamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, aminobutanetriol, and zinc salts. Hemisalts that form both acids and bases can also be formed, such as hemisulfates and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0381] II. Examples

[0382] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0383] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in ppm. NMR was determined using an AVANCE NEO 400MHz Bruker instrument with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as the internal standard. MS was determined using an ISQ-EC Thermo Fisher LC-MS instrument. The preparative HPLC was performed using a GX-281 Gilson chromatograph. Separation methods included: (1) Sun Prep C18OBDTM 5μL, 30x 150mm Column, 0.04% HCl aqueous solution / acetonitrile; (2) Sun Prep C18OBDTM 5μL, 30x 150mm Column, 0.02% TFA aqueous solution / acetonitrile; (3) Sun Prep C18OBDTM 5μL, 30x 150mm Column, 0.06% formic acid aqueous solution / acetonitrile; (4) PrepC18OBDTM 5μL, 30x 150mm column, 10mM NH4HCO3 aqueous solution / acetonitrile; (5) Prep C18OBDTM 5μL, 30x 150mm Column, 0.6% NH3.H2O aqueous solution / acetonitrile.

[0384] The solvent used in this invention is commercially available.

[0385] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0386] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0387] HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate;

[0388] DIPEA refers to diisopropylethylamine;

[0389] DMSO refers to dimethyl sulfoxide;

[0390] Pd2(dba)3 refers to tris(dibenzylacetone)dipalladium;

[0391] DCE refers to dichloroethane;

[0392] DCM refers to dichloromethane;

[0393] DMF stands for N,N-dimethylformamide;

[0394] NMP refers to N-methylpyrrolidone;

[0395] TFA refers to trifluoroacetic acid;

[0396] NBS refers to N-bromosuccinimide;

[0397] TfOH refers to trifluoromethanesulfonic acid;

[0398] DPPA refers to diphenyl azidophosphate.

[0399] Example 1

[0400] Preparation of (6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-2-phenylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[0401]

[0402] Step a): Preparation of methyl 6-methyl-2-phenylpyrimidine-4-carboxylic acid ester

[0403] Methyl 2-chloro-6-methylpyrimidin-4-carboxylic acid ester (1.0 g, 5.3 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), P(t-Bu)3 (1.95 g, 9.6 mmol), KF (934 mg, 9.3 mmol), and phenylboronic acid (1.044 g, 8.0 mmol) were rapidly added to a flask, followed by the addition of tetrahydrofuran (10 mL) using a syringe. The flask was then removed and backfilled with nitrogen three times, and the mixture was stirred at 90 °C for 8 h under a nitrogen atmosphere. When LC-MS showed that the reaction was complete, the crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give methyl 6-methyl-2-phenylpyrimidin-4-carboxylic acid ester, in 98.1% yield.

[0404] 1 H NMR (400MHz, DMSO-d6) δppm 8.40 (dd, J=4.8, 2.8Hz, 2H), 7.83 (m, 1H), 7.60-7.39 (m, 3H), 3.94 (m, 3H), 2.62 (m, 3H).

[0405] ESI-MS m / z: 229.1 [M+H] + .

[0406] Step b): Preparation of 6-methyl-2-phenylpyrimidine-4-carboxylic acid

[0407] Methyl 6-methyl-2-phenylpyrimidine-4-carboxylic acid (1.2 g, 5.2 mmol) was dissolved in tetrahydrofuran (10 mL). An aqueous solution of LiOH-H₂O (0.88 g, 21.1 mmol) was added at 0 °C, and the mixture was stirred for 0.5 hours, then heated to room temperature and stirred for 4 hours. When LS-MS showed complete reaction, impurities were extracted with petroleum ether / ethyl acetate (4:1, 20 mL). The pH of the aqueous phase was adjusted to approximately 4-5 using HCl (1 N), and the product solution was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-methyl-2-phenylpyrimidine-4-carboxylic acid, with a yield of 80.7%.

[0408] 1H NMR (400MHz, DMSO-d6) δppm 13.79 (s, 1H), 8.47 (dt, J = 7.4, 3.6Hz, 2H), 7.83 (s, 1H), 7.66-7.45 (m, 3H), 2.65 (s, 3H).

[0409] ESI-MS m / z: 214.2 [M+H] + .

[0410] Step c): Preparation of (6-methyl-2-phenylpyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0411] 6-Methyl-2-phenylpyrimidin-4-carboxylic acid (1.0 g, 4.8 mmol) and 1-(methanesulfonyl)piperazine (782 mg, 4.8 mmol) were added to DMF (20 mL). HATU (1.81 g, 4.8 mmol) and DIPEA (1.54 g, 11.9 mmol) were added at 0 °C. The reaction was stirred at room temperature for 1 h. LC-MS showed that the reaction was complete. The reaction was quenched with 40 mL of water and extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 7) to give (6-methyl-2-phenylpyrimidin-4-yl)(4-(methanesulfonyl)piperazine-1-yl) methyl ketone, yield 87.5%.

[0412] 1 H NMR(400MHz,DMSO-d6)δppm 8.40(dt,J=7.8,3.8Hz,2H),7.65-7.47(m,4H),3.86-3.73(m,2H),3.66-3.53 (m,2H),3.32-3.25(m,2H),3.19(d,J=26.8Hz,2H),2.95(s,3H),2.62(s,3H).

[0413] ESI-MS m / z: 361.4 [M+H] + .

[0414] Step d): Preparation of 6-(4-(methanesulfonyl)piperazine-1-carbonyl)-2-phenylpyrimidine-4-carboxaldehyde

[0415] (6-Methyl-2-phenylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (500 mg, 1.4 mmol) and SeO2 (740 mg, 6.66 mmol) were added to a reaction flask containing 1,4-dioxane (15 mL). The reaction temperature was raised to 110 °C and stirred for 8 h. LC-MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution (40 mL), extracted with ethyl acetate (40 mL × 2), and the organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(4-(methanesulfonyl)piperazin-1-carbonyl)-2-phenylpyrimidin-4-carboxaldehyde, with a yield of 66.4%.

[0416] 1 H NMR(400MHz,DMSO-d6)δppm 10.07(s,1H),8.56-8.31(m,2H),7.93(s,1H),7.77-7.47(m,3H),3.89-3.71(m,2H),3.70-3.53(m,2H),3.35 -3.15(m,4H),2.95(s,3H).

[0417] ESI-MS m / z: 393 [M+H2O] + .

[0418] Step e): Preparation of (6-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-2-phenylpyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0419] 6-(4-(methylsulfonyl)piperazin-1-carbonyl)-2-phenylpyrimidin-4-carboxaldehyde (100 mg, 0.27 mmol) was added to DCE (2 mL), and stirred at 25 °C for 3 h. Then, MeOH (0.8 mL), AcOH (0.1 mL), and (1R,2S)-2-(4-fluorophenyl)cyclopropyl-1-amine (60 mg, 0.27 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 h. When LC-MS showed complete reaction, NaBH3CN (67 mg, 1.07 mmol) was added. After LC-MS showed complete reaction, the crude product was concentrated and sent to Prep-HPLC for further preparation (separation method 4) to obtain (6-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-2-phenylpyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl) methyl ketone, yield 18.5%.

[0420] 1H NMR(400MHz,Methanol-d4)δppm 8.44(d,J=7.6Hz,2H),7.58-7.43(m,4H),7.02(dd,J=8.2,5.6Hz,2H),6.9 0(t,J=8.6Hz,2H),4.12(s,2H),4.07-3.84(m,2H),3.74-3.63(m,2H),3.5 9-3.38(m,2H),3.40(d,J=5.0Hz,2H),2.90(s,3H),2.42(dt,J=7.2,3.8Hz ,1H),2.32-1.91(m,1H),1.22-1.09(m,1H),1.00(dd,J=12.4,6.2Hz,1H).

[0421] ESI-MS m / z: 510.2 [M+H] + .

[0422] Example 2

[0423] Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0424]

[0425] Step a): Preparation of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-carboxylic acid

[0426] Methyl 2-chloro-6-methylpyrimidin-4-carboxylic acid ester (1 g, 5.3 mmol), Pd2(dba)3 (73 mg, 0.08 mmol), P(t-Bu)3 (1.95 g, 9.6 mmol), KF (934 mg, 9.3 mmol), and (4-(1H-pyrazol-1-yl)phenyl)boronic acid (1.5 g, 8.0 mmol) were rapidly added to a flask, followed by the addition of tetrahydrofuran (10 mL) using a syringe. The flask was then removed and backfilled with nitrogen three times, and the mixture was stirred at 90 °C for 8 h under a nitrogen atmosphere. When the reaction was complete as indicated by LC-MS, the crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-carboxylic acid ester, in 84.9% yield.

[0427] 1H NMR (400MHz, DMSO-d6) δppm 8.85-8.36(m,3H),8.24-7.67(m,4H),6.60(s,1H),3.96(s,3H),2.65(s,3H).

[0428] ESI-MS m / z: 295.2 [M+H] + .

[0429] Step b): Preparation of 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidine-4-carboxylic acid

[0430] Methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-carboxylic acid (1.5 g, 5.1 mmol) was added to tetrahydrofuran (10 mL). At 0 °C, an aqueous solution of LiOH-H₂O (299 mg, 7.14 mmol) was added to the mixture. After stirring for 0.5 hours, the mixture was brought to room temperature and stirred for another 4 hours. When LS-MS showed complete reaction, impurities were extracted with petroleum ether / ethyl acetate at a ratio of 4:1 (20 mL). The pH of the aqueous phase was adjusted to approximately 4-5 using HCl (1N), and the product solution was extracted with ethyl acetate (20 mL × 3). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-carboxylic acid, in 89.5% yield.

[0431] 1 H NMR (400MHz, DMSO-d6) δppm 13.82 (s, 1H), 8.60 (dd, J = 27.4, 5.6Hz, 3H), 8.04 (d, J = 8.8Hz, 2H), 7.82 (s, 2H), 6.61 (d, J = 1.8Hz, 1H), 2.66 (s, 3H).

[0432] ESI-MS m / z: 281.1 [M+H] + .

[0433] Step c): Preparation of (2-(4-(1h-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0434] 2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-carboxylic acid (900 mg, 3.21 mmol) and 1-(methanesulfonyl)piperazine (633 mg, 3.85 mmol) were dissolved in DMF (20 mL). HATU (1.470 g, 3.85 mmol) and DIPEA (1.25 g, 9.64 mmol) were added at 0 °C. The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction... Completely quenched with 40 mL of water, extracted with ethyl acetate (40 mL × 2), combined organic phases, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated to obtain crude product, the residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 7) to give (2-(4-(1h-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, yield 86.3%.

[0435] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(d,J=2.6Hz,1H),8.50(d,J=8.8Hz,2H),8.01(t,J=18.5Hz,2H),7.82(d,J=1.4Hz,1H),7.50(s,1H),6.61(t,J =1.8Hz,1H),3.86-3.76(m,2H),3.67-3.54(m,2H),3.32-3.25(m,2H),3.25-3.17(m,2H),2.96(s,3H),2.63(s,3H).

[0436] ESI-MS m / z: 427.3 [M+H] + .

[0437] Step d): Preparation of 2-(4-(1h-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidine-4-carboxaldehyde

[0438] (2-(4-(1h-pyrazol-1-yl)phenyl)-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone (1.2 g, 2.8 mmol) was added to 1,4-dioxane (25 mL), and SeO2 (6.66 g, 60 mmol) was added at 25 °C. The reaction was heated to 110 °C and stirred for 8 h. LC-MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate aqueous solution (40 mL), extracted with ethyl acetate (40 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 2-(4-(1h-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-carboxaldehyde, with a yield of 65.8%.

[0439] 1 H NMR(400MHz,DMSO-d6)δppm 10.09(s,1H),8.69-8.43(m,3H),8.17-7.99(m,2H),7.94-7.76(m,1H),6.74-6.47(m,1H),3.94 -3.70(m,2H),3.61(dd,J=15.8,10.9Hz,2H),3.40-3.24(m,4H),3.24-3.12(m,2H),2.96(s,3H).

[0440] ESI-MS m / z: 459.2 [M+H2O] + .

[0441] Step e): Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0442] 2-(4-(1h-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidine-4-carboxaldehyde (100 mg, 0.23 mmol) was added to DCE (2 mg). In L), after stirring at 25°C for 3 h, MeOH (0.5 mL), AcOH (0.1 mL), and (1R,2S)-2-(4-fluorophenyl)cyclopropyl-1-amine (51 mg, 0.23 mmol) were added. When TLC showed that the starting material was completely consumed, NaBH3CN (57 mg, 0.91 mmol) was added. After stirring at room temperature for 2 h, and LC-MS showed that the reaction was complete, the crude product was concentrated and sent to Prep-HPLC for preparation (separation method 4) to obtain (2-(4-(1H-pyrazol-1-yl)phenyl)-6-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, with a yield of 20.2%.

[0443] 1 H NMR(400MHz,Methanol-d4)δppm 8.57(d,J=8.6Hz,2H),8.34(d,J=2.2Hz,1H),7.90(d,J=8.6Hz,2H),7.78(s,1H),7.56(s,1H),7.02(dd,J=8.2,5.6Hz,2H),6.91(t,J=8.6Hz,2 H),6.58(s,1H),4.13(s,2H),4.05-3.87(m,2H),3.81-3.63(m,2H),3.5 0-3.35(m,4H),2.91(s,3H),2.57-2.20(m,1H),2.01-1.84(m,1H),1.28

[0444] -0.81(m,2H).

[0445] ESI-MS m / z: 576.2 [M+H] + .

[0446] Example 3

[0447] Preparation of (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile

[0448]

[0449] Step a): Preparation of methyl 4-(4-cyanophenyl)-1H-pyrrole-2-carboxylic acid

[0450] Methyl 4-bromo-1H-pyrrole-2-carboxylate (1.0 g, 4.9 mmol), (4-cyanophenyl)boronic acid (1.1 g, 7.4 mmol), Cs₂CO₃ (4.8 g, 14.7 mmol), and Pd(dppf)Cl₂ (358 mg, 0.5 mmol) were added to 20 mL of dioxane, followed by 4 mL of water. The mixture was purged with nitrogen under nitrogen protection. The reaction was carried out in a microwave reactor at 110 °C for 1 h. After the reaction was confirmed to be complete by LC-MS, the crude product was concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 4) to give methyl 4-(4-cyanophenyl)-1H-pyrrole-2-carboxylate, with a yield of 53.1%.

[0451] 1 H NMR (400MHz, DMSO-d6) δppm 12.30 (s, 1H), 7.85 (d, J = 8.4Hz, 2H), 7.78-7.70 (m, 3H), 7.34 (d, J = 1.7Hz, 1H), 3.80 (s, 3H).

[0452] ESI-MS m / z: 227.1 [M+H] + .

[0453] Step b): Preparation of methyl 5-bromo-4-(4-cyanophenyl)-1H-pyrrole-2-carboxylic acid

[0454] Methyl 4-(4-cyanophenyl)-1H-pyrrole-2-carboxylic acid (4.5 g, 19.9 mmol) was dissolved in DMF (50 mL), cooled to 0 °C, and NBS (3.7 g, 20.9 mmol) was added in portions. The reaction was carried out at 0 °C for 1 h. When the LCMS showed that the reaction was complete, 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 the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 9) to give methyl 5-bromo-4-(4-cyanophenyl)-1H-pyrrole-2-carboxylic acid, with a yield of 60.8%.

[0455] 1 H NMR (400MHz, DMSO-d6) δppm 13.12 (s, 1H), 7.89-7.80 (m, 4H), 7.21 (s, 1H), 3.81 (s, 3H).

[0456] ESI-MS m / z: 304.9 [M+H] + .

[0457] Step c): Preparation of methyl 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxylic acid

[0458] Methyl 5-bromo-4-(4-cyanophenyl)-1H-pyrrole-2-carboxylic acid (3.7 g, 12.1 mmol), p-tolylboronic acid (2.5 g, 18.2 mmol), Na₂CO₃ (3.8 g, 36.3 mmol), and Pd(dppf)Cl₂ (880 mg, 1.2 mmol) were added to 80 mL of DMF. The mixture was purged with nitrogen three times and reacted at 110 °C for 12 hours. When the reaction was complete as indicated by LC-MS, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1) to give methyl 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxylic acid, with a yield of 78.5%.

[0459] 1 H NMR(400MHz,DMSO-d6)δppm 12.31(s,1H),7.79-7.66(m,3H),7.42-7.36(m,2H),7.25(d,J=8.2Hz,2H),7.21-7.17(m,2H),3.81(s,3H),2.33(s,3H).

[0460] ESI-MS m / z: 317.1 [M+H] + .

[0461] Step d): Preparation of 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxamide

[0462] Methyl 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxylic acid (1.0 g, 3.16 mmol) was dissolved in 20 mL of 7M ammonia in methanol. The solution was placed in a sealed container and reacted at 100 °C for 12 hours. When the reaction was complete as indicated by LC-MS, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1) to give 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxamide, in a yield of 22.1%.

[0463] 1H NMR(400MHz,DMSO-d6)δppm 11.06(s,1H),10.90(d,J=1.8Hz,1H),8.30(q,J=4.2,3.6Hz,2H),8.15(dd,J=8.4,1.2 Hz, 2H), 7.61 (t, J = 7.8 Hz, 3H), 7.25 (t, J = 7.6 Hz, 1H), 7.19-7.14 (m, 1H), 2.31 (s, 3H).

[0464] ESI-MS m / z: 302.1 [M+H] + .

[0465] Step e): Preparation of 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile

[0466] 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrolo-2-carboxamide (200 mg, 0.66 mmol) was dissolved in 5 mL of DMF, and 2-bromo-1,1-dimethoxyethane (225 mg, 1.3 mmol) and Cs₂CO₃ (648 mg, 1.99 mmol) were added. The mixture was heated to 100 °C and reacted for 24 h. When the reaction was complete as indicated by LCMS, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile, with a yield of 60.6%.

[0467] ESI-MS m / z: 326.1 [M+H] + .

[0468] Step f): Preparation of 4-(1-chloro-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile

[0469] 120 mg (0.37 mmol) of 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile was dissolved in 5 mL of 1,2-dichloroethane, and 2.5 mL of phosphorus oxychloride was added. The mixture was heated to 80 °C and reacted for 8 h. After the reaction was complete as indicated by LC-MS, the mixture was concentrated under vacuum, and the solid was dissolved in 3 mL of anhydrous dichloromethane. 0.2 mL of triethylamine was added, and the mixture was concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give 62.2% 4-(1-chloro-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile.

[0470] ESI-MS m / z: 344.1 [M+H] + .

[0471] Step g): Preparation of (R)-(1-(7-(4-cyanophenyl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-1-yl)piperidin-3-yl)tert-butyl carbamate

[0472] 4-(1-chloro-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile (70 mg, 0.20 mmol) and (R)-piperidin-3-ylcarbamate tert-butyl ester (60 mg, 0.30 mmol) were dissolved in 3 mL of DMSO, and DIPEA (103 mg, 0.80 mmol) was added. The system was heated to 55 °C under nitrogen protection and reacted for 8 h. After the LCMS showed that the reaction was 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 the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 4) to give (R)-(1-(7-(4-cyanophenyl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-1-yl)piperidin-3-yl)tert-butyl carbamate, with a yield of 95.0%.

[0473] 1 H NMR(400MHz,DMSO-d6)δppm 7.70(d,J=7.8Hz,2H),7.57-7.44(m,3H),7.37(d,J=7.6Hz,2H),7.27(d, J=7.8Hz,2H),7.07(t,J=3.8Hz,2H),4.42(d,J=12.8Hz,1H),4.23(d,J=1 3.0Hz,1H),3.57(s,1H),2.95(t,J=11.2Hz,1H),2.83(t,J=11.2Hz,1H), 2.-2.35(s,3H),2.03-1.75(m,3H),1.61(d,J=11.4Hz,1H),1.41(s,9H).

[0474] ESI-MS m / z: 508.2 [M+H] + .

[0475] Step h): Preparation of (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile

[0476] (R)-(1-(7-(4-cyanophenyl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-1-yl)piperidin-3-yl)tert-butyl carbamate (90 mg, 0.18 mmol) was dissolved in 5 mL of ethyl acetate, and 5 mL of 4 M HCl ethyl acetate solution was added. The reaction was carried out at room temperature for 1 h. A large amount of solid was generated in the reaction system. When LC-MS showed that the reaction was complete, the crude product was concentrated and sent to Prep-HPLC for preparation (separation method 4) to obtain (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-a]pyrazin-7-yl)benzyl nitrile, yield: 72.2%.

[0477] 1 H NMR(400MHz,DMSO-d6)δppm 7.79(d,J=7.8Hz,3H),7.56(d,J=8.2Hz,2H),7.46-7.36(m,3H),7.29(d,J=7.8Hz,2H),7.05(d,J=5.6Hz,1H),4.56(d,J= 13.0Hz, 1H), 4.16 (d, J = 13.2Hz, 1H), 3.66 (s, 3H), 2.42 (s, 3H), 2.15 (d, J = 6.4Hz, 1H), 1.97 (s, 1H), 1.77 (t, J = 8.4Hz, 2H).

[0478] ESI-MS m / z: 408.2 [M+H] + .

[0479] Example 4

[0480] Preparation of (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzyl nitrile

[0481]

[0482] Step a): Preparation of 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carbonylhydrazine

[0483] Methyl 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carboxylic acid (1.0 g, 3.16 mmol) was dissolved in a 1:1 mixture of hydrazine hydrate and ethanol (10 mL). The mixture was placed in a sealed container and reacted at 80 °C for 5 h. When LC-MS showed that the reaction was complete, the crude product was concentrated. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrole-2-carbazide, with a yield of 64.9%.

[0484] 1 H NMR(400MHz,DMSO-d6)δppm 9.36(s,1H),7.74-7.69(m,2H),7.34(d,J=8.2Hz,2H),7.24(d,J=7.8Hz,2H),7.17(d, J=7.8Hz,2H),7.03(d,J=2.6Hz,1H),4.46(s,2H),3.17(d,J=5.2Hz,1H),2.32(s,3H).

[0485] ESI-MS m / z: 317.1 [M+H] + .

[0486] Step b): Preparation of 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazine-7-yl)benzyl nitrile

[0487] 4-(4-cyanophenyl)-5-(p-tolyl)-1H-pyrrolo-2-carbazide (650 mg, 2.05 mmol) was dissolved in triethyl orthoformate (5 mL) and refluxed for 1 h. When the reaction was complete as indicated by LC-MS, the mixture was concentrated under vacuum to obtain the crude product. The crude product was then dissolved in 15 mL of anhydrous ethanol, and potassium hydroxide (460 mg, 8.2 mmol) was added and refluxed for 1 h. The mixture was concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazine-7-yl)benzyl nitrile, yield 29.7%.

[0488] ESI-MS m / z: 327.1 [M+H] + .

[0489] Step c): Preparation of 4-(1-chloro-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazine-7-yl)benzyl nitrile

[0490] 4-(1-hydroxy-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzyl nitrile (200 mg, 0.61 mmol) was dissolved in 1,2-dichloroethane (5 mL), and phosphorus oxychloride (2.5 mL) was added. The system was heated to 75 °C and reacted for 3 h. When the reaction was complete as indicated by alkaline LC-MS, the mixture was concentrated under vacuum, and the solid was dissolved in 3 mL of anhydrous dichloromethane. 0.2 mL of triethylamine was added, and the mixture was concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give 4-(1-chloro-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzyl nitrile, with a yield of 37.7%.

[0491] ESI-MS m / z: 345.1 [M+H] + .

[0492] Step d): Preparation of (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazine-7-yl)benzyl nitrile

[0493] 4-(1-chloro-6-(p-toluyl)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzyl nitrile (80 mg, 0.23 mmol) and tert-butyl(R)-piperidin-3-yl carbamate (93.1 mg, 0.47 mmol) were dissolved in 3 mL of DMSO, and DIPEA (90.2 mg, 0.7 mmol) was added. The system was heated to 55 °C for 3 h under nitrogen protection. After the reaction was complete as indicated by alkaline LC-MS, the crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give tert-butyl(R)-(1-(7-(4-cyanophenyl)-6-(p-toluyl)pyrrolo[1,2-d][1,2,4]triazin-1-yl)piperidin-3-yl) carbamate. 80 mg (0.16 mmol) of tert-butyl(R)-(1-(7-(4-cyanophenyl)-6-(p-toluene)pyrrolo[1,2-d][1,2,4]triazin-1-yl)piperidin-3-yl)carbamate was dissolved in 3 mL of 4 M HCl ethyl acetate solution and reacted at room temperature for 30 minutes. When the reaction was complete as indicated by alkaline LC-MS, the crude product was concentrated and sent to Prep-HPLC for further preparation (separation method 4) to obtain (R)-4-(1-(3-aminopiperidin-1-yl)-6-(p-toluene)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzyl nitrile, with a yield of 8.3%.

[0494] 1 H NMR(400MHz,Methanol-d4)δppm 8.55(d,J=16.4Hz,2H),7.67-7.62(m,2H),7.54-7.49(m,2H),7.38(d,J=7.8 Hz,2H),7.30(d,J=7.8Hz,3H),4.33-4.24(m,1H),4.12(d,J=13.4Hz,1H),3.5 2-3.44(m,2H),3.39(dd,J=12.8,8.4Hz,1H),2.44(s,3H),2.19(d,J=11.6Hz ,1H),1.99(d,J=16.0Hz,1H),1.82(dd,J=9.6,4.0Hz,1H),1.79-1.70(m,1H).

[0495] ESI-MS m / z: 409.2 [M+H] + .

[0496] Example 5

[0497] Preparation of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-2-yl)benzyl nitrile hydrochloride

[0498]

[0499] Step a): Preparation of 4-(8-chloroimidazolo[1,2-a]pyrazin-2-yl)benzonitrile

[0500] 3-Chloropyrazin-2-amine (1 g, 4.6 mmol) was added sequentially to a reaction flask with 4-(2-bromoacetyl)benzonitrile (1 g, 4.6 mmol), diethylaniline (2.1 g, 13.9 mmol), and DMSO (10 mL). The mixture was heated to 130 °C and reacted overnight. After the reaction was complete, the reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The solutions were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 4-(8-chloroimidazolo[1,2-a]pyrazin-2-yl)benzonitrile, with a yield of 30.5%.

[0501] ESI-MS m / z = 255.1 [M+H] + .

[0502] Step b): Preparation of 4-(3-bromo-8-chloroimidazole[1,2-a]pyrazin-2-yl)benzonitrile

[0503] 4-(8-chloroimidazole[1,2-a]pyrazin-2-yl)benzonitrile (310 mg, 1.2 mmol) and NBS (233 mg, 1.32 mmol) were dissolved in DMF (5 mL) and the mixture was stirred in an ice bath for 2 h. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(3-bromo-8-chloroimidazole[1,2-a]pyrazin-2-yl)benzonitrile, in 75.0% yield.

[0504] ESI-MS m / z = 334.2 [M+H] + .

[0505] Step c): Preparation of tert-butyl(R)-(1-(3-bromo-2-(4-cyanophenyl)imidazol[1,2-a]pyrazin-8-yl)piperidin-3-yl)carbamate

[0506] 4-(3-bromo-8-chloroimidazole[1,2-a]pyrazin-2-yl)benzonitrile (300 mg, 0.90 mmol), tert-butyl(R)-piperidin-3-yl carbamate (263 mg, 0.90 mmol), and DIPEA (348 mg, 2.7 mmol) were dissolved in DMSO (5 mL). The reaction mixture was heated to 55 °C and reacted for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl(R)-(1-(3-bromo-2-(4-cyanophenyl)imidazole[1,2-a]pyrazin-8-yl)piperidin-3-yl) carbamate, with a yield of 35.0%.

[0507] ESI-MS m / z = 498.1 [M+H] + .

[0508] Step d): Preparation of tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-8-yl)piperidin-3-yl)carbamate

[0509] tert-butyl(R)-(1-(3-bromo-2-(4-cyanophenyl)imidazol[1,2-a]pyrazin-8-yl)piperidin-3-yl)carbamate (150 mg, 0.30 mmol), p-tolylboronic acid (61.2 mg, 0.45 mmol), Cs₂CO₃ (295 mg, 0.90 mmol), Pd(dppf)Cl₂ (44.2 mg, 0.06 mmol), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to the reaction flask. After purging with nitrogen three times, the reaction was heated to 100 °C and allowed to proceed for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-8-yl)piperidin-3-yl)carbamate, with a yield of 56.0%.

[0510] 1H NMR(400MHz,DMSO-d6)δppm 7.76(d,J=2.8Hz,4H),7.44(d,J=8.0Hz,2H),7.39(d,J=7.8Hz,2H),7.33(d,J=4.6Hz,1H),7.25(d,J=4.6Hz,1H),6.95(d,J=7.8H z,1H),5.31(s,1H),5.09(s,1H),3.21(d,J=11.8Hz,2H),2.44(s,4H),1.87(d,J=32.6Hz,2H),1.55(q,J=9.4Hz,2H),1.39(s,9H).

[0511] ESI-MS m / z = 509.1 [M+H] + .

[0512] Step e): Preparation of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-2-yl)benzonitrile hydrochloride

[0513] 90 mg (0.17 mmol) of tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-8-yl)piperidin-3-yl)carbamate was dissolved in 5 mL of 4M HCl ethyl acetate (5 mL) and reacted at room temperature for 1 h. The reaction was complete, and a solid was formed in the reaction solution. The mixture was filtered, the filter cake was collected, and dried to give (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)imidazo[1,2-a]pyrazin-2-yl)benzonitrile hydrochloride in 82.3% yield.

[0514] 1 H NMR(400MHz,DMSO-d6)δppm 8.34(d,J=5.4Hz,3H),7.81(s,4H),7.46(d,J=7.8Hz,2H),7.41-7.35(m,4H),5.09(d,J=65.2H z, 2H), 3.38 (s, 1H), 2.45 (s, 3H), 2.12 (d, J = 11.2Hz, 1H), 1.97-1.86 (m, 1H), 1.80-1.66 (m, 2H).

[0515] ESI-MS m / z: 409.2 [M+H] + .

[0516] Example 6

[0517] Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(2-fluoro-4-methylphenyl)thiophene-3-yl)-2-fluorobenzyl nitrile hydrochloride

[0518]

[0519] Step a): Preparation of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0520] Tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (600 mg, 0.938 mmol), (2-fluoro-4-methylphenyl)boronic acid (173 mg, 1.13 mmol), K₂CO₃ (915 mg, 2.81 mmol), and Pd(dppf)Cl₂ (69 mg, 0.09 mmol) were dissolved in 1,4-dioxane (8.4 mL), and water (1.6 mL) was added. The mixture was purged with nitrogen under nitrogen protection. The reaction was carried out in a microwave reactor at 100 °C for 1 h. After the reaction was complete, the mixture was extracted with ethyl acetate (20 mL × 2), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 43.7% yield.

[0521] 1 H NMR(400MHz,Chloroform-d)δppm 7.55-7.46(m,2H),7.19(tt,J=7.6,2.8Hz,1H),7.14-7.04(m,2H),6.98(t,J=5.8Hz,1H),6.92-6.83(m,1H),4.80(s,2H),4.45- 4.33(m,1H),4.12(tt,J=9.4,6.0Hz,1H),2.38(t,J=3.2Hz,3H),2.21-2.02(m,4H),1.89(s,2H),1.69-1.56(m,2H),1.43(s,9H).

[0522] ESI-MS m / z: 564.2 [M+H] + .

[0523] Step b): Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(2-fluoro-4-methylphenyl)thiophene-3-yl)-2-fluorobenzonitrile hydrochloride

[0524] At room temperature, tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (50 mg, 0.09 mmol) was dissolved in 1 M HCl ethyl acetate solution (1.5 mmol, 2 mL). The mixture was stirred for 2 h under nitrogen protection. After the starting material was completely converted, a white precipitate was formed. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (5 mL) and dried to give a white solid 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(2-fluoro-4-methylphenyl)thiophene-3-yl)-2-fluorobenzonitrile hydrochloride, with a yield of 66.7%.

[0525] 1 H NMR(400MHz,Methanol-d4)δppm 7.72(d,J=2.0Hz,1H),7.67(t,J=7.4Hz,1H),7.29(t,J=7.4Hz,2H),7.23(d,J=8.2Hz,1H),7.10(d,J=7.8Hz,1H),7.00(d,J=1 1.2Hz,1H),4.90-4.89(m,2H),3.78(dt,J=12.4,6.4Hz,1H),2.40(d,J=2.4Hz,3H),2.15(d,J=12.8Hz,4H),1.98-1.81(m,4H).

[0526] ESI-MS m / z: 464.2 [M+H] + .

[0527] Example 7

[0528] Preparation of 4-(5-((3-amino-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-(2-fluoro-4-methylphenyl)thiophene-3-yl)-2-fluorobenzyl nitrile trifluoroacetate

[0529]

[0530] Step a): Preparation of tert-butyl(8-((4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0531] 175 mg (0.30 mmol) of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was dissolved in anhydrous acetonitrile (10 mL), and 2 M borane dimethyl sulfide solution (138 mg, 1.81 mmol, 0.9 mL) was added. Under nitrogen protection, the mixture was heated to 50 °C and reacted for 16 hours until the reaction was complete. The reaction mixture was quenched with methanol, and the solution was concentrated under vacuum to remove tetrahydrofuran. 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)-5-(2-fluoro-4-methylphenyl)thiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 36.7% yield.

[0532] 1 H NMR(400MHz,Chloroform-d)δppm 7.46(t,J=7.4Hz,1H),7.17(t,J=7.8Hz,1H),7.07(t,J=9.4Hz,2H),7.00- 6.91(m,2H),6.85(d,J=10.8Hz,1H),4.36(d,J=8.6Hz,1H),3.73(s,2H),3. 34(s,1H),2.37(s,3H),2.04-1.96(m,2H),1.91-1.81(m,2H),1.74(d,J=8 .4Hz,2H),1.52(t,J=12.8Hz,2H),1.43(s,9H),1.26(q,J=7.8,6.6Hz,2H).

[0533] ESI-MS m / z: 550.2 [M+H] + .

[0534] Step b): Preparation of 4-(5-((3-amino-8-azabicyclo[3.2.1]octane-8-yl)methyl)-2-(2-fluoro-4-methylphenyl)thiophene-3-yl)-2-fluorobenzonitrile trifluoroacetate

[0535] 30 mg (0.05 mmol) of tert-butyl(8-((4-(4-cyano-3-fluorophenyl)-5-(2-fluoro-4-methylphenyl)thiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was dissolved in TFA / DCM (1:3, 2.5 mL) solution and stirred at room temperature for 30 minutes under nitrogen protection until the reaction was complete. The reaction solution was concentrated to obtain a solid, which was then lyophilized to give 4-(5-((3-amino-8-azabicyclo[3.2.1]octane-8-yl)methyl)-2-(2-fluoro-4-methylphenyl)thiophen-3-yl)-2-fluorobenzonitrile trifluoroacetate in 80.0% yield.

[0536] 1 H NMR(400MHz,Methanol-d4)δppm 7.69-7.55(m,2H),7.30-7.17(m,3H),7.08(d,J=7.8Hz,1H),6.98(d,J=11.0Hz,1H),4.59(s,2H),4.20(d,J=5.2Hz ,2H),3.78(dq,J=11.2,5.8,4.8Hz,1H),2.59-2.43(m,2H),2.38(d,J=2.0Hz,3H),2.31-2.11(m,6H),1.28(s,2H).

[0537] ESI-MS m / z: 450.2 [M+H] + .

[0538] Example 8

[0539] Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophen-3-yl)-2-fluorobenzyl nitrile

[0540]

[0541] Step a): Preparation of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0542] 128 mg (0.24 mmol) of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, 100 mg (0.36 mmol) of 5-fluoro-3-pentyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)benzo[d]isoxazole, 51 mg (0.482 mmol) of Na2CO3, and 35.2 mg (0.05 mmol) of Pd(dppf)Cl2 were added to a 10 mL microwave-safe reaction tube. 1,4-Dioxane (4 mL) and water (0.8 mL) were added to dissolve the mixture. The mixture was purged with nitrogen and protected with nitrogen. The reaction was carried out in a microwave reactor at 100 °C for 30 minutes. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 25.4% yield.

[0543] 1 H NMR(400MHz,DMSO-d6)δppm 7.98(d,J=5.4Hz,1H),7.92-7.74(m,3H),7.63(d,J=10.4Hz,1H),7.21(d,J=8.2Hz,1H),6.79(d,J=8.0Hz,1H),4.71(d,J=41.8Hz,2 H), 3.90 (s, 1H), 2.95 (q, J = 7.8Hz, 2H), 2.13-1.73 (m, 8H), 1.65-1.54 (m, 2H), 1.36 (s, 9H), 1.33-1.19 (m, 4H), 0.86 (d, J = 6.6Hz, 3H).

[0544] ESI-MS m / z: 661.2 [M+H] + .

[0545] Step b): Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophen-3-yl)-2-fluorobenzyl nitrile

[0546] Under nitrogen protection, tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophen-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate (40 mg, 0.06 mmol) was dissolved in TFA / DCM (1:3, 1 mL) solution and reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by Prep-HPLC (separation method 4) to obtain a white solid 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-pentylbenzo[d]isoxazol-6-yl)thiophen-3-yl)-2-fluorobenzyl nitrile, with a yield of 36.7%.

[0547] 1 H NMR(400MHz,DMSO-d6)δppm 8.40(s,1H),7.93(d,J=5.4Hz,1H),7.85-7.74(m,3H),7.54(d,J=10.4Hz,1H),7.21(d,J=8.0Hz,1H),4.72(d,J=37.4Hz,2H),2 .95(t,J=7.4Hz,2H), 1.99(d,J=36.8Hz,4H), 1.74(q,J=7.8Hz,4H), 1.58(t,J=11.8Hz,2H), 1.30(h,J=3.6Hz,4H), 0.82(s,3H).

[0548] ESI-MS m / z: 561.2 [M+H] + .

[0549] Example 9

[0550] Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiophen-3-yl)-2-fluorobenzyl nitrile carboxylate

[0551]

[0552] Step a): Preparation of tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]sintan-3-yl)carbamate

[0553] 4-Bromothiophene-2-carboxylic acid (2.0 g, 9.71 mmol) was dissolved in DMF (25 mL), and HATU (5.53 g, 14.56 mmol) was added. The mixture was stirred at room temperature for 0.5 h under nitrogen protection. Then, DIPEA (3.76 g, 29.12 mmol) and the compound tert-butyl(8-azabicyclo[3.2.1]sintan-3-yl)carbamate (2.41 g, 10.68 mmol) were added, and the mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was complete as shown by LC-MS, water (60 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]sintan-3-yl) carbamate, in 87.0% yield.

[0554] 1H NMR(400MHz,Chloroform-d)δppm 7.36(d,J=1.4Hz,1H),7.27(d,J=1.4Hz,1H),4.70(d,J=63.6Hz,2H),4.37(d,J =8.6Hz,1H),4.11(s,1H),2.03(s,4H),1.87(s,2H),1.59(s,2H),1.43(s,9H).

[0555] ESI-MS m / z: 415.1 [M+H] + .

[0556] Step b): Preparation of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic[3.2.1]sintan-3-acyl)carbamate

[0557] 3.50 g (8.43 mmol) of tert-butyl (8-(4-bromothiophene-2-carbonyl)-8-azabicyclo[3.2.1]sintan-3-yl) carbamate, (4-cyano-3-fluorophenyl)boronic acid (1.93 g (11.71 mmol), Cs2CO3 (9.51 g (29.27 mmol), and Pd(dppf)Cl2 (716 mg (0.98 mmol)) were added to a 30 mL microwave-safe reaction tube. 1,4-dioxane (15 mL) and water (3 mL) were added to dissolve the mixture. The mixture was purged with nitrogen gas under nitrogen protection. The reaction was carried out in a microwave reactor at 120 °C for 35 minutes. When the reaction was complete as indicated by TLC and LC-MS, water (60 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined and washed with brine (15 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to obtain tert-butyl(8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic [3.2.1]sintan-3-acyl)carbamate, with a yield of 93.6%.

[0558] 1 H NMR(400MHz,Chloroform-d)δppm 7.36(d,J=1.4Hz,2H),7.27(d,J=1.4Hz,3H),4.71(s,2H),4.37(d,J=8.6Hz,1H), 4.12(q,J=7.2Hz,1H),2.07-2.02(m,4H),1.87(s,2H),1.59(s,2H),1.44(s,9H).

[0559] ESI-MS m / z: 456.2 [M+H] + .

[0560] Step c): Preparation of tert-butyl(8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic [3.2.1]sintan-3-ylcarbamate

[0561] tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic [3.2.1]sintan-3-acyl)carbamate (3.6 g, 7.89 mmol) was dissolved in dry DMF (20 mL), followed by the addition of NBS (1.5 g, 8.44 mmol). The mixture was then heated to 60 °C and reacted under nitrogen protection for 6 h. When LC-MS showed that the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / dichloromethane = 1:2) to give tert-butyl(8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic [3.2.1]sintan-3-ylcarbamate, yield 44.3%.

[0562] 1 H NMR(400MHz,Methanol-d4)δppm 7.87(t,J=7.4Hz,1H),7.65(dd,J=17.0,9.2Hz,2H),7.54(s,1H),4.79-4.70(m,2H ), 4.09-3.99 (m, 1H), 1.98 (d, J = 24.8Hz, 4H), 1.63 (t, J = 12.6Hz, 4H), 1.43 (s, 9H).

[0563] ESI-MS m / z: 534.1 [M+H] + .

[0564] Step d): Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-bromothiophene-3-yl)-2-fluorobenzonitrile

[0565] 200 mg (0.37 mmol) of tert-butyl(8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiophene-2-carbonyl)-8-azidoheterocyclic [3.2.1]sintan-3-ylcarbamate was dissolved in TFA / DCM (2 mL, 1:3) solution and reacted at room temperature under nitrogen protection for 24–41 h. The reaction was detected by TLC and LC-MS. After the reaction was completed, the mixture was concentrated at low temperature, and the residue was purified by pre-HPLC (separation method 4) to obtain 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-bromothiophene-3-yl)-2-fluorobenzonitrile, with a yield of 75.7%.

[0566] ESI-MS m / z: 434.0 [M+H] + .

[0567] Step e): Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazo-6-yl)thiophene-3-yl)-2-fluorobenzonitrile carboxylate

[0568] Dissolve 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-bromothiophene-3-yl)-2-fluorobenzonitrile (61 mg, 0.14 mmol), 5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)benzo[d]isoxazole (59.8 mg, 0.22 mmol), Na2CO3 (29.9 mg, 0.29 mmol), and Pd(dppf)Cl2 (20.9 mg, 0.03 mmol) in 5 mL of dioxane, and add 1 mL of water. The mixture was purged with nitrogen under nitrogen protection and reacted in a microwave reactor at 100°C for 30 minutes. When the reaction was complete as indicated by TLC and LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was then washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1:10), and the purity was determined by LC-MS. The residue was then purified by pre-HPLC (separation method 3) and lyophilized to obtain 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazo-6-yl)thiophene-3-yl)-2-fluorobenzonitrile carboxylate, with a yield of 21.4%.

[0569] 1 H NMR(400MHz,Methanol-d4)δppm 8.55(s,1H),7.87-7.66(m,2H),7.61(dt,J=23.6,8.2Hz,2H),7.35(d,J=9.8Hz,1H),7.21(d,J=8 .2Hz,1H),4.86(s,2H),3.59(dp,J=11.8,5.8Hz,1H),2.55(d,J=17.6Hz,3H),2.32-1.69(m,8H).

[0570] ESI-MS m / z: 505.1 [M+H] + .

[0571] Example 10

[0572] Preparation of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)indoleazin-2-yl)benzyl nitrile carbamate

[0573]

[0574] Step a): Preparation of 4-(8-bromo-2-yl)benzonitrile

[0575] 3-Bromo-2-methylpyridine (500 mg, 2.94 mmol) and 4-(2-bromoacetyl)benzonitrile (791 mg, 3.53 mmol) were dissolved in toluene (12 mL), purged with nitrogen, and refluxed overnight to form a solid. Then, 10 mL of potassium carbonate aqueous solution (1.35 g, 9.78 mmol) was added, and the mixture was stirred at 80 °C for 3 h. When TLC and LC-MS showed the reaction was complete, the reaction solution was concentrated under vacuum, filtered, and washed to obtain a brown solid. This solid was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 4-(8-bromo-2-yl)benzonitrile, in 21.4% yield.

[0576] ESI-MS m / z: 297.9 [M+H] + .

[0577] Step b): Preparation of tert-butyl(R)-(1-(2-(4-cyanophenyl)-N-8-yl)piperidin-3-ylcarbamate

[0578] 4-(8-bromo-2-yl)benzonitrile (160 mg, 0.54 mmol), tert-butyl(R)-piperidine-3-carbamate (129.8 mg, 0.65 mmol), Pd₂(dba)₃ (99.0 mg, 0.11 mmol), Cs₂CO₃ (325.5 mg, 1.08 mmol), and X-phos (125.2 mg, 0.22 mmol) were dissolved in toluene (12 mL) and reacted at 110 °C for 22 h under nitrogen protection. The reaction progress was monitored by TLC and LC-MS. When the starting material spot disappeared, indicating the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain tert-butyl(R)-(1-(2-(4-cyanophenyl)-8-yl)piperidine-3-ylcarbamate, yield 79.6%.

[0579] 1H NMR(400MHz,Chloroform-d)δppm7.78(d,J=8.2Hz,2H),7.69-7.54(m,4H),6.83(s,1H),6.45(t,J=7.0Hz,1H),6.13(d,J=7.2Hz ,1H),5.16(s,1H),4.02(s,1H),3.40(d,J=11.8Hz,1H),3.20(s,1H),3.07(s,2H),1.99-1.84(m,2H),1.64(s,2H),1.48(s,9H).

[0580] ESI-MS m / z: 417.2 [M+H] + .

[0581] Step c): Preparation of tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)indolizine-8-yl)piperidin-3-ylcarbamate

[0582] tert-butyl(R)-(1-(2-(4-cyanophenyl)-N-8-yl)piperidin-3-ylcarbamate (75 mg, 0.18 mmol), p-bromotoluene (37 mg, 0.22 mmol), and potassium acetate (35 mg, 0.36 mmol) were dissolved in NMP (2 mL) and heated to 100 °C under nitrogen protection for 1 h, with 1 drop of water added dropwise. The reaction was then continued under reflux overnight under nitrogen protection. The reaction progress was monitored by TLC and LC-MS. After the reaction was completed, the reaction solution was cooled and concentrated under vacuum. The concentrate was then dissolved in ethyl acetate and washed with brine (5 mL x 100 mL). 2) The product was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)indolizine-8-yl)piperidin-3-ylcarbamate, with a yield of 44.4%.

[0583] 1 H NMR(400MHz,Chloroform-d)δppm 7.60-7.39(m,7H),7.28(s,1H),7.22(d,J=8.0Hz,2H),6.80(s,1H),6.39(t,J=7.0Hz,1H),6.16(d ,J=7.2Hz,1H),4.03(s,1H),3.43-3.02(m,4H),2.43(s,3H),1.86(t,J=12.2Hz,4H),1.46(s,9H).

[0584] ESI-MS m / z: 507.3 [M+H] + .

[0585] Step d): Preparation of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)-2-yl)benzonitrile formate

[0586] 43 mg (0.08 mmol) of tert-butyl(R)-(1-(2-(4-cyanophenyl)-3-(p-tolyl)indolizine-8-yl)piperidin-3-yl carbamate was dissolved in 2.4 mL of 1 M ethyl acetate hydrochloride solution and stirred at room temperature for 30 min under nitrogen protection. The reaction progress was monitored by TLC and LC-MS. After the reaction was completed, the crude product was concentrated at low temperature. This crude product was purified by pre-HPLC (separation method 3) and lyophilized to obtain (R)-4-(8-(3-aminopiperidin-1-yl)-3-(p-tolyl)-2-yl)benzonitrile carbamate, with a yield of 50.0%.

[0587] 1 H NMR(400MHz,Methanol-d4)δppm 8.55(s,1H),7.60-7.45(m,5H),7.33(d,J=7.6Hz,2H),7.21(d,J=7.8Hz,2H),6.79(s,1H),6.45(t,J=7.0Hz,1H),6.29(d ,J=7.0Hz,1H),3.64-3.54(m,1H),3.35(d,J=10.2Hz,1H),2.90(dt,J=52.4,10.8Hz,2H),2.43(s,3H),2.28-1.35(m,5H).

[0588] ESI-MS m / z: 407.2 [M+H] + .

[0589] Example 11

[0590] Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)-2-fluorobenzyl nitrile carbamate

[0591]

[0592] Step a): Preparation of tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate

[0593] 4-(benzyloxy)-2,6-dichloropyridine (1.8 g, 7.1 mmol), tert-butylpiperidine-4-carbamate (1.4 g, 7.1 mmol), and DIPEA (415 mg, 14.2 mg) were dissolved in NMP (20 mL) and the mixture was heated to 130 °C and reacted for 2 h. When the reaction was complete as monitored by LC-MS, the reaction mixture was cooled to room temperature, and then water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give tert-butyl(1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidine-4-yl)carbamate, yield 77.4%.

[0594] ESI-MS m / z = 418.1 [M+H] + .

[0595] Step b): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0596] 2.3 g (5.5 mmol) of tert-butyl (1-(4-(benzyloxy)-6-chloropyridin-2-yl)piperidin-4-yl)carbamate, 909 mg (5.5 mmol) of (4-cyano-3-fluorophenyl)boronic acid, 3.5 g (11.0 mmol) of Cs2CO3, and 77.2 mg (0.11 mmol) of Pd(dppf)Cl2 were dissolved in dioxane (40 mL), and water (4 mL) was added. The mixture was purged with nitrogen three times, and the reaction was heated to 100 °C. The reaction was monitored after 2 h. When 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 x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and 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, yield 76.0%.

[0597] 1H NMR(400MHz,Chloroform-d)δppm 7.83(dd,J=17.8,9.4Hz,2H),7.65(t,J=6.8Hz,1H),7.46-7.35(m,5H),6.26(s,1H),5.14(d,J=2.6H z, 2H), 4.28 (d, J = 13.2Hz, 2H), 3.03 (t, J = 12.6Hz, 2H), 2.06 (d, J = 12.2Hz, 2H), 1.46 (d, J = 2.6Hz, 9H).

[0598] ESI-MS m / z = 503.1 [M+H] + .

[0599] Step c): Preparation of tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0600] 1.8 g (3.58 mmol) of tert-butyl (1.8 g, 3.58 mmol) and 687 mg (2.41 mmol) of NBS were dissolved in 30 mL of DMF and the reaction was monitored at room temperature for 2 h. When the reaction was complete as indicated by LC-MS, 80 mL of water was added, and the mixture was extracted with 40 mL x 3 ethyl acetates. The organic layers were combined, washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in 81.0% yield.

[0601] ESI-MS m / z = 582.1 [M+H] + .

[0602] Step d): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0603] 1.7 g (2.9 mmol) of tert-butyl (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, 498 mg (2.9 mmol) of (3-fluoro-4-methoxyphenyl)boronic acid, 1.9 g (5.8 mmol) of Cs₂CO₃, and 214 mg (0.29 mmol) of Pd(dppf)Cl₂ were dissolved in dioxane (30 mL) and water (6 mL) was added. The mixture was purged with nitrogen three times, and the reaction was heated to 100 °C. The reaction was monitored after 2 h. The reaction was considered complete when the starting material disappeared on LC-MS. The reaction solution was cooled to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and 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-fluoro-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield 43.8%.

[0604] ESI-MS m / z = 627.1 [M+H] + .

[0605] Step e): Preparation of tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)piperidin-4-ylcarbamate

[0606] 200 mg (0.32 mmol) of tert-butyl(1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate was dissolved in 20 mL of methanol. 100 mg of 10% Pd(OH)₂ was added, and the mixture was purged with hydrogen three times. The reaction was monitored after 4 h at room temperature. When LC-MS showed the reaction was complete, the reaction solution was sonicated for 15 minutes and filtered. The filtrate was concentrated under vacuum to obtain tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)piperidin-4-ylcarbamate, with a yield of 96.8%.

[0607] ESI-MS m / z = 537.1 [M+H] + .

[0608] Step f): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)-2-fluorobenzonitrile carboxylate

[0609] 170 mg (0.31 mmol) of tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl carbamate was dissolved in TFA / DCM (4 mL, 1:3) solution and reacted at room temperature for 1 h. A solid was formed in the reaction solution, and LC-MS detection showed that the reaction was complete. The reaction solution was filtered to obtain a solid, which was then purified by pre-HPLC (separation method 3) to obtain 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-hydroxypyridin-2-yl)-2-fluorobenzonitrile carbamate in 6.5% yield.

[0610] 1 H NMR(400MHz,DMSO-d6)δppm 8.71(s,1H),8.30(s,1H),7.75(t,J=7.6Hz,1H),7.33(d,J=10.8Hz,1H),7.13(d,J=8.2Hz,1H),7.04-6.88(m,2H),6.72(d,J=8.6Hz,1H),6.41 (s,1H),4.26(d,J=13.2Hz,2H),3.81(s,3H),3.44-3.21(m,3H),2.90(t,J=12.8Hz,2H),1.94(d,J=12.2Hz,2H),1.48(qd,J=12.2,4.0Hz,2H).

[0611] ESI-MS m / z = 437.1 [M+H] + .

[0612] Example 12

[0613] Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0614]

[0615] Step a): Preparation of methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid

[0616] 2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidine-4-carboxaldehyde (200.0 mg, 0.45 mmol), methoxymethyltriphenylphosphine chloride (212.0 mg, 0.73 mmol), and tris(3,6-dioxaheptyl)amine (161.7 mg, 0.5 mmol) were added to a mixture of 10 mL dichloromethane and 10 mL saturated potassium carbonate aqueous solution. The mixture was heated to 45 °C and refluxed for 18 hours. When LC-MS monitoring showed that the reaction was complete, water (20 mL) was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (30 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 = 2 / 1) to give a yellow solid (E)-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-methoxyvinyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, with a yield of 46.7%.

[0617] ESI-MS m / z: 469.5 [M+H] + .

[0618] Step b): Preparation of 2-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methylsulfonyl)piperazine-1-carbonyl)pyrimidin-4-yl)acetaldehyde

[0619] Compound (E)-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-methoxyvinyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (95.5 mg, 0.21 mmol) was dissolved in 4 mL of 1,4-dioxane, and then 4 mL of 6M hydrochloric acid aqueous solution was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. When LC-MS monitoring showed that the reaction was complete, the reaction solution was added to saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 2-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-yl)acetaldehyde.

[0620] ESI-MS m / z: 455.1 [M+H] + .

[0621] Step c): Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[0622] The crude product obtained in step two, 2-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidin-4-yl)acetaldehyde (41.2 mg, 0.22 mmol), 0.5 mL of methanol, and 0.1 mL of acetic acid were added to 2 mL of DCE. After stirring at room temperature for 1 hour, the reaction solution was cooled to 5 °C, and sodium cyanoborohydride (55.4 mg, 0.88 mmol) was added in portions. After reacting at room temperature for 1 hour, LC-MS monitoring showed that the reaction was complete. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, concentrated to dryness, and purified by Prep-HPLC (separation method 4) to obtain (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, with an overall yield of 4.1% for both steps.

[0623] 1 H NMR (400MHz, DMSO-d6) δppm: 8.42 (dd, J=8.7, 1.8Hz, 2H), 7.96 (s, 1H), 7.83-7.63 (m, 3H), 7.42(s,1H),6.96(dd,J=8.2,5.4Hz,2H),6.87(td,J=8.6,1.8Hz,2H),6.46(q,J=2.0Hz,1 H),3.79(dd,J=40.8,5.2Hz,4H),3.34(dt,J=18.9,6.2Hz,5H),3.17(d,J=6.6Hz,2H),2.8 0(d,J=1.6Hz,3H),2.43(d,J=5.8Hz,1H),1.19(s,2H),0.98(t,J=6.2Hz,1H),0.79(s,1H).

[0624] ESI-MS m / z: 590.7 [M+H] + .

[0625] Example 13

[0626] Preparation of 2-fluoro-4-(2-(6-fluoro-1-methyl-1H-indol-5-yl)-6-(4-methylpiperazin-1-carbonyl)pyrimidin-4-yl)benzyl nitrile

[0627]

[0628] Step a): Preparation of methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid

[0629] The starting materials methyl 2,6-dichloropyrimidine-4-carboxylic acid (1 g, 4.83 mmol), pyrimidine-4-carboxylic acid (796 mg, 4.83 mmol), K₂CO₃ (1.99 g, 14.49 mmol), and Pd(dppf)Cl₂ (70.6 mg, 0.966 mmol) were dissolved in 15 mL of dioxane. 3 mL of water was added, and the mixture was purged with nitrogen three times. The reaction was heated to 80 °C and monitored after 2 h. When LC-MS showed that the starting materials had reacted completely, the reaction solution was allowed to cool to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined and washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid, a white solid, in 19.9% ​​yield.

[0630] ESI-MS m / z = 292.1 [M+H] + .

[0631] Step b): Preparation of methyl 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidine-4-carboxylic acid

[0632] Methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylic acid (140 mg, 0.50 mmol), 6-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-indole (275 mg, 1.0 mmol), Cs₂CO₃ (325 mg, 1.0 mmol), and Pd(dppf)Cl₂ (70.1 mg, 0.1 mmol) were dissolved in 5 mL of dioxane. 1 mL of water was added, and the mixture was purged three times with nitrogen. The reaction was heated to 100 °C and monitored after 2 h. When LC-MS showed complete reaction, the reaction solution was allowed to cool to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give methyl 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidine-4-carboxylic acid, in 64.0% yield.

[0633] ESI-MS m / z = 405.1 [M+H] + .

[0634] Step c): Preparation of 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidine-4-carboxylic acid

[0635] Methyl 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidine-4-carboxylic acid (140 mg, 0.32 mmol) and lithium hydroxide (53.6 mg, 1.28 mmol) were dissolved in 5 mL THF and 1 mL H₂O. The reaction was monitored after 1 h at room temperature. When LC-MS showed that the reaction was complete, the pH of the reaction solution was adjusted to 5 by adding 1 N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a white solid of 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidine-4-carboxylic acid, in 96.9% yield.

[0636] ESI-MS m / z = 391.1 [M+H] + .

[0637] Step d): Preparation of 2-fluoro-4-(2-(6-fluoro-1-methyl-1H-indol-5-yl)-6-(4-methylpiperazin-1-carbonyl)pyrimidin-4-yl)benzyl nitrile

[0638] Compounds 6-(4-cyano-3-fluorophenyl)-2-(6-fluoro-1-methyl-1H-indol-5-yl)pyrimidin-4-carboxylic acid (130 mg, 0.33 mmol), 1-methylpiperazine (19.2 mg, 0.192 mmol), HATU (53.6 mg, 0.141 mmol), and DIPEA (49.6 mg, 0.385 mmol) were dissolved in 5 mL of DMF and reacted at room temperature for 2 h. The reaction was monitored afterward. When LC-MS showed complete reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted three times with 10 mL of ethyl acetate each time. The organic layers were combined, washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was then purified by Prep-HPLC (separation method 4) to give a white solid compound 2-fluoro-4-(2-(6-fluoro-1-methyl-1H-indol-5-yl)-6-(4-methylpiperazin-1-carbonyl)pyrimidin-4-yl)benzyl nitrile, with a yield of 54.5%.

[0639] 1H NMR(400MHz,Methanol-d4)δppm 8.44-8.39(m,1H),8.33(t,J=10.8Hz,2H),8.11(d,J=1.7Hz,1H),7.96(s,1H),7.31-7.21(m,2H),6.62-6.55(m,1 H), 3.87 (d, J = 5.4Hz, 2H), 3.83 (d, J = 1.6Hz, 3H), 3.73 (t, J = 5.0Hz, 2H), 2.62 (dt, J = 18.2, 5.0Hz, 4H), 2.39 (s, 3H).

[0640] ESI-MS m / z = 473.1 [M+H] + .

[0641] Compounds 14-63 in Examples were prepared according to the synthetic method of Example 11 (isolation methods of the compounds: free base, hydrochloride and formate were prepared by isolation methods 4, 1 and 3, respectively), and their structures and characterization data are as follows:

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] Example 64

[0653] Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)amino)-4-hydroxypyridin-2-yl)-2-fluorobenzonitrile hydrochloride

[0654]

[0655] Step a): Preparation of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)amino)pyridin-2-ylpiperidin-4-yl)carbamate

[0656] Weigh out (1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (200 mg, 0.34 mmol), 3-fluoro-4-methoxyaniline (96 mg, 0.68 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (32 mg, 0.07 mmol), and sodium tert-butoxide (96 mg, 1.02 mmol), add anhydrous toluene (2 mL), and microwave-heat the mixture under nitrogen protection for 1.5 hours. After the reaction was complete as shown by LCMS, the sample was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)amino)pyridin-2-ylpiperidin-4-yl)carbamate, yield 27.2%.

[0657] ESI-MS m / z: 642.3 [M+H] + .

[0658] Step b): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)amino)-4-hydroxypyridin-2-yl)-2-fluorobenzonitrile hydrochloride

[0659] 63 mg (0.10 mmol) of tert-butyl (1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)amino)pyridin-2-ylpiperidin-4-yl)carbamate was weighed into a sealed tube and added to 2 mL of trifluoroacetic acid. The mixture was heated to 70°C in an oil bath under nitrogen protection and reacted for 16 hours. After the reaction was complete as indicated by LC-MS, the solution was concentrated to dryness, dissolved in 2 mL of methanol, and purified by pre-HPLC column chromatography (Separation Method 1) to obtain 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)amino)-4-hydroxypyridin-2-yl)-2-fluorobenzonitrile hydrochloride, with a yield of 10.7%.

[0660] 1H NMR(400MHz,Methanol-d4)δppm 7.84–7.75(m,1H),7.63(d,J=9.8Hz,1H),7.55(dd,J=8.2,1.6Hz,1H),6.82( t,J=9.0Hz,1H),6.67(d,J=2.4Hz,1H),6.39–6.25(m,2H),4.16(dt,J=14.0,2 .8Hz,2H),3.74(s,3H),3.50(tt,J=12.0,4.2Hz,1H),3.37–3.33(m,1H),3.28 (d, J=2.8Hz, 1H), 2.20 (dd, J=12.8, 3.8Hz, 2H), 1.83 (qd, J=12.4, 3.8Hz, 2H).

[0661] ESI-MS m / z: 452.2 [M+H] + .

[0662] Example 65

[0663] Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-methylpyridin-2-yl)-2-fluorobenzonitrile hydrochloride

[0664]

[0665] Step a): Preparation of tert-butyl 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0666] Dissolve 1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate tert-butyl ester (300 mg, 0.518 mmol), (3-hydroxy-4-methylphenyl)boronic acid (118 mg, 0.76 mmol), Cs2CO3 (337 mg, 1.03 mmol), and Pd(dppf)Cl2 (38 mg, 0.05 mmol) in 8 mL of dioxane and add 0.8 mL of water. Purge this mixture with nitrogen gas and protect it with nitrogen. The reaction was carried out in a microwave reactor at 120°C for 30 minutes. LCMS showed that the reaction was complete. The crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield: 90.4%).

[0667] 1H NMR(400MHz,DMSO-d6)δppm 9.83(s,1H),7.76(t,J=7.6Hz,1H),7.41–7.17(m,9H),6.55(d,J=17.8Hz,2H),5.24–5.09(m,2H),4.44– 4.19(m,2H),3.51(s,2H),3.02–2.85(m,2H),2.09(s,3H),1.99(s,1H),1.88–1.73(m,2H),1.40(s,9H).

[0668] ESI-MS m / z: 609.3 [M+H] +

[0669] Step b): Preparation of tert-butyl (1-(4-(benzyl)-3-bromo-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0670] 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (200 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (10 mL), and NBS (140 mg, 0.039 mmol) was added at 0 °C with stirring. LS-MS showed that the reaction was complete. Quenching with water (20 mL), extraction with ethyl acetate (20 mL × 2), combining the organic phases, washing with saturated brine (15 mL × 2), drying to anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (1-(4-(benzyl)-3-bromo-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield 64.5%.

[0671] ESI-MS (m / z) = 687.2 [M+H] + .

[0672] Step c): Preparation of tert-butyl 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)-3-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0673] tert-butyl (1-(4-(benzyl)-3-bromo-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (50 mg, 0.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxoborane (100 μL, 0.2 mmol), K2CO3 (30 mg, 0.22 mmol), and Pd(pph3)4 (8 mg, 0.014 mmol) were dissolved in 4 mL of dioxane. The mixture was then purged with nitrogen gas under nitrogen protection. The reaction was carried out at 100°C for 16 hours. When TLC and LCMS showed that the reaction was complete, the crude product was concentrated. This crude product was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 3) to give 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)-3-methylpyridin-2-yl)piperidin-4-yl)tert-butyl carbamate, yield: 70.2%.

[0674] ESI-MS m / z: 623.3 [M+H] + .

[0675] Step d): Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-methylpyridin-2-yl)-2-fluorobenzonitrile hydrochloride

[0676] 1-(4-(benzyloxy)-6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methylphenyl)-3-methylpyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (67 mg, 0.107 mmol) was added to 3 mL of trifluoroacetic acid solution and reacted at 75 °C for 16 hours. LC-MS showed that the reaction was complete. The solvent was evaporated, and the crude product was prepared by Prep-HPLC (separation method 1) to give 4-(6-(4-aminopiperidin-1-yl)-4-hydroxy-3-(3-hydroxy-4-methylphenyl)-5-methylpyridin-2-yl)-2-fluorobenzonitrile hydrochloride, yield: 20.4%.

[0677] 1H NMR(400MHz,Methanol-d4)δppm 7.55(t,J=7.4Hz,1H),7.29(d,J=9.8Hz,1H),7.14(d,J=8.0Hz,1H),6.75(s,1H),6.47(s,1H),6.18(s,1H),4.05(d,J=13.6Hz,2H),3.36(d dt,J=11.4,8.6,4.2Hz,1H),3.21(d,J=13.2Hz,2H),2.06(dd,J=13.0,3.8Hz,2H),1.96(s,3H),1.82(s,3H),1.69(qd,J=12.4,4.2Hz,2H).

[0678] ESI-MS m / z: 433.2 [M+H] + .

[0679] Example 66

[0680] Preparation of 2-(4-aminopiperidin-1-yl)-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)nicotinonitrile hydrochloride

[0681]

[0682] Step a): Preparation of tert-butyl (4-(3-bromo-4-iodopyridin-2-yl)cyclohexyl)carbamate

[0683] 3-Bromo-2-chloro-4-iodopyridine (1.0 g, 3.155 mmol), piperidin-4-ylcarbamate tert-butyl ester (0.946 g, 4.732 mmol), and NMP (10 mL) were added to a microwave reactor and stirred at 130 °C for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 2). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (4-(3-bromo-4-iodopyridine-2-yl)cyclohexyl)carbamate, in 43.0% yield.

[0684] 1 H NMR(400MHz,DMSO-d6)δppm 7.88(d,J=5.0Hz,1H),7.53(d,J=5.0Hz,1H),3.66–3.49(m,2H),3.41(s,1H),2 .87–2.68(m,2H),1.90–1.71(m,2H),1.52(qd,J=11.8,3.6Hz,2H),1.39(s,9H).

[0685] ESI-MS (m / z) = 482.0 [M+H] + .

[0686] Step b): Preparation of tert-butyl (1-(3-bromo-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0687] 653 mg (1.357 mmol) of tert-butyl (4-(3-bromo-4-iodopyridin-2-yl)cyclohexyl)carbamate, 336 mg (2.036 mmol) of (4-cyano-3-fluorophenyl)boronic acid, 0.885 g (2.714 mmol) of Cs₂CO₃, 100 mg (0.136 mmol) of Pd(dppf)Cl₂, 10 mL of 1,4-dioxane, and 2.5 mL of H₂O 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 give tert-butyl (1-(3-bromo-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, in 47.0% yield.

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=4.8Hz,1H),8.17–7.95(m,1H),7.69(dd,J=10.2,1.6Hz,1H),7.47(dd,J=8.0,1.6Hz,1H),7.00(d,J=4. 8Hz, 1H), 3.66 (d, J = 12.6Hz, 2H), 3.44 (s, 1H), 2.86 (t, J = 11.8Hz, 2H), 1.84 (d, J = 12.4Hz, 2H), 1.56 (tt, J = 12.4, 6.2Hz, 2H), 1.39 (s, 9H).

[0689] ESI-MS (m / z) = 475.1 [M+H] + .

[0690] Step c): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0691] (303 mg, 0.638 mmol) of tert-butyl (1-(3-bromo-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate (115 mg, 1.276 mmol), DMSO (10 mL) was added to a reaction flask and stirred at 80 °C for 12 hours. After the reaction was complete, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 2), concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield 21.0%. ESI-MS (m / z) = 422.2 [M+H] + .

[0692] Step d): Preparation of tert-butyl(1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate

[0693] (57 mg, 0.134 mmol) of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate and 2 mL of DMF were added to a reaction flask. NBS (29 mg, 0.161 mmol) was added in portions with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine (40 mL × 2). The organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield 77.0%.

[0694] ESI-MS (m / z) = 500.2 [M+H] + .

[0695] Step e): Preparation of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate

[0696] The following ingredients were added to a reaction flask: (1-(5-bromo-3-cyano-4-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (52 mg, 0.103 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenol (39 mg, 0.155 mmol), Cs2CO3 (67 mg, 0.206 mmol), Pd(dppf)Cl2 (7 mg, 0.010 mmol), 1,4-Dioxane (4 mL), and H2O (1 mL). The mixture was 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 = 1 / 1) to give tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate, yield 67.0%.

[0697] ESI-MS (m / z) = 544.3 [M+H] + .

[0698] Step f): Preparation of 2-(4-aminopiperidin-1-yl)-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)nicotinonitrile hydrochloride

[0699] (38 mg, 0.069 mmol) of tert-butyl (1-(3-cyano-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (4 M, 2.5 mL) was added to a reaction flask, followed by ethyl hydrogen chloride solution. The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of a large amount of solid. The solid was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (Separation Method 1) to obtain 2-(4-aminopiperidin-1-yl)-4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)nicotinamide hydrochloride, with a yield of 52.5%.

[0700] 1H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.45 (s, 1H), 8.17 (s, 3H), 7.96 (dd, J = 8.0 ,6.8Hz,1H),7.67(dd,J=10.2,1.6Hz,1H),7.28(dd,J=8.0,1.6Hz,1H),6.89–6. 70(m,1H),6.47(d,J=7.0Hz,2H),4.25(d,J=13.6Hz,2H),3.72(s,3H),3.42(d,J =5.0Hz,1H),3.16(t,J=12.4Hz,2H),2.05(d,J=11.0Hz,2H),1.75–1.61(m,2H).

[0701] ESI-MS (m / z) = 444.2 [M+H] +

[0702] Compounds 67-86 in Examples were prepared according to the synthetic method of Example 66 (isolation methods of the compounds: free base, hydrochloride and formate were prepared by isolation methods 4, 1 and 3, respectively), and their structures and characterization data are as follows:

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709] Example 87

[0710] Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0711]

[0712] Step a): Preparation of 2,6-dichloro-4-methoxypyridine

[0713] 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 was complete, 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 phase 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 2,6-dichloro-4-methoxypyridine in 60.5% yield.

[0714] 1 H NMR (400MHz, Chloroform-d) δppm 6.79 (s, 2H), 3.87 (s, 3H).

[0715] ESI-MS (m / z) = 178.6 [M+H] + .

[0716] Step b): Preparation of tert-butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0717] 2,6-Dichloro-4-methoxypyridine (1.2 g, 6.629 mmol), piperidin-4-ylcarbamate tert-butyl ester (2.7 g, 13.258 mmol), and NMP (15 mL) were added to a microwave reactor and stirred at 130 °C for 2 hours. After the reaction was complete, 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 give (1-(6-chloro-4-methoxypyridine-2-yl)piperidin-4-yl)carbamate tert-butyl ester, yield 52.0%.

[0718] ESI-MS (m / z) = 342.5 [M+H] + .

[0719] Step c): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0720] (1.2 g, 3.447 mmol) of tert-butyl (1-(6-chloro-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, (4-cyano-3-fluorophenyl)boronic acid (853 mg, 5.170 mmol), Cs₂CO₃ (2.2 g, 6.894 mmol), Pd(dppf)Cl₂ (253 mg, 0.345 mmol), 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 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 give (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, yield 73.0%).

[0721] 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).

[0722] ESI-MS (m / z) = 427.3 [M+H] + .

[0723] Step d): Preparation of tert-butyl (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0724] (1.1 g, 2.516 mmol) of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (20 mL) was added to a reaction flask, and NBS (448 mg, 2.516 mmol) was added in portions with stirring in an ice bath. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 2), and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3) to give (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate (72.0%).

[0725] SI-MS(m / z) = 505.2 [M+H]+ .

[0726] Step e): Preparation of tert-butyl 1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0727] (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (200 mg, 0.396 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (101 mg, 0.595 mmol), Cs2CO3 (258 mg, 0.702 mmol), Pd(dppf)Cl2 (29 mg, 0.039 mmol), 1,4-dioxane (8 mL) and H2O (2 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 give 1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate in 87.0% yield.

[0728] ESI-MS (m / z) = 551.3 [M+H] + .

[0729] Step f): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0730] 1-(6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (190 mg, 0.345 mmol) was added to a reaction flask, followed by ethyl hydrogen chloride 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 solid was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 4) to obtain 4-(6-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile, with a yield of 51.0%.

[0731] 1H NMR(400MHz,DMSO-d6)δppm 7.74(t,J=7.4Hz,1H),7.30(d,J=10.8Hz,1H),7.14(d,J=7.8Hz,1H),7.07–6.84(m,2H),6.72(d,J=8.4Hz,1H),6.49(s,1H ),4.29(dt,J=13.4,3.8Hz,2H),3.79(d,J=6.8Hz,6H),3.02–2.85(m,2H),2.80(tt,J=9.8,4.0Hz,1H),1.88–1.51(m,4H).

[0732] ESI-MS (m / z) = 451.5 [M+H] + .

[0733] Compounds 88-100 in Examples were prepared according to the synthetic method of Example 87 (the compounds were isolated by methods 4, 1, and 3, respectively, for the free base, hydrochloride, and formate). Their structures and characterization data are as follows:

[0734]

[0735]

[0736]

[0737]

[0738] Example 101

[0739] Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxy-5-methylpyridin-2-yl)-2-fluorobenzonitrile

[0740]

[0741] Step a): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0742] (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (400 mg, 0.794 mmol), (3-(benzyloxy)-4-methoxyphenyl)boronic acid (307 mg, 1.191 mmol), Cs2CO3 (518 mg, 1.588 mmol), Pd(dppf)Cl2 (58 mg, 0.079 mmol), 1,4-Dioxane (12 mL) and H2O (3 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 = 1 / 1) to give tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, yield 48.0%.

[0743] ESI-MS (m / z) = 639.3 [M+H] + .

[0744] Step b): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0745] (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (244 mg, 0.381 mmol) and DMF (20 mL) were added to a reaction flask, and NBS (102 mg, 0.572 mmol) was added in portions with stirring in an ice bath. The mixture was stirred at room temperature for 30 minutes. After the reaction was complete, 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 phase was concentrated to dryness under reduced pressure, and 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)-3-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, yield 72.0%.

[0746] 1H NMR(400MHz,DMSO-d6)δppm 7.71(dt,J=7.8,6.2Hz,1H),7.39–7.25(m,6H),7.16–7.05(m,1H),6.98–6.84(m,2H),6.68(dd,J=8.4,2.0Hz,1H),4.99(s,2H ), 3.78 (s, 3H), 3.38 (s, 3H), 3.31 (s, 2H), 2.87 (t, J = 11.8Hz, 2H), 1.99 (s, 1H), 1.84 (d, J = 12.0Hz, 2H), 1.42 (d, J = 17.0Hz, 9H).

[0747] ESI-MS (m / z) = 717.2 [M+H] + .

[0748] Step c): Preparation of tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxy-3-methylpyridin-2-yl)piperidin-4-yl)carbamate

[0749] (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-3-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (100 mg, 0.140 mmol), potassium methyltrifluoroborate (34 mg, 0.280 mmol), Cs2CO3 (95 mg, 0.290 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), 1,4-dioxane (4 mL) and H2O (1 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 = 1 / 1) to give tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxy-3-methylpyridin-2-yl)piperidin-4-yl)carbamate, yield 25.0%.

[0750] ESI-MS (m / z) = 653.1 [M+H] + .

[0751] Step d): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxy-5-methylpyridin-2-yl)-2-fluorobenzonitrile

[0752] (23 mg, 0.035 mmol) of tert-butyl carbamate (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-methoxy-3-methylpyridin-2-yl)piperidin-4-yl)carbamate and tert-butyl carbamate (TFA) were added to a reaction flask and stirred to dissolve. The mixture was stirred at 70 °C for 16 hours, and a large amount of solid precipitated out. The solid was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 4) to obtain 4-(6-(4-aminopiperidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxy-5-methylpyridin-2-yl)-2-fluorobenzonitrile, with a yield of 62.5%.

[0753] 1 H NMR(400MHz,DMSO-d6)δppm 7.86–7.63(m,1H),7.30(dd,J=11.0,1.8Hz,1H),7.19(dt,J=8.0,1.8Hz,1 H),6.86(d,J=8.4Hz,1H),6.58(d,J=2.0Hz,1H),6.50(dd,J=8.2,2.0Hz,1H ),3.76(s,3H),3.48(d,J=12.4Hz,2H),3.39(s,3H),2.79(p,J=13.4,12.4H z, 3H), 2.20 (s, 3H), 1.83 (d, J = 12.4Hz, 2H), 1.50 (dt, J = 57.4, 11.4Hz, 2H).

[0754] ESI-MS (m / z) = 463.5 [M+H] + .

[0755] Example 102

[0756] Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-(3-fluoro-4-methoxyphenyl)-3-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0757]

[0758] Step a): Preparation of 6-chloro-4-(3-fluoro-4-methoxyphenyl)pyridine-3-ol

[0759] 6-Chloro-4-iodopyridin-3-ol (500 mg, 1.961 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (400 mg, 2.353 mmol), Pd(dppf)Cl2 (143 mg, 0.196 mmol), Cs2CO3 (1.3 g, 3.922 mmol), 1,4-dioxane (12 mL), and water (3 mL) were sequentially added to a microwave reactor. The reactor was purged with nitrogen three times, and the mixture was heated to 80 °C and stirred for 1 minute. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 6-chloro-4-(3-fluoro-4-methoxyphenyl)pyridin-3-ol in 80.0% yield.

[0760] ESI-MS (m / z) = 253.2 [M+H] + .

[0761] Step b): Preparation of 2-chloro-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridine

[0762] 6-Chloro-4-(3-fluoro-4-methoxyphenyl)pyridin-3-ol (397 mg, 1.569 mmol), iodomethane (267 mg, 1.883 mmol), K₂CO₃ (433 mg, 3.138 mmol), and DMF (5 mL) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times and stirred at 80 °C for 2 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 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 = 2 / 1) to give 2-chloro-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridine, in 71.4% yield.

[0763] ESI-MS (m / z) = 268.0 [M+H] + .

[0764] Step c): Preparation of tert-butyl (1-(4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0765] 2-Chloro-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridine (300 mg, 1.120 mmol), piperidin-4-ylcarbamate tert-butyl ester (448 mg, 2.240 mmol), Ruphos (10 mg, 0.011 mmol), Cs2CO3 (730 mg, 2.240 mmol), toluene (10 mL), and Pd(dba)2 (19 mg, 0.033 mmol) were added sequentially to the reaction flask, purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 3 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and washed with saturated brine (30 mL × 1). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (1-(4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)carbamate, yield 28.4%.

[0766] 1 H NMR(400MHz,DMSO-d6)δppm 7.93(s,1H),7.53–7.37(m,2H),7.23(t,J=8.8Hz,1H),6.84(s,1H),4.23–4.06(m,2H),3.88( s, 3H), 3.74 (s, 3H), 3.45 (s, 3H), 2.86 (t, J = 12.2Hz, 2H), 1.77 (d, J = 11.8Hz, 2H), 1.38 (s, 9H).

[0767] ESI-MS (m / z) = 432.3 [M+H] + .

[0768] Step d): Preparation of tert-butyl (1-(6-bromo-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[0769] (162 mg, 0.318 mmol) of tert-butyl (1-(4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)carbamate (5 mL) was added to a reaction flask, and NBS (68 mg, 0.381 mmol) was added in portions with stirring in an ice bath. The reaction mixture was stirred in an ice bath for 30 minutes. After the reaction was complete, the mixture was added to an aqueous sodium bicarbonate solution (40 mL) and 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. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 2) to give (1-(6-bromo-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)carbamate (70.0%).

[0770] ESI-MS (m / z) = 510.2 [M+H] + .

[0771] Step e): Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-(3-fluoro-4-methoxyphenyl)-3-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0772] The following ingredients were added sequentially to a microwave reactor: (1-(6-bromo-4-(3-fluoro-4-methoxyphenyl)-5-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (114 mg, 0.223 mmol), (3-fluoro-4-cyanophenyl)boronic acid (74 mg, 0.446 mmol), Pd(dppf)Cl2 (17 mg, 0.023 mmol), Cs2CO3 (145 mg, 0.446 mmol), 1,4-dioxane (4 mL), and water (1 mL). The reactor was purged with nitrogen three times, and the temperature was raised to 120 °C and stirred for 30 minutes. After the reaction was completed, the product was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 4) to obtain 4-(6-(4-aminopiperidin-1-yl)-4-(3-fluoro-4-methoxyphenyl)-3-methoxypyridin-2-yl)-2-fluorobenzonitrile, with a yield of 34.0%.

[0773] 1 H NMR(400MHz,Methanol-d4)δppm 7.95(s,1H),7.85(t,J=7.4Hz,1H),7.68–7.47(m,3H),7.42(t,J=1.8Hz,1H),6.89(s,1H),4.19(d ,J=13.2Hz,2H),3.95–3.74(m,6H),3.09–2.82(m,3H),2.09–1.96(m,2H),1.51(t,J=10.4Hz,2H).

[0774] ESI-MS (m / z) = 451.2 [M+H] + .

[0775] Example 103

[0776] Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-ethoxy-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzyl nitrile

[0777]

[0778] Step a): Preparation of tert-butyl 1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate

[0779] Dissolve 1-(4-(benzyloxy)-5-bromo-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)carbamate in 20 ml of dichloromethane (3 g, 5.1 mmol). Stir at -78°C for 15 minutes, then add 20 ml of 1 M boron hexane solution. Let the reaction proceed for 1 hour. Once the reaction is complete, quench with saturated sodium bicarbonate solution. Remove the organic solvent by osmosis. Adjust the pH to 8-9 with sodium carbonate in an ice bath, then add di-tert-butyl dicarbonate and react. After 30 minutes, add water. Quenching with 200 mL of the solution, extracting with ethyl acetate (200 mL × 2), combining the organic phases, washing with saturated brine (150 mL × 2), drying with anhydrous sodium sulfate, filtering, concentrating to obtain the crude product, and purifying the residue by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give tert-butyl(1-(5-(3-(benzyl)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate, yield: 70.2%.

[0780] 1 H NMR(400MHz,DMSO-d6)δppm 11.62(s,1H),8.10–7.93(m,1H),7.74(d,J=10.2Hz,1H),7.65(d,J=8.0Hz,1H),7.05(d,J=1.6Hz,1H),6.85(d,J=7.8Hz ,1H),4.23(d,J=13.4Hz,2H),3.54(d,J=10.6Hz,1H),2.98(t,J=12.4Hz,2H),1.89–1.74(m,2H),1.39(d,J=1.8Hz,11H).

[0781] ESI-MS m / z = 491.1 [M+H] + .

[0782] Step b): Preparation of tert-butyl(1-(5-(3-(benzyl)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate

[0783] Dissolve 1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (400 mg, 0.16 mmol), (4-(benzyloxy)-3-methoxyphenyl)boronic acid (237 mg, 0.25 mmol), Cs2CO3 (532 mg, 1.6 mmol), and Pd(dppf)Cl2 (60 mg, 0.08 mmol) in 10 mL of dioxane and add 1 mL of water. Purge this mixture with nitrogen gas and protect it with nitrogen. The reaction was carried out under microwave at 120°C for 30 minutes. LCMS showed that the reaction was complete. The crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give tert-butyl(1-(5-(3-(benzyl)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate, yield: 63.4%.

[0784] ESI-MS m / z = 625.3 [M+H] + .

[0785] Step c): Preparation of tert-butyl carbamate (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-ethoxypyridin-2-yl)piperidin-4-yl)carbamate

[0786] (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (50 mg, 0.08 mmol), iodoethane (37 mg, 0.24 mmol), and K₂CO₃ (33 mg, 0.24 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The mixture was purged with nitrogen under nitrogen protection. The reaction was carried out at 60 °C for 2 hours. When the reaction was complete as indicated by LC-MS, the crude product was concentrated and sent to Prep-HPLC (separation method 4) to prepare (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-ethoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate, yield: 43.6%.

[0787] ESI-MS m / z = 653.3 [M+H] + .

[0788] Step d): Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-ethoxy-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzyl nitrile: 24 mg (0.034 mmol) of tert-butyl carbamate (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-ethoxypyridin-2-yl)piperidin-4-yl)carbamate was added to 4 mL of trifluoroacetic acid solution and reacted at 70 °C for 2 hours. LC-MS showed that the reaction was complete. The solvent was evaporated at low temperature. The crude product was sent to Prep-HPLC for preparation (separation method 4) to obtain 4-(6-(4-aminopiperidin-1-yl)-4-ethoxy-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzyl nitrile, yield: 41.5%.

[0789] 1 H NMR(400MHz,Methanol-d4)δppm 7.51(dd,J=8.0,6.8Hz,1H),7.29–7.20(m,2H),6.81(d,J=8.4Hz,1H),6.59(d,J=2.2Hz,1H),6.54–6.38(m,2H),4.42(s,2H),4. 10(t,J=7.0Hz,2H),3.85(s,3H),3.03–2.81(m,3H),1.96(d,J=12.2Hz,2H),1.47(dd,J=11.8,4.0Hz,2H),1.32(t,J=7.0Hz,3H).

[0790] ESI-MS m / z = 463.2 [M+H] + .

[0791] Example 104

[0792] 4-(6-(4-aminopiperidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-4-isopropoxypyridin-2-yl)-2-fluorobenzyl nitrile was prepared according to the synthetic method of Example 103 (separation method 4), and its structure and characterization data are as follows:

[0793]

[0794] 1H NMR(400MHz,Methanol-d4)δppm 7.39(dd,J=8.0,6.8Hz,1H),7.18–7.02(m,2H),6.68(d,J=8.4Hz,1H),6.46(d,J=2.0Hz,1H),6.39–6.28(m,2H),4.60(d,J=6.2Hz,1 H),4.29(d,J=13.2Hz,2H),3.73(s,3H),2.93–2.76(m,3H),1.90–1.76(m,2H),1.34(qd,J=12.2,4.2Hz,2H),1.16(d,J=6.0Hz,6H).

[0795] ESI-MS m / z = 477.2 [M+H] + .

[0796] Example 105

[0797] 4-(6-(4-aminopiperidin-1-yl)-4-(cyclopentyloxy)-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzyl nitrile was prepared according to the synthetic method of Example 103 (separation method 4), and its structure and characterization data are as follows:

[0798]

[0799] 1 H NMR(400MHz,Methanol-d4)δppm 7.51(dd,J=8.0,6.6Hz,1H),7.34–7.17(m,2H),6.80(d,J=8.4Hz,1H),6.57(d,J=2.0Hz,1 H),6.47–6.37(m,2H),4.94(dq,J=5.8,3.2,2.8Hz,1H),4.41(dd,J=13.2,3.4Hz,2H),3.85 (s,3H),2.97(td,J=13.0,12.6,2.6Hz,3H),1.92(dddd,J=19.2,7.8,5.4,2.8Hz,4H),1.76 (dd,J=14.0,5.4Hz,2H), 1.63(dtt,J=14.6,7.8,3.8Hz,4H), 1.45(dd,J=11.4,3.8Hz,2H).

[0800] ESI-MS m / z = 503.2 [M+H] + .

[0801] Example 106

[0802] Preparation of 4-(6-(4-aminopiperidin-1-yl)-4-(difluoromethoxy)-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzonitrile

[0803]

[0804] Step a): Synthesis of tert-butyl(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-(difluoromethoxy)pyridin-2-yl)piperidin-4-yl)carbamate

[0805] Weigh out tert-butyl (1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-hydroxypyridin-2-yl)piperidin-4-yl)carbamate (75 mg, 0.12 mmol), potassium hydroxide (20.2 mg, 0.36 mmol), and diethyl(bromofluoromethyl)phosphonate (64 mg, 0.24 mmol), dissolve them in acetonitrile (3.2 mL) and water (0.2 mL), and stir the mixture at room temperature for 16 hours under nitrogen protection. LCMS showed the reaction was complete. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to give tert-butyl(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-(difluoromethoxy)pyridin-2-yl)piperidin-4-yl)carbamate, yield 69.1%.

[0806] 1 HNMR(400MHz,DMSO-d6)δppm 7.69(dd,J=8.2,6.8Hz,1H),7.43–7.19(m,7H),7.09(dd,J=8.2,1.6Hz,1H),6.88(dd,J=20.4,8.2Hz,2H),6.76–6.67(m,2H),6.62(dd,J=8.2,2.0 Hz,1H),5.75(s,1H),4.91(s,2H),4.29(d,J=13.4Hz,2H),3.76(s,3H),3 .54(s,1H),2.98(t,J=12.4Hz,3H),1.81(d,J=12.4Hz,2H),1.39(s,9H).

[0807] ESI-MS m / z: 675.3 [M+H] + .

[0808] Step b): Synthesis of 4-(6-(4-aminopiperidin-1-yl)-4-(difluoromethoxy)-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzonitrile

[0809] 56 mg (0.08 mmol) of tert-butyl(1-(5-(3-(benzyloxy)-4-methoxyphenyl)-6-(4-cyano-3-fluorophenyl)-4-(difluoromethoxy)pyridin-2-yl)piperidin-4-yl)carbamate was dissolved in 3 mL of trifluoroacetic acid in a sealed tube and reacted at 70°C for 2 hours under nitrogen protection. After the reaction was completed, the system was concentrated to dryness to obtain crude product, which was purified by pre-HPLC column chromatography (separation method 4) and freeze-dried to obtain 4-(6-(4-aminopiperidin-1-yl)-4-(difluoromethoxy)-3-(3-hydroxy-4-methoxyphenyl)pyridin-2-yl)-2-fluorobenzonitrile, with a yield of 19.6%.

[0810] 1 HNMR (400MHz, DMSO-d6) δppm 8.92(s,1H),7.76(t,J=7.6Hz,1H),7.30(dd,J=10.8,1.4Hz,1H),7.25–7.17( m,1H),6.82(d,J=8.4Hz,1H),6.68(s,1H),6.52(d,J=2.2Hz,1H),6.43(dd,J=8 .2,2.2Hz,1H),4.25(dt,J=13.4,3.8Hz,2H),3.75(s,3H),3.04–2.92(m,2H), 2.84(tt,J=10.2,3.8Hz,1H), 1.79(dd,J=13.2,3.8Hz,2H), 1.30–1.17(m,2H).

[0811] ESI-MS m / z: 485.2 [M+H] + .

[0812] Compounds 107-109 were prepared according to the synthetic method of Example 106 (isolation method 1), and their structures and characterization data are as follows:

[0813]

[0814]

[0815] Example 110

[0816] Preparation of 2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-4-carboxamide hydrochloride

[0817]

[0818] Step a): Preparation of methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid

[0819] Methyl 2,6-dichloropyrimidin-4-carboxylate (2.1 g, 10.1 mmol), (4-cyano-3-fluorophenyl)boronic acid (1.67 g, 10.1 mmol), Cs₂CO₃ (6.6 g, 20.2 mmol), and Pd(dppf)Cl₂ (371 mg, 0.005 mmol) were dissolved in 20 mL of dioxane and 1 mL of water. The mixture was microwaved at 100 °C for 30 minutes. LC-MS monitoring showed that the reaction was complete. After the reaction solution cooled to room temperature, it was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylate in 18.2% yield.

[0820] 1 H NMR (400MHz, DMSO-d6) δppm 8.75 (d, J = 1.8 Hz, 1H), 8.45 (d, J = 10.6 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 7.8 Hz, 1H), 3.98 (d, J = 1.8 Hz, 3H).

[0821] ESI-MS m / z = 292.0 [M+H] + .

[0822] Step b): Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid

[0823] Methyl 2-chloro-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylate (520 mg, 1.78 mmol), tert-butylpiperidin-4-ylcarbamate (357.6 mg, 1.78 mmol), and DIPEA (460 mg, 3.56 mmol) were dissolved in DMF and reacted at room temperature for 2 h. LC-MS showed that the reaction was complete. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (18 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to give methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylate, in 85.4% yield.

[0824] 1H NMR(400MHz,DMSO-d6)δppm 8.29(d,J=10.8Hz,1H),8.17(d,J=8.4Hz,1H),8.04(t,J=7.6Hz,1H),7.67(s,1H),6.95(d,J=7.4Hz,1H),5.72(t ,J=2.0Hz,1H),4.47(d,J=12.8Hz,1H),3.91(d,J=2.6Hz,3H),1.92–1.77(m,2H),1.56–1.45(m,2H),1.39(s,9H).

[0825] ESI-MS m / z = 456.2 [M+H] + .

[0826] Step c): Preparation of methyl 5-bromo-2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidine-4-carboxylic acid

[0827] Methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylic acid (750 mg, 1.64 mmol) and NBS (879.7 mg, 4.94 mmol) were dissolved in DMF, purged three times with nitrogen, and reacted in an ice bath for 2 h. LC-MS showed that the reaction was complete. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 2) to give methyl 5-bromo-2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylic acid, yield 91.3%.

[0828] ESI-MS m / z = 534.1 [M+H] + .

[0829] Step d): Preparation of methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-4-carboxylic acid

[0830] Methyl 5-bromo-2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)pyrimidin-4-carboxylic acid (430 mg, 0.80 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (136 mg, 0.80 mmol), Cs₂CO₃ (524.2 mg, 1.60 mmol), and Pd(dppf)Cl₂ (58.8 mg, 0.080 mmol) were dissolved in 1,4-Dioxane / H₂O (10 / 1), purged with nitrogen three times, and microwaved at 100 °C for 30 minutes. The reaction was monitored afterward. LCMS showed that the reaction was complete. After the reaction solution cooled to room temperature, it was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 3) to give methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-4-carboxylic acid, with a yield of 71.4%.

[0831] 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 7.84(t,J=7.4Hz,1H),7.60–7.49(m,1H),7.22(d,J=8.2Hz,1H),7.09(t,J= 8.8Hz,1H),6.98–6.94(m,1H),6.89–6.79(m,1H),4.43(d,J=12.8Hz,1H),3 .82(s,3H),3.62(s,3H),3.57(s,1H),3.45–3.36(m,1H),3.11(s,2H),1.91 –1.86(m,1H),1.81–1.74(m,1H),1.51–1.44(m,2H),1.38(d,J=2.4Hz,9H).

[0832] ESI-MS m / z = 580.2 [M+H] + .

[0833] Step e): Preparation of tert-butyl carbamate [1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl]carbamate

[0834] Methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-4-carboxylic acid (50 mg, 0.086 mmol) and NaOH (21 mg, 0.172 mmol) were dissolved in MeOH / H₂O and reacted at room temperature for 2 h. LC-MS showed that the starting material had reacted completely. The reaction solution was adjusted to pH 5 with 1N hydrochloric acid, then ethyl acetate was added, and the mixture was repeatedly extracted three times with saturated brine. The organic phase was dried and concentrated under vacuum to obtain 60 mg of crude product. The crude product was then dissolved in DMF, and DIPEA (41 mg, 0.318 mmol), NH4Cl (22.6 mg, 0.424 mmol), and HATU (60.5 mg, 0.159 mmol) were added. The reaction was continued at room temperature for 1 hour, and LCMS showed that the reaction was complete. The mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 5 / 2) to obtain tert-butyl 1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-yl)piperidin-4-yl]carbamate, with a yield of 67.3%.

[0835] 1 H NMR (400MHz, DMSO-d6) δppm: 7.95 (s, 1H), 7.79 (t, J = 7.4Hz, 1H), 7.52 (s, 1H), 7.19 (d, J = 8.2Hz, 1H), 7.07–6.91 (m, 3H), 6.84 (d, J = 8.4Hz, 1H), 4 .46(d,J=35.0Hz,2H),3.81(s,3H),3.02(d,J=41.2Hz,2H),1.88(s,1H) ,1.79(s,1H),1.47(d,J=9.0Hz,2H),1.38(s,9H),1.24(d,J=9.2Hz,1H).

[0836] ESI-MS m / z = 565.2 [M+H] + .

[0837] Step f): Preparation of 2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-4-carboxamide hydrochloride. Tert-butyl [1-(4-carbamoyl-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-2-yl)piperidin-4-yl]carbamate (40 mg, 0.07 mmol) was dissolved in 4 M HCl and ethyl acetate. The reaction was monitored after 0.5 h at room temperature. LCMS showed that the reaction was complete. The solution was concentrated under vacuum, and the solid was sent to Prep-HPLC for preparation (separation method 1) to obtain 2-(4-aminopiperidin-1-yl)-6-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidine-4-carboxamide hydrochloride, yield 91.2%.

[0838] 1 H NMR(400MHz,DMSO-d6)δppm 8.20(s,2H),7.93(s,1H),7.84(dd,J=8.2,6.8Hz,1H),7.58(s,1H),7.48(d,J=10.2Hz,1H),7.2 0(dd,J=8.2,1.6Hz,1H),7.08–6.97(m,2H),6.82(dd,J=8.4,2.1Hz,1H),4.68–4.59(m,1H),4.34 (dt,J=13.8,4.2Hz,1H),3.81(s,3H),3.35(dd,J=12.8,9.2Hz,1H),3.29–3.17(m,2H),2.07(dd, J=12.6,5.2Hz,1H),1.88–1.79(m,1H),1.67(q,J=9.8,6.8Hz,1H),1.54(td,J=10.8,5.8Hz,1H).

[0839] ESI-MS m / z = 465.2 [M+H] + .

[0840] Example 111

[0841] Preparation of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile trifluoroacetate

[0842]

[0843] Step a): Preparation of 4-(2-chloro-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0844] Compound 2,4-dichloro-6-methoxypyrimidine (750 mg, 4.2 mmol), (4-cyano-3-fluorophenyl)boronic acid (695 mg, 4.2 mmol), Cs₂CO₃ (2.746 g, 8.26 mmol), and Pd(dppf)Cl₂ (155 mg, 0.21 mmol) were dissolved in 15 mL of dioxane and 1.5 mL of water were added. This mixture was purged with nitrogen under nitrogen bubbling and protected with nitrogen. The reaction was carried out in a microwave at 100 °C for 60 minutes. Four parallel reactions were performed. When the reaction was complete as indicated by TLC and LCMS, the mixture was extracted three times with ethyl acetate (20 mL each time), washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give 4-(2-chloro-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile, in 20.3% yield.

[0845] 1 H NMR (400MHz, DMSO-d6) δppm 8.32 (t, J = 10.6 Hz, 2H), 8.13 (t, J = 7.4 Hz, 1H), 7.27 (s, 1H), 4.10 (s, 3H).

[0846] ESI-MS m / z = 264.0 [M+H] + .

[0847] Step b): 2-Fluoro-4-(2-(3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile

[0848] 4-(2-chloro-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (450 mg, 1.71 mmol), 3-aminoadamantane alcohol (572 mg, 3.42 mmol), and Cs₂CO₃ (1.112 g, 3.42 mmol) were dissolved in dimethyl sulfoxide (20 mL). The reaction was carried out at 60 °C for 36 h, and LS-MS showed that the starting material was consumed. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), 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 the residue. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give 2-fluoro-4-(2-(3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile, yield 24.5%.

[0849] ESI-MS m / z = 395.2 [M+H] + .

[0850] Step c): 4-(5-bromo-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0851] 2-Fluoro-4-(2-(3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile (100 mg, 0.253 mmol) was dissolved in N,N-dimethylformamide (4 mL), and NBS (68 mg, 0.381 mmol) was added at 0 °C with stirring. LS-MS showed that 2-fluoro-4-(2-(3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile was consumed. Quenching with water (20 mL), extraction with ethyl acetate (20 mL × 2), combining the organic phases, washing with saturated brine (15 mL × 2), drying to anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 9) to give 4-(5-bromo-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile, yield 98.5%.

[0852] ESI-MS m / z = 473.1 [M+H] + .

[0853] Step d): Preparation of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile trifluoroacetate

[0854] 4-(5-bromo-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (110 mg, 0.233 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (60 mg, 0.349 mmol), Cs2CO3 (152 mg, 0.466 mmol), and Pd(dppf)Cl2 (17 mg, 0.0233 mmol) were dissolved in 6 mL of dioxane and 0.6 mL of water were added. The mixture was purged with nitrogen gas under nitrogen protection. The reaction was carried out under microwave at 100℃ for 60 minutes. When TLC and LCMS showed that the reaction was complete, the product was extracted three times with ethyl acetate (20 mL each time), washed with 20 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then sent to Prep-HPLC for preparation (separation method 2) to obtain 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile trifluoroacetate, with a yield of 50.2%.

[0855] 1H NMR(400MHz,Methanol-d4)δppm 7.67(t,J=7.4Hz,1H),7.40–7.10(m,2H),7.04–6.82(m,2H),6.76(d,J=8.4Hz,1H),4.02(s,3H),3.90(d,J=1.8H z, 1H), 3.84 (d, J = 1.8Hz, 3H), 2.32 (s, 2H), 2.20 (d, J = 11.8Hz, 2H), 2.07 (d, J = 11.Hz, 2H), 1.70 (d, J = 37.6Hz, 4H).

[0856] ESI-MS m / z = 519.2 [M+H] + .

[0857] Example 112

[0858] Preparation of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-carbonyl-1,6-dihydropyrimidin-4-yl)benzonitrile

[0859]

[0860] Step a): Preparation of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-carbonyl-1,6-dihydropyrimidin-4-yl)benzonitrile

[0861] 50 mg (0.0965 mmol) of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-methoxypyrimidin-4-yl)benzonitrile (2 mL of 2 M hydrochloric acid (2 mL of 4 M dioxane hydrochloride and 2 mL of water)) was added to 4 mL of the solution and reacted at 100 °C for 12 hours. LC-MS showed that the reaction was half complete. The solvent was evaporated, and the crude product was sent to Prep-HPLC (Separation Method 4) to obtain 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-((3-hydroxyadamantane-1-yl)amino)-6-carbonyl-1,6-dihydropyrimidin-4-yl)benzonitrile in 22.2% yield.

[0862] 1H NMR(400MHz,Methanol-d4)δppm 7.58(t,J=7.6Hz,1H),7.28(dd,J=23.8,9.4Hz,2H),6.99–6.86(m,2H),6.74(d,J=8.6Hz,1H),3.83( d,J=2.4Hz,3H),2.27(s,2H),2.13(d,J=11.6Hz,4H),2.02(d,J=11.8Hz,2H),1.65(d,J=38.2Hz,6H).

[0863] ESI-MS m / z = 505.2 [M+H] + .

[0864] Example 113

[0865] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-6-methoxy-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)benzonitrile was prepared according to the synthetic method of Example 111 (separation method 4), and its structure and characterization data are as follows:

[0866]

[0867] 1 H NMR(400MHz,Methanol-d4)δppm 8.36(dd,J=39.6,9.4Hz,2H),7.85(t,J=7.4Hz,1H),7.24–7.08(m,3H),3.99( s, 3H), 3.91 (s, 3H), 3.36 (t, J = 5.0Hz, 4H), 2.38 (t, J = 5.0Hz, 4H), 2.26 (s, 3H).

[0868] ESI-MS m / z = 452.2 [M+H] + .

[0869] Example 114

[0870] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-6-methoxy-2-(3-(methylamino)piperidin-1-yl)pyrimidin-4-yl)benzonitrile hydrochloride was prepared according to the synthetic method of Example 111 (isolation method 1), and its structure and characterization data are as follows:

[0871]

[0872] 1H NMR(400MHz,Methanol-d4)δppm 8.43(dd,J=8.0,1.6Hz,1H),8.34(d,J=10.6Hz,1H),7.87(t,J=7.4Hz,1H),7.19( d,J=13.0Hz,3H),4.29(dd,J=12.4,3.4Hz,1H),4.00(s,3H),3.92(s,3H),3.51(d d,J=13.6,4.2Hz,1H),3.22(dt,J=8.8,3.8Hz,2H),3.13(dd,J=12.6,9.6Hz,1H), 2.85–2.73(m,3H),2.69(s,1H),2.16(dd,J=11.8,5.2Hz,1H),1.70–1.38(m,3H).

[0873] ESI-MS m / z = 466.2 [M+H] + .

[0874] Example 115

[0875] Preparation of 4-(6-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0876]

[0877] Step a): Preparation of 6-(4-cyano-3-fluorophenyl)-4-methoxypyridinecarboxylic acid

[0878] Methyl 6-chloro-4-methoxypyridinecarboxylate (500 mg, 2.488 mmol), (4-cyano-3-fluorophenyl)boronic acid (616 mg, 3.732 mmol), Cs₂CO₃ (1.6 g, 4.976 mmol), Pd(PPh₃)Cl₂ (174 mg, 0.249 mmol), 1,4-Dioxane (8 mL), and H₂O (2 mL) were added to a reaction flask and stirred at 120 °C for 2 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 8 / 1) to give 6-(4-cyano-3-fluorophenyl)-4-methoxypyridinecarboxylic acid, in 73.0% yield.

[0879] ESI-MS (m / z) = 273.3 [M+H] + .

[0880] Step b): Preparation of tert-butyl (8-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0881] 4-(6-(4-aminopiperidin-1-yl)-4-(3-fluoro-4-methoxyphenyl)-3-methoxypyridin-2-yl)-2-fluorobenzonitrile (496 mg, 1.816 mmol), tert-butyl(8-azabicyclo[3.2.1]octane-3-yl)carbamate (410 mg, 1.816 mmol) and DMF (10 mL) were added to the reaction flask. HATU (962 mg, 2.178 mmol) and DIPEA (703 mg, 5.448 mmol) were added to the reaction flask with stirring in an ice bath. The reaction was maintained at room temperature for 1 hour. After the reaction was completed, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give tert-butyl(8-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 63.1%.

[0882] ESI-MS (m / z) = 481.2 [M+H] + .

[0883] Step c): Preparation of tert-butyl (8-(5-chloro-6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0884] 550 mg (1.144 mmol) of tert-butyl (8-(6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate and 10 mL of DMF were added to a reaction flask. NCS (152 mg, 1.144 mmol) was added in portions with stirring in an ice bath, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, 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 phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give tert-butyl (8-(5-chloro-6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 45.0%.

[0885] 1H NMR(400MHz,DMSO-d6)δppm 8.35–8.17(m,2H),8.09(dd,J=8.2,6.8Hz,1H),7.92(s,1H),4.74–4.60(m,1H),4 .13(s,3H),3.89(d,J=38.6Hz,1H),3.65(s,1H),1.97–1.56(m,8H),1.38(s,9H).

[0886] ESI-MS (m / z) = 515.2 [M+H] + .

[0887] Step d): Preparation of tert-butyl(8-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[0888] (8-(5-chloro-6-(4-cyano-3-fluorophenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl) tert-butyl carbamate (80 mg, 0.155 mmol), (3-hydroxy-4-methoxyphenyl)boronic acid (58 mg, 0.233 mmol), Cs2CO3 (101 mg, 0.310 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), 1,4-Dioxane (4 mL) and H2O (1 mL) were added to a reaction flask and stirred at 120 °C for 1 hour. The residue was concentrated to dryness under reduced pressure, and purified by silica gel chromatography (eluent: dichloromethane / methanol = 15 / 1) to give tert-butyl(8-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 40.0% yield.

[0889] ESI-MS (m / z) = 603.1 [M+H] + .

[0890] Step e): Preparation of 4-(6-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[0891] 37 mg (0.062 mmol) of tert-butyl(8-(6-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was added to a reaction flask, followed by ethyl hydrogen chloride 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 solid was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 4) to obtain 4-(6-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile, with a yield of 54.0%.

[0892] 1H NMR(400MHz,DMSO-d6)δppm 8.46–8.20(m,2H),8.10(dd,J=8.2,6.8Hz,1H),7.84(s,1H),6.93(d,J=8.4Hz,1H),6.87–6.54(m,2H),4.50–4 .33(m,1H),3.97(s,3H),3.79(s,3H),3.56(d,J=6.6Hz,1H),2.95(tt,J=11.2,5.6Hz,1H),1.77–1.11(m,8H).

[0893] ESI-MS (m / z) = 503.2 [M+H] + .

[0894] Example 116

[0895] (3-Amino-8-azabicyclo[3.2.1]octane-8-yl)(6-(3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)-4-methoxypyridin-2-yl) methyl ketone was prepared according to the synthetic method of Example 115 (isolation method 4), and its structure and characterization data are as follows:

[0896]

[0897] 1H NMR(400MHz,DMSO-d6)δppm 8.13–7.90(m,2H),7.69(s,1H),7.57(td,J=8.0,6.0Hz,1H),7.31(td,J=8.6,2.8Hz,1H),6.93(d,J=8.4Hz,1H),6.79(d,J=2.0Hz,1H),6.73(dd ,J=8.4,2.2Hz,1H),4.48–4.25(m,1H),3.95(s,3H),3.79(s,3H),3.58( dd,J=6.6,3.2Hz,1H),2.95(tt,J=11.0,5.4Hz,1H),1.77–1.13(m,8H).

[0898] ESI-MS (m / z) = 478.2 [M+H] + .

[0899] Example 117

[0900] Preparation of 4-(5-(4-aminopiperidin-1-yl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile hydrochloride

[0901]

[0902] Step a): Preparation of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0903] 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, 0.006 mol) were dissolved in an aqueous solution of 1,4-dioxane (150 ml, 5:1), bubbled with nitrogen and under nitrogen protection. The reaction was carried out in an oil bath at 95°C. Once the LCMS showed the reaction was complete, the reaction solution was concentrated under vacuum, dissolved in ethyl acetate (20 mL), washed with water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile, yield 88.6%.

[0904] ESI-MS m / z: 245.1 [M+H] + .

[0905] Step b): Preparation of 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile

[0906] 2.0 g (0.008 mol) of 4-(6-amino-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile was dissolved in 10 mL of dry DMSO and 50 mL of anhydrous acetonitrile. Under nitrogen protection in an ice-water bath, 1.45 g (0.008 mol) of NBS was added, and the reaction was continued for 2 hours. The reaction was detected by LCMS to be complete. The reaction was quenched with water (40 mL), 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 give 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile, yield 78.5%.

[0907] ESI-MS m / z: 323.0 [M+H] + .

[0908] Step c): Preparation of 4-(8-bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile

[0909] 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)-2-fluorobenzonitrile (500 mg, 1.553 mmol) was dissolved in isopropanol (13 mL), and then chloroacetaldehyde (6.09 g, 31.055 mmol) was added. The mixture was purged with nitrogen and reacted overnight at 110 °C. The reaction progress was monitored by TLC and LCMS. When the LCMS indicated that the reaction was complete, the reaction solution was concentrated under vacuum and dissolved in 5 mL of dichloromethane. The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 4-(8-bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile, in 85.7% yield.

[0910] 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).

[0911] ESI-MS m / z: 333.0 [M+H] + .

[0912] Step d): Preparation of 2-fluoro-4-(8-(3-fluoro-4-methoxyphenyl)-5-hydroxyimino[1,2-c]pyrimidin-7-yl)benzonitrile

[0913] Weigh 4-(8-bromo-5-hydroxyimidazopyrimidin-7-yl)-2-fluorobenzonitrile (380 mg, 1.144 mmol), 3-fluoro-4-methoxyphenylboronic acid (292 mg, 1.717 mmol), Pd(dppf)Cl2 (167 mg, 0.208 mmol), and Na2CO3 (243 mg, 2.289 mmol) and dissolve them in 1,4-dioxane (15 mL) and add water (3 mL). Bubble the mixture with N2 and allow it to react under N2 protection in a microwave reactor at 105 °C for 30 minutes. When the reaction is complete as indicated by LCMS, extract with ethyl acetate (10 mL x 3), wash with 10 mL of brine, dry with anhydrous sodium sulfate, filter, and concentrate. The residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 2-fluoro-4-(8-(3-fluoro-4-methoxyphenyl)-5-hydroxyimino[1,2-c]pyrimidin-7-yl)benzonitrile in 89.7% yield.

[0914] 1 H NMR(400MHz,DMSO-d6)δppm 12.02(s,1H),7.94–7.87(m,2H),7.65–7.58(m,2H),7.54–7.50(m,1H),7.28( dd,J=8.2,1.6Hz,1H),7.16–7.13(m,1H),7.05(t,J=8.8Hz,1H),3.81(s,3H).

[0915] ESI-MS m / z: 379.1 [M+H] + .

[0916] Step e): Preparation of tert-butyl(1-(7-(4-cyano-3-fluorophenyl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate

[0917] 2-Fluoro-4-(8-(3-fluoro-4-methoxyphenyl)-5-hydroxyimino[1,2-c]pyrimidin-7-yl)benzonitrile (200 mg, 0.530 mmol), tert-butylpiperidine-4-carbamate (318 mg, 1.57 mmol), and Carter's condensing agent (352 mg, 0.795 mmol) were dissolved in 16 mL of anhydrous acetonitrile, and then DIPEA (206 mg, 1.590 mmol) was added. The mixture was then purged with nitrogen and heated to 60 °C overnight under nitrogen protection. The reaction process was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was cooled and concentrated under vacuum. The concentrate was directly purified by thin-layer chromatography (methanol / dichloromethane = 1 / 10) to give tert-butyl(1-(7-(4-cyano-3-fluorophenyl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamic acid, with a yield of 58.4%.

[0918] 1 H NMR(400MHz,Methanol-d4)δppm 7.80(d,J=1.6Hz,1H),7.63–7.55(m,2H),7.45(dd,J=10.8,1.6Hz,1H),7.33 (dd,J=8.2,1.6Hz,1H),7.19–7.06(m,2H),7.00(dt,J=8.4,1.6Hz,1H),4.05 –3.96(m,2H),3.91(s,3H),3.68(dq,J=10.6,6.4,5.2Hz,1H),3.25–3.15(m, 2H), 2.07 (dd, J=13.2, 3.8Hz, 2H), 1.76 (qd, J=11.6, 3.8Hz, 2H), 1.46 (s, 9H).

[0919] ESI-MS m / z: 561.2 [M+H] + .

[0920] Step f): Preparation of 4-(5-(4-aminopiperidin-1-yl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile hydrochloride

[0921] 173 mg (0.309 mmol) of tert-butyl(1-(7-(4-cyano-3-fluorophenyl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamic acid was dissolved in 5 mL of 4 M ethyl acetate hydrochloride solution and stirred at room temperature for 40 minutes under nitrogen protection. After the reaction was completed, the solution was concentrated at room temperature, the precipitated solid was filtered, washed with ethyl acetate, concentrated under vacuum, and lyophilized to obtain 4-(5-(4-aminopiperidin-1-yl)-8-(3-fluoro-4-methoxyphenyl)imidazo[1,2-c]pyrimidin-7-yl]-2-fluorobenzonitrile hydrochloride, yield 23.6%.

[0922] 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 8.48(d,J=5.2Hz,3H),8.20(d,J=2.0Hz,1H),8.07(s,1H),7.88(t,J=7.6Hz, 1H),7.58(dd,J=10.6,1.6Hz,1H),7.34–7.27(m,2H),7.24(t,J=8.6Hz,1H), 7.06–6.97(m,1H),4.09(d,J=13.2Hz,2H),3.89(s,3H),3.38(d,J=12.2Hz,1 H), 3.27 (t, J = 12.6Hz, 2H), 2.19–2.05 (m, 2H), 1.90 (qd, J = 12.2, 3.8Hz, 2H).

[0923] ESI-MS m / z: 461.2 [M+H] + .

[0924] Compounds 118-186 in Examples were prepared according to the synthetic method of Example 117 (the compounds were isolated by separation methods 4, 1, and 3, respectively, for the free base, hydrochloride, and formate). Their structures and characterization data are as follows:

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944] Example 187

[0945] Preparation of 4-(5-(4-aminopiperidin-1-yl)-8-(3-hydroxy-4-methoxyphenyl)-3-methylimidazolium[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile

[0946]

[0947] Step a): Synthesis of tert-butyl (1-(8-(3-(benzyloxy)-4-methoxyphenyl)-3-bromo-7-(4-cyano-3-fluorophenyl)imidazolium[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate

[0948] 100 mg (0.15 mmol) 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 was dissolved in acetonitrile (3 mL), cooled to 0°C in an ice-water bath, and under nitrogen protection, NBS (27.5 mg, 0.15 mmol) was added, and the reaction was stirred for another 30 minutes. After the reaction was complete as shown by LCMS, water (3 mL) was added, followed by extraction with ethyl acetate (10 mL x 3), washing with brine (10 mL), drying with anhydrous sodium sulfate, filtration and concentration, and purification of the residue by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(1-(8-(3-(benzyloxy)-4-methoxyphenyl)-3-bromo-7-(4-cyano-3-fluorophenyl)imidazolium[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate, yield 94.6%.

[0949] 1 H NMR(400MHz,DMSO-d6)δppm 7.73(ddd,J=8.2,7.0,5.2Hz,1H),7.66–7.64(m,2H),7.60(s,1H),7.56(ddd,J=7.2, 3.2,1.0Hz,5H),7.39(d,J=1.2Hz,1H),7.33(d,J=4.0Hz,1H),7.00(d,J=8.4Hz,1H), 6.95(t,J=1.8Hz,1H),4.93(d,J=2.2Hz,2H),3.81(s,3H),3.54(d,J=12.8Hz,2H),3. 15–3.05(m,1H),2.72(s,2H),1.90(s,2H),1.75–1.64(m,2H),1.40(d,J=1.4Hz,9H).

[0950] ESI-MS m / z: 727.2 [M+H] + .

[0951] Step b): Synthesis of tert-butyl(1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)-3-methylimidazolium[1,2-c]pyrimidin-5-yl)piperidin-4-ylcarbamate

[0952] tert-butyl (1-(8-(3-(benzyloxy)-4-methoxyphenyl)-3-bromo-7-(4-cyano-3-fluorophenyl)imidazol[1,2-c]pyrimidin-5-yl)piperidin-4-yl)carbamate (106 mg, 0.15 mmol), 2,4,6-methyl-1,3,5,2,4,6-trioxatetraborane (339 mg, 2.68 mmol), potassium carbonate (74 mg, 0.54 mmol), tetraphenylphosphine palladium (42 mg, 0.04 mmol) ), added 1,4-dioxane (10 mL) to dissolve, and heated to 100 degrees Celsius for 1 hour. After the reaction was completed as indicated by LCMS, the mixture was transferred to a rotary evaporator and concentrated to dryness. The residue was purified by silica gel thin-layer chromatography (petroleum ether / ethyl acetate = 1 / 2) to give tert-butyl(1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)-3-methylimidazolium[1,2-c]pyrimidin-5-yl)piperidin-4-yl carbamate, yield 94.0%.

[0953] ESI-MS m / z: 663.3 [M+H] + .

[0954] Step c): Synthesis of 4-(5-(4-aminopiperidin-1-yl)-8-(3-hydroxy-4-methoxyphenyl)-3-methylimidazolium[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile

[0955] 90 mg (0.14 mmol) of tert-butyl(1-(8-(3-(benzyloxy)-4-methoxyphenyl)-7-(4-cyano-3-fluorophenyl)-3-methylimidazolium[1,2-c]pyrimidin-5-yl)piperidin-4-yl carbamate was dissolved in 3 mL of trifluoroacetic acid in a sealed tube. The mixture was heated to 70°C for 2 hours under nitrogen protection. After the reaction was complete, the system was concentrated to dryness.

[0956] The crude product was purified by pre-HPLC column chromatography (separation method 4) to obtain 4-(5-(4-aminopiperidin-1-yl)-8-(3-hydroxy-4-methoxyphenyl)-3-methylimidazolium[1,2-c]pyrimidin-7-yl)-2-fluorobenzonitrile, with a yield of 18.3%.

[0957] 1¹H NMR (400MHz, DMSO-d⁶) δppm 9.02(s,1H),7.79(dd,J=8.2,7.0Hz,1H),7.47(dd,J=11.2,1.6Hz,1H),7.39 (d,J=1.2Hz,1H),7.32(dd,J=8.2,1.6Hz,1H),6.90(d,J=8.4Hz,1H),6.82(d, J=2.2Hz,1H),6.65(dd,J=8.4,2.2Hz,1H),3.79(s,3H),3.55(d,J=12.6Hz,2 H), 2.94 (s, 3H), 2.73 (s, 3H), 1.91 (d, J = 12.4Hz, 2H), 1.61 (t, J = 11.4Hz, 2H).

[0958] ESI-MS m / z: 473.2 [M+H] + .

[0959] Compounds 188-194 in Examples were prepared according to the synthetic method of Example 3 (the compounds were isolated by separation methods 4, 1, and 3, respectively, for the free base, hydrochloride, and formate). Their structures and characterization data are as follows:

[0960]

[0961]

[0962]

[0963] Example 195

[0964] 4-(1-(4-methylpiperazin-1-yl)-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazin-7-yl)benzonitrile was prepared according to the synthesis method of Example 4 (isolation method 4), and its structure and characterization data are as follows:

[0965]

[0966] 1 H NMR(400MHz,Chloroform-d)δppm 8.57(s,1H),7.55(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.30(d,J=7.8Hz,2H),7.21(d,J= 7.8Hz, 2H), 6.90 (s, 1H), 3.88 (t, J = 4.8Hz, 4H), 2.72-2.61 (m, 4H), 2.44 (s, 3H), 2.40 (s, 3H).

[0967] ESI-MS m / z = 409.2 [M+H] + .

[0968] Example 196

[0969] 4-(1-(4-aminopiperidin-1-yl)-6-(p-tolyl)pyrrolo[1,2-d][1,2,4]triazine-7-yl)benzonitrile hydrochloride was prepared according to the synthesis method of Example 4 (isolation method 1), and its structure and characterization data are as follows:

[0970]

[0971] 1 H NMR(400MHz,Chloroform-d)δppm 8.58(s,3H),8.48(d,J=3.2Hz,2H),7.69(d,J=7.8Hz,2H),7.51(d,J=8.2Hz,2H),7.39(d,J=7.8Hz,2H),7.32(s,2 H), 4.59 (d, J = 13.6Hz, 2H), 3.70 (t, J = 12.8Hz, 2H), 3.57 (s, 1H), 2.46 (s, 3H), 2.33 (d, J = 13.2Hz, 2H), 2.03 (s, 2H).

[0972] ESI-MS m / z = 409.2 [M+H] + .

[0973] Example 197

[0974] Preparation of 4-(4-(3-(methylamino)piperidin-1-yl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl]benzonitrile hydrochloride

[0975]

[0976] Step a): Preparation of 1-(4-bromo-1H-pyrrole-2-yl)ethane-1-one

[0977] Acylpyrrole (10.0 g, 91.7 mmol), Amberlyst 15 resin (0.9 g, 0.09 g / 1.0 g starting material), and anhydrous tetrahydrofuran (150 mL) were added sequentially to a reaction flask. The mixture was cooled to -30°C in a cold bath, and N-bromosuccinimide (16.3 g, 91.7 mmol) was slowly added. The reaction was continued for 2 hours. TLC showed that the starting material disappeared. The reaction was quenched with saturated sodium sulfite solution (20 mL), and then extracted three times with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to give 1-(4-bromo-1H-pyrrole-2-yl)ethane-1-one, yield 91.0%.

[0978] ESI-MS m / z: 188.9 [M+H] + .

[0979] Step b): Preparation of 4-(5-acetyl-1H-pyrrole-3-yl)benzonitrile

[0980] 1-(4-bromo-1H-pyrrolo-2-yl)ethane-1-one (1.0 g, 5.35 mmol), p-cyanobenzoic acid (1.96 g, 13.37 mmol), Pd(dppf)Cl2 (1.17 g, 1.60 mmol), cesium carbonate (6.09 g, 18.7 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a reaction flask. The mixture was then microwaved at 100 °C for 60 minutes under nitrogen protection. LC-MS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under vacuum, dissolved in ethyl acetate (10 mL), washed with water (10 mL), and the aqueous phase was further washed with ethyl acetate (10 mL). x3) ​​Extracted three times, the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 4-(5-acetyl-1H-pyrrole-3-yl)benzonitrile, yield 71.4%.

[0981] 1 H NMR (400MHz, Chloroform-d) δppm 9.74 (s, 1H), 7.63 (q, J = 8.2 Hz, 4H), 7.42–7.37 (m, 1H), 7.19 (t, J = 2.0 Hz, 1H), 2.50 (s, 3H).

[0982] ESI-MS m / z: 211.1 [M+H] + .

[0983] Step c): Preparation of 4-(5-acetyl-2-bromo-1H-pyrrole-3-yl)benzonitrile

[0984] 4-(5-acetyl-1H-pyrrolo-3-yl)benzonitrile (510 mg, 2.43 mmol), Amberlyst 15 resin (46 mg, 0.09 g / 1.0 g starting material), and anhydrous tetrahydrofuran (60 mL) were added sequentially to a reaction flask. The mixture was cooled to -30°C in a cold bath, and NBS (432 mg, 2.43 mmol) was slowly added. The reaction was continued for 2 hours. TLC showed that the starting material disappeared. The reaction was quenched with saturated sodium sulfite solution (10 mL), and then extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 4-(5-acetyl-2-bromo-1H-pyrrolo-3-yl)benzonitrile, with a yield of 65.9%.

[0985] 1 H NMR (400MHz, Chloroform-d) δppm 9.53 (s, 1H), 7.70 (s, 4H), 7.02 (d, J = 2.8Hz, 1H), 2.46 (s, 3H).

[0986] ESI-MS m / z: 290.0 [M+H] + .

[0987] Step d): Preparation of 4-(5-acetyl-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile

[0988] 4-(5-acetyl-2-bromo-1H-pyrrolo-3-yl)benzonitrile (460 mg, 1.60 mmol), p-methylphenylboronic acid (434 mg, 3.20 mmol), Pd(dppf)Cl2 (117 mg, 0.16 mmol), cesium carbonate (1.56 g, 4.80 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a reaction flask. The mixture was reacted under nitrogen protection at 100 °C for 60 minutes using microwave. LC-MS showed the disappearance of the starting material and the formation of the product. The reaction solution was concentrated under vacuum, dissolved in ethyl acetate (10 mL), washed with water (10 mL), and the aqueous phase was extracted three times with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 4:1) to give 4-(5-acetyl-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile, yield 62.5%.

[0989] 1 HNMR(400MHz,Chloroform-d)δppm 9.39(s,1H),7.60–7.52(m,2H),7.40(dd,J=8.4,2.0Hz,2H),7.23(d,J=7.8Hz,2H) ,7.18(d,J=7.8Hz,2H),7.05(d,J=2.6Hz,1H),2.48(d,J=2.2Hz,3H),2.38(s,3H).

[0990] ESI-MS m / z: 301.1 [M+H] + .

[0991] Step e): Preparation of (E)-4-(5-(3-(dimethylamino)acryloyl)-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile

[0992] 300 mg (0.99 mmol) of 4-(5-acetyl-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile was dehydrated with toluene, dissolved in 15 mL of N,N-dimethylformamide dimethyl acetal, and reacted at 80 °C for 16 hours to form a yellow solid. The starting material disappeared by TLC. The reaction mixture was filtered, the filter cake was washed with petroleum ether, and dried to obtain crude (E)-4-(5-(3-(dimethylamino)acryloyl)-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile in 96.2% yield, which was directly used in the next step.

[0993] ESI-MS m / z: 356.2 [M+H] + .

[0994] Step f): Preparation of 4-(4-hydroxy-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl]benzonitrile

[0995] Crude (E)-4-(5-(3-(dimethylamino)acryloyl)-2-(p-tolyl)-1H-pyrrolo-3-yl)benzonitrile (345 mg, 0.97 mmol) was dissolved in N-methylpyrrolidone (5 mL), and then potassium tert-butoxide (163 mg, 1.45 mmol) was added.

[0996] Stir for 30 minutes, add O-p-nitrobenzoylhydroxylamine (353 mg, 1.94 mmol), and react at 30°C for 2 hours. The reaction was confirmed to be complete by LCMS. Quench with saturated ammonium chloride (1 mL), precipitate the solid with dilute hydrochloric acid (1 mL), and extract with ethyl acetate (5 mL x 3). No residue was found in the aqueous phase. Concentrate, and purify the residue by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 4-(4-hydroxy-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl]benzonitrile, yield 69.5%.

[0997] 1 H NMR(400MHz,DMSO-d6)δppm 11.65(s,1H),7.92(d,J=5.2Hz,1H),7.73(d,J=8.0Hz,2H),7.47(d,J=8.0H z, 2H), 7.34–7.20 (m, 4H), 6.95 (s, 1H), 6.10 (d, J = 5.4Hz, 1H), 2.36 (s, 3H).

[0998] ESI-MS m / z: 326.1 [M+H] + .

[0999] Step g): Preparation of 6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazine-4-trifluoromethanesulfonate

[1000] 4-(4-hydroxy-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl]benzonitrile (120 mg, 0.36 mmol) was dehydrated with toluene, dissolved in dichloromethane (5 ml), and triethylamine (55 mg, 0.46 mmol) was added. The mixture was cooled to -30°C. A dichloromethane solution of trifluoromethanesulfonic anhydride (126 mg, 0.44 mmol) (0.5 ml) was added dropwise, and the reaction was continued for 30 minutes. TLC analysis showed that the reaction was complete. The reaction was quenched with ice water (10 ml), extracted with ethyl acetate (5 ml x 3), and the organic phases were combined. The mixture was washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-4-trifluoromethanesulfonate in 94.8% yield, which was used directly in the next step.

[1001] ESI-MS m / z: 458.1 [M+H] + .

[1002] Step h): Preparation of tert-butyl(1-(6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-4-yl)piperidin-3-yl)carbamate.

[1003] 6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazine-4-trifluoromethanesulfonate (156 mg, 0.31 mmol), triethylamine (62 mg, 0.62 mmol, 85 μL), and tert-butyl methyl(piperidin-3-yl)carbamate (132 mg, 0.62 mmol) were dissolved in N-methylpyrrolidone (5 mL) and reacted at 100 °C for 2 h. LC-MS showed no change in the product, indicating the reaction was complete. The reaction was quenched with water (5 mL) and then extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified using a pre-HPLC column (separation method 4), and then lyophilized with acetonitrile and ultrapure water to obtain tert-butyl(1-(6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-4-yl)piperidin-3-yl)carbamate, with a yield of 26%.

[1004] ESI-MS m / z: 522.3 [M+H] + .

[1005] Step i): Preparation of 4-(4-(3-(methylamino)piperidin-1-yl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl]benzonitrile hydrochloride.

[1006] Methyl tert-butyl(1-(6-(4-cyanophenyl)-7-(p-tolyl)pyrrolo[1,2-b]pyrrolo[1,2-b]pyrrolo[4-b]pyrrolo[6-b]pyrrolo[6-b]]benzonitrile hydrochloride (38 mg, 0.07 mmol) was dissolved in 2 mL of 4 M dioxane hydrochloride solution under nitrogen protection and stirred at room temperature for 30 minutes. LC-MS showed that the reaction was complete and the starting material disappeared. The reaction mixture was concentrated to dryness at low temperature, and then freeze-dried with acetonitrile and water (5 mL) to give 4-(4-(3-(methylamino)piperidin-1-yl)-7-(p-tolyl)pyrrolo[1,2-b]pyrrolo[6-b]pyrrolo[6-b]]benzonitrile hydrochloride in 47.4% yield.

[1007] 1H NMR(400MHz,DMSO-d6)δppm 9.27-9.12(m,1H),9.01-8.88(m,1H),7.98-7.91(m,1H),7.79-7.70(m,2H),7.57-7.50 (m,2H),7.26(q,J=8.0Hz,4H),7.04(s,1H),6.17(d,J=5.4Hz,1H),4.19(d,J=12.4Hz,1H ),3.72(d,J=12.6Hz,1H),3.11(q,J=10.8,10.4Hz,2H),2.63(d,J=5.6Hz,3H),2.36(s, 3H), 2.17 (d, J = 10.6Hz, 1H), 1.95 (d, J = 13.2Hz, 1H), 1.68 (t, J = 8.8Hz, 2H), 1.23 (s, 1H).

[1008] ESI-MS m / z: 422.2 [M+H] + .

[1009] Example 198

[1010] 4-(4-(4-aminopiperidin-1-yl)-7-(p-tolyl)pyrrolo[1,2-b]pyridazin-6-yl)benzonitrile hydrochloride was prepared according to the synthetic method of Example 197 (isolation method 1), and its structure and characterization data are as follows:

[1011]

[1012] 1 H NMR(400MHz,DMSO-d6)δppm 8.24–8.12(m,3H),7.91(d,J=5.4Hz,1H),7.77–7.71(m,2H),7.55–7.47(m,2H),7.25(q,J=8.0Hz,4H),6.99(s,1H),6.10(d,J=5.6Hz, 1H), 4.08 (d, J = 13.0Hz, 2H), 3.33 (d, J = 9.4Hz, 1H), 3.06 (t, J = 12.6Hz, 2H), 2.36 (s, 3H), 2.07 (d, J = 12.4Hz, 2H), 1.75 (d, J = 1.8Hz, 2H).

[1013] ESI-MS m / z: 408.2 [M+H] + .

[1014] Compounds 199-218 in Examples were prepared according to the synthetic method of Example 9 (isolation methods of the compounds: free base, hydrochloride and formate were isolated according to separation methods 4, 1 and 3, respectively), and their structures and characterization data are as follows:

[1015]

[1016]

[1017]

[1018]

[1019]

[1020] Example 219

[1021] Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-3-yl)-2-fluorobenzonitrile hydrochloride

[1022]

[1023] Step a): Preparation of tert-butyl (8-(4-bromofuran-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1024] 4-Bromofuran-2-carboxylic acid (500 mg, 2.63 mmol) and tert-butyl(8-azabicyclo[3.2.1]octane-3-yl)carbamate (650 mg, 2.879 mmol) were dissolved in N,N-dimethylformamide (20 mL), and HATU (1.29 g, 3.40 mmol) and DIPEA (1.15 mL, 7.08 mmol) were added. The mixture was stirred at room temperature for 30 minutes. When the reaction was complete as indicated by TLC and LCMS, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate (80 mL each time), washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 3) to give tert-butyl(8-(4-bromofuran-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 96.4%.

[1025] ESI-MS (m / z) = 399.1 [M+H] + .

[1026] Step b): Preparation of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1027] 1 g (2.5 mmol) of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, 0.581 g (3.5 mmol) of (4-cyano-3-fluorophenyl)boronic acid, 2.86 g (8.79 mmol) of Cs2CO3, and 186 mg (0.25 mmol) of Pd(dppf)Cl2 were dissolved in 14 mL of dioxane and 0.4 mL of water were added. The mixture was purged with nitrogen gas and heated to 120 °C with stirring for 45 min. After the reaction was completed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 83.2%.

[1028] ESI-MS (m / z) = 440.2 [M+H] + .

[1029] Step c): Preparation of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1030] 300 mg (0.683 mmol) of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was dissolved in N,N-dimethylformamide (10 mL), and NBS (136 mg (0.751 mmol) was added at 0 °C. The mixture was stirred at room temperature, and the reaction was completed by LS-MS. Quenching with water (50 mL), extraction with ethyl acetate (50 mL × 2), combining the organic phases, washing with saturated brine (60 mL × 2), drying with anhydrous sodium sulfate, filtering, concentrating to obtain the crude product, and purifying the residue by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, yield 64.5%.

[1031] ESI-MS (m / z) = 518.1 [M+H] + .

[1032] Step d): Preparation of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1033] 70 mg (0.135 mmol) of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, 75 mg (0.27 mmol), 43 mg (0.406 mmol) of Na2CO3, and 10 mg (0.0137 mmol) of Pd(dppf)Cl2 were dissolved in 4 mL of dioxane and 0.4 mL of water were added. The mixture was purged with nitrogen gas and heated to 100 °C with stirring for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 67.2% yield.

[1034] ESI-MS (m / z) = 589.2 [M+H] +

[1035] Step e): Preparation of 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-3-yl)-2-fluorobenzonitrile hydrochloride

[1036] 52 mg (0.11 mmol) of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was added to 10 mL of 4 M ethyl acetate hydrochloride solution and reacted at room temperature for 2 hours. A small amount of solid was formed in the reaction system, and LC-MS showed that the reaction was complete. The solvent was evaporated at low temperature, and 4 mL of acetonitrile and 5 mL of pure water were added and freeze-dried to obtain 4-(5-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)furan-3-yl)-2-fluorobenzonitrile hydrochloride in 92.5% yield.

[1037] 1H NMR(400MHz,DMSO-d6)δppm 8.07(d,J=5.1Hz,1H),8.03–7.80(m,5H),7.76–7.62(m,2H),7.37(dd,J=17.8,8.2Hz,1 H),5.02(s,1H),4.74(s,1H),3.63(s,1H),2.59(s,3H),2.14–1.90(m,4H),1.76(s,4H).

[1038] ESI-MS m / z = 489.2 [M+H] + .

[1039] Example 220

[1040] Preparation of 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl)-2-fluorobenzonitrile hydrochloride

[1041]

[1042] Step a): Preparation of tert-butyl (8-(4-bromothiazol-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1043] 4-Bromothiazol-2-carboxylic acid (300 mg, 1.44 mmol) and tert-butyl(8-azabicyclo[3.2.1]octane-3-yl)carbamate (360 mg, 1.58 mmol) were dissolved in N,N-dimethylformamide (8 mL). HATU (173 mg, 1.87 mmol) and DIPEA (558 mg, 4.3 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. When the reaction was complete as indicated by TLC and LCMS, water was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL x 3), washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give tert-butyl(8-(4-bromothiazol-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 96.4%.

[1044] ESI-MS (m / z) = 416.1 [M+H] + .

[1045] Step b): Preparation of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiazole-2-carbonyl)bicyclo[3.2.1]octane-3-yl)carbamate

[1046] 0.6 g (1.4 mmol) of tert-butyl (8-(4-bromothiazol-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl) carbamate, 0.334 g (2.02 mmol) of (4-cyano-3-fluorophenyl)boronic acid, 1.6 g (5.06 mmol) of Cs2CO3, and 106 mg (0.144 mmol) of Pd(dppf)Cl2 were dissolved in 14 mL of dioxane and 0.4 mL of water were added. The mixture was purged with nitrogen gas and heated to 120 °C with stirring for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 3) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)thiazol-2-carbonyl)bicyclo[3.2.1]octane-3-yl)carbamate, with a yield of 83.5%.

[1047] ESI-MS (m / z) = 456.2 [M+H] + .

[1048] Step c): Preparation of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazolyl-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1049] 262 mg (0.58 mmol) of tert-butyl (8-(4-(4-cyano-3-fluorophenyl)thiazolyl-2-carbonyl)bicyclo[3.2.1]octane-3-yl)carbamate was dissolved in 10 mL of dichloromethane. Dibromohydantoin (166 mg (0.575 mmol)) and trifluoroacetic acid (65 mg (0.575 mmol)) were added and stirred at room temperature. The reaction was completed by LS-MS. Quenching with saturated sodium bicarbonate, extraction with ethyl acetate (40 mL x 3), washing with 50 mL of brine, drying and filtering, and concentrating under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 5 / 3) to give tert-butyl(8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazolyl-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, yield 64.5%.

[1050] ESI-MS (m / z) = 535.1 [M+H] + .

[1051] Step d): tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate

[1052] 45 mg (0.084 mmol) of tert-butyl (8-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazol-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, 47 mg (0.168 mmol) of benzo[d]isoxazole, 22 mg (0.17 mmol) of potassium trimethylsilanolate, and 6 mg (0.0084 mmol) of Pd(dppf)Cl2 were dissolved in 4 mL of dioxane and 0.4 mL of water were added. The mixture was purged with nitrogen gas and heated to 80 °C with stirring for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 5 / 3) to give tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate, in 39.5% yield.

[1053] ESI-MS (m / z) = 606.2 [M+H] +

[1054] Step e): Preparation of 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl)-2-fluorobenzonitrile hydrochloride

[1055] 52 mg (0.11 mmol) of tert-butyl(8-(4-(4-cyano-3-fluorophenyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl-2-carbonyl)-8-azabicyclo[3.2.1]octane-3-yl)carbamate was added to 10 mL of 4 M ethyl acetate hydrochloride solution and reacted at room temperature for 1 hour. A small amount of solid was formed in the reaction system, and LC-MS showed that the reaction was complete. The solvent was evaporated at low temperature and the solution was sent to Prep-HPLC for preparation (separation method 1) to obtain 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)thiazolyl)-2-fluorobenzonitrile hydrochloride, with a yield of 65.3%.

[1056] 1H NMR(400MHz,DMSO-d6)δppm 8.11(s,3H),8.03(s,1H),7.97–7.77(m,2H),7.61(d,J=10.6Hz,1H),7.36(d,J=8.2Hz,1H),5.69(d,J=7.2Hz,1H), 4.75(d,J=6.8Hz,1H),3.82–3.68(m,1H),2.50(q,J=1.8Hz,3H),2.19–1.95(m,4H),1.81(dt,J=55.4,12.2Hz,4H).

[1057] ESI-MS m / z = 506.2 [M+H] + .

[1058] Example 221

[1059] 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(1-(cyanomethyl)-5-fluoro-1-hydro-indazol-6-yl)thiazolyl)-2-fluorobenzyl nitrile hydrochloride was prepared according to the synthetic method of Example 220 (isolation method 1), and its structure and characterization data are as follows:

[1060]

[1061] 1 H NMR(400MHz,Methanol-d4)δppm 8.22(d,J=1.0Hz,1H),7.93(d,J=5.6Hz,1H),7.72–7.60(m,2H),7.53(dd,J=10.6,1.6Hz,1H),7.38(dd,J=8.2,1.6Hz,1H),5. 98–5.83(m,1H),5.61(s,2H),4.95(dd,J=7.4,3.4Hz,1H),3.84(tt,J=11.6,5.8Hz,1H),2.33–2.10(m,4H),2.10–1.84(m,4H).

[1062] ESI-MS m / z = 530.2 [M+H] + .

[1063] Example 222

[1064] Preparation of 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)oxazol-4-yl)-2-fluorobenzonitrile hydrochloride

[1065]

[1066] Step a): Preparation of compound (8-(oxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)tert-butyl carbamate

[1067] The compounds oxazole-2-carboxylic acid (1.0 g, 8.844 mmol), (8-azabicyclo[3.2.1]octyl-3-yl)carbamate tert-butyl ester (2.2 g, 9.728 mmol), and HATU (4.37 g, 11.497 mmol) were dissolved in DMF (50 mL) at 0 °C. DIEA (3.42 g, 26.532 mmol) was added with stirring at 0 °C, and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with water (300 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give compound (8-(oxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester, yield 91.6%.

[1068] 1 H NMR(400MHz,DMSO-d6)δppm 8.31(s,1H),7.47(s,1H),6.74(d,J=9.4Hz,1H),5.21-5.20(m,1H),4.65-4.62(m,1H),3 .92-3.88(m,1H),2.07-1.93(m,1H),1.91-1.74(m,5H),1.65-1.48(m,2H),1.36(s,9H).

[1069] ESI-MS (m / z) = 322.1 [M+H] + .

[1070] Step b): Preparation of compound (8-(5-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)tert-butyl carbamate

[1071] Compound (700 mg, 2.180 mmol) of tert-butyl carbamate (8-(oxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was cooled to -78 °C, and n-butyllithium (2.7 mL, 1.6 M, 4.362 mmol) was added dropwise to the reaction flask. The mixture was stirred at -78 °C for 30 minutes. NBS (815 mg, 4.579 mmol) was dissolved in THF (2 mL) and added dropwise to the reaction flask. The mixture was then reacted at -78 °C for 4 hours. After the reaction was completed, the mixture was quenched with saturated sodium sulfite solution (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to give compound (8-(5-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester, yield 14.3%.

[1072] 1 H NMR(400MHz,DMSO-d6)δppm 7.58(s,1H),6.73(d,J=8.2Hz,1H),5.13-5.12(m,1H),4.63-4.62(m,1H),3.96-3 .76(m,1H),1.99-1.98(m,1H),1.90-1.73(m,5H),1.65-1.46(m,2H),1.36(s,9H).

[1073] ESI-MS (m / z) = 400.2 [M+H] + .

[1074] Step c): Preparation of compound tert-butyl 8-(4-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate

[1075] Compound (8-(5-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl) tert-butyl carbamate (110 mg, 0.276 mmol) and tetrahydrofuran (4 mL) were added to a reaction flask, cooled to -78 °C, and lithium diisopropylamino (0.3 mL, 2.0 M, 0.407 mmol) was added dropwise to the reaction flask. The mixture was stirred at -78 °C for 4 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) to give compound 8-(4-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)tert-butyl carbamate, with a yield of 36.3%.

[1076] 1H NMR(400MHz, DMSO-d6)δ8.57(s,1H),6.72(d,J=8.0Hz,1H),5.07-5.06(m,1H),4.64-4.62(m, 1H),3.96-3.81(m,1H),2.07-1.95(m,1H),1.92-1.65(m,5H),1.64-1.44(m,2H),1.36(s,9H).

[1077] ESI-MS (m / z) = 400.2 [M+H] + .

[1078] Step d): Preparation of compound (8-(4-(4-cyano-3-fluorophenyl)oxazol-2-carbonyl)-8-azabicyclo[3.2.1]octyl-3-yl)carbamate tert-butyl ester

[1079] Compound 8-(4-bromooxazol-2-carbonyl)-8-azabicyclo[3.2.1]oct-3-yl)carbamate tert-butyl ester (35 mg, 0.0877 mmol), compound (4-cyano-3-fluorophenyl)boronic acid (29 mg, 0.175 mmol), Cs2CO3 (85 mg, 0.263 mmol), Pd(dppf)Cl2 (6.4 mg, 0.00877 mmol), 1,4-dioxane (2 mL) and water (1 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, and the temperature was raised to 110 °C and stirred for 2 hours. After the reaction was completed, water (10 mL) was added 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, 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 compound (8-(4-(4-cyano-3-fluorophenyl)oxazol-2-carbonyl)-8-azabicyclo[3.2.1]octyl-3-yl)carbamate tert-butyl ester, yield 57.1%.

[1080] 1 H NMR(400MHz,DMSO-d6)δppm 9.05(s,1H),8.05(t,J=9.0Hz,1H),7.96(d,J=10.4Hz,1H),7.87(d,J=8.0Hz,1H),6.73(d,J=8.4Hz,1H),5.27-5.25(m,1H),4.69- 4.64(m,1H),3.99-3.86(m,1H),2.10-1.98(m,1H),1.97-1.73(m,5H),1.68(t,J=12.8Hz,1H),1.55(t,J=12.0Hz,1H),1.36(s,9H).

[1081] ESI-MS (m / z) = 441.4 [M+H] + .

[1082] Step e): Preparation of compound (4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-bromooxazol-4-yl)-2-fluorobenzonitrile

[1083] Compound (8-(4-(4-cyano-3-fluorophenyl)oxazol-2-carbonyl)-8-azabicyclo[3.2.1]octyl-3-yl) tert-butyl carbamate (50 mg, 0.114 mmol), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to a reaction flask, followed by the addition of 1,3-dibromo-5,5-dimethylhydantoin (38 mg, 0.136 mmol). The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by C18 silica gel column chromatography (eluent: acetonitrile / water = 1.5 / 1) to give compound (4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-bromooxazol-4-yl)-2-fluorobenzonitrile, yield 79.5%.

[1084] ESI-MS (m / z) = 419.0 [M+H] + .

[1085] Step f): Preparation of compound 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)oxazol-4-yl)-2-fluorobenzonitrile hydrochloride

[1086] Compound (4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-bromooxazol-4-yl)-2-fluorobenzonitrile (38 mg, 0.090 mmol), compound 5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]isoxazole (62 mg, 0.227 mmol), Pd(dppf)Cl2 (8.3 mg, 0.0113 mmol), potassium trimethylsilanolate (29 mg, 0.227 mmol), and 1,4-dioxane (2 mL) were added sequentially. The mixture was transferred to a reaction flask, purged three times with nitrogen, and heated to 80°C with stirring for 1 hour. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give compound 4-(2-(3-amino-8-azabicyclo[3.2.1]octane-8-carbonyl)-5-(5-fluoro-3-methylbenzo[d]isoxazol-6-yl)oxazol-4-yl)-2-fluorobenzonitrile, with a yield of 34.1%.

[1087] 1H NMR(400MHz,Methanol-d4)δppm 8.03(d,J=4.8Hz,1H),7.84-7.75(m,2H),7.64(d,J=10.4Hz,1H),7.53(d,J=8.0Hz,1H),5.67-5.6 6(m,1H),5.00-4.98(m,1H),3.88-3.82(m,1H),2.64(s,3H),2.35-2.23(m,2H),2.21-1.83(m,6H).

[1088] ESI-MS (m / z) = 490.2 [M+H] + .

[1089] Example 223

[1090] Preparation of 4-(2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-4-yl)-2-fluorobenzyl nitrile

[1091]

[1092] Step a): Preparation of tert-butyl (1-(4-chlorothiazol-2-yl)piperidin-4-yl)carbamate

[1093] 2,4-Dichlorothiazolium (800 mg, 5.2 mmol) and DIPEA (1.3 g, 10.4 mmol) were dissolved in acetonitrile (30 mL). Tert-butylpiperidin-4-ylcarbamate (1.03 g, 5.2 mmol) was added under ice bath conditions. The mixture was reacted overnight at room temperature. After evaporation to dryness, the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 5 / 3) to give tert-butyl (1-(4-chlorothiazol-2-yl)piperidin-4-yl)carbamate, yield 50.2%.

[1094] ESI-MS m / z = 318.1 [M+H] + .

[1095] Step b): Preparation of tert-butyl(1-(4-(4-cyano-3-fluorophenyl)thiazolyl-2-yl)piperidin-4-yl)carbamate

[1096] 600 mg (1.89 mmol) of tert-butyl (1-(4-chlorothiazol-2-yl)piperidin-4-yl)carbamate, 342 mg (2.07 mmol) of (4-cyano-3-fluorophenyl)boronic acid, 1.6 g (5.06 mmol) of Cs₂CO₃, and 106 mg (0.144 mmol) of Pd(dppf)Cl₂ were dissolved in 14 mL of dioxane, and 0.4 mL of water was added. The mixture was purged with nitrogen gas and heated to 120 °C with stirring for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give tert-butyl (1-(4-(4-cyano-3-fluorophenyl)thiazol-2-yl)piperidin-4-yl)carbamate, in 80.3% yield.

[1097] ESI-MS (m / z) = 403.2 [M+H] + .

[1098] Step c): Preparation of tert-butyl [1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazolyl-2-yl)piperidin-4-yl]carbamate

[1099] 300 mg (0.744 mmol) of tert-butyl(1-(4-(4-cyano-3-fluorophenyl)thiazol-2-yl)piperidin-4-yl)carbamate was dissolved in N,N-dimethylformamide (10 mL). NBS (133 mg (0.744 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature. LS-MS showed the reaction was complete. The reaction was quenched with 20 mL of sodium sulfite aqueous solution, extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 7) to give tert-butyl [1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazol-2-yl)piperidin-4-yl]carbamate, yield 50.5%.

[1100] ESI-MS (m / z) = 481.1 [M+H] + .

[1101] Step d): Preparation of tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-2-yl)piperidin-4-yl)carbamate tert-butyl

[1102] Dissolve tert-butyl (1-(5-bromo-4-(4-cyano-3-fluorophenyl)thiazolyl-2-yl)piperidin-4-yl)carbamate (80 mg, 0.16 mmol), (3-hydroxy-4-methoxyphenyl)boronic acid (63 mg, 0.25 mmol), Cs2CO3 (162 mg, 0.5 mmol), and Pd(dppf)Cl2 (10 mg, 0.016 mmol) in 4 mL of dioxane, add 0.4 mL of water, and purge the mixture with nitrogen gas. The reaction was carried out in a microwave reactor at 120°C for 30 minutes. LCMS showed that the reaction was complete. The crude product was concentrated, and the residue was purified by silica gel chromatography (eluent: dichloromethane / ethyl acetate = 10 / 3) to give tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-2-yl)piperidin-4-yl)carbamate, yield 70.5%).

[1103] ESI-MS m / z = 525.2 [M+H] +

[1104] Step e): Preparation of 4-(2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-4-yl)-2-fluorobenzyl nitrile

[1105] 60 mg (0.114 mol) of tert-butyl (1-(4-(4-cyano-3-fluorophenyl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-2-yl)piperidin-4-yl)carbamate was added to 10 mL of 4 M ethyl acetate hydrochloride solution and reacted at room temperature for 2 hours. A small amount of solid was formed in the reaction system, and LC-MS showed that the reaction was complete. The solvent was evaporated at low temperature, and the crude product was sent to Prep-HPLC for further preparation (separation method 4) to obtain 4-(2-(4-aminopiperidin-1-yl)-5-(3-hydroxy-4-methoxyphenyl)thiazolyl-4-yl)-2-fluorobenzyl nitrile, with a yield of 70.2%.

[1106] 1H NMR(400MHz,DMSO-d6)δppm 7.80(dd,J=8.2,7.2Hz,1H),7.48(dd,J=11.2,1.6Hz,1H),7.39(dd,J=8.2,1.6Hz,1H),6.94(d,J=8.2Hz,1H),6.71(d,J=7.4Hz,2H),3.85(dt,J= 13.2,4.0Hz,2H),3.79(s,3H),3.11(ddd,J=13.4,11.2,3.0Hz,2H),2.83 (tt,J=9.8,3.8Hz,1H),1.81(dd,J=13.2,3.6Hz,2H),1.45–1.17(m,2H).

[1107] ESI-MS m / z: 425.1 [M+H] + .

[1108] Compounds 224-249 in Examples were prepared according to the synthetic method of Example 2 (the compounds were isolated by separation methods 4, 1 and 3, respectively, for the free base, hydrochloride and formate). Their structures and characterization data are as follows:

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117] Example 250

[1118] Preparation of (4-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1119]

[1120] Step a): Preparation of 2-chloro-4-methoxy-6-phenyl-1,3,5-triazine

[1121] 2,4-Dichloro-6-methoxy-1,3,5-triazine (5.0 g, 25.0 mmol), phenylboronic acid (4.6 g, 38.0 mmol), Pd(PPh3)2 (1.8 g, 2.5 mmol), Cs2CO3 (18.0 g, 56.0 mmol), 1,4-dioxane (50 mL), and water (12 mL) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times, and the mixture was heated to 65 °C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 2-chloro-4-methoxy-6-phenyl-1,3,5-triazine in 54.2% yield.

[1122] ESI-MS(m / z) = 222.1 [M+H] + .

[1123] Step b): Preparation of 2-(4-methoxy-6-phenyl-1,3,5-triazine-2-yl)malononitrile

[1124] Malononitrile (3.3 g, 50.0 mmol) and DMSO (20 mL) were added to a reaction flask. NaH (1.0 g, 50.0 mmol, 60%) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. 2-Chloro-4-methoxy-6-phenyl-1,3,5-triazine (5.5 g, 25.0 mmol) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, the mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL × 2). The organic phase was concentrated to dryness under reduced pressure. The residue was purified by slurry mixing with petroleum ether / ethyl acetate (3 / 1, 100 mL), and filtered to give 2-(4-methoxy-6-phenyl-1,3,5-triazine-2-yl)malononitrile, in 61.0% yield.

[1125] ESI-MS (m / z) = 252.1 [M+H] + .

[1126] Step c): Preparation of (4-methoxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1127] 2-(4-methoxy-6-phenyl-1,3,5-triazin-2-yl)malononitrile (3.8 g, 15.25 mmol), m-CPBA (7.9 g, 45.75 mmol, 82%) and THF (40 mL) were added to a reaction flask and stirred at room temperature for 35 minutes. Then 1-(methanesulfonyl)piperazine (7.5 g, 45.75 mmol) was added and the reaction was maintained at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, and washed successively with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give (4-methoxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, in 15.5% yield.

[1128] ESI-MS (m / z) = 378.1 [M+H] + .

[1129] Step d): Preparation of 4-hydroxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1130] Ethyl mercaptan (219 mg, 3.54 mmol) and DMF (10 mL) were added to a reaction flask. NaH (142 mg, 3.54 mmol, 60%) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. Then, (4-methoxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (884 mg, 2.36 mmol) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, the mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (4-hydroxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, yield 53.0%.

[1131] 1 H NMR(400MHz,DMSO-d6)δppm 13.40(s,1H),8.38–8.14(m,2H),7.69(td,J=7.2,1.4Hz,1H),7.58(t,J=7.8Hz,2H),3.73(t,J =5.2Hz, 2H), 3.60 (t, J = 5.2Hz, 2H), 3.24 (t, J = 5.2Hz, 2H), 3.15 (t, J = 5.2Hz, 2H), 2.95 (s, 3H).

[1132] ESI-MS (m / z) = 364.1 [M+H] + .

[1133] Step e): Preparation of (4-chloro-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1134] (4-hydroxy-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (455 mg, 1.25 mmol), phosphorus oxychloride (288 mg, 1.88 mmol), DIPEA (243 mg, 1.88 mmol), and acetonitrile (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at 60 °C for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 3) to give (4-chloro-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone in 75.3% yield.

[1135] ESI-MS (m / z) = 382.1 [M+H] + .

[1136] Step f): Preparation of (4-(methanesulfonyl)piperazin-1-yl)(4-phenyl-6-vinyl-1,3,5-triazin-2-yl)methyl ketone

[1137] (4-chloro-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (341 mg, 0.94 mmol), vinyltri-tert-butyltin (444 mg, 1.41 mmol), Pd(dppf)Cl2 (68 mg, 0.09 mmol), and THF (10 mL) were sequentially added to a sealed reactor. The reactor was purged with nitrogen three times, and the mixture was heated to 70 °C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 4-(methanesulfonyl)piperazin-1-yl)(4-phenyl-6-vinyl-1,3,5-triazin-2-yl) methyl ketone in 40.5% yield.

[1138] 1H NMR(400MHz,DMSO-d6)δppm 8.63–8.44(m,2H),7.71(t,J=7.4Hz,1H),7.64(s,1H),7.07–6.83(m,2H),6.15(dd,J=10.2,1.8Hz,2H),3.80 (t, J = 5.0 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.28 (d, J = 6.0 Hz, 2H), 3.13 (t, J = 5.0 Hz, 2H), 2.95 (d, J = 6.2 Hz, 3H).

[1139] ESI-MS (m / z) = 374.1 [M+H] + .

[1140] Step g): Preparation of 4-(4-(methanesulfonyl)piperazine-1-carbonyl)-6-phenyl-1,3,5-triazine-2-carbonal

[1141] 4-(methanesulfonyl)piperazin-1-yl)(4-phenyl-6-vinyl-1,3,5-triazin-2-yl) methyl ketone (142 mg, 0.38 mmol), NMO (133 μL, 0.57 mmol, 50%), potassium osmium tetroxide (14 mg, 0.04 mmol), THF (6 mL) and water (2 mL) were added to a reaction flask and the mixture was stirred for 1 hour. After the reaction was complete, sodium periodate (244 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 4-(4-(methanesulfonyl)piperazine-1-carbonyl)-6-phenyl-1,3,5-triazine-2-carbonal, yield 53.0%.

[1142] ESI-MS (m / z) = 376.1 [M+H] + .

[1143] Step h): Preparation of (4-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1144] 4-(4-(methanesulfonyl)piperazine-1-carbonyl)-6-phenyl-1,3,5-triazine-2-carbonal (76 mg, 0.201 mmol), (1R,2S)-2-(4-fluorophenyl)cyclopropane-1-amine (36 mg, 0.201 mmol), acetic acid (71 μL), methanol (400 μL), and DCE (5 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (64 mg, 1.005 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give (4-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-6-phenyl-1,3,5-triazin-2-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, with a yield of 10.5%.

[1145] 1 H NMR(400MHz,DMSO-d6)δppm 8.46(d,J=7.8Hz,2H),7.70(t,J=7.4Hz,1H),7.60(t,J=7.6Hz,2H),7.09–6.90(m,4H),4.07(s,2H),3.78(s,2H),3.48(d,J=26.8Hz ,2H),3.10(d,J=5.2Hz,2H),2.93(s,3H),1.93(s,1H),1.24(s,2H),1.12–1.04(m,1H),0.94(t,J=6.2Hz,1H),0.85(d,J=7.4Hz,1H).

[1146] ESI-MS (m / z) = 511.2 [M+H] + .

[1147] Example 251

[1148] Preparation of (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1149]

[1150] Step a): Preparation of 2-chloro-6-methylpyrimidine-4-carboxylic acid

[1151] Methyl 2-chloro-6-methylpyrimidin-4-carboxylic acid (200 mg, 1.075 mmol), lithium hydroxide monohydrate (135 mg, 3.225 mmol), tetrahydrofuran (2 mL), and water (2 mL) were added to a reaction flask and stirred at room temperature for 2 hours. The organic phase was removed by concentration under reduced pressure. Concentrated hydrochloric acid (1 mL) and water (10 mL) were slowly added dropwise to the residue with stirring in an ice bath. The residue 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. The residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 2-chloro-6-methylpyrimidin-4-carboxylic acid in 90.2% yield.

[1152] ESI-MS (m / z) = 173.0 [M+H] + .

[1153] Step b): Preparation of (2-chloro-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1154] 2-Chloro-6-methylpyrimidin-4-carboxylic acid (167 mg, 0.968 mmol), 1-(methanesulfonyl)piperazine (159 g, 0.968 mmol), and DMF (5 mL) were added to a reaction flask. HATU (191 mg, 1.162 mmol) and DIPEA (375 mg, 2.904 mmol) were added to the flask with stirring in an ice bath, and the reaction was maintained at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined. The mixture was washed successively with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (20 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: dichloromethane / methanol = 10 / 1) to give (2-chloro-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazine-1-yl) methyl ketone, yield 64.1%.

[1155] 1 H NMR (400MHz, Chloroform-d) δppm 7.39 (s, 1H), 3.86–3.79 (m, 2H), 3.64 (q, J = 9.2, 7.0Hz, 2H), 3.29 (dt, J = 7.2, 5.0Hz, 4H), 2.77 (s, 3H), 2.54 (s, 3H).

[1156] ESI-MS (m / z) = 319.1 [M+H] + .

[1157] Step c): Preparation of (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-methylpyrimidin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[1158] (2-chloro-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (197 mg, 0.620 mmol), 4-(1H-pyrazol-1-yl)phenol (149 mg, 0.930 mmol), potassium carbonate (257 mg, 1.860 mmol), and DMF (5 mL) were added sequentially to a reaction flask and stirred at 80 °C for 12 hours. After the reaction was completed, the reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to give (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, yield 50.0%.

[1159] ESI-MS (m / z) = 443.1 [M+H] + .

[1160] Step d): Preparation of 2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidine-4-aminocarboxaldehyde

[1161] (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-methylpyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (206 mg, 0.465 mmol), tin dioxide (258 mg, 2.325 mmol), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-aminocarboxaldehyde, in 62.0% yield.

[1162] ESI-MS (m / z) = 457.1 [M+H] + .

[1163] Step e): Preparation of (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1164] 2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidine-4-aminocarboxaldehyde (132 mg, 0.288 mmol), (1R,2S)-2-(4-fluorophenyl)cyclopropane-1-amine (54 mg, 0.288 mmol), acetic acid (132 μL), methanol (660 μL), and DCE (10 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (120 mg, 1.440 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give (2-(4-(1H-pyrazol-1-yl)phenoxy)-6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, yield 55.5%.

[1165] 1 H NMR(400MHz,DMSO-d6)δppm 8.48(d,J=2.4Hz,1H),8.00–7.81(m,2H),7.75(d,J=1.8Hz,1H),7.49(s, 1H),7.42–7.29(m,2H),7.21–6.87(m,4H),6.55(t,J=2.2Hz,1H),3.96(s ,1H),3.67(t,J=5.2Hz,2H),3.46(t,J=4.8Hz,2H),3.13(t,J=5.4Hz,2H) ,2.91(t,J=5.2Hz,2H),2.72(s,3H),1.92(s,3H),1.02(d,J=39.4Hz,2H).

[1166] ESI-MS (m / z) = 592.2 [M+H] + .

[1167] Example 252

[1168] Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-((2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[1169]

[1170] Step a): Preparation of (E)-3-(3-fluoro-4-methoxyphenyl)acrylate ethyl acrylate

[1171] Ethyl diethoxyphosphoryl)formate (4.1 g, 19.481 mmol) and THF (20 mL) were added to a reaction flask. NaH (779 mg, 19.481 mmol, 60%) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. 3-fluoro-4-methoxybenzaldehyde (2 g, 12.987 mmol) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give ethyl (E)-3-(3-fluoro-4-methoxyphenyl)acrylate, in 80.5% yield.

[1172] ESI-MS (m / z) = 225.1 [M+H] + .

[1173] Step b): Preparation of ethyl (2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylate)

[1174] Trimethyl sulfoxide (3.1 g, 15.585 mmol) and DMSO (20 mL) were added to a reaction flask. NaH (623 mg, 15.585 mmol, 60%) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. Ethyl (E)-3-(3-fluoro-4-methoxyphenyl)acrylate (2.3 g, 10.390 mmol) was added with stirring in an ice bath, and the reaction was carried out at room temperature for 30 minutes. After the reaction was complete, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give ethyl 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid, yield 42.5%.

[1175] 1 H NMR(400MHz,Chloroform-d)δppm 6.92–6.77(m,3H),4.17(q,J=7.2Hz,2H),3.86(s,3H),2.46(ddd,J=9.2,6.4,4.2Hz,1H) ,1.82(ddd,J=8.4,5.4,4.2Hz,1H),1.56(ddd,J=9.2,5.4,4.6Hz,2H),1.32–1.18(m,3H).

[1176] ESI-MS (m / z) = 239.1 [M+H]+ .

[1177] Step c): Preparation of 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid

[1178] Ethyl 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid (1.1 g, 4.416 mmol), lithium hydroxide monohydrate (556 mg, 13.248 mmol), tetrahydrofuran (10 mL), and water (10 mL) were added to a reaction flask and stirred at 40 °C for 2 hours. The organic phase was removed by concentration under reduced pressure. Concentrated hydrochloric acid (3 mL) and water (20 mL) were slowly added dropwise with stirring in an ice bath. 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 phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid in 85.0% yield.

[1179] 1 H NMR(400MHz,Chloroform-d)δ6.99–6.62(m,3H),3.87(s,3H),2.54(ddd,J=9.2,6.6,4.2Hz,1H), 1.83(ddd,J=8.4,5.2,4.2Hz,1H), 1.63(dt,J=9.8,4.8Hz,1H), 1.34(ddd,J=8.4,6.8,4.8Hz,1H).

[1180] ESI-MS (m / z) = 210.0 [M+H] + .

[1181] Step d): Preparation of 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-amine

[1182] 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-carboxylic acid (200 mg, 0.952 mmol), DPPA (393 mg, 1.428 mmol), TEA (144 mg, 1.428 mmol), and toluene (5 mL) were added to a reaction flask and stirred at 100 °C for 30 minutes. Then, concentrated hydrochloric acid (1 mL) was added dropwise to the reaction mixture under reflux. After the reaction was complete, the reaction mixture was poured into an aqueous sodium bicarbonate solution (40 mL) under ice bath conditions and extracted with ethyl acetate (40 mL × 3). The organic phases were combined and washed with saturated brine (40 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 = 1 / 2) to give 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-amine, in 91.5% yield.

[1183] ESI-MS (m / z) = 182.2 [M+H] + .

[1184] Step e): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-4-methoxy-5-vinylpyridin-2-yl)piperidin-4-yl)carbamate

[1185] (1-(5-bromo-6-(4-cyano-3-fluorophenyl)-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (110 mg, 0.218 mmol), potassium vinyltrifluoroborate (45 mg, 0.327 mmol), Cs₂CO₃ (142 mg, 0.436 mmol), Pd(dppf)Cl₂ (16 mg, 0.022 mmol), 1,4-Dioxane (4 mL), and H₂O (1 mL) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times, and the reaction was 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 = 1 / 1) to give (1-(6-(4-cyano-3-fluorophenyl)-4-methoxy-5-vinylpyridin-2-yl)piperidin-4-yl)tert-butyl carbamate, yield 85.0%.

[1186] ESI-MS (m / z) = 453.1 [M+H] + .

[1187] Step f): Preparation of tert-butyl (1-(6-(4-cyano-3-fluorophenyl)-5-formyl-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[1188] Add tert-butyl carbamate (84 mg, 0.185 mmol), NMO (133 μL, 0.555 mmol, 50%), potassium osmium tetroxide (14 mg, 0.019 mmol), THF (6 mL) and water (2 mL) to a reaction flask and stir for 1 hour. After the reaction was complete, sodium periodate (244 mg, 0.555 mmol) was added, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. Sodium sulfite aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 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-(6-(4-cyano-3-fluorophenyl)-5-formyl-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, yield 75.0%.

[1189] ESI-MS (m / z) = 455.3 [M+H] + .

[1190] Step g): Preparation of tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate

[1191] (1-(6-(4-cyano-3-fluorophenyl)-5-formyl-4-methoxypyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (63 mg, 0.139 mmol), 2-(3-fluoro-4-methoxyphenyl)cyclopropane-1-amine (25 mg, 0.139 mmol), acetic acid (63 μL), methanol (315 μL) and DCE (5 mL) were added sequentially to the reaction flask, the mixture was purged with nitrogen three times, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (56 mg, 0.695 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate, with a yield of 73.0%.

[1192] ESI-MS (m / z) = 620.3 [M+H] + .

[1193] Step h): Preparation of 4-(6-(4-aminopiperidin-1-yl)-3-((2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile

[1194] 63 mg (0.101 mmol) of tert-butyl(1-(6-(4-cyano-3-fluorophenyl)-5-(2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)piperidin-4-yl)carbamate was added to a reaction flask, followed by 2.5 mL of 4 M ethyl hydrochloride solution. The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of a large amount of solid. The solid was concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (separation method 4) to obtain 4-(6-(4-aminopiperidin-1-yl)-3-((2-(3-fluoro-4-methoxyphenyl)cyclopropyl)amino)methyl)-4-methoxypyridin-2-yl)-2-fluorobenzonitrile, with a yield of 63.0%.

[1195] 1 H NMR(400MHz,DMSO-d6)δppm 7.94(dd,J=8.0,7.0Hz,1H),7.78(dd,J=10.8,1.6Hz,1H),7.67(dd,J=8.0,1.4Hz,1H),6.99(t,J=8.8Hz ,1H),6.81–6.64(m,2H),6.41(d,J=8.4Hz,1H),4.25(t,J=15.0Hz,2H),3.81(d,J=10.4Hz,6H),3.64–3.5 0(m,2H),3.01–2.84(m,2H),2.77(dq,J=9.8,4.8,3.8Hz,1H),2.13(dt,J=7.4,3.8Hz,1H),1.75(d,J=12. 8Hz, 2H), 1.68 (ddd, J=9.0, 5.6, 2.8Hz, 1H), 1.21 (s, 2H), 0.93 (dt, J=9.4, 4.8Hz, 1H), 0.89–0.80 (m, 1H).

[1196] ESI-MS (m / z) = 520.2 [M+H] + .

[1197] Example 253

[1198] Preparation of 6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide hydrochloride

[1199]

[1200] Step a): Synthesis of 6-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide

[1201] 2-Chloro-6-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-carboxamide (550 mg, 2.16 mmol), 10% palladium on carbon (55 mg), sodium acetate (55 mg, 0.67 mmol), and anhydrous methanol (5 mL) were added sequentially to a reaction flask. The mixture was purged with hydrogen three times and reacted for 3 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth and concentrated to dryness. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 6-methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-carboxamide, with a yield of 55.2%.

[1202] 1H NMR(400MHz,DMSO-d6)δppm 9.15(d,J=1.4Hz,1H),8.83(d,J=8.4Hz,1H),7.91(s,1H),4.09–3.96(m,1H),3.87(dt,J= 11.4, 3.4Hz, 2H), 3.38 (ddd, J = 11.6, 7.8, 5.4Hz, 2H), 2.57 (s, 3H), 1.70 (h, J = 4.0Hz, 4H).

[1203] ESI-MS m / z: 222.1 [M+H] + .

[1204] Step b): Synthesis of 6-formyl-n-(tetrahydropyran-4-yl)pyrimidine-4-carboxamide

[1205] 6-Methyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (170 mg, 0.77 mmol), selenium dioxide (427 mg, 3.85 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask and heated to 110 °C under nitrogen protection, with stirring for 16 hours. After the reaction was complete as determined by LCMS, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-formyl-n-(tetrahydropyran-4-yl)pyrimidine-4-carboxamide, in 46.4% yield.

[1206] ESI-MS m / z: 236.1 [M+H] + .

[1207] Step c): Synthesis of 6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide

[1208] 6-Formyl-n-(tetrahydropyran-4-yl)pyrimidin-4-carboxamide (84 mg, 0.36 mmol) was dissolved in 1,2-dichloroethane (2 ml), and then acetic acid (214 mg, 3.57 mmol), methanol (574 mg, 17.87 mmol), and (1R,2S)-2-(4-fluorophenyl)cyclopropane-1-amine (67.0 mg, 0.36 mmol) were added. The mixture was stirred under nitrogen protection for 1.5 hours, and then sodium cyanoborohydride (90 mg, 1.43 mmol) was added. The reaction was continued for 16 hours. After the reaction was detected by LCMS, water (3 mL) was added to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtration and concentration, pre-purification by pre-HPLC (separation method 1), and freeze-drying to obtain 6-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide hydrochloride, with a yield of 3.2%.

[1209] 1 H NMR(400MHz,Methanol-d4)δppm 8.52(s,1H),7.34(s,1H),6.42–6.35(m,2H),6.27–6.19(m,2H),3.93(s,2H),3.33(dddt,J=1 2.6,8.2,6.8,4.4Hz,1H),3.19(ddd,J=12.0,4.2,2.2Hz,2H),2.73(td,J=11.8,2.2Hz,2H),2. 29(ddd,J=8.0,4.4,3.6Hz,1H),1.74(ddd,J=10.4,6.6,3.6Hz,1H),1.08(ddd,J=12.6,4.6,2 .2Hz,2H),0.99-0.88(m,2H),0.78(ddd,J=10.4,6.8,4.4Hz,1H),0.60(dt,J=7.8,6.8Hz,1H).

[1210] ESI-MS m / z: 371.2 [M+H] + .

[1211] Example 254

[1212] Preparation of 3-(2-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)aminoethoxy)-5-(4-(methanesulfonyl)piperazin-1-yl)-[1,1-biphenyl]-4-nitrile

[1213]

[1214] Step a): Synthesis of compound 1,3-dibromo-5-(2,2-dimethoxy)benzene

[1215] Compound 3,5-dibromophenol (2.00 g, 8.01 mmol), 2-bromo-1,1-dimethoxyethane (2.03 g, 12.01 mmol), cesium carbonate (7.82 g, 24.03 mmol), and 40 mL of dry DMF were added sequentially to a reaction flask. Under nitrogen protection, the reaction was carried out overnight in an oil bath at 80 °C. When LC-MS showed that the reaction was complete, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to give 1,3-dibromo-5-(2,2-dimethoxy)benzene in 93.6% yield.

[1216] 1 H NMR (400MHz, Methanol-d4) δppm 7.28 (t, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6 Hz, 2H), 4.68 (t, J = 5.2 Hz, 1H), 3.99 (d, J = 5.2 Hz, 2H), 3.43 (s, 6H).

[1217] Step b): Synthesis of compound 3'-bromo-5'-(2,2-dimethoxyethoxy)-[1,1'-biphenyl]-4-carbamate

[1218] 1,3-Dibromo-5-(2,2-dimethoxy)benzene (1.35 g, 3.99 mmol), p-cyanobenzoboronic acid (587 mg, 3.99 mmol), Pd(dppf)Cl2 (584 mg, 0.79 mmol), Na2CO3 (847 mg, 7.98 mmol), 15 mL of 1,4-dioxane, and 3 mL of water were added sequentially to a reaction flask. The mixture was purged with nitrogen and reacted in a microwave reactor at 80 °C for 30 minutes. The reaction progress was monitored by TLC (petroleum ether / ethyl acetate = 3 / 1) and LCMS. When the reaction was complete, the mixture was filtered through a sintered glass funnel. The filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 1 / 6) to give 3'-bromo-5'-(2,2-dimethoxyethoxy)-[1,1'-biphenyl]-4-carbamate, with a yield of 68.44%.

[1219] 1H NMR(400MHz,Chloroform-d)δppm 7.75-7.70(m,2H),7.65-7.61(m,2H),7.32(t,J=1.6Hz,1H),7.13(t,J=2.0Hz,1H) ,7.07(t,J=1.8Hz,1H), 4.73(t,J=5.2Hz,1H), 4.04(d,J=5.2Hz,2H), 3.47(s,6H).

[1220] Step c): Synthesis of 3'-(2,2-dimethoxyethoxy)-5'-(4-(methanesulfonyl)piperazin-1-yl)-[1,1'-biphenyl]-4-carbon

[1221] 3'-bromo-5'-(2,2-dimethoxyethoxy)-[1,1'-biphenyl]-4-carbazene (300 mg, 0.83 mmol), 1-(methanesulfonyl)piperazine (204 mg, 1.25 mmol), Pd2(dba)3 (152 mg, 0.16 mmol), RuPhos (155 mg, 0.33 mmol), Cs2CO3 (811 mg, 2.49 mmol) and 13 mL of toluene were added sequentially to a reaction flask, the mixture was purged with nitrogen three times, and the mixture was heated to 90 °C and reacted overnight. The reaction process was monitored by TLC (petroleum ether / ethyl acetate = 3 / 1) and LCMS. After the reaction was completed, the mixture was cooled and filtered through a sintered glass funnel. The filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 2 / 1) to give 3'-(2,2-dimethoxyethoxy)-5'-(4-(methanesulfonyl)piperazin-1-yl)-[1,1'-biphenyl]-4-carbon, in 75.9% yield.

[1222] 1 HNMR(400MHz,DMSO-d6)δppm 7.87(s,4H),6.87(s,1H),6.73(s,1H),6.58(d,J=2.8Hz,1H),4.67(t,J=5.2Hz,1H ), 4.03 (d, J = 5.2Hz, 2H), 3.59 (d, J = 2.2Hz, 6H), 3.33 (d, J = 5.2Hz, 8H), 2.90 (s, 3H).

[1223] ESI-MS m / z: 446.2 [M+H] + .

[1224] Step d): Synthesis of 3'-(4-(methanesulfonyl)piperazin-1-yl)-5'-(2-oxoethoxy)-[1,1'-biphenyl]-4-carbamate

[1225] 3'-(2,2-dimethoxyethoxy)-5'-(4-(methanesulfonyl)piperazin-1-yl)-[1,1'-biphenyl]-4-carbon (120 mg, 0.27 mmol) was dissolved in 4M dioxane hydrochloride solution (8 mL) and stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed by TLC and LCMS, the mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3'-(4-(methanesulfonyl)piperazin-1-yl)-5'-(2-oxoethoxy)-[1,1'-biphenyl]-4-carbonitrile. The crude product was used directly in the next step.

[1226] ESI-MS m / z: 400.1 [M+H] + .

[1227] Step e): Synthesis of 3'-(2-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)aminoethoxy)-5'-(4-(methanesulfonyl)piperazin-1-yl)-[1,1'-biphenyl]-4-nitrile

[1228] Weigh 134 mg (0.34 mmol) of 3'-(4-(methanesulfonyl)piperazin-1-yl)-5'-(2-oxoethoxy)-[1,1'-biphenyl]-4-carbamate and 50.6 mg (0.34 mmol) of (1R,2S)-2-(4-fluorophenyl)cyclopropylamine hydrochloride, dissolve them in 5 mL of dry 1,2-dichloroethane, add 33 μL of acetic acid and 166 μL of anhydrous methanol, and stir at room temperature for 2 h under nitrogen protection. LCMS showed that the starting material disappeared. Add 142 mg (0.67 mmol) of sodium triacetoxyborohydride and continue the reaction for 2 h. LCMS showed that the reaction was complete. Quench with 3 mL of saturated ammonium chloride aqueous solution, extract with 10 mL x 3 of dichloromethane, wash with 6 mL of saturated brine, dry with anhydrous sodium sulfate, and LCMS showed no residue in the aqueous phase. The mixture was then concentrated to dryness under reduced pressure and purified directly using silica gel chromatography (methanol / dichloromethane = 1 / 12). After concentration and freeze-drying, 3'-(2-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)aminoethoxy)-5'-(4-(methanesulfonyl)piperazin-1-yl)-[1,1'-biphenyl]-4-nitrile was obtained, with a yield of 11.7%.

[1229] 1HNMR(400MHz,DMSO-d6)δppm 7.85(q,J=8.2Hz,4H),7.03(p,J=8.6Hz,4H),6.84(s,1H),6.68(s,1H),6.52(s,1H),4.08(t,J=5.8Hz,2H),3.30(d,J=5.0Hz,4H) ,3.23(d,J=4.6Hz,4H),2.94(d,J=5.8Hz,2H),2.89(s,3H),2.28(dd,J=7.2,3.8Hz,1H),1.82(d,J=8.4Hz,1H),1.03-0.86(m,2H).

[1230] ESI-MS m / z: 535.2 [M+H] + .

[1231] Example 255

[1232] Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyridin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1233]

[1234] Step a): Preparation of (2-chloro-6-methylpyridin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[1235] 2-Chloro-6-methylisonicotinic acid (2 g, 11.70 mmol), 1-(methanesulfonyl)piperazine (133.6 mg, 0.26 mmol), Pd(dppf)Cl2 (2.3 g, 14.02 mmol), HATU (5.3 g, 13.95 mmol), DIEA (4.5 g, 34.88 mmol) and N,N-dimethylformamide (30 mL) were added sequentially to a 50 mL reaction flask and reacted at room temperature with stirring for 1 hour. After the reaction was completed, the reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give (2-chloro-6-methylpyridin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, with a yield of 97.2%.

[1236] 1H NMR(400MHz,DMSO-d6)δppm 7.38(t,J=1.0Hz,1H),7.31(d,J=1.2Hz,1H),3.71(t,J=5.0Hz,2H),3.36(t,J= 5.0Hz,2H),3.21(t,J=5.2Hz,2H),3.15–3.10(m,2H),2.91(s,3H),2.69(s,3H).

[1237] ESI-MS (m / z) = 318.1 [M+H] + .

[1238] Step b): Preparation of (2-(4-(1H-pyrazol-1-yl)benzene)-6-methylamphetamine-4-yl)(4-(methylsulfonamide)piperazin-1-yl)methyl ketone

[1239] (2-chloro-6-methylpyridin-4-yl)(4-(methylsulfonyl)piperazin-1-yl) methyl ketone (4 g, 3.79 mmol), (4-(1H-pyrazol-1-yl)phenyl)boronic acid (2.85 g, 4.55 mmol), Pd(dppf)Cl2 (924 mg, 0.38 mmol), cesium carbonate (8.23 g, 7.64 mmol), 1,4-dioxane (40 mL), and water (10 mL) were added sequentially to a reaction flask, and the mixture was reacted in a microwave oven at 120 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give (2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylphenylpropylamine-4-yl)(4-(methylsulfonyl)piperazin-1-yl) methyl ketone, in 76.5% yield.

[1240] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(d,J=2.6Hz,1H),8.33–8.25(m,3H),8.04–8.00(m,2H),7.81(d,J=1.8Hz,1H),7.70(d,J=1.8Hz,1H),6.60(t,J=2.2Hz ,1H),3.82(t,J=5.0Hz,2H),3.66(t,J=4.8Hz,2H),3.29(t,J=5.2Hz,2H),3.22(t,J=5.0Hz,2H),2.96(s,3H),2.51(s,3H).

[1241] ESI-MS (m / z) = 426.0 [M+H] + .

[1242] Step c): Preparation of 6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methanesulfonyl)piperazine-1-carbonyl)pyridinecarboxaldehyde

[1243] (2-(4-(1H-pyrazol-1-yl)phenyl)-6-methylamphetamine-4-yl)(4-(methylsulfonyl)piperazin-1-yl) methyl ketone (2.0 g, 4.71 mmol), tin dioxide (8.36 g, 65.32 mmol), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask, and the mixture was stirred at 110 °C for 24 hours. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methylsulfonyl)piperazin-1-carbonyl)pyridinecarboxaldehyde, yield 48.5%.

[1244] ESI-MS (m / z) = 458.0 [M + H₂O + H] + .

[1245] Step d): Preparation of (E)-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-methoxyvinyl)pyridin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[1246] 6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methanesulfonyl)piperazine-1-carbonyl)pyridinecarboxaldehyde (1 g, 2.28 mmol), TDA-1 (883 mg, 2.73 mmol) and (methoxymethyl)triphenylphosphine chloride (620 mg, 1.81 mmol) were added sequentially to a reaction flask containing a 10 ml / 2 ml aqueous solution of dichloromethane / 5M potassium carbonate and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with 10 mL of sodium bicarbonate aqueous solution, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give (E)-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-methoxyvinyl)pyridin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, yield 9.4%.

[1247] 1H NMR(400MHz,DMSO-d6)δppm 8.61(t,J=2.2Hz,2H),8.31–8.24(m,2H),8.01–7.96(m,3H),7.80(t,J=1.4Hz,2H),6.60(s ,1H),6.05(d,J=12.6Hz,1H),3.88(s,4H),3.76(s,3H),3.17(d,J=5.2Hz,4H),2.94(s,3H).

[1248] ESI-MS (m / z) = 468.2 [M+H] + .

[1249] Step e): Preparation of 2-(6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methylsulfonyl)piperazine-1-carbonyl)pyridin-2-yl)acetaldehyde

[1250] (E)-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-methoxyvinyl)pyridin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (100 g, 0.19 mmol) and 4M dioxane hydrochloride solution (10 mL) were added sequentially to a reaction flask and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methanesulfonyl)piperazin-1-carbonyl)pyridin-2-yl)acetaldehyde, yield 82.5%.

[1251] ESI-MS (m / z) = 472.0 [M + H₂O + H] + .

[1252] Step f): Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyridin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methyl ketone

[1253] 2-(6-(4-(1H-pyrazol-1-yl)phenyl)-4-(4-(methanesulfonyl)piperazin-1-carbonyl)pyridin-2-yl)acetaldehyde (80 mg, 0.18 mmol), (1R,2S)-2-(4-fluorophenyl)cyclopropyl-1-amine (39.6 mg, 0.211 mmol), and 1,2-dichloroethane (10 ml) were added sequentially to a reaction flask and stirred at room temperature for 1 hour. After detecting the formation of the reaction intermediate, sodium cyanoborohydride (22.2 mg, 0.354 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, 10 mL of sodium bicarbonate aqueous solution 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 (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyridin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, with a yield of 3.5%.

[1254] 1 H NMR (400MHz, Acetonitrile-d3) δppm 8.24(d,J=2.4Hz,2H),8.22(s,1H),7.96–7.87(m,2H),7.77(d,J=1.8Hz,1H),7.70(d,J=1.2 Hz,1H),7.20(d,J=1.2Hz,1H),7.14–7.05(m,2H),7.04–6.96(m,2H),6.57(t,J=2.2Hz,1H), 3.84(s,2H),3.48(s,2H),3.31(s,2H),3.20(t,J=6.8Hz,3H),3.06(t,J=7.2Hz,2H),2.84(s ,3H),2.38(ddd,J=7.2,4.3,3.1Hz,1H),1.88–1.76(m,2H),1.31(s,1H),1.02–0.86(m,2H).

[1255] ESI-MS (m / z) = 589.0 [M+H] + .

[1256] Example 256

[1257] (6-(4-(1H-pyrazol-1-yl)phenyl)-4-(2-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)ethyl)pyridin-2-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone was prepared according to the synthetic method of Example 255 (isolation method 4), and its structure and characterization data are as follows:

[1258]

[1259] 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 8.60(d,J=2.6Hz,1H),8.22(d,J=8.6Hz,2H),7.99(d,J=7.8Hz,3H),7.79(d,J= 1.6Hz,1H),7.46(s,1H),7.15–6.96(m,4H),6.59(t,J=2.2Hz,1H),3.80(t,J=5. 2Hz,2H),3.67(t,J=5.0Hz,2H),2.98(d,J=6.4Hz,3H),2.94(s,5H),2.87(t,J= 7.2Hz,2H),2.46(s,1H),2.31–2.25(m,1H),1.81(t,J=3.2Hz,1H),0.92(s,2H).

[1260] ESI-MS (m / z) = 589.2 [M+H] + .

[1261] Example 257

[1262] Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1263]

[1264] Step a): Preparation of (E)-(6-(2-(1,3-dioxane-2-yl)vinyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1265] 2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-aminocarboxaldehyde (230 mg, 0.523 mmol), TDA-1 (370 mg, 0.836 mmol), ((1,3-dioxolane-2-yl)methyl)bromotriphenyl-5-phosphine (186 mg, 0.575 mmol), saturated potassium carbonate aqueous solution (10 ml), and dichloromethane (20 ml) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, and the temperature was raised to 45 °C with stirring for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated brine (100 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 = 1 / 1) to give (E)-(6-(2-(1,3-dioxane-2-yl)vinyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, yield 31.0%.

[1266] ESI-MS (m / z) = 511.2 [M+H] + .

[1267] Step b): Preparation of (6-(2-(1,3-dioxane-2-yl)ethyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1268] (E)-(6-(2-(1,3-dioxane-2-yl)vinyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone (83 mg, 0.162 mmol), 5% palladium on carbon (10 mg), and methanol (10 mL) were added sequentially to a reaction flask. The mixture was purged with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give (6-(2-(1,3-dioxane-2-yl)ethyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl) methyl ketone, in 100% yield.

[1269] ESI-MS (m / z) = 513.2 [M+H] + .

[1270] Step c): Preparation of 3-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazine-1-carbonyl)pyrimidin-4-yl)propionaldehyde

[1271] (6-(2-(1,3-dioxane-2-yl)ethyl)-2-(4-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone (83 mg, 0.162 mmol) and tetrahydrofuran (2.5 mL) were added to a reaction flask, stirred to dissolve, and then concentrated hydrochloric acid (2.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to give 3-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-yl)propionaldehyde, yield 30.5%.

[1272] ESI-MS (m / z) = 469.2 [M+H] + .

[1273] Step d): Preparation of (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone

[1274] 3-(2-(4-(1H-pyrazol-1-yl)phenyl)-6-(4-(methanesulfonyl)piperazin-1-carbonyl)pyrimidin-4-yl)propanal (23 mg, 0.049 mmol), (1R,2S)-2-(4-fluorophenyl)cyclopropane-1-amine (14 mg, 0.074 mmol), acetic acid (23 μL), methanol (70 μL), and DCE (2 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times and stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (21 mg, 0.245 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 4) to give (2-(4-(1H-pyrazol-1-yl)phenyl)-6-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)pyrimidin-4-yl)(4-(methanesulfonyl)piperazin-1-yl)methyl ketone, with a yield of 20.5%.

[1275] 1H NMR(400MHz,Chloroform-d)δppm 8.51(d,J=8.4Hz,2H),8.03(d,J=2.4Hz,1H),7.96–7.73(m,3H),7.39(s,1H),7. 13–6.85(m,4H),6.53(d,J=2.0Hz,1H),3.92(dt,J=37.8,5.0Hz,4H),3.40(dt,J =16.8,5.0Hz,4H),3.12–2.75(m,7H),2.40–2.28(m,1H),2.08(t,J=7.4Hz,2H), 1.92(d,J=6.4Hz,1H), 1.09(dq,J=11.4,6.6,5.8Hz,1H), 0.94(q,J=6.2Hz,1H).

[1276] ESI-MS (m / z) = 604.2 [M+H] + .

[1277] Compound No. 258 was prepared according to the synthetic method of Example 257 (isolation method 1), and its structure and characterization data are as follows:

[1278] 4-(4-(4,4-difluoropiperidin-1-carbonyl)-6-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)pyrimidin-2-yl)benzyl nitrile hydrochloride

[1279]

[1280] 1 H NMR(400MHz,DMSO-d6+D2O)δppm 8.67–8.41(m,2H),8.16–7.94(m,2H),7.65(s,1H),7.22(ddd,J=8.6,5.5, 2.8Hz,2H),7.20–7.03(m,2H),3.80(t,J=6.0Hz,2H),3.56(d,J=6.2Hz,2H ),3.19(q,J=6.0,4.0Hz,2H),3.12–2.92(m,3H),2.14(dtd,J=41.8,14.8, 14.2,7.6Hz,7H),1.49(dd,J=6.4,4.4Hz,1H),1.30(dt,J=8.0,6.4Hz,1H).

[1281] ESI-MS m / z = 520.2 [M+H] + .

[1282] Example 259

[1283] Preparation of 4-(4-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile

[1284]

[1285] Step a): Preparation of 2,4-dichloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazine

[1286] 2,4,6-trichloro-1,3,5-triazine (3.0 g, 16.393 mmol), 1-(methanesulfonyl)piperazine (5.4 g, 32.787 mmol), DIPEA (2.1 g, 16.393 mmol), and DCM (50 mL) were added sequentially to a reaction flask. The mixture was purged with nitrogen three times, and the mixture was heated to 50 °C and stirred for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2,4-dichloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazine in 65.3% yield.

[1287] ESI-MS (m / z) = 312.0 [M+H] + .

[1288] Step b): Preparation of 4-(4-chloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile

[1289] 2,4-Dichloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazine (3.3 g, 10.655 mmol), (4-cyanophenyl)boronic acid (1.5 g, 10.655 mmol), K₂CO₃ (2.9 g, 21.310 mmol), Pd(dppf)Cl₂ (780 mg, 1.066 mmol), 1,4-Dioxane (40 mL), and water (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at 75 °C for 6 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(4-chloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile, yield 31.1%.

[1290] ESI-MS (m / z) = 379.1 [M+H] + .

[1291] Step c): Preparation of 4-(4-(2-(1,3-dioxolane-2-yl)ethyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile

[1292] 4-(4-chloro-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile (1.256 g, 3.313 mmol), (2-(1,3-dioxolane-2-yl)ethyl)zinc bromide(II) (5 mL, 1 M, 4.970 mmol), Pd(dppf)Cl2 (242 mg, 0.331 mmol), and THF (15 mL) were added to a 30 mL microwave-safe tube. The mixture was purged with nitrogen three times and reacted in a microwave oven at 75 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(4-(2-(1,3-dioxolane-2-yl)ethyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile, in a yield of 31.5%.

[1293] 1 H NMR(400MHz,DMSO-d6)δppm 8.64–8.46(m,2H),8.14–7.89(m,2H),4.94(d,J=4.8Hz,1H),4.13–3.74(m,8H),3.24(d ,J=5.8Hz,4H),2.90(d,J=1.8Hz,3H),2.80(t,J=7.8Hz,2H),2.10(q,J=6.8,6.4Hz,2H).

[1294] ESI-MS (m / z) = 445.2 [M+H] + .

[1295] Step d): Preparation of 4-(5-(4-(methanesulfonyl)piperazin-1-yl)-6-oxy-3-(3-oxopropyl)pyridazin-1(6H)-yl)benzonitrile

[1296] 4-(4-(2-(1,3-dioxolane-2-yl)ethyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile (465 mg, 1.043 mmol), THF (3 mL), and 4N hydrochloric acid aqueous solution (3 mL) were added sequentially to a reaction flask and stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was poured into an aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4-(5-(4-(methanesulfonyl)piperazin-1-yl)-6-oxy-3-(3-oxopropyl)pyridazin-1(6H)-yl)benzonitrile, yield 45.5%.

[1297] ESI-MS (m / z) = 401.1 [M+H] + .

[1298] Step e): Preparation of 4-(4-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile

[1299] 4-(5-(4-(methanesulfonyl)piperazin-1-yl)-6-oxy-3-(3-oxopropyl)pyridazin-1(6H)-yl)benzonitrile (190 mg, 0.475 mmol), (1R,2S)-2-(4-fluorophenyl)cyclopropane-1-amine (89 mg, 0.475 mmol), acetic acid (190 μL), methanol (950 μL) and DCE (5 mL) were added sequentially to the reaction flask, the mixture was purged with nitrogen three times, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium cyanoborohydride (61 mg, 0.950 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by Prep-HPLC (separation method 3) to give 4-(4-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-6-(4-(methanesulfonyl)piperazin-1-yl)-1,3,5-triazin-2-yl)benzonitrile, with a yield of 41.5%.

[1300] 1H NMR(400MHz,DMSO-d6)δppm 8...

Claims

1. The following compounds or their salts: 。 2. A pharmaceutical composition comprising a therapeutically effective dose of the compound or a salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier, diluent, adjuvant, mediator, or excipient; the composition may further comprise one or more other therapeutic agents.

3. The use of the compound of claim 1 or a salt thereof, or the composition of claim 2, in the preparation of LSD1 inhibitor-related drugs.

4. The application according to claim 3, characterized in that, The LSD1 inhibitor-related drugs are drugs used for tumors.

5. The application according to claim 3, characterized in that, The LSD1 inhibitor-related drugs are used for lung cancer.

6. The application according to claim 3, characterized in that, The LSD1 inhibitor-related drugs are used for small cell lung cancer.

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