Naphthylamide compound as well as preparation method and application thereof

Abstract

The invention relates to a naphthamide compound as shown in a formula (I), a preparation method of the naphthamide compound and application of the naphthamide compound in treatment and / or prevention of diseases related to biological activity of protein kinase. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of December 27, 2023, application number CN202311820205.X, and invention name “A naphthamide compound, its preparation method and its application”. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a naphthamide compound as a protein kinase inhibitor, a preparation method thereof, and an application thereof in treating and / or preventing diseases associated with the biological activity of the protein kinase. Background Art

[0003] Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor tyrosine kinases (RTKs) that include three structurally similar transmembrane protein members, namely: VEGFR1 (also known as feline McDonough sarcoma (fms)-related tyrosine kinase-1, Flt-1), VEGFR2 (also known as kinase insert domain receptor (KDR)) and VEGFR3 (also known as Flt-4) (Moser C, et al., Clin. Colorectal Cancer., 2007, 6 (8): 564-71). VEGFRs are expressed in endothelial cells, non-endothelial cells including tumor cells, and this type of receptor can bind to five natural ligands including VEGF-A, VEGF-B, VEGF-C, VEGF-D and PlGF (Placental Growth Factor). Among them, VEGF-A plays an irreplaceable role in the process of angiogenesis and maintenance, while VEGF-C and VEGF-D are ligands that mediate lymphangiogenesis. Among all receptors, VEGFR2 plays the most important role and is crucial in the regulation of angiogenesis, vascular development, vascular permeability and embryonic hematopoiesis.

[0004] Since the diffusion limit of oxygen in mammalian tissue is about 100-200 μM, if there is no new blood vessels to provide sufficient blood oxygen supply and only tissue diffusion is relied on, the growth diameter of metabolically active solid tumor tissue will be limited to 0.2-2.0 mm due to hypoxia. Therefore, anti-angiogenesis has become an effective treatment for various solid tumors (Adair TH, et al., Angiogenesis, Morgan & Claypool Life Sciences: San Rafael, CA, USA, 2010.).

[0005] At present, there are two main types of approved drugs targeting tumor angiogenesis and VEGF-VEGFRs pathway: one is monoclonal antibodies, such as Bevacizumab, which was first approved in 2004, and Ramucirumab, which was approved in 2014. The other is VEGFRs small molecule inhibitors, mainly including Sorafenib, Axitinib, Apatinib, Sunitinib, Regorafenib, Vandetanib, Pazopanib, Lenvatinib, Ponatinib, Cabozantinib, Fruquintinib, etc.

[0006] Anti-angiogenic drugs have greatly improved the treatment prospects of various solid tumors, but hypertension is one of the most common toxic side effects of VEGF-VEGFRs inhibitors, and almost 100% of patients treated with this type of drug experience elevated blood pressure. Studies have shown that hypertension caused by VEGF-VEGFRs inhibitors is a mechanism-dependent target toxicity, which usually leads to dose adjustments or interruptions during treatment (Camarda N, et al., Curr. Oncol. Rep., 2022Apr; 24(4): 463-74).

[0007] Aurora kinases (AURKs) are an important class of serine / threonine protein kinases that regulate the cell cycle. The human AURKs family includes three members: Aurora A, Aurora B, and Aurora C. In all somatic cells, only Aurora A and Aurora B are expressed at detectable levels (Tang A, et al., Oncotarget., 2017, 8: 23937-54).

[0008] Aurora B is overexpressed in tumors of many different tissue sources relative to normal adjacent tissues. This kinase is encoded by the AURORA B gene located on chromosome 17, also known as AIK2, AIM1, ARK2, AIRK2, IPL1, STK1, STK5 and STK12. Its phosphorylation and modification of the Ser10 site of histone H3 is essential for sister chromatid separation. Exogenous overexpression of Aurora B can increase the phosphorylation of histone H3 and chromosomal aneuploidy in normal cells, and injection of these Aurora B overexpressing cells into BALB / c nu / nu mice will lead to tumor formation, indicating that Aurora B has a driving effect on tumorigenesis (Ota T, et al., Cancer Res., 2002, 62(18): 5168-77).

[0009] Taking Aurora B as an anti-tumor target and inhibiting its activity can block the abnormal connection between kinetochores and microtubules, prevent the arrangement and separation of chromosomes, and then cause mitotic catastrophes and cell apoptosis. In addition, the loss of Aurora B kinase activity will lead to the failure of cytokinesis and the formation of tetraploidy (or polyploidy). Such severe genomic instability will eventually lead to cell death. Aurora B is only expressed in dividing and proliferating cells and is mostly in a stable state in normal cells. Therefore, targeted inhibition of Aurora B has a strong selectivity for tumor cells with active division and proliferation, and will have greater advantages compared with other non-specific cytotoxic drugs.

[0010] To date, no AURKs inhibitors have been approved for marketing worldwide, but clinical research on this type of inhibitor is currently relatively active, including AURKs pan-inhibitors such as VX-680 / MK-0475 (Tozasertib), PHA-793358 (Danusertib), AT-9283, AMG 900, KW-2449, ABT-348 (Ilorasertib) and TT00420, Aurora A selective inhibitors such as MLN8237, ENMD 2076, VX-689 and LY3295668, and Aurora B selective inhibitors such as AZD1152 (Barasertib) and Chiauranib (Jing X, et al., Expert. Opin. Ther. Pat., 2021, 31(7): 625-44.). Existing evidence has shown to some extent that Aurora A or Aurora B selective inhibitors can avoid more toxicity than AURKs pan-inhibitors and therefore have better drugability.

[0011] Chiauranib is a small molecule inhibitor developed by Shenzhen Chipscreen Biotech Co., Ltd. that targets multiple kinase pathways such as VEGFR, PDGFR, and Aurora B. Clinical trials for tumor treatment are ongoing. According to the results of the Phase I clinical trial of Chiauranib, the dose-limiting toxicity (DLT) of Chiauranib occurred in the 65mg group, which manifested as grade 3 hypertension, a toxicity associated with VEGFR pathway inhibition. The Phase II clinical recommended dose is 50mg. Under this dose condition, the drug is administered once a day, and the highest blood drug exposure (C max ) is about 2.6μM, and the steady-state blood drug exposure (C trough ) is about 1μM (Sun Y, et al., J. Hematol. Oncol., 2019, 12(1): 9.). The DLT of sioroni in humans is related to the inhibition of the VEGFR pathway, suggesting that the VEGFR pathway may be the dominant pathway for the in vivo efficacy of sioroni. According to in vitro cellular experiments, sioroni has relatively weak inhibitory activity against Aurora B kinase under 1-3μM conditions (equivalent to the in vivo drug exposure level), suggesting that there may be limited drug target mechanism in the treatment of Aurora B kinase-dependent tumors. Therefore, the development of multi-target kinase inhibitors that are more selective for Aurora B kinase and relatively more potent in inhibiting Aurora B than VEGFR2 may achieve better efficacy against Aurora B kinase-dependent tumors within a similar human exposure and maximum tolerated dose (MTD) range. Summary of the invention

[0012] Problems to be solved by the invention:

[0013] In view of the relatively weak inhibitory activity of Aurora B kinase in the prior art, and the excessive inhibitory activity of VEGFR2 will produce toxic side effects such as hypertension, especially when the selectivity of Aurora B kinase relative to VEGFR2 is weak, the full play of the therapeutic effect in the treatment of tumors related to the biological activity of Aurora B kinase is limited. At the same time, in view of the treatment requirements for primary and metastatic tumors of the central nervous system, the therapeutic drug needs to be able to cross the blood-brain barrier and reach an effective exposure amount in the brain to exert an anti-tumor effect. Therefore, the purpose of the present invention is to provide a compound with higher selectivity for Aurora B kinase relative to VEGFR2, and the related compound has a more significant inhibitory activity on Aurora B kinase at the cellular level under the condition of blood drug accessible exposure, which can achieve better efficacy / safety comprehensive benefits for related diseases. At the same time, the compound of the present invention has a good ability to cross the blood-brain barrier and is suitable for the treatment and / or prevention of central nervous system diseases.

[0014] Solutions used to solve the problem:

[0015] In order to solve the above problems, the inventors of the present application conducted intensive research and found that naphthamide compounds with specific structures can achieve the desired purpose, resulting in the completion of the present invention.

[0016] The present invention relates to the following naphthamide compounds.

[0017] A compound represented by formula (I), or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof:

[0018] in:

[0019] R 1 is selected from methyl or ethyl, the methyl or ethyl being unsubstituted or substituted by one or more identical or different R a replace;

[0020] Each R a are each independently selected from halogen, C 1-6 Alkoxy, -NR'R", halogenated C 1-6 Alkoxy; wherein R' and R" are each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, or R' and R" together with the N atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S;

[0021] R 2 and R 3 Each independently selected from: H, halogen, C 1-6 alkyl;

[0022] Ring A is selected from C 4-10 Cycloalkyl or 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains 1 to 4 heteroatoms selected from N, O, S; the C 4-10 The cycloalkyl or 4-10 membered heterocyclic group is unsubstituted or substituted by one or more identical or different R b replace;

[0023] Each R b are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0024] Alternatively, ring A is selected from the group

[0025] in,

[0026] In A1, R4 Selected from F, Cl, C 1-6 Alkyl, haloC 1-6 alkyl;

[0027] In A2, R 5 Selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl;

[0028] In A3, R 4 and R 5 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl;

[0029] A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 Alkyl, when R 6 When it is Cl, R 1 is methyl or ethyl;

[0030] A5, R 5 and R 6 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl;

[0031] Furthermore, when ring A is When R 1 is ethyl or is replaced by one or more R a Substituted methyl or ethyl.

[0032] In some specific embodiments, R 1 is selected from methyl and ethyl; the methyl and ethyl groups are unsubstituted or substituted with 1, 2 or 3 identical or different R a replace.

[0033] In some specific embodiments, each R a are each independently selected from halogen, C 1-4 Alkoxy, -NR'R", halogenated C 1-4 Alkoxy; wherein R' and R" are each independently selected from H, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S.

[0034] In some specific embodiments, each R aare each independently selected from halogen, C 5-6 Alkoxy, -NR'R", halogenated C 5-6 Alkoxy; wherein R' and R" are each independently selected from H, C 5-6 Alkyl, C 5-6 Cycloalkyl, or R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S.

[0035] In some specific embodiments, each R a are each independently selected from halogen, C 1-3 Alkoxy, -NR'R", halogenated C 1-3 Alkoxy; wherein R' and R" are each independently selected from H, C 1-3 Alkyl, C 3-4 Cycloalkyl, or R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S.

[0036] In some specific embodiments, each R a Each is independently selected from halogen, methoxy, ethoxy, propoxy, -NR'R", halogenated methoxy, halogenated ethoxy, halogenated propoxy; wherein R' and R" are each independently selected from H, methyl, ethyl, or R' and R" together with the N atom to which they are connected form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may additionally contain 1-2 heteroatoms selected from N, O, and S.

[0037] In some specific embodiments, each R a Each is independently selected from F, Cl, Br, methoxy, ethoxy, propoxy, -NR'R", halomethoxy, haloethoxy, halopropoxy; wherein R' and R" are each independently selected from H, methyl, ethyl, or R' and R" together with the N atom to which they are connected form a 4-7 membered nitrogen-containing heterocyclic group, and the 4-7 membered nitrogen-containing heterocyclic group may additionally contain 1-2 heteroatoms selected from N, O, and S.

[0038] In some specific embodiments, each R a Each is independently selected from F, Cl, Br, methoxy, ethoxy, -NR'R", methoxy or ethoxy substituted by 1-3 F or Cl; wherein R' and R" are each independently selected from methyl, ethyl, or R' and R" together with the N atom to which they are connected form a 4-7 membered nitrogen-containing heterocyclic group, and the 4-7 membered nitrogen-containing heterocyclic group may additionally contain 1-2 heteroatoms selected from N, O, and S.

[0039] In some specific embodiments, each R aEach independently selected from F, Cl, methoxy, ethoxy, -NR'R", -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3; wherein R' and R" are each independently selected from methyl, ethyl, or R' and R" together with the N atom to which they are connected form

[0040]

[0041] In some specific embodiments, each R a Each independently selected from F, Cl, methoxy, N,N-dimethylamino, N-methylamino, -OCHF2,

[0042] In some specific embodiments, R 1 Selected from methyl, ethyl, -CH2CH2F, -CH2CHF2, -CH2CH2Cl, methoxyethyl,

[0043] In some specific embodiments, when Ring A is When R 1 It is ethyl or -CH2CH2F.

[0044] In some specific embodiments, R 1 Selected from methyl and ethyl, wherein the methyl and ethyl are unsubstituted.

[0045] In some specific embodiments, Ring A is selected from C 4-7 Monocyclic alkyl, C 5-10 Spirobicycloalkyl, 4-7 membered monoheterocyclic group or 6-10 membered spirobicycloalkyl; the 4-7 membered monoheterocyclic group or 6-10 membered spirobicycloalkyl contains 1 to 4 heteroatoms selected from N, O, S, the C 4-7 Monocyclic alkyl, C 5-10 The spiro bicycloalkyl, 4-7 membered monoheterocyclic group, 6-10 membered spiro bicycloheterocyclic group is unsubstituted or substituted by 1, 2 or 3 identical or different R b replace.

[0046] In some specific embodiments, Ring A is selected from C 4-6 Monocyclic alkyl, C 6-8 Spirobicycloalkyl, 4-7 membered monoheterocyclic group or 6-8 membered spirobicycloalkyl, wherein the 4-7 membered monoheterocyclic group or 6-8 membered spirobicycloalkyl contains 1 to 2 heteroatoms selected from N, O, S, and the C 4-6 Monocyclic alkyl, C 6-8 The spiro bicycloalkyl, 4-7 membered monoheterocyclic group, 6-8 membered spiro bicycloheterocyclic group is unsubstituted or substituted by 1, 2 or 3 identical or different R b replace.

[0047] In some specific embodiments, Ring A is selected from Said

[0048] is unsubstituted or substituted with 1, 2 or 3 identical or different R b replace.

[0049] In some specific embodiments, each R b are each independently selected from halogen, C 1-6 alkyl.

[0050] In some specific embodiments, each R b Each independently selected from F, Cl, Br, C 1-4 Alkyl, C 5-6 alkyl.

[0051] In some specific embodiments, each R b Each is independently selected from F, Cl, Br, methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl.

[0052] In some specific embodiments, each R b Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and sec-butyl.

[0053] In some specific embodiments, each R b Each is independently selected from F, Cl, Br, and methyl.

[0054] In some specific embodiments, each R b are each independently selected from F.

[0055] In some specific embodiments, Ring A is selected from

[0056]

[0057] In some specific embodiments, in A1, R 4 Selected from F, Cl, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl.

[0058] In some specific embodiments, in A1, R 4 Selected from F, Cl, C 1-4 Alkyl, haloC 1-4 alkyl.

[0059] In some specific embodiments, in A1, R 4Selected from F, Cl, methyl, ethyl, propyl, isopropyl, C 1-4 Alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4alkyl.

[0060] In some specific embodiments, in A1, R 4 Selected from F, Cl, methyl, ethyl, methyl substituted with fluorine or chlorine, ethyl substituted with fluorine or chlorine.

[0061] In some specific embodiments, in A1, R 4 Selected from F, Cl, methyl.

[0062] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl.

[0063] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl.

[0064] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, C 5-6 Alkyl, haloC 5-6 alkyl.

[0065] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl.

[0066] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, methyl, ethyl, methyl substituted with fluorine or chlorine, ethyl substituted with fluorine or chlorine.

[0067] In some specific embodiments, in A2, R 5 Selected from F, Cl, Br, methyl.

[0068] In some specific embodiments, in A2, R 5 Selected from F.

[0069] In some specific embodiments, in A3, R 4 and R 5 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC1-4 Alkyl, haloC 5-6 alkyl.

[0070] In some specific embodiments, in A3, R 4 and R 5 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl.

[0071] In some specific embodiments, in A3, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, and haloC4 alkyl.

[0072] In some specific embodiments, in A3, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl.

[0073] In some specific embodiments, in A3, R 4 and R 5 Each is independently selected from F or Cl.

[0074] In some specific embodiments, in A3, R 4 For F, R 5 is F or Cl.

[0075] In some specific embodiments, Ring A is selected from

[0076] In some specific embodiments, in A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 Alkyl, when R 6 When it is Cl, R 1 It is methyl or ethyl.

[0077] In some specific embodiments, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 Alkyl; when R 6 When it is Cl, R 1It is methyl or ethyl.

[0078] In some specific embodiments, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl; when R 6 When it is Cl, R 1 It is methyl or ethyl.

[0079] In some specific embodiments, in A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from F, Cl, Br, methyl, ethyl, methyl substituted with fluorine or chlorine, ethyl substituted with fluorine or chlorine; when R 6 When it is Cl, R 1 It is methyl or ethyl.

[0080] In some specific embodiments, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each independently selected from F or Cl; when R 6 When it is Cl, R 1 It is methyl or ethyl.

[0081] In some specific embodiments, in A5, R 5 and R 6 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl.

[0082] In some specific embodiments, in A5, R 5 and R 6 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl.

[0083] In some specific embodiments, in A5, R 5 and R 6 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, and haloC4 alkyl.

[0084] In some specific embodiments, in A5, R 5 and R 6Each is independently selected from F, Cl, Br, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl.

[0085] In some specific embodiments, in A5, R 5 and R 6 Each is independently selected from F or Cl.

[0086] In some specific embodiments, Ring A is selected from

[0087] In some specific embodiments, Ring A is selected from When ring A is selected from When R 1 It is methyl or ethyl.

[0088] In some embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from R 1 It is ethyl or -CH2CH2F.

[0089] In some specific embodiments, Ring A is selected from R 1 It is ethyl or -CH2CH2F.

[0090] In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from In some specific embodiments, Ring A is selected from R 1 It is methyl or ethyl.

[0091] In some specific embodiments, Ring A is selected from R 1 It is methyl or ethyl.

[0092] In some specific embodiments, R 2 and R 3 are each independently selected from H, halogen, C 1-4 Alkyl, C 5-6 alkyl.

[0093] In some specific embodiments, R 2 and R 3 Each is independently selected from H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl.

[0094] In some specific embodiments, R 2 and R 3 Each is independently selected from H, F, Cl, Br.

[0095] In some specific embodiments, R 2 and R 3 Each is independently selected from H and F.

[0096] In some specific embodiments, R 2 and R 3 At the same time, H.

[0097] In some specific embodiments, R 2 and R 3 One of them is H and the other is F.

[0098] In some specific embodiments, R 2 For H, R 3 For F.

[0099] In some specific embodiments, R 2 For F, R 3 For H.

[0100] In some specific embodiments, the above compound is selected from:

[0101]

[0102]

[0103] As used herein, the term "pharmaceutically acceptable salt of the compound represented by formula (I)" is exemplified by organic acid addition salts formed with organic acids that form pharmaceutically acceptable anions.

[0104] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent.

[0105] The term "prodrug" refers to derivatives of the compounds of formula (I) with specific substituents discovered in the present invention, which may have weak activity or even no activity themselves, but after administration, they are converted into compounds with specific substituents discovered in the present invention under physiological conditions (for example, by metabolism, solvent decomposition or other means), and produce corresponding biological activity in vivo.

[0106] The term "metabolite" refers to the product obtained by the metabolism of the compound of formula (I) with specific substituents found in the present invention in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by the test methods described in the present invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes the metabolites of the compound, including the metabolites produced by contacting the compound of the present invention with a mammal for a period of time.

[0107] The term "deuterated compound" refers to a compound of the invention that includes at least one deuterium atom, specifically one or more hydrogen atoms in the compound of the invention that can be replaced or substituted by a deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.

[0108] When the structural formula of the compound of general formula (I) described in the present invention is inconsistent with the Chinese name, the structural formula shall prevail.

[0109] Preparation method:

[0110] Therefore, another aspect of the present invention also provides the preparation method of the above-mentioned compound according to the present invention. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following illustrative methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of synthetic methods known in the art and the method described in the present invention. The product obtained by each step of the reaction is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0111] The following synthetic routes describe the preparation methods of the compounds of formula (I) of the present invention. The raw materials, reagents, catalysts, solvents, etc. used in the following synthetic schematics can be prepared by methods well known to those of ordinary skill in the field of organic chemistry or can be commercially available. All final derivatives of the present invention can be prepared by the methods described in the schematics or similar methods thereof, which are well known to those of ordinary skill in the field of organic chemistry. All variable factors used in these schematics are defined as above and below.

[0112] The definitions of the following variables are as described above, and the definitions of new variables are as described in this section. In addition, the compounds described in the general formula (I) and the intermediates involved can be purified by common separation methods, such as extraction, recrystallization and silica gel column chromatography. The 200-300 mesh silica gel and thin layer chromatography silica gel plates used are all produced by Qingdao Ocean Chemical Plant. The chemical reagents used are analytically pure or chemically pure commercial products of general reagents and are not further purified when used.

[0113] The present invention provides a method for preparing a compound represented by general formula (I), comprising the following steps:

[0114]

[0115] 1) The compound represented by formula (Ia) is reacted in a first solvent with a compound represented by formula (Ib) through a nucleophilic substitution reaction after being catalyzed by a first base to obtain a compound represented by formula (Ic); or the compounds represented by formula (Ia) and formula (Ib) are reacted through a Mitsunobu reaction in the presence of triphenylphosphine (PPh3) / diethyl azodiacid (DEAD) or triphenylphosphine (PPh3) / diisopropyl azodiacid (DIAD) to obtain a compound represented by formula (Ic);

[0116] 2) the compound represented by formula (Ic) reacts with the compound represented by formula (Id) in a second solvent under the action of a second base to obtain a compound represented by formula (Ie) through a nucleophilic substitution reaction;

[0117] 3) The compound represented by formula (Ie) and the compound represented by (If) undergo condensation reaction in a third solvent under the action of a condensation agent and a third base to obtain a compound represented by formula (I).

[0118] in:

[0119] R 1 , R 2 , R 3 , Ring A is as defined above;

[0120] X is selected from bromine, iodine, -OMs, -OTf, -OTs, -OH.

[0121] In some embodiments, in step 1), the first solvent is selected from dichloromethane (DCM), 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N-methylpyrrolidone (NMP) or a combination thereof.

[0122] In some embodiments, in step 1), the first base is selected from potassium carbonate (K2CO3), cesium carbonate (Cs2CO3) or a combination thereof.

[0123] In some embodiments, in step 2), the second solvent is selected from 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N-methylpyrrolidone (NMP), isopropanol, N,N'-dimethyl sulfoxide (DMSO) or a combination thereof.

[0124] In some embodiments, in step 2), the second base is selected from potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), diisopropylethylamine (DIEA) or a combination thereof.

[0125] In some embodiments, in step 3), the condensing agent is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl), 1-hydroxybenzotriazole (HOBt), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) and N-methylimidazole, among which TCFH is particularly suitable for the condensation of sterically hindered larger amines, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (PyBOP) or a combination thereof.

[0126] In some embodiments, in step 3), the third solvent is selected from dichloromethane (DCM), 1,4-dioxane (1,4-dioxane), tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF) or a combination thereof.

[0127] In some embodiments, the third base is selected from triethylamine (TEA) and diisopropylethylamine (DIEA).

[0128] Pharmaceutical composition:

[0129] The present invention also provides a pharmaceutical composition, which comprises any of the aforementioned compounds, or their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and optional pharmaceutical carriers and / or adjuvants and / or diluents.

[0130] In some embodiments, the pharmaceutical composition may further comprise other drugs for treating and / or preventing diseases associated with the biological activity of Aurora B kinase.

[0131] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredients are known or will be apparent to those skilled in the art based on the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0132] Medical Uses:

[0133] Another aspect of the present invention relates to the above-mentioned compounds according to the present invention, or their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and compositions thereof, for use in treating and / or preventing diseases associated with the biological activity of Aurora B kinase.

[0134] Another aspect of the present invention relates to the use of the above-mentioned compounds according to the present invention, or their stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and the above-mentioned compositions in the preparation of drugs for treating and / or preventing diseases related to the biological activity of Aurora B kinase.

[0135] A method for treating and / or preventing a disease associated with the biological activity of Aurora B kinase, comprising administering to an individual in need thereof a therapeutically / preventively effective amount of the above-mentioned compound, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the above-mentioned combinations.

[0136] According to a preferred embodiment of the present invention, the disease associated with the biological activity of Aurora B kinase is selected from tumors or hyperproliferative diseases.

[0137] In the present invention, "treatment" refers to the administration of drugs or other adjunctive therapies to a subject in order to obtain the desired pharmacological and / or physiological effects. The effect may be preventive, based on the complete or partial prevention of a disease or its symptoms; and / or therapeutic, based on partial or complete stabilization or cure of a disease and / or side effects caused by a disease. As used herein, "treatment" covers any treatment of a patient's disease, including: (a) preventing a disease or symptom from occurring in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) inhibiting the symptoms of a disease, i.e., preventing its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0138] In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

[0139] In the present invention, "effective amount" refers to an amount that is effective in achieving the desired therapeutic or preventive effect at the required dose and time. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to induce the desired response in the individual. The therapeutically effective amount also encompasses the amount in which the therapeutic beneficial effects of the substance / molecule outweigh any toxic or harmful consequences. "Preventively effective amount" refers to an amount that is effective in achieving the desired preventive effect at the required dose and time. Usually, but not necessarily, since the preventive dose is used for the subject before the onset of the disease or in the early stages of the disease, the preventively effective amount will be lower than the therapeutically effective amount. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0140] Definition of terms:

[0141] According to the practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0142] A dash "-" not appearing between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -NR'R" is attached through the N atom.

[0143] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently, or "C 1-4 Alkyl", or independently disclosed "C 1-3 alkyl".

[0144] The term "alkyl" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. 1-6 "Alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0145] The term "alkoxy" refers to any of the above alkyl groups (e.g., C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 alkyl, etc.), which is attached to the rest of the molecule through an oxygen atom (—O—).

[0146] The term "halogenated C 1-6 Alkyl" or "halogenated C 1-6 "Alkoxy" refers to an alkyl or alkoxy group in which one or more (such as 2 or 3) hydrogen atoms are replaced by halogen atoms, such as fluorine, chlorine, bromine, or iodine. The alkyl or alkoxy group is defined as above. In some embodiments, the term "halogenated C 1-6 "Alkyl" is preferably fluorinated or chlorinated, for example, it can be -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CF3, etc. In some embodiments, the term "halogenated C 1-6 The "alkoxy" is preferably fluorinated, for example, it may be -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, etc.

[0147] As used herein, the term "substituted" means that any one or more hydrogens on a designated atom or group are replaced with the selection of a designated group, provided that the normal valency of the designated atom is not exceeded.

[0148] The term "cycloalkyl" refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic system. When the cycloalkyl group is bicyclic or polycyclic, each ring should be a saturated carbocyclic ring or a carbocyclic residue. The connection between each two rings of the bicyclic or polycyclic cycloalkyl group may include bridging, fusion or spiro connection. For example, C3-10 Cycloalkyl refers to C3, C4, C5, C6, C7, C8, C9 and C 10 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0149] The term "carbocycle" or "carbocycle residue" refers to any stable 3-, 4-, 5-, 6- or 7-membered monocyclic ring or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-membered bicyclic or polycyclic ring, any one of which may be saturated, partially saturated, unsaturated or aromatic. The bicyclic or polycyclic carbocycles may be connected in a manner that includes bridging, fusion or spiro connection. Examples of these carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2,2,2]bicyclooctane, wait.

[0150] The terms "heterocycle", "heterocyclic" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 4-8 membered monocyclic or bicyclic groups, 8-10 membered bicyclic or tricyclic groups and 10-14 membered tricyclic or polycyclic groups, wherein at least one ring has at least one heteroatom (O, S or N), preferably 1, 2 or 3 heteroatoms selected from O, S and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further provided that the ring contains at least one carbon atom. In some preferred embodiments, the heteroatom refers to only N or O, and the total number does not exceed 3, preferably only 1-2 heteroatoms. Carbon and sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and when valence permits, ring atoms on the heterocycle may be optionally substituted with =O (oxo). (For example: ). The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or fully unsaturated, aromatic or non-aromatic. The heterocyclic group may be attached at any available nitrogen or carbon atom. As used herein, "heterocycle" does not include a fully aromatic ring.

[0151] The term "halogen" refers to fluorine, chlorine, bromine, iodine.

[0152] The term "heteroatom" shall include oxygen, sulfur and nitrogen.

[0153] The term "XXX is unsubstituted or substituted by one or more identical or different YYY" means that XXX may be unsubstituted or substituted by YYY. Substituted by one or more YYY means that XXX may be substituted by one YYY (i.e., there is only one substituent YYY), or there may be multiple substituents YYY, and each YYY is independent of each other, they may be the same or different substituents selected from the corresponding range, and they may be substituted at any substitutable position. Among them, multiple means 2 or more, preferably 2, 3 or 4, more preferably 2 or 3.

[0154] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds and compounds useful as pharmaceutically acceptable compounds and / or intermediate compounds useful in preparing pharmaceutically acceptable compounds.

[0155] Effect of the invention:

[0156] The naphthamide compounds of formula (I) of the present invention with a specific structure show excellent Aurora B kinase inhibitory activity, and at the same time have higher Aurora B kinase inhibitory selectivity relative to VEGFR2, and have a certain effect on the tumor cell cycle, which can achieve better efficacy / safety comprehensive benefits for related diseases. At the same time, in the brain penetration test, the ratio of the compound concentration of the compound of the present invention in brain tissue to the concentration in plasma is significantly higher than that of the control molecule 01 (Chiauranib) and the control molecule 02; this test result shows that the compound of the present invention has excellent brain barrier permeability, can pass through the blood-brain barrier, has the potential to reach an effective blood drug concentration in brain tissue, and can be used to treat and prevent central nervous system related diseases. In addition, in the anti-tumor efficacy experiment of mice, the tumor volume of the compound of the present invention is significantly reduced relative to the control molecules 01 and 02, and the tumor volume inhibition rate is significantly improved; this experimental result shows that the compound of the present invention has excellent in vivo anti-tumor efficacy and can significantly inhibit tumor growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0157] Figure 1 The graph represents the changes in subcutaneous tumor volume of each group of mice during treatment with the compound I-9 of the present invention and the control molecule 01 (Chiauranib) and the control molecule 02. The vertical axis is the average tumor volume (mm 3 ), the horizontal axis is the number of treatment days after grouping (days). DETAILED DESCRIPTION

[0158] The examples and preparations provided in the present invention further illustrate and illustrate the compounds and preparation methods of the present invention. It should be understood that the following preparations and examples do not limit the scope of the present invention in any way.

[0159] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device and material similar or equivalent to that described herein can be used to implement or test the present invention, preferred methods, devices and materials are now described.

[0160] LC-MS analysis method:

[0161] Mass spectrometry conditions: instrument Thermo ISQ EC; ion source ESI (EA+EA-); source temperature 300°C; sheath gas pressure 50.0 psi; auxiliary gas pressure 5.0 psi; purge gas pressure 0.5 psi; vaporization chamber temperature 300°C.

[0162] Chromatographic conditions: instrument Thermo U3000; detector DAD-3000 (RS) (diode array detector); chromatographic column Pheromone Titank C18 3μm 4.6×50mm; flow rate 2.0mL / min, split; column temperature 35°C; mobile phase A contained 0.05% formic acid and 5% acetonitrile in water; mobile phase B contained 0.05% formic acid in acetonitrile; elution method was linear elution from 100% to 5% of phase A within 0 to 1.0min, and then 5% of phase A was maintained for 1.2min.

[0163] HPLC analysis method:

[0164] Instrument: Thermo U3000; detector: VWD-3×00(RS) (UV detector); wavelength: 254nm; chromatographic column: Shimadzu inertsil 3μm 4.6×150mm; flow rate: 0.8mL / min; column temperature: 35°C; mobile phase A: water containing 0.05% formic acid and 5% acetonitrile; mobile phase B: acetonitrile containing 0.05% formic acid; elution method: first maintain 100% phase A for 1.0min, then linearly elute phase A from 100% to 5% within 1.0-8.0min, and finally maintain 5% phase A for 4.0min.

[0165] 1 H-NMR analysis method:

[0166] 1 H-NMR was measured at room temperature using a BRUKER AVANCE-400 MHz NMR spectrometer in DMSO-d6 or CDCl3 with TMS as the internal standard. Signal peaks were expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double of doublets), tt (double of triplets). The unit of coupling constant (J) is Hertz (Hz).

[0167] According to the above-described method, the present invention prepared representative compounds I-1 to I-44 (see Table 1), and detected and recorded their purity. Among them, 5 compounds (I-7, I-11, I-12, I-13 and I-14) were used as control compounds.

[0168] Table 1

[0169]

[0170] The present invention is further described below in conjunction with specific examples, but the protection scope of the present invention is not limited to these examples. The percentages described in the present invention are all weight percentages unless otherwise specified. The numerical ranges described in the specification, such as units of measurement, reaction conditions, physical states of compounds or percentages, are all for providing unambiguous written references. When implementing the present invention, those skilled in the art use temperatures, concentrations, quantities, carbon atoms, etc. outside this range or different from a single numerical value, and it is still possible to obtain the expected results. In addition, the raw materials in the following examples, if not otherwise specified, can all be commercially available, for example, can be purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical R&D Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., and Hechun Biotechnology (Shanghai) Co., Ltd.

[0171] Intermediate: Preparation of I-1c

[0172]

[0173] Dissolve the commercially available I-1a (2.0 g, 11.13 mmol, 1.0 eq) in DMF (30 mL), add Cs2CO3 (10.88 g, 33.39 mmol, 3.0 eq) and I-1b (3.64 g, 33.39 mmol, 3.0 eq), and stir at room temperature for 3 hours. The reaction solution was quenched with water (150 mL), and the precipitated solid was collected by filtration, rinsed with water (20 mL) 3 times, and dried in a blast drying oven at 50 ° C for 8 hours to obtain a yellow solid intermediate I-1a. (2.23 g, yield 96.5%). LC-MS MS-ESI (m / z) 208.0 [M+H] + .

[0174] Intermediate: Preparation of I-1e

[0175]

[0176] The intermediate I-1c (2.23 g, 10.74 mmol, 1.0 eq) was dissolved in DMSO (30 mL), Cs2CO3 (11.55 g, 35.44 mmol, 3.3 eq) and commercially available I-1d (2.02 g, 10.74 mmol, 1.0 eq) were added, heated to 140 ° C and stirred for 3 hours, and cooled to room temperature. The reaction was quenched with water (150 mL), the pH was adjusted to 6-7 with 1N dilute hydrochloric acid, the precipitated solid was collected by filtration, rinsed with water (20 mL) 3 times, and dried in a blast drying oven at 50 ° C for 8 hours to obtain a brown solid intermediate I-1e. (3.49 g, yield 90.4%). LC-MS MS-ESI (m / z) 360.1 [M+H] + .

[0177] Example 1: Preparation of Compound I-1

[0178]

[0179] The intermediate I-1e (3.49 g, 9.71 mmol, 1.0 eq) was dissolved in ultra-dry DMF (40 mL), and commercially available 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 5.54 g, 14.56 mmol, 1.5 eq), N,N'-diisopropylethylamine (DIEA, 3.76 g, 29.13 mmol, 3.0 eq) and I-1f (1.05 g, 9.71 mmol, 1.0 eq) were added, and stirred at room temperature for 18 hours. The reaction was quenched with water (200 mL), and the precipitated solid was collected by filtration, rinsed with water (20 mL) 3 times, and dried in a forced air drying oven at 50°C for 8 hours. The crude product was separated by silica gel column (200-300 mesh silica gel, ethyl acetate (EA) / petroleum ether (PE) = 0-1) and then slurried with EA / PE = 1:1 (30 mL) to obtain a yellow solid I-1. (2.30 g, yield 52.7%). LC-MS MS-ESI (m / z) 450.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.91(s,1H),8.64(d,J=5.2Hz,1H),8.44(d,J=9.2Hz,1H),8.25(d,J=9.1Hz,1H),8.09(d,J=8.2Hz, 1H),7.96-7.83(m,2H),7.67(t,J=7.6Hz,1H),7.58(dd,J=9.2,2.0Hz,1H),7.43(d,J=2.0Hz,1H),7 .38(d,J=7.6Hz,1H),7.32(dd,J=9.1,2.2Hz,1H),7.01(t,J=7.4Hz,1H),6.84(d,J=7.8Hz,1H),6.6 6(t,J=7.4Hz,1H),6.59(d,J=5.1Hz,1H),5.00(s,2H),4.23(q,J=6.9Hz,2H),1.44(t,J=6.9Hz,3H).

[0180] Example 2: Preparation of Compound I-2

[0181]

[0182] Yellow solid I-2 was prepared from intermediate I-1e (200.00 mg, 0.56 mmol, 1.0 eq), HATU (319.28 mg, 0.84 mmol, 1.5 eq), DIEA (217.06 mg, 1.68 mmol, 3.0 eq) and I-2f (79.86 mg, 0.56 mmol, 1.0 eq) according to the similar steps in Example I-1. (26.0 mg, yield 9.6%). LC-MS MS-ESI (m / z) 484.1 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.86(s,1H),8.63(d,J=5.1Hz,1H),8.42(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H) ,8.08(d,J=8.2Hz,1H),7.96-7.87(m,2H),7.66(t,J=7.6Hz,1H),7.62-7.50(m,1 H),7.46-7.36(m,2H),7.30(d,J=9.1Hz,1H),6.85(s,1H),6.65(d,J=8.3Hz,1H), 6.58(d,J=5.1Hz,1H),5.33(s,2H),4.23(q,J=6.9Hz,2H),1.43(t,J=6.9Hz,3H).

[0183] Intermediate: Preparation of I-3c

[0184]

[0185] Yellow solid intermediate I-3c was prepared from commercially available I-1a (1.79 g, 10.00 mmol, 1.0 eq), Cs2CO3 (4.15 g, 30.00 mmol, 3.0 eq) and I-3b (5.22 g, 30.00 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.86 g, yield 82.4%). LC-MS MS-ESI (m / z) 226.0 [M+H] + .

[0186] Intermediate: Preparation of I-3e

[0187]

[0188] The brown solid intermediate I-3e was prepared from intermediate I-3c (1.86 g, 8.24 mmol, 1.0 eq), Cs2CO3 (8.86 g, 27.19 mmol, 3.3 eq) and commercially available I-1d (1.55 g, 8.24 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (2.25 g, yield 72.3%). LC-MS MS-ESI (m / z) 378.1 [M+H] + .

[0189] Example 3: Preparation of Compound I-3

[0190]

[0191] Yellow solid I-3 was prepared from intermediate I-3e (377.00 mg, 1.00 mmol, 1.0 eq), HATU (570.36 mg, 1.50 mmol, 1.5 eq), DIEA (387.82 mg, 3.00 mmol, 3.0 eq) and I-3f (162.12 mg, 1.00 mmol, 1.0 eq) according to the similar steps in Example I-1. (130.0 mg, yield 24.9%). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.66(d,J=5.2Hz,1H),8.44(d,J=9.2Hz,1H),8.27(d,J=9.1Hz,1H),8 .11(d,J=8.3Hz,1H),7.95(d,J=7.0Hz,1H),7.92(d,J=2.2Hz,1H),7.67(t,J=7.7Hz ,1H),7.58(dd,J=9.2,2.4Hz,1H),7.51(dd,J=14.2,6.1Hz,2H),7.36(dd,J=9.1,2. 4Hz,1H),6.60(d,J=5.2Hz,1H),5.28(s,2H),4.98-4.74(m,2H),4.57-4.35(m,2H).

[0192] Example 4: Preparation of Compound I-4

[0193]

[0194] Yellow solid I-4 was prepared from intermediate I-1e (200.00 mg, 0.56 mmol, 1.0 eq), HATU (319.28 mg, 0.84 mmol, 1.5 eq), DIEA (217.06 mg, 1.68 mmol, 3.0 eq) and I-4f (68.43 mg, 0.56 mmol, 1.0 eq) according to the similar steps in Example I-1. (120.0 mg, yield 46.5%). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.80(s,1H),8.63(d,J=4.8Hz,1H),8.42(d,J=9.0Hz,1H),8.24(d,J=9.1Hz,1H),8.07(d ,J=8.0Hz,1H),7.96-7.81(m,2H),7.65(t,J=7.4Hz,1H),7.57(d,J=8.5Hz,1H),7.42(s,1 H),7.30(d,J=8.4Hz,1H),7.23(d,J=7.9Hz,1H),6.63(s,1H),6.58(d,J=4.7Hz,1H),6.46 (d,J=7.5Hz,1H),4.92(s,2H),4.23(d,J=6.8Hz,2H),2.21(s,3H),1.43(t,J=6.7Hz,3H).

[0195] Example 5: Preparation of Compound I-5

[0196]

[0197] Yellow solid I-5 was prepared from intermediate I-1e (200.00 mg, 0.56 mmol, 1.0 eq), HATU (319.28 mg, 0.84 mmol, 1.5 eq), DIEA (217.06 mg, 1.68 mmol, 3.0 eq) and I-5f (141.12 mg, 1.12 mmol, 2.0 eq) according to the similar steps in Example I-1. (55.0 mg, yield 21.0%). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.81(s,1H),8.64(d,J=5.2Hz,1H),8.44(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H ),8.08(d,J=8.3Hz,1H),7.94-7.88(m,2H),7.70-7.62(m,1H),7.57(dd,J=9.2, 2.5Hz,1H),7.43(d,J=2.4Hz,1H),7.38-7.26(m,2H),6.64-6.54(m,2H),6.42(t d,J=8.5,2.8Hz,1H),5.33(s,2H),4.24(q,J=6.9Hz,2H),1.44(t,J=7.0Hz,3H).

[0198] Example 6: Preparation of Compound I-6

[0199]

[0200] The intermediate I-1e (1.08g, 3.00mmol, 1.0eq) was dissolved in ultra-dry DMF (15mL), HATU (1.71g, 4.50mmol, 1.5eq), DIEA (1.16g, 9.00mmol, 3.0eq) and I-6f (432.00mg, 3.00mmol, 1.0eq) were added, and stirred at room temperature for 18h. The reaction was quenched with water (150mL), and the precipitated solid was collected by filtration, rinsed with water (5mL) 3 times, and dried in a blast drying oven at 50°C for 8 hours. The crude product was separated by a silica gel column (200-300 mesh silica gel, EA / PE=0-1 elution), and then slurried with EA / PE=1:1 (30mL) to obtain a yellow solid I-6. (682.00mg, yield 46.8%). LC-MS MS-ESI (m / z) 486.2 [M+H] + .1 H-NMR (400MHz, DMSO-d6) δppm 9.93(s,1H),8.62(d,J=5.1Hz,1H),8.41(d,J=9.2Hz,1H),8.22(d,J=9.1Hz,1 H),8.07(d,J=8.1Hz,1H),7.93(d,J=6.9Hz,1H),7.88(s,1H),7.65(t,J=7.6H z,1H),7.55(d,J=8.9Hz,1H),7.40(s,1H),7.29(d,J=9.1Hz,1H),7.20(s,1H) ,6.70-6.52(m,2H),5.35(s,2H),4.21(q,J=6.8Hz,2H),1.41(t,J=6.9Hz,3H).

[0201] Intermediate: Preparation of I-7c

[0202]

[0203] Yellow solid intermediate I-7c was prepared from commercially available I-1a (230.00 mg, 1.28 mmol, 1.0 eq), Cs2CO3 (1.25 g, 3.84 mmol, 3.0 eq) and I-7b (652.80 mg, 3.84 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (263.00 mg, yield 92.7%). LC-MS MS-ESI (m / z) 222.1 [M+H] + .

[0204] Intermediate: Preparation of I-7e

[0205]

[0206] The brown solid intermediate I-7e was prepared from the homemade intermediate I-7c (263.00 mg, 1.19 mmol, 1.0 eq), Cs2CO3 (1.28 g, 3.93 mmol, 3.3 eq) and commercially available I-1d (223.96 mg, 1.19 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (392.00 mg, yield 88.2%). LC-MS MS-ESI (m / z) 374.2 [M+H] + .

[0207] Example 7: Preparation of Compound I-7

[0208]

[0209] Yellow solid I-7 was prepared from intermediate I-7e (392.00 mg, 1.05 mmol, 1.0 eq), HATU (596.76 mg, 1.57 mmol, 1.5 eq), DIEA (406.98 mg, 3.15 mmol, 3.0 eq) and I-1f (113.55 mg, 1.05 mmol, 1.0 eq) according to the similar steps in Example I-1. (174.0 mg, yield 35.7%). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.63(d,J=5.0Hz,1H),8.44(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.08(d,J=8. 2Hz,1H),7.89(s,2H),7.66(t,J=7.6Hz,1H),7.57(d,J=9.0Hz,1H),7.43(s,1H),7.38(d,J=7. 6Hz,1H),7.28(d,J=9.0Hz,1H),7.00(t,J=7.3Hz,1H),6.83(d,J=7.8Hz,1H),6.65(t,J=7.3Hz ,1H),6.58(d,J=5.0Hz,1H),5.01(s,2H),4.87(dt,J=11.7,5.8Hz,1H),1.37(d,J=5.9Hz,6H).

[0210] Intermediate: Preparation of I-8c

[0211]

[0212] Yellow solid intermediate I-8c was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), Cs2CO3 (9.79 g, 30.06 mmol, 3.0 eq) and I-8b (4.27 g, 30.06 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.77 g, yield 91.2%). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0213] Intermediate: Preparation of I-8e

[0214]

[0215] The brown solid intermediate I-8e was prepared from homemade I-8c (1.00 g, 5.16 mmol, 1.0 eq), Cs2CO3 (5.55 g, 17.03 mmol, 3.3 eq) and commercially available I-1d (971.11 mg, 5.16 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (1.41 g, yield 79.2%). LC-MS MS-ESI (m / z) 346.1 [M+H] + .

[0216] Example 8: Preparation of Compound I-8

[0217]

[0218] Yellow solid I-8 was prepared from intermediate I-8e (104.0 mg, 0.30 mmol, 1.0 eq), HATU (171.10 mg, 0.45 mmol, 1.5 eq), DIEA (116.32 mg, 0.90 mmol, 3.0 eq) and I-8f (53.57 mg, 0.3 mmol, 1.0 eq) according to the similar steps in Example I-1. (42.00 mg, yield 27.67%). LC-MS MS-ESI (m / z) 506.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.98(s,1H),8.63(d,J=5.2Hz,1H),8.41(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.08(d,J=8.3Hz,1H),7.94(d,J=6.9Hz,1H),7.88(d,J=2.4Hz ,1H),7.69-7.61(m,1H),7.58-7.49(m,2H),7.43(d,J=2.5Hz,1H),7.30 (dd,J=9.1,2.5Hz,1H),6.57(d,J=5.2Hz,1H),5.57(s,2H),3.93(s,3H).

[0219] Intermediate: Preparation of I-9f-2

[0220]

[0221] I-9f-1 (8.0 g, 0.46 mol, 1.0 eq) and 4-dimethylaminopyridine (DMAP, 0.281 g, 2.29 mmol, 0.05 eq) were dissolved in THF (500 mL), cooled to 0 ° C with an ice bath, and NaH (60% in mineral oil, 3.68 g, 0.092 mol, 2.0 eq) was added. After warming to room temperature, di-tert-butyl dicarbonate (Boc2O, 25.07 g, 0.115 mol, 2.5 eq) was added dropwise, and stirred at room temperature for 18 hours. The reaction solution was quenched with ice / water (300 mL) and extracted twice with ethyl acetate (300.0 mL). The organic phases were combined, washed once with saturated brine (300 mL), and concentrated. The crude product was separated by a silica gel column (200-300 mesh silica gel, eluted with EA / PE = 1 / 15) to obtain a light yellow solid product I-9f-2. (15.2g, yield 88.4%). 1 H-NMR (400MHz, CDCl3) δppm7.97-7.93(m,1H),7.35-7.29(m,1H),1.43(s,18H).

[0222] Intermediate: Preparation of I-9f-3

[0223]

[0224] I-9f-2 (15.20 g, 40.63 mmol, 1.0 eq) was dissolved in isopropanol (iPrOH, 170 mL), Pd / C (2.0 g) was added, and the resulting mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration through diatomaceous earth and rinsed with isopropanol (10 mL) 3 times. The filtrate was concentrated to obtain a yellow solid product I-9f-3. (13.44 g, yield 96.1%). LC-MS MS-ESI (m / z) 345.1 [M+H] + .

[0225] Intermediate: Preparation of I-9f

[0226]

[0227] I-9f-3 (13.44 g, 39.02 mmol, 1.0 eq) was dissolved in methanol (MeOH, 150 mL), water (10 mL) and K2CO3 (15.00 g, 107.91 mmol, 2.77 eq) were added, heated to 60 ° C and stirred for 24 hours, and cooled to room temperature. The reaction solution was concentrated, the residue was diluted with water (200 mL), and extracted with ethyl acetate (200 mL) three times. The organic phases were combined, washed once with saturated brine (300 mL), and concentrated. The crude product was separated by silica gel column (200-300 mesh silica gel, EA / PE=1 / 2 elution) to obtain a light yellow solid product I-9f (9.41 g, yield 98.7%). LC-MS MS-ESI (m / z) 189.1 [M-55] + . 1 H-NMR (400MHz, CDCl3) δppm8.28(brs,1H),7.02-6.95(m,1H),6.46-6.43(m,1H),4.93(s,2H),1.43(s,9H).

[0228] Preparation of intermediate: I-9g

[0229]

[0230] The intermediate I-8e (200.00 mg, 0.58 mmol, 1.0 eq) was dissolved in ultra-dry THF (10 mL), and commercially available N-methylimidazole (NMI, 214.28 mg, 2.61 mmol, 4.5 eq), I-9f (212.45 mg, 0.87 mmol, 1.5 eq) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 243.60 mg, 0.87 mmol, 1.5 eq) were added, and stirred at room temperature for 24 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column (200-300 mesh silica gel, EA / PE=0-1 elution) to obtain yellow solid intermediate I-9g. (157.0 mg, yield 47.3%). LC-MS MS-ESI (m / z) 572.2 [M+H] + .

[0231] Example 9: Preparation of Compound I-9

[0232]

[0233] The intermediate I-9g (157.00 mg, 0.27 mmol, 1.0 eq) was dissolved in dichloromethane (DCM, 5 mL), trifluoroacetic acid (TFA, 1.5 mL) was added, and stirred at room temperature for 18 hours. The reaction was quenched with saturated sodium bicarbonate solution (100 mL), extracted twice with DCM, and the organic phases were combined and concentrated. The crude product was separated by silica gel column (200-300 mesh silica gel, EA / PE=0-1 elution) to obtain yellow solid I-9. (97.00 mg, yield 76.2%). LC-MS MS-ESI (m / z) 472.2 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.94(s,1H),8.63(d,J=5.2Hz,1H),8.41(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1 H),8.07(d,J=8.3Hz,1H),7.93(d,J=6.9Hz,1H),7.88(d,J=2.3Hz,1H),7.72-7 .60(m,1H),7.55(dd,J=9.2,2.4Hz,1H),7.43(d,J=2.4Hz,1H),7.30(dd,J=9. 1,2.5Hz,1H),7.26-7.15(m,1H),6.74-6.51(m,2H),5.36(s,2H),3.94(s,3H).

[0234] Example 10: Preparation of Compound I-10

[0235]

[0236] Yellow solid I-10 was prepared from intermediate I-8e (138.14 mg, 0.40 mmol, 1.0 eq), HATU (228.14 mg, 0.6 mmol, 1.5 eq), DIEA (155.0 mg, 1.2 mmol, 3.0 eq) and I-3f (97.27 mg, 0.60 mmol, 1.5 eq) according to the similar steps in Example I-1. (45.60 mg, yield 23.29%). LC-MS MS-ESI (m / z) 490.1 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),8.63(d,J=5.1Hz,1H),8.41(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.08(d,J=8.1Hz,1H),7.97-7.85(m,2H),7.65(t, J=7.5Hz,1H),7.59-7.46(m,2H),7.43(d,J=2.2Hz,1H),7.30(dd,J=9.1,2.2Hz,1H),6.58(d,J=5.1Hz,1H),5.24(s,2H),3.94(s,3H).

[0237] Intermediate: Preparation of I-11c

[0238]

[0239] Yellow solid intermediate I-11c was prepared from commercially available I-1a (1.80 g, 10.00 mmol, 1.0 eq), Cs2CO3 (4.15 g, 30.00 mmol, 3.0 eq) and I-11b (3.66 g, 30.00 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.65 g, yield 74.3%). LC-MS MS-ESI (m / z) 222.0 [M+H] + .

[0240] Intermediate: Preparation of I-11e

[0241]

[0242] The brown solid intermediate I-11e was prepared from the homemade intermediate I-11c (1.65 g, 7.44 mmol, 1.0 eq), Cs2CO3 (8.00 g, 24.55 mmol, 3.3 eq) and commercially available I-1d (1.40 g, 7.44 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (2.30 g, yield 82.8%). LC-MS MS-ESI (m / z) 374.1 [M+H] + .

[0243] Example 11: Preparation of Compound I-11

[0244]

[0245] Yellow solid I-11 was prepared from intermediate I-11e (1.30 g, 3.48 mmol, 1.0 eq), HATU (1.98 g, 5.22 mmol, 1.5 eq), DIEA (1.35 g, 10.44 mmol, 3.0 eq) and I-1f (376.19 mg, 3.48 mmol, 1.0 eq) according to the similar steps in Example I-1. (590.00 mg, yield 36.6%). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.88(s,1H),8.64(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H),8.08(d,J=8.2Hz,1H), 7.91-7.86(m,2H),7.66(t,J=7.7Hz,1H),7.57(dd,J=9.2,2.4Hz,1H),7.43(d,J=2.3Hz,1H),7.37(d,J= 7.7Hz,1H),7.31(dd,J=9.1,2.4Hz,1H),7.00(t,J=7.6Hz,1H),6.82(d,J=7.9Hz,1H),6.64(t,J=7.5Hz, 1H),6.59(d,J=5.2Hz,1H),5.00(s,2H),4.13(t,J=6.5Hz,2H),1.90-1.77(m,2H),1.05(t,J=7.4Hz,3H).

[0246] Example 12: Preparation of Compound I-12

[0247]

[0248] Yellow solid I-12 was prepared from intermediate I-11e (200.00 mg, 0.54 mmol, 1.0 eq), HATU (307.96 mg, 0.81 mmol, 1.5 eq), DIEA (209.14 mg, 1.62 mmol, 3.0 eq) and I-5f (136.19 mg, 1.08 mmol, 2.0 eq) according to the similar steps in Example I-1. (100.00 mg, yield 38.5%). LC-MS MS-ESI (m / z) 482.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.80(s,1H),8.64(d,J=5.2Hz,1H),8.44(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H),8. 07(d,J=8.3Hz,1H),7.93-7.88(m,2H),7.71-7.60(m,1H),7.57(dd,J=9.2,2.5Hz,1H ),7.43(d,J=2.4Hz,1H),7.37-7.26(m,2H),6.62-6.56(m,2H),6.42(td,J=8.5,2.8H z,1H),5.32(s,2H),4.13(t,J=6.5Hz,2H),1.90-1.76(m,2H),1.04(t,J=7.4Hz,3H).

[0249] Intermediate: Preparation of I-13c

[0250]

[0251] Yellow solid intermediate I-13c was prepared from commercially available I-1a (1.80 g, 10.00 mmol, 1.0 eq), Cs2CO3 (4.15 g, 30.00 mmol, 3.0 eq) and I-13b (4.11 g, 30.00 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.72 g, yield 73.0%). LC-MS MS-ESI (m / z) 236.1 [M+H] + .

[0252] Intermediate: Preparation of I-13e

[0253]

[0254] The brown solid intermediate I-13e was prepared from the homemade intermediate I-13c (705.00 mg, 3.00 mmol, 1.0 eq), Cs2CO3 (3.22 g, 9.90 mmol, 3.3 eq) and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (850.00 mg, yield 73.1%). LC-MS MS-ESI (m / z) 388.2 [M+H] + .

[0255] Example 13: Preparation of Compound I-13

[0256]

[0257] Yellow solid I-13 was prepared from intermediate I-13e (108.50 mg, 0.28 mmol, 1.0 eq), HATU (159.68 mg, 0.42 mmol, 1.5 eq), DIEA (108.53 mg, 0.84 mmol, 3.0 eq) and I-1f (30.27 mg, 0.28 mmol, 1.0 eq) according to the similar steps in Example I-1. (37.00 mg, yield 27.7%). LC-MS MS-ESI (m / z) 478.3 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.88(s,1H),8.63(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.08(d,J=8.3Hz,1H),7.91- 7.86(m,2H),7.70-7.63(m,1H),7.57(dd,J=9.2,2.4Hz,1H),7.43(d,J=2.4Hz,1H),7.37(d,J=7.4Hz,1H),7.30 (dd,J=9.1,2.4Hz,1H),7.00(t,J=7.1Hz,1H),6.82(d,J=7.5Hz,1H),6.64(t,J=7.2Hz,1H),6.59(d,J=5.2Hz,1 H), 5.00 (s, 2H), 4.17 (t, J = 6.4Hz, 2H), 1.88-1.73 (m, 2H), 1.51 (dq, J = 14.7, 7.4Hz, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0258] Example 14: Preparation of Compound I-14

[0259]

[0260] Yellow solid I-14 was prepared from intermediate I-13e (1.40 g, 3.61 mmol, 1.0 eq), HATU (2.06 g, 5.41 mmol, 1.5 eq), DIEA (1.40 g, 10.83 mmol, 3.0 eq) and I-5f (455.22 mg, 3.61 mmol, 1.0 eq) according to the similar steps in Example I-1. (1015.00 mg, yield 56.7%). LC-MS MS-ESI (m / z) 496.3 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.80(s,1H),8.63(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.07(d ,J=8.3Hz,1H),7.92-7.87(m,2H),7.69-7.62(m,1H),7.56(dd,J=9.2,2.5Hz,1H),7.43(d ,J=2.4Hz,1H),7.37-7.25(m,2H),6.67-6.51(m,2H),6.41(td,J=8.5,2.9Hz,1H),5.32(s ,2H),4.17(t,J=6.5Hz,2H),1.87-1.71(m,2H),1.61-1.44(m,2H),0.98(t,J=7.4Hz,3H).

[0261] Intermediate: Preparation of I-15g

[0262]

[0263] Yellow solid intermediate I-15g was prepared from intermediate I-1e (200.00 mg, 0.56 mmol, 1.0 eq), N-methylimidazole (206.89 mg, 2.52 mmol, 4.5 eq), I-15f (190.05 mg, 0.84 mmol, 1.5 eq), TCFH (235.70 mg, 0.84 mmol, 1.5 eq) and THF (10.0 mL) according to the similar steps in Example I-9g. (100.0 mg, yield 31.5%). LC-MS MS-ESI (m / z) 568.2 [M+H] + .

[0264] Example 15: Preparation of Compound I-15

[0265]

[0266] Yellow solid I-15 was prepared from intermediate I-15g (100.0 mg, 0.18 mmol, 1.0 eq), TFA (1.5 mL) and DCM (5.0 mL) according to the similar steps in Example I-9. (60.00 mg, yield 71.3%). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1H-NMR (400MHz, DMSO-d6) δppm 9.90(s,1H),8.61(d,J=5.2Hz,1H),8.41(d,J=9.2Hz,1H),8.21(d,J=9.1Hz,1H) ,8.07(d,J=8.2Hz,1H),7.92-7.82(m,2H),7.64(t,J=7.7Hz,1H),7.55(dd,J=9.2 ,2.4Hz,1H),7.42-7.35(m,2H),7.28(dd,J=9.1,2.4Hz,1H),6.88-6.76(m,2H), 6.56(d,J=5.2Hz,1H),4.91(s,2H),4.20(q,J=6.9Hz,2H),1.41(t,J=6.9Hz,3H).

[0267] Intermediate: Preparation of I-16g

[0268]

[0269] Yellow solid intermediate I-16g was prepared from intermediate I-1e (200.00 mg, 0.56 mmol, 1.0 eq), TCFH (235.70 mg, 0.84 mmol, 1.5 eq), NMI (206.89 mg, 2.52 mmol, 4.5 eq) and I-16f (190.05 mg, 0.84 mmol, 1.5 eq) according to the similar steps in the intermediate I-9g of the example. (100.00 mg, yield 31.5%). LC-MS MS-ESI (m / z) 568.2 [M+H] + .

[0270] Example 16: Preparation of Compound I-16

[0271]

[0272] Yellow solid I-16 was prepared from intermediate I-16g (100.00 mg, 0.18 mmol, 1.0 eq) and TFA (1.5 mL) according to the similar steps in Example I-9. (60.00 mg, yield 71.3%). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.64(d,J=5.2Hz,1H),8.42(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H),8.0 9(d,J=8.3Hz,1H),7.94-7.88(m,2H),7.67(t,J=7.7Hz,1H),7.58(dd,J=9.2,2.4Hz,1H ),7.43(d,J=2.4Hz,1H),7.34-7.26(m,2H),7.07-6.91(m,1H),6.65(dd,J=14.0,8.0Hz ,1H),6.59(d,J=5.2Hz,1H),4.99(s,2H),4.23(q,J=6.9Hz,2H),1.43(t,J=6.9Hz,3H).

[0273] Intermediate: Preparation of I-17a-3

[0274]

[0275] Dissolve the commercially available I-17a-2 (51.10 g, 354.60 mmol, 1.0 eq) in trimethylorthoformate (300.0 mL), replace nitrogen 3 times, heat to 105 ° C, stir for 1 hour, add I-17a-1 (50.00 g, 354.60 mmol), continue to stir at this temperature for 1 hour, and cool to room temperature. Add n-pentane (300 mL), filter and collect the precipitated solid, rinse with n-pentane (30 mL) 3 times, and dry in a 50 ° C forced air drying oven for 8 hours to obtain a yellow solid intermediate I-17a-3. (86.00 g, yield 82.2%). LC-MS MS-ESI (m / z) 296.1 [M+H] + .

[0276] Intermediate: Preparation of I-17a-4

[0277]

[0278] Heat a mixture of I-17a-3 (60.00 g, 203.30 mmol, 1.0 eq) and diphenyl ether (500 mL) to 220 ° C, stir for 1 hour, and cool to room temperature. Add petroleum ether (500 mL), filter and collect the precipitated solid, rinse with petroleum ether (50 mL) 3 times, and dry. The crude product was separated by a reverse phase C18 column (acetonitrile / water / 0.1% TFA, 12-13%) to obtain a white solid I-17a-4. (18.00 g, yield 46.0%). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0279] Intermediate: Preparation of I-17a-5

[0280]

[0281] A mixture of intermediate I-17a-4 (18.00 g, 93.30 mmol, 1.0 eq) and phosphorus oxychloride (50 mL) was heated to 110 ° C, stirred for 3 hours, and cooled to room temperature. The reaction solution was slowly added to ice / water to quench, and the pH was adjusted to 6-7 with 10% NaOH solution. The precipitated solid was collected by filtration, rinsed with water (10 mL) 3 times, and dried. The crude product was separated by silica gel column (200-300 mesh silica gel, EA / PE=1:1 elution) to obtain yellow solid intermediate I-17a-5. (16.10 g, yield 81.8%). LC-MS MS-ESI (m / z) 212.0 [M+H] + .

[0282] Intermediate: Preparation of I-17a

[0283]

[0284] The intermediate I-17a-5 (12.00 g, 87.60 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (DCE, 100.0 mL), cooled to 0 ° C, and a 1.0 M dichloromethane solution of boron tribromide (198.80 mL, 198.80 mmol, 2.27 eq) was added dropwise. After the addition, the mixture was heated to 100 ° C, stirred for 8 hours, and cooled to room temperature. Methanol (100 mL) was slowly added to quench the reaction, water (300 mL) was added, and the pH was adjusted to 12-13 with a 10% NaOH solution. The organic phase and the aqueous phase were separated, and the pH of the aqueous phase was adjusted to 5-6 with 2M dilute hydrochloric acid. The precipitated solid was collected by filtration, rinsed with water (10.0 mL) 3 times, and dried in a blast drying oven at 50 ° C for 8 hours to obtain a yellow solid intermediate I-17a. (9.10 g, yield 80.2%). LC-MS MS-ESI (m / z) 198.0 [M+H] + .1 H-NMR (400MHz, DMSO-d6) δppm 10.82 (s, 1H), 8.67 (d, J = 4.8Hz, 1H), 7.48 (d, J = 4.8Hz, 1H), 7.19 (s, 1H), 7.08 (dd, J = 14.0, 2.3Hz, 1H).

[0285] Intermediate: Preparation of I-17c

[0286]

[0287] The light yellow solid intermediate I-17c was prepared from intermediate I-17a (800.00 mg, 4.05 mmol, 1.0 eq), Cs2CO3 (3.96 g, 12.15 mmol, 3.0 eq) and I-1b (1.32 g, 12.15 mmol, 3.0 eq) according to the similar steps of intermediate I-1c in the example. (810.00 mg, yield 88.7%). LC-MS MS-ESI (m / z) 226.0 [M+H] + .

[0288] Intermediate: Preparation of I-17e

[0289]

[0290] The brown solid intermediate I-17e was prepared from intermediate I-17c (450.00 mg, 2.00 mmol, 1.0 eq), Cs2CO3 (2.15 g, 6.60 mmol, 3.3 eq) and commercially available I-1d (376.40 mg, 2.00 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (640.00 mg, yield 84.8%). LC-MS MS-ESI (m / z) 378.2 [M+H] + .

[0291] Example 17: Preparation of Compound I-17

[0292]

[0293] Yellow solid I-17 was prepared from intermediate I-17e (340.00 mg, 0.90 mmol, 1.0 eq), HATU (513.57 mg, 1.35 mmol, 1.5 eq), DIEA (348.69 mg, 2.70 mmol, 3.0 eq) and I-1f (97.31 mg, 0.90 mmol, 1.0 eq) according to the similar steps in Example I-1. (99.00 mg, yield 23.5%). LC-MS MS-ESI (m / z) 467.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.86(s,1H),8.63(d,J=5.0Hz,1H),8.41(d,J=9.1Hz,1H),8.04(d,J=8.1Hz,1H),7.8 5(d,J=6.7Hz,1H),7.81(s,1H),7.63(t,J=7.5Hz,1H),7.54(d,J=8.6Hz,1H),7.35(d, J=7.5Hz,1H),7.29(s,1H),7.12(d,J=13.2Hz,1H),6.98(t,J=7.2Hz,1H),6.80(d,J= 7.7Hz,1H),6.71-6.52(m,2H),4.98(s,2H),4.33-4.12(m,2H),1.40(t,J=6.7Hz,3H).

[0294] Example 18: Preparation of Compound I-18

[0295]

[0296] Yellow solid I-18 was prepared from intermediate I-17e (340.00 mg, 0.90 mmol, 1.0 eq), HATU (513.57 mg, 1.35 mmol, 1.5 eq), DIEA (348.69 mg, 2.70 mmol, 3.0 eq) and I-18f (113.53 mg, 0.90 mmol, 1.0 eq) according to the similar steps in Example I-1. (282.00 mg, yield 64.5%). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1H-NMR (400MHz, DMSO-d6) δppm 10.03(s,1H),8.65(d,J=5.0Hz,1H),8.41(d,J=9.1Hz,1H),8.08(d,J=8.0Hz ,1H),7.90(d,J=6.6Hz,1H),7.83(s,1H),7.66(t,J=7.4Hz,1H),7.56(d,J=9 .0Hz,1H),7.38-7.23(m,2H),7.14(d,J=13.3Hz,1H),7.06-6.91(m,1H),6.6 5(d,J=4.9Hz,2H),4.99(s,2H),4.24(q,J=6.9Hz,2H),1.42(t,J=6.7Hz,3H).

[0297] Example 19: Preparation of Compound I-19

[0298]

[0299] Yellow solid I-19 was prepared from intermediate I-17e (340.00 mg, 0.90 mmol, 1.0 eq), HATU (513.57 mg, 1.35 mmol, 1.5 eq), DIEA (348.69 mg, 2.70 mmol, 3.0 eq) and I-6f (129.60 mg, 0.90 mmol, 1.0 eq) according to the similar steps in Example I-1. (164.00 mg, yield 36.2%). LC-MS MS-ESI (m / z) 504.2 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.95(s,1H),8.66(d,J=5.2Hz,1H),8.42(d,J=9.2Hz,1H),8.07(d,J=8.2Hz, 1H),7.94(d,J=7.0Hz,1H),7.83(s,1H),7.66(t,J=7.6Hz,1H),7.55(dd,J=9. 2,2.0Hz,1H),7.31(s,1H),7.28-7.18(m,1H),7.14(dd,J=13.4,1.9Hz,1H), 6.69-6.58(m,2H),5.37(s,2H),4.24(q,J=6.9Hz,2H),1.42(t,J=6.9Hz,3H).

[0300] Preparation of Intermediate: I-20g

[0301]

[0302] Yellow solid intermediate I-20g was prepared from intermediate I-17e (340.00 mg, 0.90 mmol, 1.0 eq), TCFH (378.00 mg, 1.35 mmol, 1.5 eq), NMI (332.50 mg, 4.05 mmol, 4.5 eq) and I-15f (203.58 mg, 0.90 mmol, 1.0 eq) according to the similar steps in Example I-9g. (152.00 mg, yield 28.8%). LC-MSMS-ESI (m / z) 586.2 [M+H] + .

[0303] Example 20: Preparation of Compound I-20

[0304]

[0305] Yellow solid I-20 was prepared from intermediate I-20g (152.0 mg, 0.26 mmol, 1.0 eq) and TFA (1.5 mL) according to the similar steps in Example I-9. (32.00 mg, yield 25.3%). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 9.93(s,1H),8.66(d,J=5.2Hz,1H),8.42(d,J=9.2Hz,1H),8.07(d,J=8.2Hz,1 H),7.87(d,J=6.9Hz,1H),7.83(s,1H),7.66(t,J=7.7Hz,1H),7.60-7.51(m,1H ),7.40(d,J=8.1Hz,1H),7.31(s,1H),7.20-7.08(m,1H),6.92-6.75(m,2H),6. 66(d,J=5.2Hz,1H),4.93(s,2H),4.24(q,J=6.9Hz,2H),1.42(t,J=6.9Hz,3H).

[0306] Intermediate: Preparation of I-21b

[0307]

[0308] The commercially available I-21b-1 (3.0 g, 24.01 mmol, 1.0 eq) was dissolved in DCM / H2O (30 mL / 30 mL), KOAc (14.50 g, 148.00 mmol, 6.16 eq) was added, and after cooling to 0°C with an ice / salt bath, I-21b-2 (15 mL, 96.45 mmol, 4.0 eq) was added dropwise, the ice / salt bath was removed, and the mixture was stirred at room temperature for 18 hours. The reaction solution was quenched with saturated NaHCO3 solution (100 mL) and extracted twice with DCM (50 mL). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure below 5°C to obtain the yellow oily intermediate I-21b. (1.10 g, yield 26.2%). LC-MS MS-ESI (m / z) 175.0 [M+H] + .

[0309] Intermediate: Preparation of I-21c

[0310]

[0311] Yellow solid intermediate I-21c was prepared from commercially available I-1a (2.0 g, 11.13 mmol, 1.0 eq), Cs2CO3 (10.88 g, 33.39 mmol, 3.0 eq) and homemade intermediate I-21b (2.92 g, 16.69 mmol, 1.5 eq) according to the similar steps in the intermediate I-1c in the example. (2.46 g, yield 80.7%). LC-MS MS-ESI (m / z) 274.0 [M+H] + .

[0312] Intermediate: Preparation of I-21e

[0313]

[0314] The brown solid intermediate I-21e was prepared from intermediate I-21c (2.46 g, 8.99 mmol, 1.0 eq), Cs2CO3 (9.67 g, 29.67 mmol, 3.3 eq) and commercially available I-1d (1.69 g, 8.99 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (3.42 g, yield 89.4%). LC-MS MS-ESI (m / z) 426.1 [M+H] + .

[0315] Example 21: Preparation of Compound I-21

[0316]

[0317] Yellow solid I-21 was prepared from intermediate I-21e (1.27 g, 2.98 mmol, 1.0 eq), HATU (1.70 g, 4.47 mmol, 1.5 eq), DIEA (1.54 g, 11.92 mmol, 4.0 eq) and I-21f (427.93 mg, 2.98 mmol, 1.0 eq) according to the similar steps in Example I-1. (514.00 mg, yield 33.4%). LC-MS MS-ESI (m / z) 515.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.05(d,J=6.5Hz,1H),8.62(d,J=5.2Hz,1H),8.35(d,J=9.2Hz,1H),8.23(d,J=9.1Hz,1H),8.03(d,J=8.1Hz,1H),7.85(d,J=2.4Hz,1 H),7.66(d,J=6.3Hz,1H),7.63-7.56(m,1H),7.53(dd,J=9.2,2.5Hz,1H),7.46(d,J=2.4Hz,1H),7.32(dd,J=9.1,2.4Hz,1H),6.78(t, 2 J F-H =75.7Hz,1H),6.57(d,J=5.2Hz,1H),4.49-4.28(m,3H),4.28-4.18(m,2H),3.12-2.88(m,2H),2.85-2.66(m,2H).

[0318] Example 22: Preparation of Compound I-22

[0319]

[0320] Yellow solid I-22 was prepared from intermediate I-21e (1.27 g, 2.98 mmol, 1.0 eq), HATU (1.70 g, 4.47 mmol, 1.5 eq), DIEA (1.15 g, 8.94 mmol, 3.0 eq) and I-6f (429.42 mg, 2.98 mmol, 1.0 eq) according to the similar steps in Example I-1. (596.00 mg, yield 36.3%). LC-MS MS-ESI (m / z) 552.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.66(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.27(d,J=9.2Hz,1H),8.09(d,J=8.3Hz,1H),7.96(d,J=7.0Hz,1H),7.91(d,J= 2.4Hz,1H),7.75-7.63(m,1H),7.58(dd,J=9.2,2.5Hz,1H),7.49(d,J=2.5Hz,1H),7.35(dd,J=9.2,2.5Hz,1H),7.30-7.16(m,1H),6.81(t, 2 J F-H =75.7Hz,1H),6.70-6.55(m,2H),5.38(s,2H),4.40(dd,J=5.4,2.9Hz,2H),4.27(dd,J=5.2,3.0Hz,2H).

[0321] Intermediate: Preparation of I-23c

[0322]

[0323] Yellow solid intermediate I-23c was prepared from commercially available I-1a (2.0 g, 11.13 mmol, 1.0 eq), Cs2CO3 (10.88 g, 33.39 mmol, 3.0 eq) and commercially available I-23b (4.64 g, 33.39 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (2.10 g, yield 79.4%). LC-MS MS-ESI (m / z) 238.1 [M+H] + .

[0324] Intermediate: Preparation of I-23e

[0325]

[0326] The brown solid intermediate I-23e was prepared from intermediate I-23c (2.10 g, 8.83 mmol, 1.0 eq), Cs2CO3 (9.50 g, 29.14 mmol, 3.3 eq) and commercially available I-1d (1.66 g, 8.83 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (3.12 g, yield 90.7%). LC-MS MS-ESI (m / z) 390.1 [M+H] + .

[0327] Example 23: Preparation of Compound I-23

[0328]

[0329] Yellow solid I-23 was prepared from intermediate I-23e (1.50 g, 3.85 mmol, 1.0 eq), HATU (2.19 g, 5.77 mmol, 1.5 eq), DIEA (1.99 g, 15.40 mmol, 4.0 eq) and I-21f (552.86 mg, 3.85 mmol, 1.0 eq) according to the similar steps in Example I-1. (385.00 mg, yield 20.9%). LC-MS MS-ESI (m / z) 479.2 [M+H] + . 1 H-NMR (400MHz, CDCl3) δppm8.62(d,J=5.2Hz,1H),8.47(d,J=9.2Hz,1H),8.29(d,J=9.2 Hz,1H),7.91(d,J=8.4Hz,1H),7.67-7.61(m,2H),7.53(t,J=7.7Hz,1H),7.48-7.41(m, 2H),7.33(d,J=9.2Hz,1H),6.51(d,J=5.2Hz,1H),6.31(d,J=6.8Hz,1H),4.62(s,1H),4 .37-4.29(m,2H),3.92-3.82(m,2H),3.52(s,3H),3.27-3.14(m,2H),2.73-2.60(m,2H).

[0330] Example 24: Preparation of Compound I-24

[0331]

[0332] Yellow solid I-24 was prepared from intermediate I-23e (155.76 mg, 0.40 mmol, 1.0 eq), HATU (228.14 mg, 0.6 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-24f (59.85 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (85.00 mg, yield 43.8%). LC-MS MS-ESI (m / z) 485.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 8.82(d,J=7.3Hz,1H),8.64(d,J=5.2Hz,1H),8.33(d,J=9.2Hz,1H),8.25(d,J=9.1Hz,1H),8 .05-8.00(m,1H),7.87(d,J=2.4Hz,1H),7.63-7.59(m,2H),7.55(dd,J=9.2,2.5Hz,1H),7.47 (d,J=2.4Hz,1H),7.34(dd,J=9.1,2.4Hz,1H),6.58(d,J=5.2Hz,1H),4.67(s,2H),4.53(s,2 H),4.40-4.21(m,3H),3.79-3.74(m,2H),3.37(s,3H),2.71-2.59(m,2H),2.33-2.22(m,2H).

[0333] Example 25: Preparation of Compound I-25

[0334]

[0335] Yellow solid I-25 was prepared from intermediate I-23e (155.76 mg, 0.40 mmol, 1.0 eq), HATU (228.14 mg, 0.6 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-25f (44.47 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (93.00 mg, yield 48.2%). LC-MS MS-ESI (m / z) 483.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 8.78(d,J=6.8Hz,1H),8.64(d,J=4.5Hz,1H),8.32(d,J=8.8Hz,1H),8.25(d,J=8 .9Hz,1H),8.02(s,1H),7.86(s,1H),7.66-7.50(m,3H),7.46(s,1H),7.33(d,J=8 .1Hz,1H),6.58(d,J=4.5Hz,1H),4.46-4.19(m,3H),3.84-3.72(m,2H),3.36(s, 3H),2.45-2.35(m,2H),2.13-2.00(m,4H),1.98-1.88(m,2H),1.87-1.76(m,2H).

[0336] Example 26: Preparation of Compound I-26

[0337]

[0338] Yellow solid I-26 was prepared from intermediate I-23e (150.00 mg, 0.39 mmol, 1.0 eq), HATU (220.40 mg, 0.58 mmol, 1.5 eq), DIEA (201.24 mg, 1.56 mmol, 4.0 eq) and I-26f (38.69 mg, 0.39 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 21.8%). LC-MS MS-ESI (m / z) 471.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 8.64(d,J=5.1Hz,1H),8.49(d,J=7.9Hz,1H),8.32(d,J=9.2Hz,1H),8.25(d,J=9.1Hz,1H),8.01(d ,J=6.9Hz,1H),7.86(d,J=2.1Hz,1H),7.64-7.51(m,3H),7.47(d,J=2.0Hz,1H),7.34(dd,J=9.1,2 .1Hz,1H),6.58(d,J=5.1Hz,1H),4.39-4.25(m,2H),3.86(s,1H),3.82-3.72(m,2H),3.37(s,3H), 2.00-1.89(m,2H),1.85-173(m,2H),1.63(d,J=12.1Hz,1H),1.45-1.26(m,4H),1.23-1.09(s,1H).

[0339] Example 27: Preparation of Compound I-27

[0340]

[0341] Yellow solid I-27 was prepared from intermediate I-23e (150.00 mg, 0.39 mmol, 1.0 eq), HATU (220.40 mg, 0.58 mmol, 1.5 eq), DIEA (201.24 mg, 1.56 mmol, 4.0 eq) and I-27f (34.75 mg, 0.39 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 22.3%). LC-MS MS-ESI (m / z) 461.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 8.96(d,J=6.9Hz,1H),8.64(d,J=5.2Hz,1H),8.34(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H),8 .03(d,J=7.9Hz,1H),7.87(d,J=2.3Hz,1H),7.69-7.58(m,2H),7.54(dd,J=9.2,2.4Hz,1H),7 .46(d,J=2.3Hz,1H),7.33(dd,J=9.1,2.4Hz,1H),6.58(d,J=5.2Hz,1H),5.41-5.15(m,1H), 4.64(d,J=3.7Hz,1H),4.36-4.25(m,2H),3.80-3.71(m,2H),3.35(s,3H),2.64-2.43(m,4H).

[0342] Intermediate: Preparation of I-28c

[0343]

[0344] The light yellow solid intermediate I-28c was prepared from intermediate I-17a (394.00 mg, 2.00 mmol, 1.0 eq), Cs2CO3 (1.96 g, 6.00 mmol, 3.0 eq) and homemade intermediate I-21b (1.05 g, 6.00 mmol, 3.0 eq) according to the similar steps of intermediate I-1c in the example. (541.00 mg, yield 92.8%). LC-MS MS-ESI (m / z) 292.0 [M+H] + .

[0345] Intermediate: Preparation of I-28e

[0346]

[0347] The brown solid intermediate I-28e was prepared from intermediate I-28c (541.00 mg, 1.86 mmol, 1.0 eq), Cs2CO3 (2.00 g, 6.14 mmol, 3.3 eq) and commercially available I-1d (349.68 mg, 1.86 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (702.00 mg, yield 85.1%). LC-MS MS-ESI (m / z) 444.1 [M+H] + .

[0348] Example 28: Preparation of Compound I-28

[0349]

[0350] Yellow solid I-28 was prepared from intermediate I-28e (640.00 mg, 1.44 mmol, 1.0 eq), HATU (820.60 mg, 2.16 mmol, 1.5 eq), DIEA (557.28 mg, 4.32 mmol, 3.0 eq) and I-18f (181.58 mg, 1.44 mmol, 1.0 eq) according to the similar steps in Example I-1. (259.00 mg, yield 32.6%). LC-MS MS-ESI (m / z) 552.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.68(d,J=4.9Hz,1H),8.42(d,J=9.1Hz,1H),8.09(d,J=7.9Hz,1H),7.91(d,J=6.7Hz,1H),7.85(s,1H),7.67(t ,J=7.5Hz,1H),7.58(d,J=8.7Hz,1H),7.38(s,1H),7.30(d,J=7.7Hz,1H),7.21(d,J=13.0Hz,1H),7.02-6.94(m,1H),6.80(t, 2 J F-H =72.0Hz,1H),6.73-6.63(m,2H),5.00(s,2H),4.48-4.38(m,2H),4.31-4.22(m,2H).

[0351] Example 29: Preparation of Compound I-29

[0352]

[0353] Yellow solid I-29 was prepared from intermediate I-28e (443.00 mg, 1.00 mmol, 1.0 eq), HATU (570.00 mg, 1.50 mmol, 1.5 eq), DIEA (516.00 mg, 4.0 mmol, 4.0 eq) and I-21f (143.56 mg, 1.0 mmol, 1.0 eq) according to the similar steps in Example I-1. (182.00 mg, yield 34.2%). LC-MS MS-ESI (m / z) 533.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.06(d,J=6.4Hz,1H),8.66(d,J=5.1Hz,1H),8.36(d,J=9.2Hz,1H),8.03(d,J=7.9Hz,1H),7.81(s,1H),7. 67(d,J=6.8Hz,1H),7.64-7.57(m,1H),7.53(d,J=9.2Hz,1H),7.37(s,1H),7.20(d,J=13.2Hz,1H),6.79(t, 2 J F-H =75.7Hz,1H),6.65(d,J=5.1Hz,1H),4.52-4.31(m,3H),4.25(s,2H),3.15-2.95(m,2H),2.90-2.67(m,2H).

[0354] Example 30: Preparation of Compound I-30

[0355]

[0356] Yellow solid I-30 was prepared from intermediate I-3e (1.60 g, 4.24 mmol, 1.0 eq), HATU (2.42 g, 6.36 mmol, 1.5 eq), DIEA (1.64 g, 12.72 mmol, 3.0 eq) and I-1f (458.34 mg, 4.24 mmol, 1.0 eq) according to the similar steps in Example I-1. (1.20 g, yield 60.5%). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.88(s,1H),8.65(d,J=5.2Hz,1H),8.45(d,J=9.2Hz,1H),8.27(d,J=9.1Hz,1H),8.08(d,J=8.3Hz ,1H),7.89(t,J=4.5Hz,2H),7.71-7.62(m,1H),7.58(dd,J=9.2,2.5Hz,1H),7.48(t,J=9.4Hz,1H), 7.42-7.29(m,2H),7.05-6.96(m,1H),6.85-6.80(m,1H),6.68-6.62(m,1H),6.61(d,J=5.2Hz,1H), 5.00(s,2H),4.94-4.87(m,1H),4.79(dd,J=4.5,2.9Hz,1H),4.52-4.46(m,1H),4.47-4.37(m,1H).

[0357] Example 31: Preparation of Compound I-31

[0358]

[0359] Yellow solid I-31 was prepared from intermediate I-3e (250.00 mg, 0.66 mmol, 1.0 eq), HATU (376.20 mg, 0.99 mmol, 1.5 eq), DIEA (255.42 mg, 1.98 mmol, 3.0 eq) and I-18f (83.23 mg, 0.66 mmol, 1.0 eq) according to the similar steps in Example I-1. (187.00 mg, yield 58.1%). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 10.04(s,1H),8.66(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.27(d,J=9.1Hz,1H),8.10(d,J=8.3Hz ,1H),7.95-7.87(m,2H),7.73-7.62(m,1H),7.59(dd,J=9.2,2.5Hz,1H),7.49(d,J=2.5Hz,1H),7.3 6(dd,J=9.1,2.5Hz,1H),7.29(d,J=8.0Hz,1H),7.05-6.95(m,1H),6.70-6.63(m,1H),6.61(d,J=5. 2Hz,1H),4.99(s,2H),4.93-4.88(m,1H),4.83-4.75(m,1H),4.53-4.47(m,1H),4.45-4.37(m,1H).

[0360] Example 32: Preparation of Compound I-32

[0361]

[0362] Yellow solid I-32 was prepared from intermediate I-3e (200.00 mg, 0.53 mmol, 1.0 eq), HATU (302.10 mg, 0.79 mmol, 1.5 eq), DIEA (205.11 mg, 1.59 mmol, 3.0 eq) and I-6f (76.37 mg, 0.53 mmol, 1.0 eq) according to the similar steps in Example I-1. (80.00 mg, yield 30.0%). LC-MS MS-ESI (m / z) 504.2 [M+H] +. 1 H-NMR(400MHz,DMSO-d6)δppm 9.93(s,1H),8.63(d,J=5.2Hz,1H),8.41(d,J=9.2Hz,1H),8.25(d,J=9.1Hz,1H),8.07(d,J=8 .3Hz,1H),7.93(d,J=7.0Hz,1H),7.89(d,J=2.3Hz,1H),7.69-7.62(m,1H),7.56(dd,J=9.2,2. 4Hz,1H),7.47(d,J=2.4Hz,1H),7.34(dd,J=9.1,2.5Hz,1H),7.26-7.15(m,1H),6.66-6.54(m, 2H),5.35(s,2H),4.92-4.83(m,1H),4.82-4.70(m,1H),4.54-4.45(m,1H),4.43-4.32(m,1H).

[0363] Example 33: Preparation of Compound I-33

[0364]

[0365] Yellow solid I-33 was prepared from intermediate I-3e (150.95 mg, 0.4 mmol, 1.0 eq), HATU (228.14 mg, 0.6 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-21f (57.42 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (66.00 mg, yield 35.3%). LC-MS MS-ESI (m / z) 467.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.09(d,J=6.6Hz,1H),8.66(d,J=5.2Hz,1H),8.38(d,J=9.2Hz,1H),8.27(d,J=9.1Hz,1H ),8.06(d,J=8.2Hz,1H),7.89(d,J=2.5Hz,1H),7.71-7.67(m,1H),7.66-7.60(m,1H),7. 57(dd,J=9.2,2.5Hz,1H),7.50(d,J=2.4Hz,1H),7.37(dd,J=9.2,2.5Hz,1H),6.60(d,J= 5.2Hz,1H),4.97-4.74(m,2H),4.54-4.31(m,3H),3.13-2.94(m,2H),2.85-2.70(m,2H).

[0366] Example 34: Preparation of Compound I-34

[0367]

[0368] Yellow solid I-34 was prepared from intermediate I-3e (150.95 mg, 0.4 mmol, 1.0 eq), HATU (228.14 mg, 0.60 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-34f (53.45 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (57.00 mg, yield 31.2%). LC-MS MS-ESI (m / z) 457.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 8.96(d,J=7.2Hz,1H),8.66(d,J=5.1Hz,1H),8.35(d,J=9.2Hz,1H),8.28(d,J=9.1Hz,1H), 8.04(d,J=7.7Hz,1H),7.88(d,J=2.1Hz,1H),7.69-7.58(m,2H),7.56(dd,J=9.2,2.2Hz,1H ),7.50(d,J=2.0Hz,1H),7.37(dd,J=9.1,2.2Hz,1H),6.60(d,J=5.2Hz,1H),4.86(d,J=47. 8Hz,2H),4.75-4.65(m,1H),4.47(d,J=30.3Hz,2H),2.46-2.28(m,4H),0.57-0.40(m,4H).

[0369] Example 35: Preparation of Compound I-35

[0370]

[0371] Yellow solid I-35 was prepared from intermediate I-3e (150.95 mg, 0.4 mmol, 1.0 eq), HATU (228.14 mg, 0.60 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-26f (39.68 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 21.8%). LC-MS MS-ESI (m / z) 459.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 8.64(d,J=5.1Hz,1H),8.49(d,J=7.9Hz,1H),8.29(dd,J=19.6,9.2Hz,2H),8.00(d,J=5.2Hz,1H),7.86(d,J=1.7Hz,1H),7.63 -7.51(m,3H),7.48(s,1H),7.35(dd,J=9.1,1.9Hz,1H),6.57(d,J=5.1Hz,1H),4.85(d,J=47.9Hz,2H),4.46(d,J=30. 2Hz,2H),3.86(s,1H),1.96-1.87(m,2H),1.81-1.70(m,2H),1.65-1.57(m,1H),1.42-1.26(m,4H),1.20-1.08(m,1H).

[0372] Intermediate: Preparation of I-36e

[0373]

[0374] The brown solid intermediate I-36e was prepared from the intermediate I-17a-5 (800.00 mg, 3.78 mmol, 1.0 eq), Cs2CO3 (4.07 g, 12.47 mmol, 3.3 eq) and commercially available I-1d (710.64 mg, 3.78 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (1.00 g, yield 72.8%). LC-MS MS-ESI (m / z) 364.1 [M+H] + .

[0375] Example 36: Preparation of Compound I-36

[0376]

[0377] Yellow solid I-36 was prepared from intermediate I-36e (200.00 mg, 0.55 mmol, 1.0 eq), HATU (313.50 mg, 0.82 mmol, 1.5 eq), DIEA (212.85 mg, 1.65 mmol, 3.0 eq) and commercially available I-36f (131.70 mg, 0.82 mmol, 1.5 eq) according to the similar steps in Example I-1. (120.00 mg, yield 43.1%). LC-MS MS-ESI (m / z) 506.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.93(s,1H),8.66(d,J=4.7Hz,1H),8.44(d,J=9.0Hz,1H),8.07(d,J=7.9Hz,1H),7.96(d,J=6.6Hz,1H),7.83(s,1H),7.66(t, J=7.3Hz,1H),7.55(d,J=8.7Hz,1H),7.45-7.30(m,2H),7.16(d,J=13.2Hz,1H),6.72-6.60(m,2H),5.55(s,2H),3.96(s,3H).

[0378] Intermediate: Preparation of I-37g

[0379]

[0380] Yellow solid intermediate I-37g was prepared from intermediate I-36e (700.00 mg, 1.93 mmol, 1.0 eq), NMI (712.63 mg, 8.68 mmol, 4.5 eq), I-9f (705.74 mg, 2.89 mmol, 1.5 eq), TCFH (809.20 mg, 2.89 mmol, 1.5 eq) and THF (20.0 mL) according to the similar steps in Example I-9g. (462.00 mg, yield 40.6%). LC-MS MS-ESI (m / z) 590.2 [M+H] + .

[0381] Example 37: Preparation of Compound I-37

[0382]

[0383] Yellow solid I-37 was prepared from intermediate I-37g (462.00 mg, 0.78 mmol, 1.0 eq), TFA (6 mL) and DCM (20 mL) according to the similar steps in Example I-9. (263.0 mg, yield 68.9%). LC-MS MS-ESI (m / z) 490.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.95(s,1H),8.67(d,J=5.3Hz,1H),8.42(d,J=9.2Hz,1H),8.08(d,J=8.2 Hz,1H),7.94(d,J=6.8Hz,1H),7.84(d,J=2.4Hz,1H),7.76-7.60(m,1H), 7.56(dd,J=9.2,2.5Hz,1H),7.34(d,J=2.2Hz,1H),7.27-7.19(m,1H),7. 17(dd,J=13.4,2.4Hz,1H),6.77-6.51(m,2H),5.37(s,2H),3.96(s,3H).

[0384] Intermediate: Preparation of I-38c

[0385]

[0386] The light yellow solid intermediate I-38c was prepared from intermediate I-17a (396.00 mg, 2.00 mmol, 1.0 eq), Cs2CO3 (1.95 g, 6.00 mmol, 3.0 eq) and I-30b (1.04 g, 6.00 mmol, 3.0 eq) according to the similar steps of intermediate I-1c in the example. (460.00 mg, yield 94.4%). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0387] Intermediate: Preparation of I-38e

[0388]

[0389] The brown solid intermediate I-38e was prepared from intermediate I-38c (460.00 mg, 1.89 mmol, 1.0 eq), Cs2CO3 (2.03 g, 6.24 mmol, 3.3 eq) and commercially available I-1d (355.70 mg, 1.89 mmol, 1.0 eq) according to the similar steps of intermediate I-1e in the example. (680.00 mg, yield 91.0%). LC-MS MS-ESI (m / z) 396.1 [M+H]+ .

[0390] Example 38: Preparation of Compound I-38

[0391]

[0392] Yellow solid I-38 was prepared from intermediate I-38e (680.00 mg, 1.72 mmol, 1.0 eq), HATU (980.40 mg, 2.58 mmol, 1.5 eq), DIEA (665.64 mg, 5.16 mmol, 3.0 eq) and commercially available I-6f (247.85 mg, 1.72 mmol, 1.0 eq) according to the similar steps in Example I-1. (396.00 mg, yield 44.1%). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.67(d,J=5.2Hz,1H),8.42(d,J=9.2Hz,1H),8.08(d,J=8.3Hz,1H),7.94(d,J=7.0Hz,1H),7.84(d,J=2.3Hz,1H),7.71 -7.62(m,1H),7.56(dd,J=9.2,2.5Hz,1H),7.38(d,J=2.1Hz,1H),7.26-7.18( m,2H),6.71-6.57(m,2H),5.37(s,2H),4.94-4.71(m,2H),4.55-4.38(m,2H).

[0393] Intermediate: Preparation of I-39a-3

[0394]

[0395] I-39a-1 (10.00 g, 70.85 mmol, 1.0 eq) was dissolved in isopropanol (200 mL), and I-39a-2 (15.80 g, 84.87 mmol, 1.2 eq) was added. The resulting mixture was heated to 70°C and stirred for 2 hours. After cooling to room temperature, n-pentane (200 mL) was added, and the precipitated solid was collected by filtration, washed with isopropanol / n-pentane (1:1, 10 mL) 3 times, and dried in a 50°C forced air drying oven for 8 hours to obtain a white solid intermediate I-39a-3. (17.0 g, yield 81.2%). LC-MS MS-ESI (m / z) 296.1 [M+H] + .

[0396] Intermediate: Preparation of I-39a-4

[0397]

[0398] White solid intermediate I-39a-4 was prepared from intermediate I-39a-3 (12.00 g, 40.64 mmol, 1.0 eq) and diphenyl ether (300 mL) according to the similar steps in Example I-17a-4. (5.50 g, yield 70.0%). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0399] Intermediate: Preparation of I-39a-5

[0400]

[0401] White solid intermediate I-39a-5 was prepared from intermediate I-39a-4 (5.50 g, 28.47 mmol, 1.0 eq) and phosphorus oxychloride (30.0 mL) according to the similar steps in Example I-17a-5. (4.50 g, yield 74.7%). LC-MS MS-ESI (m / z) 212.0 [M+H] + .

[0402] Intermediate: Preparation of I-39a

[0403]

[0404] Yellow solid intermediate I-39a was prepared from intermediate I-39a-5 (4.50 g, 21.27 mmol, 1.0 eq), 1.0 M dichloromethane solution of boron tribromide (75 mL, 75.00 mmol, 3.53 eq) and 1,2-dichloroethane (DCE, 210 mL) according to the similar steps in Example I-17a. (2.10 g, yield 50.0%). LC-MS MS-ESI (m / z) 198.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δppm 11.22 (s, 1H), 8.68 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 12.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H).

[0405] Intermediate: Preparation of I-39c

[0406]

[0407] The light yellow solid intermediate I-39c was prepared from intermediate I-39a (396.00 mg, 2.00 mmol, 1.0 eq), Cs2CO3 (1.95 g, 6.00 mmol, 3.0 eq) and I-30b (1.04 g, 6.00 mmol, 3.0 eq) according to the similar steps of intermediate I-1c in the example. (480.00 mg, yield 98.5%). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0408] Intermediate: Preparation of I-39e

[0409]

[0410] The brown solid intermediate I-39e was prepared from intermediate I-39c (480.00 mg, 1.97 mmol, 1.0 eq), Cs2CO3 (2.12 g, 6.50 mmol, 3.3 eq) and commercially available I-1d (370.75 mg, 1.97 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (710.00 mg, yield 91.1%). LC-MS MS-ESI (m / z) 396.1 [M+H] + .

[0411] Example 39: Preparation of Compound I-39

[0412]

[0413] Yellow solid I-39 was prepared from intermediate I-39e (710.00 mg, 1.80 mmol, 1.0 eq), HATU (1.03 g, 2.70 mmol, 1.5 eq), DIEA (696.60 mg, 5.40 mmol, 3.0 eq) and commercially available I-6f (259.38 mg, 1.80 mmol, 1.0 eq) according to the similar steps in Example I-1. (54.00 mg, yield 5.8%). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.65(d,J=5.1Hz,1H),8.44(d,J=9.2Hz,1H),8.09(t,J=10.8Hz,2H),8.02-7.87(m,2H),7.79-7.62(m,2H), 7.58(d,J=8.8Hz,1H),7.29-7.17(m,1H),6.76-6.53(m,2H),5.37(s,2H),4.88(d,J=47.8Hz,2H),4.56(d,J=29.7Hz,2H).

[0414] Intermediate: Preparation of I-40c

[0415]

[0416] The light yellow solid intermediate I-40c was prepared from I-1a (1.79 g, 10.0 mmol, 1.0 eq), Cs2CO3 (9.77 g, 30.0 mmol, 3.0 eq) and I-40b (4.30 g, 30.0 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (2.25 g, yield 92.9%). LC-MS MS-ESI (m / z) 242.0 [M+H] + .

[0417] Intermediate: Preparation of I-40e

[0418]

[0419] The brown solid intermediate I-40e was prepared from intermediate I-40c (2.25 g, 9.29 mmol, 1.0 eq), Cs2CO3 (9.98 g, 30.65 mmol, 3.3 eq) and commercially available I-1d (1.75 g, 9.29 mmol, 1.0 eq) according to the similar steps in the intermediate I-1e in the example. (3.20 g, yield 87.46%). LC-MS MS-ESI (m / z) 394.1 [M+H] + .

[0420] Example 40: Preparation of Compound I-40

[0421]

[0422] Yellow solid I-40 was prepared from intermediate I-40e (157.53 mg, 0.40 mmol, 1.0 eq), HATU (228.14 mg, 0.6 mmol, 1.5 eq), DIEA (155.00 mg, 1.2 mmol, 3.0 eq) and I-40f (28.45 mg, 0.40 mmol, 1.0 eq) according to the similar steps in Example I-1. (42.00 mg, yield 23.5%). LC-MS MS-ESI (m / z) 447.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 8.86(d,J=7.6Hz,1H),8.66(d,J=5.1Hz,1H),8.34(d,J=9.2Hz,1H),8.28(d,J=9.1Hz,1H ),8.03(d,J=7.0Hz,1H),7.88(d,J=2.3Hz,1H),7.64-7.58(m,2H),7.55(dd,J=9.2,2.4H z,1H),7.49(d,J=2.2Hz,1H),7.37(dd,J=9.1,2.3Hz,1H),6.60(d,J=5.2Hz,1H),4.55-4 .45(m,3H),4.12-4.03(mm,2H),2.35-2.25(m,2H),2.15-2.02(m,2H),1.76-1.67(m,2H).

[0423] Intermediate: Preparation of I-41c

[0424]

[0425] Yellow solid intermediate I-41c was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), Cs2CO3 (9.79 g, 30.06 mmol, 3.0 eq) and I-41b (4.36 g, 30.06 mmol, 3.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.70 g, yield 69.6%). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0426] Intermediate: Preparation of I-41e

[0427]

[0428] The brown solid intermediate I-41e was prepared from the homemade intermediate I-41c (731.00 mg, 3.00 mmol, 1.0 eq), Cs2CO3 (3.22 g, 9.90 mmol, 3.3 eq) and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) according to the similar steps as the intermediate I-1e in the example. (800.00 mg, yield 67.4%). LC-MS MS-ESI (m / z) 396.1 [M+H] + .

[0429] Example 41: Preparation of Compound I-41

[0430]

[0431] Yellow solid I-41 was prepared from intermediate I-41e (110.70 mg, 0.28 mmol, 1.0 eq), HATU (159.68 mg, 0.42 mmol, 1.5 eq), DIEA (108.53 mg, 0.84 mmol, 3.0 eq) and I-21f (40.20 mg, 0.28 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 29.5%). LC-MS MS-ESI (m / z) 485.1 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 9.09(d,J=6.5Hz,1H),8.68(d,J=5.1Hz,1H),8.39(d,J=9.2Hz,1H),8.29(d,J=9.2 Hz,1H),8.06(d,J=8.1Hz,1H),7.89(d,J=2.2Hz,1H),7.70(d,J=6.7Hz,1H),7.67-7 .60(m,1H),7.59-7.53(m,2H),7.40(dd,J=9.2,2.3Hz,1H),6.62(d,J=5.2Hz,1H), 6.52(tt,J=56.0,3.2Hz,1H),4.57(td,J=14.7,3.2Hz,2H),4.45-4.30(m,1H),3.13 -2.96(m,2H),2.88-2.70(m,2H).

[0432] Intermediate: Preparation of I-42c

[0433]

[0434] Yellow solid intermediate I-42c was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), Cs2CO3 (9.79 g, 30.06 mmol, 3.0 eq) and I-42b (2.33 g, 10.02 mmol, 1.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.60 g, yield 63.7%). LC-MS MS-ESI (m / z) 251.1 [M+H] + .

[0435] Intermediate: Preparation of I-42e

[0436]

[0437] The brown solid intermediate I-42e was prepared from the homemade intermediate I-42c (752.10 mg, 3.00 mmol, 1.0 eq), Cs2CO3 (3.22 g, 9.90 mmol, 3.3 eq) and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) according to the similar steps as the intermediate I-1e in the example. (800.00 mg, yield 66.2%). LC-MS MS-ESI (m / z) 403.2 [M+H] + .

[0438] Example 42: Preparation of Compound I-42

[0439]

[0440] Yellow solid I-42 was prepared from intermediate I-42e (112.67 mg, 0.28 mmol, 1.0 eq), HATU (159.68 mg, 0.42 mmol, 1.5 eq), DIEA (108.53 mg, 0.84 mmol, 3.0 eq) and I-21f (40.21 mg, 0.28 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 29.1%). LC-MS MS-ESI (m / z) 492.2 [M+H] + .

[0441] Intermediate: Preparation of I-43c

[0442]

[0443] Yellow solid intermediate I-43c was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), Cs2CO3 (9.79 g, 30.06 mmol, 3.0 eq) and I-43b (1.78 g, 10.02 mmol, 1.0 eq) according to the similar steps in the intermediate I-1c in the example. (1.60 g, yield 57.7%). LC-MS MS-ESI (m / z) 277.1 [M+H] + .

[0444] Intermediate: Preparation of I-43e

[0445]

[0446] The brown solid intermediate I-43e was prepared from the homemade intermediate I-43c (830.40 mg, 3.00 mmol, 1.0 eq), Cs2CO3 (3.22 g, 9.90 mmol, 3.3 eq) and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) according to the similar steps as the intermediate I-1e in the example. (850.00 mg, yield 66.1%). LC-MS MS-ESI (m / z) 429.2 [M+H] + .

[0447] Example 43: Preparation of Compound I-43

[0448]

[0449] Yellow solid I-43 was prepared from intermediate I-43e (119.98 mg, 0.28 mmol, 1.0 eq), HATU (159.68 mg, 0.42 mmol, 1.5 eq), DIEA (108.53 mg, 0.84 mmol, 3.0 eq) and I-6f (40.32 mg, 0.28 mmol, 1.0 eq) according to the similar steps in Example I-1. (40.00 mg, yield 25.7%). LC-MS MS-ESI (m / z) 555.2 [M+H] + . 1H-NMR(400MHz,DMSO-d6)δppm 9.96(s,1H),8.64(d,J=5.2Hz,1H),8.43(d,J=9.2Hz,1H),8.24(d,J=9.1Hz,1H),8.09(d,J=8.3Hz,1H),7.95(d,J=6.6Hz,1H), 7.90(d,J=2.4Hz,1H),7.71-7.63(m,1H),7.57(dd,J=9.2,2.5Hz,1H),7.46(d,J=2.5Hz,1H),7.32(dd,J=9.1,2.5Hz,1H),7.27 -7.19(m,1H),6.72-6.56(m,2H),5.38(s,2H),4.27(t,J=5.8Hz,2H),2.89(t,J=5.7Hz,2H),2.65-2.52(m,4H),1.83-1.58(mm,4H).

[0450] Example 44: Preparation of Compound I-44

[0451]

[0452] Yellow solid I-44 was prepared from intermediate I-1e (205.0 mg, 0.57 mmol, 1.0 eq), HATU (325.10 mg, 0.855 mmol, 1.5 eq), DIEA (221.00 mg, 1.71 mmol, 3.0 eq) and I-3f (92.41 mg, 0.57 mmol, 1.0 eq) according to the similar steps in Example I-1. (65.00 mg, yield 22.65%). LC-MS MS-ESI (m / z) 504.2 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δppm 10.03(s,1H),8.64(d,J=4.9Hz,1H),8.43(d,J=9.1Hz,1H),8.24(d,J=9.1Hz,1H),8.10(d,J=8.1Hz,1H),7.98-7.87(m,2H),7.67(t,J=7.6Hz ,1H),7.60-7.46(m,2H),7.42(s,1H),7.30(d,J=9.0Hz,1H),6.58(d,J=4.9Hz,1H),5.27(s,2H),4.23(d,J=6.9Hz,2H),1.43(t,J=6.7Hz,3H).

[0453] In addition, other compounds of the present invention can be prepared according to similar steps to those in the above examples.

[0454] In vitro biological evaluation

[0455] Example A Test of the inhibitory activity and relative selectivity of the compounds of the present invention on Aurora B and VEGFR2 kinases

[0456] Prepare DMSO working solutions of compound gradient concentrations: prepare the compound into 0.2 mM DMSO solution, and dilute it into 10 working solutions of gradient concentrations with DMSO (corresponding to final concentrations of the compound in the reaction system of 1000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, and 0.03 nM).

[0457] Aurora B kinase and VEGFR2 inhibitory activity test: The half inhibitory concentration (IC50) of the compound on Aurora B kinase and VEGFR2 was tested by HTRF KinEASE-TK kit (Cisbio, Cat#62TK0PEC) and HTRF KinEASE-STK kit (Cisbio, Cat#61ST2BLE), respectively. 50 ). According to the instructions of the kit, prepare 2×kinase&Metal solution (Aurora B / Cat#05-102 and VEGFR2 / Cat#08-191 are purchased from Carna) and 2×Substrate&ATP solution (substrates S2 and TK are used for Aurora B and VEGFR2, respectively). Add 25nL of working solution of the compound to be tested at each gradient concentration and 2.5μL of 2×kinase&Metal solution to each well of the 384-well plate, seal the plate with a sealing film, mix well, centrifuge, and incubate at 25°C for 10 minutes. Then add 2.5μL of 2×Substrate&ATP solution to each well and incubate again at 25°C for 30 minutes. Finally, add 5μL of 2×XL665&Antibody kinase detection reaction solution to each well, incubate at 25°C for 60 minutes, and read the fluorescence signals of each well at 665nm and 620nm wavelengths using an enzyme reader.

[0458] The 665 nm / 620 nm fluorescence signal ratio (X) of each well was calculated, and the well without compound was used as the negative reference (Y) and the well without enzyme was used as the positive reference (Z). The inhibition rate of the compound in each test well on the corresponding kinase was calculated by the formula: Inhibition (%) = 100% - (XZ) / (YZ) × 100%, and the half inhibitory concentration (IC) of each compound on the corresponding kinase was calculated by GraphPad 7.0 software. 50 ).

[0459] Relative selectivity of Aurora B kinase inhibition, measured by IC values ​​of compounds against VEGFR2 50 With IC for Aurora B 50 The ratio of IC 50-VEGFR2 / IC 50-Aurora B The larger the ratio, the stronger the compound's inhibitory effect on Aurora B is relative to that on VEGFR2. The specific data are shown in Table 2 below:

[0460] Table 2 Inhibitory activity and relative selectivity of the compounds of the present invention on Aurora B and VEGFR2 kinases

[0461]

[0462] Compound No. 31 (Chiauranib) and Compound No. 32 are examples disclosed in patent CN101906076A. The inventors synthesized the two compounds with reference to the synthesis method therein for use as reference molecules. The structural formulas of the two compounds are as follows:

[0463]

[0464] The results in Table 2 show that the compounds of the present invention have excellent Aurora B kinase inhibitory activity and very high Aurora B kinase selectivity relative to VEGFR2. Specifically, compared with the control molecule 01 (Chiauranib), the control molecule 02, and the control examples I-7, I-11, I-12, I-13, and I-14, the compounds of the present invention not only have a stronger inhibitory effect on Aurora B kinase in terms of activity, with an IC50 of Aurora B below 10 nM, but also have very high Aurora B kinase selectivity relative to VEGFR2, with IC50-VEGFR2 / IC50-Aurora B being above 7, achieving unexpected technical effects.

[0465] Example B Testing of the Effects of the Compounds of the Invention on Tumor Cell Cycle

[0466] When the activity of Aurora B kinase in tumor cells is inhibited, the arrangement and separation of chromosomes are blocked, resulting in the failure of cytokinesis to form tetraploid or polyploid cells, and the severe instability of the genome and mitotic catastrophes cause cell apoptosis. The fluorescent dye propidium iodide (PI) that specifically binds to nucleic acids can be used to calibrate the DNA content in cells, so that the cell state can be distinguished into sub-G0 / G1 (apoptosis), G0 / G1, S, G2 / M (tetraploid) and polyploid states. Among them, sub-G0 / G1 means that the DNA content is less than 2N, and it is generally believed that the cells are in the process of apoptosis (random DNA degradation, cell membrane permeability); polyploid means that the DNA content is greater than 4N.

[0467] Experimental process:

[0468] Human acute lymphoblastic leukemia cell Molt-4 (CRL-1582) was purchased from American Type Culture Collection (ATCC). Molt-4 cells in suspension culture and logarithmic growth phase were collected and counted. 6 Cells were inoculated into six-well plates and cultured overnight. The test compound was prepared into 1mM and 3mM DMSO solutions, and then the DMSO solution was diluted 50 times with culture medium. Finally, the above solution was added to the culture system at a volume ratio of 1:19, so that the final concentration of the compound in each well reached 1μM or 3μM, respectively. After continuing to culture for 48 hours, the cells were collected by centrifugation. Each cell sample was resuspended in 300μl PBS and dripped dropwise into pre-cooled 700μl anhydrous ethanol, and then gently inverted several times to mix. At this point, the cell collection and fixation were completed. The samples were left to stand at 4°C for more than 12 hours before flow cytometric analysis.

[0469] Mix PBS with 10mg / mL PI stock solution and 10mg / mL RNase A solution at a ratio of 1000:5:2 to form a working staining solution. Centrifuge the fixed cell sample at 4°C, 1000rpm for 10 minutes, aspirate the supernatant and wash twice with PBS, and resuspend in the above working staining solution at 300μL per tube. After incubation at 37°C in the dark for 30 minutes, filter the cells with a 200-mesh stainless steel mesh, and load the filtrate for flow cytometry analysis (10,000 cells are counted for each sample).

[0470] The histogram showing the DNA content was obtained by flow cytometry, and the cycle distribution in each sample was analyzed by flow cytometry data analysis software FlowJo, and the mean (X) and standard deviation (SD) were calculated. The data were expressed as X±SD. After Molt-4 was treated with the test compounds at different doses, the apoptosis, tetraploidy and polyploidy ratios of the cells were shown in Table 3 below.

[0471] Table 3 Test results of the effects of the compounds of the present invention on the Molt-4 cell cycle

[0472]

[0473] The results in Table 3 show that: whether under the 1 μM dose condition or the 3 μM dose condition, compared with the control molecule 01 (Chiauranib) and the control molecule 02, the effect of the compound of the present invention on inducing tetraploidy, polyploidy and cell apoptosis in Molt-4 cells is significantly improved, indicating that the compound of the present invention has a stronger inhibitory effect on the Aurora B kinase activity in tumor cells, thereby affecting the cell cycle of tumor cells, which can achieve better efficacy / safety comprehensive benefits for related diseases.

[0474] Example C Brain Penetration Test of the Compounds of the Invention

[0475] In order to test whether the compound of the present invention can cross the blood-brain barrier (BBB), 6-week-old B / C female mice (purchased from Guangdong Medical Animal Experiment Center) were taken, and the compound of the present invention was formulated in a solvent containing 5% dimethyl sulfoxide, 60% 1,3-propylene glycol and 35% purified water. The compound of the present invention was administered by gavage at 5 mg / kg. The animals were killed 4 hours after administration, and blood and brain tissue were collected. The blood was anticoagulated with K2-EDTA, centrifuged at 5000rpm for 5 minutes, and plasma was separated. The brain tissue was accurately weighed, homogenized with a certain amount of phosphate buffered saline (PBS) solution, and the biological sample was frozen at -80°C for testing. After sample extraction, the compound concentration was determined by liquid chromatography-mass spectrometry (LC-MS / MS). Brain penetration is defined as the ratio of the compound concentration in brain tissue to the concentration in plasma.

[0476] Table 4 Brain penetration experimental data

[0477]

[0478] The results in Table 4 show that in the brain penetration test, the ratio of the compound concentration in brain tissue to the concentration in plasma of the compound of the present invention is significantly higher than that of the control molecule 01 (Chiauranib) and the control molecule 02. The test results show that the compound of the present invention has excellent brain barrier permeability, can pass through the blood-brain barrier, has the potential to reach an effective blood drug concentration in brain tissue, and can be used to treat and prevent central nervous system related diseases. Example D Antitumor efficacy experiment of the compound of the present invention in the pancreatic cancer model of PANC02 mice

[0479] The mouse PANC02 pancreatic cancer transplant tumor model was constructed. The experimental animals were C57BL / 6 mice (female, 6 weeks old), the tumor cells were PANC02 (mouse pancreatic cancer cells), and the cell culture medium was DMEM medium containing 1% double antibody and 10% fetal bovine serum. PANC02 cells in the logarithmic growth phase and growing well were collected and plated at 0.9×10 6 The tumors were inoculated subcutaneously on the left side of C57BL / 6 mice at a concentration of 0.2 mL. The long diameter (a, mm) and short diameter (b, mm) of the tumors and the tumor volume (V, mm) were measured with a vernier caliper. 3 ) The calculation formula is V = 1 / 2a*b 2 Tumor volume was measured 2-3 times a week using a vernier caliper. The average tumor volume reached 190 mm in mice 3 The mice were divided into groups and administered when the dose was higher than 10 mg / kg / day, with 8 mice in each group. The grouping day was Day 0 (i.e., Day 0), and the mice were divided into 4 groups, namely, the solvent control group (0.2% CMC-Na aqueous solution), the compound I-9 group (10 mg / kg / day), the control molecule 01 group (Chiauranib) (10 mg / kg / day), and the control molecule 02 group (10 mg / kg / day). All 4 groups were administered by gavage, once a day, for continuous administration, and the experiment was terminated on the day of the last administration.

[0480] Tumor volume results are expressed as mean ± SEM. Comparison between the two groups will be detected using the MannWhitney test. If p < 0.05, it is considered to be statistically significant. The calculation formula for tumor volume inhibition rate (TGI) is TGI (%) = [1-(Ti-T0) / (Vi-V0)] × 100%. (Ti: mean tumor volume of the treatment group on the i-th day of administration, T0: mean tumor volume of the treatment group on the 0th day of administration; Vi: mean tumor volume of the solvent control group on the i-th day of administration, V0: mean tumor volume of the solvent control group on the 0th day of administration)

[0481] The average tumor volume and tumor volume inhibition rate of each group of mice on different dosing days are shown in Table 5. The statistical results of the average tumor volume are shown in Figure 1 shown.

[0482] Table 5: Average tumor volume and tumor volume inhibition rate

[0483]

[0484] Depend on Figure 1It can be seen that: on the 9th day of group administration, compared with the control molecule 01 (Chiauranib) group, the tumor volume of mice in the compound I-9 group was significantly reduced (p<0.01). Compared with the control molecule 02 group, the tumor volume of mice in the compound I-9 group was significantly reduced (p<0.05). Compared with the solvent control group, the tumor volume of mice in the compound I-9 group was significantly reduced (p<0.001).

[0485] As shown in Table 5, the tumor volume inhibition rate of the representative compound I-9 group (TGI is 114.0%) is significantly better than that of the control molecule 01 (Chiauranib) group (TGI is 74.6%) and the control molecule 02 group (TGI is 68.9%).

[0486] In summary, the compounds of the present invention have excellent anti-tumor efficacy in vivo and can significantly inhibit the growth of tumors.

[0487] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof: in: R 1 is selected from methyl or ethyl, the methyl or ethyl being unsubstituted or substituted by one or more identical or different R a replace; Each R a are each independently selected from halogen, C 1-6 Alkoxy, -NR'R", halogenated C 1-6 Alkoxy; wherein R' and R" are each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, or R' and R" together with the N atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; R 2 and R 3 Each independently selected from: H, halogen, C 1-6 alkyl; Ring A is selected from C 4-10 Cycloalkyl or 4-10 membered heterocyclic group; the 4-10 membered heterocyclic group contains 1 to 4 heteroatoms selected from N, O, S; the C 4-10 The cycloalkyl or 4-10 membered heterocyclic group is unsubstituted or substituted by one or more identical or different R b replace; Each R b are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; Alternatively, ring A is selected from the group in, In A1, R 4 Selected from F, Cl, C 1-6 Alkyl, haloC 1-6 alkyl; In A2, R 5 Selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl; In A3, R 4 and R 5 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl; A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 Alkyl, when R 6 When it is Cl, R 1 is methyl or ethyl; A5, R 5 and R 6 are each independently selected from halogen, C 1-6 Alkyl, haloC 1-6 alkyl; When ring A is When R 1 is ethyl or is replaced by one or more R a Substituted methyl or ethyl.

2. The compound according to claim 1, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, wherein: R 1 is selected from methyl and ethyl; the methyl and ethyl groups are unsubstituted or substituted with 1, 2 or 3 identical or different R a replace; Preferably, each R a are each independently selected from halogen, C 1-4 Alkoxy, -NR'R", halogenated C 1-4 Alkoxy; wherein R' and R" are each independently selected from H, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R' and R" together with the N atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; Preferably, each R a are each independently selected from halogen, C 5-6 Alkoxy, -NR'R", halogenated C 5-6 Alkoxy; wherein R' and R" are each independently selected from H, C 5-6 Alkyl, C 5-6 Cycloalkyl, or R' and R" together with the N atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; Preferably, each R a are each independently selected from halogen, C 1-3 Alkoxy, -NR'R", halogenated C 1-3 Alkoxy; wherein R' and R" are each independently selected from H, C 1-3 Alkyl, C 3-4 Cycloalkyl, or R' and R" together with the N atom to which they are attached form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; Preferably, each R a Each is independently selected from halogen, methoxy, ethoxy, propoxy, -NR'R", halogenated methoxy, halogenated ethoxy, halogenated propoxy; wherein R' and R" are independently selected from H, methyl, ethyl, or R' and R" together with the N atom to which they are connected form a 4-8 membered nitrogen-containing heterocyclic group; the 4-8 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; Preferably, each R a Each is independently selected from F, Cl, Br, methoxy, ethoxy, propoxy, -NR'R", halomethoxy, haloethoxy, halopropoxy; wherein R' and R" are independently selected from H, methyl, ethyl, or R' and R" together with the N atom to which they are attached form a 4-7 membered nitrogen-containing heterocyclic group, and the 4-7 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, and S; Preferably, each R a Each is independently selected from F, Cl, Br, methoxy, ethoxy, -NR'R", methoxy or ethoxy substituted by 1-3 F or Cl; wherein R' and R" are each independently selected from methyl, ethyl, or R' and R" together with the N atom to which they are connected form a 4-7 membered nitrogen-containing heterocyclic group, and the 4-7 membered nitrogen-containing heterocyclic group may further contain 1-2 heteroatoms selected from N, O, S; Preferably, each R a Each independently selected from F, Cl, methoxy, ethoxy, -NR'R", -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3; wherein R' and R" are each independently selected from methyl, ethyl, or R' and R" together with the N atom to which they are connected form Preferably, each R a Each independently selected from F, Cl, methoxy, N,N-dimethylamino, N-methylamino, -OCHF2, Preferably, R 1 Selected from methyl, ethyl, -CH2CH2F, -CH2CHF2, -CH2CH2Cl, methoxyethyl, Preferably, when ring A is When R 1 is ethyl or -CH2CH2F; Preferably, R 1 Selected from methyl and ethyl, wherein the methyl and ethyl are unsubstituted.

3. The compound according to claim 1, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, wherein: Ring A is selected from C 4-7 Monocyclic alkyl, C 5-10 Spirobicycloalkyl, 4-7 membered monoheterocyclic group or 6-10 membered spirobicycloalkyl; the 4-7 membered monoheterocyclic group or 6-10 membered spirobicycloalkyl contains 1 to 4 heteroatoms selected from N, O, S, the C 4-7 Monocyclic alkyl, C 5-10 The spiro bicycloalkyl, 4-7 membered monoheterocyclic group, 6-10 membered spiro bicycloheterocyclic group is unsubstituted or substituted by 1, 2 or 3 identical or different R b replace; Ring A is selected from C 4-6 Monocyclic alkyl, C 6-8 Spirobicycloalkyl, 4-7 membered monoheterocyclic group or 6-8 membered spirobicycloalkyl, wherein the 4-7 membered monoheterocyclic group or 6-8 membered spirobicycloalkyl contains 1 to 2 heteroatoms selected from N, O, S, and the C 4-6 Monocyclic alkyl, C 6-8 The spiro bicycloalkyl, 4-7 membered monoheterocyclic group, 6-8 membered spiro bicycloheterocyclic group is unsubstituted or substituted by 1, 2 or 3 identical or different R b replace; Preferably, ring A is selected from Said is unsubstituted or substituted with 1, 2 or 3 identical or different R b replace; Preferably, each R b are each independently selected from halogen, C 1-6 alkyl; Preferably, each R b Each independently selected from F, Cl, Br, C 1-4 Alkyl, C 5-6 alkyl; Preferably, each R b Each is independently selected from F, Cl, Br, methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl; Preferably, each R b Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl; Preferably, each R b Each is independently selected from F, Cl, Br, methyl; Preferably, each R b Each independently selected from F; Preferably, ring A is selected from 4. The compound according to claim 1, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, wherein: In A1, R 4 Selected from F, Cl, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl; Preferably, in A1, R 4 Selected from F, Cl, C 1-4 Alkyl, haloC 1-4 alkyl; Preferably, in A1, R 4 Selected from F, Cl, methyl, ethyl, propyl, isopropyl, C 1-4 Alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4alkyl; Preferably, in A1, R 4 is selected from F, Cl, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl; Preferably, in A1, R 4 Selected from F, Cl, methyl; or, In A2, R 5 Selected from F, Cl, Br, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl; Preferably, in A2, R 5 Selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl; Preferably, in A2, R 5 Selected from F, Cl, Br, C 5-6 Alkyl, haloC 5-6 alkyl; Preferably, in A2, R 5 Selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl; Preferably, in A2, R 5 is selected from F, Cl, Br, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl; Preferably, in A2, R 5 Selected from F, Cl, Br, methyl; Preferably, in A2, R 5 Selected from F; or, In A3, R 4 and R 5 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl; Preferably, in A3, R 4 and R 5 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl; Preferably, in A3, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl; Preferably, in A3, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl; Preferably, in A3, R 4 and R 5 Each independently selected from F or Cl; Preferably, in A3, R 4 For F, R 5 is F or Cl; or, A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 Alkyl, when R 6 When it is Cl, R 1 is methyl or ethyl; Preferably, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 Alkyl; when R 6 When it is Cl, R 1 is methyl or ethyl; Preferably, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl; when R 6 When it is Cl, R 1 is methyl or ethyl; Preferably, in A4, R 6 Selected from F or Cl, R 4 and R 5 are each independently selected from F, Cl, Br, methyl, ethyl, methyl substituted with fluorine or chlorine, ethyl substituted with fluorine or chlorine; when R 6 When it is Cl, R 1 is methyl or ethyl; Preferably, in A4, R 6 Selected from F or Cl, R 4 and R 5 Each independently selected from F or Cl; when R 6 When it is Cl, R 1 is methyl or ethyl; or, A5, R 5 and R 6 are each independently selected from halogen, C 1-4 Alkyl, C 5-6 Alkyl, haloC 1-4 Alkyl, haloC 5-6 alkyl; Preferably, in A5, R 5 and R 6 Each independently selected from F, Cl, Br, C 1-4 Alkyl, haloC 1-4 alkyl; Preferably, in A5, R 5 and R 6 Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, C4 alkyl, halomethyl, haloethyl, halopropyl, haloisopropyl, haloC4 alkyl; Preferably, in A5, R 5 and R 6 Each is independently selected from F, Cl, Br, methyl, ethyl, fluoro or chloro substituted methyl, fluoro or chloro substituted ethyl; Preferably, in A5, R 5 and R 6 Each independently selected from F or Cl; Preferably, ring A is selected from When ring A is selected from When R 1 is methyl or ethyl; Preferably, ring A is selected from 5. The compound according to claim 1, or a stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently selected from H, halogen, C 1-4 Alkyl, C 5-6 alkyl; Preferably, R 2 and R 3 Each is independently selected from H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl; Preferably, R 2 and R 3 Each independently selected from H, F, Cl, Br; Preferably, R 2 and R 3 Each independently selected from H, F; Preferably, R 2 and R 3 At the same time, it is H; Or preferably, R 2 and R 3 One of them is H and the other is F; Preferably, R 2 For H, R 3 is F; Or preferably, R 2 For F, R 3 For H.

6. The compound according to any one of claims 1 to 5, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, wherein the compound is selected from:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, and optional pharmaceutically acceptable carriers and / or adjuvants and / or diluents.

8. Use of the compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, polymorphs, cocrystals, solvates, metabolites, prodrugs, deuterated compounds, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating and / or preventing diseases associated with Aurora B kinase.

9. The use according to claim 8, wherein The disease associated with Aurora B kinase is selected from tumors.

10. The use according to claim 8, wherein The disease associated with Aurora B kinase is selected from hyperproliferative diseases.

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