Naphthylamide compounds, their production method and applications

Abstract

The present invention relates to naphthylamide compounds of formula (I), their preparation process, and their use in the treatment and / or prevention of diseases associated with the biological activity of said protein kinases. [Formula 1] JPEG2026500760000154.jpg47160

Description

[Technical Field]

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to naphthylamide compounds as protein kinase inhibitors, their preparation methods, and their application in the treatment and / or prevention of diseases associated with the biological activity of said protein kinases. [Background technology]

[0002] Vascular endothelial growth factor receptors (VEGFRs) are a family of receptor tyrosine kinases (RTKs) that includes three structurally similar transmembrane protein members: 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 both endothelial and non-endothelial cells, including tumor cells, and these receptors can bind to five natural ligands, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). Among them, VEGF-A plays an indispensable role in the process of angiogenesis and maintenance, and VEGF-C and VEGF-D are ligands that mediate lymphangiogenesis. Among all receptors, VEGFR2 plays the most major role and is crucial for regulating angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis.

[0003] Because the diffusion limit of oxygen in mammalian tissue is approximately 100–200 μM, the growth diameter of metabolically active solid tumor tissue is limited to within 0.2–2.0 mm due to oxygen deficiency if new blood vessels do not provide sufficient blood oxygen supply through tissue diffusion alone. Therefore, antiangiogenesis has become an effective treatment for various solid tumors (Adair TH, et al., Angiogenesis, Morgan & Claypool Life Sciences: San Rafael, CA, USA, 2010).

[0004] Currently, there are two main classes of approved drugs targeting the VEGF-VEGFRs pathway for tumor angiogenesis. One class is monoclonal antibodies, such as bevacizumab, which was first approved in 2004, and ramucirumab, which was approved in 2014. The other class is VEGFRs small molecule inhibitors, which mainly include sorafenib, axitinib, apatinib, sunitinib, regorafenib, vandetanib, pazopanib, lenvatinib, ponatinib, cabozantinib, and fruquintinib.

[0005] Antiangiogenic drugs have significantly improved the therapeutic prospects for several types of solid tumors, but hypertension is one of the most common toxic side effects of VEGF-VEGFR inhibitors, with nearly 100% of patients treated with these drugs experiencing elevated blood pressure. Studies have shown that hypertension caused by VEGF-VEGFR inhibitors is a mechanism-dependent target toxicity that typically leads to dose adjustments or treatment discontinuation during the course of treatment (Camarda N, et al., Curr. Oncol. Rep., 2022 Apr;24(4):463-74).

[0006] Aurora kinases (AURKs) are a class of serine / threonine protein kinases that play an important role in regulating the cell cycle. The human AURKs family contains three members: Aurora kinase A (Aurora A), Aurora kinase B (Aurora B), and Aurora kinase C (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).

[0007] Aurora B is overexpressed in tumors derived from many different tissues compared with normal tumor tissues. This kinase, encoded by the AURORA B gene located on chromosome 17 and also known as AIK2, AIM1, ARK2, AIRK2, IPL1, STK1, STK5, and STK12, phosphorylates histone H3 at Ser10, which is crucial for sister chromatid separation. Exogenous overexpression of Aurora B can increase histone H3 phosphorylation and chromosomal aneuploidy in normal cells, and injection of these Aurora B-overexpressing cells into BALB / c nu / nu mice resulted in tumor formation, indicating that Aurora B functions as a driver of tumor development (Ota T, et al., Cancer Res., 2002, 62(18):5168-77).

[0008] Inhibition of Aurora B, an antitumor target, can disrupt abnormal kinetochore-microtubule connections, prevent chromosome alignment and segregation, and even cause mitotic catastrophe and cell apoptosis. Loss of Aurora B kinase activity can lead to cytokinesis failure, resulting in tetraploidy (or polyploidy), and this severe genomic instability ultimately leads to cell death. Because Aurora B is expressed only in dividing and proliferating cells and remains largely stable in normal cells, targeted inhibition of Aurora B offers strong selectivity for actively dividing tumor cells, a significant advantage over other nonspecific cytotoxic drugs.

[0009] To date, no AURK inhibitors have been approved for sale worldwide. However, clinical studies of such inhibitors are currently active, including pan-AURK inhibitors such as VX-680 / MK-0475 (Tozasertib), PHA-793358 (Danusertib), AT-9283, AMG 900, KW-2449, ABT-348 (Ilorasertib), and TT00420; selective Aurora A inhibitors such as MLN8237, ENMD2076, VX-689, and LY3295668; and selective Aurora B inhibitors such as AZD1152 (Barasertib) and Chiauranib (Jing X, et al., Expert. Opin. Ther. Pat., 2021, 31(7):625-44). Existing evidence indicates that selective Aurora A or Aurora B inhibitors have better druggability compared to pan-AURKs inhibitors, in part because they can avoid more toxicity.

[0010] Thiauranib, developed by Shenzhen Weixin Biotechnology Co., Ltd., is a small molecule inhibitor targeting various kinase channels, including VEGFR, PDGFR, and Aurora B, and is currently undergoing clinical trials for tumor treatment. According to the results of a Phase I clinical trial of thiauranib, a dose-limiting toxicity (DLT) of thiauranib occurred in the 65 mg group, showing grade 3 hypertension, a toxicity associated with VEGFR pathway inhibition. The recommended dose for Phase II clinical trials is 50 mg, administered once daily at this dose, with a maximum blood drug exposure (C ) of 100 mg after 28 days of continuous administration. max ) was approximately 2.6 μM, and the steady-state blood drug exposure (C trough ) is approximately 1 μM (Sun Y, et al., J. Hematol. Oncol., 2019, 12(1):9). In humans, DLTs of tiauranib are associated with inhibition of the VEGFR pathway, suggesting that the VEGFR pathway may be the dominant pathway for tiauranib's in vivo efficacy. In vitro cytological studies have shown that tiauranib exhibits relatively weak inhibitory activity against Aurora B kinase at concentrations of 1–3 μM (equivalent to in vivo drug exposure levels), suggesting that the drug's targeting mechanism may be limited in the treatment of Aurora B kinase-dependent tumors. Therefore, the development of multi-targeted kinase inhibitors with stronger selectivity for Aurora B kinase and greater potency in inhibiting Aurora B than VEGFR2 may offer better therapeutic efficacy for Aurora B kinase-dependent tumors within similar human exposure and maximum tolerated dose (MTD) ranges. Summary of the Invention [Problem to be solved by the invention]

[0011] In the prior art, Aurora B kinase inhibitory activity is relatively weak, but strong VEGFR2 inhibitory activity can cause toxic side effects such as hypertension. In particular, the relatively weak selectivity of Aurora B kinase over VEGFR2 limits the therapeutic effect in treating tumors associated with the biological activity of Aurora B kinase. At the same time, in view of the need for treatment of primary and metastatic tumors of the central nervous system, therapeutic drugs must be able to cross the blood-brain barrier and achieve effective intracranial exposure to exert their anti-tumor effects. Therefore, the object of the present invention is to provide compounds with higher selectivity for Aurora B kinase compared to VEGFR2, which have more significant inhibitory activity against Aurora B kinase at the cellular level under conditions of blood drug-reachable exposure, thereby achieving the overall benefits of better therapeutic efficacy / safety for related diseases. At the same time, the compounds of the present invention have the ability to cross the blood-brain barrier well, making them suitable for the treatment and / or prevention of central nervous system diseases. [Means for solving the problem]

[0012] In order to solve the above problems, the present inventors have conducted extensive research and found that naphthylamide compounds having a specific structure can achieve the desired object, and as a result have completed the present invention.

[0013] The present invention relates to the following naphthylamide compounds:

[0014] A compound of formula (I) or a stereoisomer, tautomer, crystalline polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, [ka] Among them, R 1 is selected from a methyl group or an ethyl group, and the methyl group or the ethyl group is unsubstituted or has one or more of the same or different R a is replaced by Each R aare each independently a halogen, C 1-6 Alkoxy group, -NR'R'', haloC 1-6 alkoxy groups, wherein R' and R'' are each independently selected from H, C 1-6 Alkyl group, C 3-6 or R' and R" together with the N atom to which they are linked form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; R 2 and R 3 are each independently H, halogen, or C 1-6 selected from alkyl groups, Ring A is C 4-10 a cycloalkyl group or a 4- to 10-membered heterocyclic group, the 4- to 10-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, O and S, and the C 4-10 The cycloalkyl group or the 4- to 10-membered heterocyclic group may be unsubstituted or may have one or more of the same or different R b is replaced by Each R b are each independently a halogen, C 1-6 Alkyl group, halo C 1-6 selected from alkyl groups, Alternatively, ring A is a group [ka] Selected from, among which: In A1, R 4 are F, Cl, C 1-6 Alkyl group, halo C 1-6 selected from alkyl groups, In A2, R 5 is a halogen, C 1-6 Alkyl group, halo C 1-6 selected from alkyl groups, In A3, R 4 and R 5 are each independently a halogen, C 1-6 Alkyl group, halo C 1-6 alkyl groups, In A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently a halogen, C 1-6 Alkyl group, halo C 1-6 alkyl groups, R 6 When is Cl, R 1 is a methyl group or an ethyl group, In A5, R 5 and R 6 are each independently a halogen, C 1-6 Alkyl group, halo C 1-6 alkyl groups, Furthermore, ring A is [ka] If R 1 is an ethyl group or one or more R a is a methyl or ethyl group substituted with

[0015] In some specific embodiments, R 1 is selected from a methyl group and an ethyl group, and the methyl group and the ethyl group are unsubstituted or have one, two or three identical or different R a is replaced by

[0016] In some specific embodiments, each R a are each independently a halogen, C 1-4 Alkoxy group, -NR'R'', haloC 1-4 alkoxy groups, wherein R' and R'' are each independently selected from H, C 1-4 Alkyl group, C 3-5 Alternatively, R' and R'' may form a 4- to 8-membered nitrogen-containing heterocyclic group together with the N atom to which they are linked, and the 4- to 8-membered nitrogen-containing heterocyclic group may further contain 1 to 2 heteroatoms selected from N, O and S.

[0017] In some specific embodiments, each Ra are each independently a halogen, C 5-6 Alkoxy group, -NR'R'', haloC 5-6 alkoxy groups, wherein R' and R'' are each independently selected from H, C 5-6 Alkyl group, C 5-6 Alternatively, R' and R'' may form a 4- to 8-membered nitrogen-containing heterocyclic group together with the N atom to which they are linked, and the 4- to 8-membered nitrogen-containing heterocyclic group may further contain 1 to 2 heteroatoms selected from N, O and S.

[0018] In some specific embodiments, each R a are each independently a halogen, C 1-3 Alkoxy group, -NR'R'', haloC 1-3 alkoxy groups, wherein R' and R'' are each independently selected from H, C 1-3 Alkyl group, C 3-4 Alternatively, R' and R'' may form a 4- to 8-membered nitrogen-containing heterocyclic group together with the N atom to which they are linked, and the 4- to 8-membered nitrogen-containing heterocyclic group may further contain 1 to 2 heteroatoms selected from N, O and S.

[0019] In some specific embodiments, each R a are each independently selected from halogen, a methoxy group, an ethoxy group, a propoxy group, —NR′R″, a halomethoxy group, a haloethoxy group, and a halopropoxy group, wherein R′ and R″ are each independently selected from H, a methyl group, and an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O, and S.

[0020] In some specific embodiments, each R aare each independently selected from F, Cl, Br, a methoxy group, an ethoxy group, a propoxy group, —NR′R″, a halomethoxy group, a haloethoxy group, and a halopropoxy group, wherein R′ and R″ are each independently selected from H, a methyl group, and an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 7-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O, and S.

[0021] In some specific embodiments, each R a are each independently selected from F, Cl, Br, a methoxy group, an ethoxy group, —NR′R″, and a methoxy group or ethoxy group substituted with 1 to 3 F or Cl, wherein R′ and R″ are each independently selected from a methyl group or an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 7-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O, and S.

[0022] In some specific embodiments, each R a are each independently selected from F, Cl, a methoxy group, an ethoxy group, -NR'R'', -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, and -OCH2CF3, wherein R' and R'' are each independently selected from a methyl group, an ethyl group, or R' and R'' together with the N atom to which they are attached are [ka] Form.

[0023] In some specific embodiments, each R a are each independently F, Cl, a methoxy group, an N,N-dimethylamino group, an N-methylamino group, -OCHF2, [ka] Selected from.

[0024] In some specific embodiments, R 1 is a methyl group, an ethyl group, -CH2CH2F, -CH2CHF2, -CH2CH2Cl, a methoxyethyl group, [ka] Selected from.

[0025] In some specific embodiments, ring A is [ka] If R 1 is an ethyl group or -CH2CH2F.

[0026] In some specific embodiments, R 1 is selected from a methyl group and an ethyl group, and the methyl group and the ethyl group are unsubstituted.

[0027] In some specific embodiments, ring A is C 4-7 Monocycloalkyl groups, C 5-10 a spirobicycloalkyl group, a 4- to 7-membered monoheterocyclic group, or a 6- to 10-membered spirobiheterocyclic group, wherein the 4- to 7-membered monoheterocyclic group or the 6- to 10-membered spirobiheterocyclic group contains 1 to 4 heteroatoms selected from N, O, and S; 4-7 Monocycloalkyl groups, C 5-10 The spirobicycloalkyl group, the 4- to 7-membered monoheterocyclic group, and the 6- to 10-membered spirobiheterocyclic group may be unsubstituted or may have one, two, or three identical or different R b is replaced by

[0028] In some specific embodiments, ring A is C 4-6 Monocycloalkyl groups, C 6-8a spirobicycloalkyl group, a 4- to 7-membered monoheterocyclic group, or a 6- to 8-membered spirobiheterocyclic group, wherein the 4- to 7-membered monoheterocyclic group or the 6- to 8-membered spirobiheterocyclic group contains 1 to 2 heteroatoms selected from N, O, and S; 4-6 Monocycloalkyl groups, C 6-8 The spirobicycloalkyl group, the 4- to 7-membered monoheterocyclic group, and the 6- to 8-membered spirobiheterocyclic group may be unsubstituted or may have one, two, or three of the same or different R b is replaced by

[0029] In some specific embodiments, ring A is [ka] Selected from the above [ka] is unsubstituted or contains one, two or three identical or different R b is replaced by

[0030] In some specific embodiments, each R b are each independently a halogen, C 1-6 It is selected from alkyl groups.

[0031] In some specific embodiments, each R b are each independently F, Cl, Br, C 1-4 Alkyl group, C 5-6 It is selected from alkyl groups.

[0032] In some specific embodiments, each R b are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, and a C6 alkyl group.

[0033] In some specific embodiments, each R bare each independently selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a sec-butyl group.

[0034] In some specific embodiments, each R b are each independently selected from F, Cl, Br, and a methyl group.

[0035] In some specific embodiments, each R b are each independently selected from F.

[0036] In some specific embodiments, ring A is [ka] Selected from.

[0037] In some specific embodiments, in A1, R 4 are F, Cl, C 1-4 Alkyl group, C 5-6 Alkyl group, halo C 1-4 Alkyl group, halo C 5-6 It is selected from alkyl groups.

[0038] In some specific embodiments, in A1, R 4 are F, Cl, C 1-4 Alkyl group, halo C 1-4 It is selected from alkyl groups.

[0039] In some specific embodiments, in A1, R 4 is F, Cl, methyl group, ethyl group, propyl group, isopropyl group, C 1-4 It is selected from an alkyl group, a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, and a haloC4 alkyl group.

[0040] In some specific embodiments, in A1, R 4is selected from F, Cl, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group.

[0041] In some specific embodiments, in A1, R 4 is selected from F, Cl, and a methyl group.

[0042] In some specific embodiments, in A2, R 5 are F, Cl, Br, C 1-4 Alkyl group, C 5-6 Alkyl group, halo C 1-4 Alkyl group, halo C 5-6 It is selected from alkyl groups.

[0043] In some specific embodiments, in A2, R 5 are F, Cl, Br, C 1-4 Alkyl group, halo C 1-4 It is selected from alkyl groups.

[0044] In some specific embodiments, in A2, R 5 are F, Cl, Br, C 5-6 Alkyl group, halo C 5-6 It is selected from alkyl groups.

[0045] In some specific embodiments, in A2, R 5 is selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C4 alkyl group, a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, and a haloC4 alkyl group.

[0046] In some specific embodiments, in A2, R 5 is selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group.

[0047] In some specific embodiments, in A2, R 5 is selected from F, Cl, Br and a methyl group.

[0048] In some specific embodiments, in A2, R 5 is chosen from F.

[0049] In some specific embodiments, in A3, R 4 and R 5 are each independently a halogen, C 1-4 Alkyl group, C 5-6 Alkyl group, halo C 1-4 Alkyl group, halo C 5-6 It is selected from alkyl groups.

[0050] In some specific embodiments, in A3, R 4 and R 5 are each independently F, Cl, Br, C 1-4 Alkyl group, halo C 1-4 It is selected from alkyl groups.

[0051] In some specific embodiments, in A3, R 4 and R 5 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C4 alkyl group, a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, and a haloC4 alkyl group.

[0052] In some specific embodiments, in A3, R 4 and R 5 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group.

[0053] In some specific embodiments, in A3, R 4 and R 5 are each independently selected from F or Cl.

[0054] In some specific embodiments, in A3, R 4 is F and R 5is F or Cl.

[0055] In some specific embodiments, ring A is [ka] Selected from.

[0056] In some specific embodiments, in A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently a halogen, C 1-4 Alkyl group, C 5-6 Alkyl group, halo C 1-4 Alkyl group, halo C 5-6 alkyl groups, R 6 When is Cl, R 1 is a methyl group or an ethyl group.

[0057] In some specific embodiments, in A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently F, Cl, Br, C 1-4 Alkyl group, halo C 1-4 alkyl groups, R 6 When is Cl, R 1 is a methyl group or an ethyl group.

[0058] In some specific embodiments, in A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C4 alkyl group, a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, and a haloC4 alkyl group; R 6 When is Cl, R 1 is a methyl group or an ethyl group.

[0059] In some specific embodiments, in A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; R 6 When is Cl, R 1 is a methyl group or an ethyl group.

[0060] In some specific embodiments, in A4, R 6 is selected from F or Cl, R 4 and R 5 are each independently selected from F or Cl, and R 6 When is Cl, R 1 is a methyl group or an ethyl group.

[0061] In some specific embodiments, in A5, R 5 and R 6 are each independently a halogen, C 1-4 Alkyl group, C 5-6 Alkyl group, halo C 1-4 Alkyl group, halo C 5-6 It is selected from alkyl groups.

[0062] In some specific embodiments, in A5, R 5 and R 6 are each independently F, Cl, Br, C 1-4 Alkyl group, halo C 1-4 It is selected from alkyl groups.

[0063] In some specific embodiments, in A5, R 5 and R 6 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a C4 alkyl group, a halomethyl group, a haloethyl group, a halopropyl group, a haloisopropyl group, and a haloC4 alkyl group.

[0064] In some specific embodiments, in A5, R 5 and R 6 are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group.

[0065] In some specific embodiments, in A5, R 5 and R 6 are each independently selected from F or Cl.

[0066] In some specific embodiments, ring A is [ka] Selected from.

[0067] In some specific embodiments, ring A is [ka] and ring A is selected from [ka] If selected from 1 is a methyl group or an ethyl group.

[0068] In some embodiments, ring A is [ka] Selected from.

[0069] In some specific embodiments, ring A is [ka] Selected from.

[0070] In some specific embodiments, ring A is [ka] Selected from.

[0071] In some specific embodiments, ring A is [ka] Selected from.

[0072] In some specific embodiments, ring A is [ka] Selected from.

[0073] In some specific embodiments, ring A is [ka] Selected from R 1 is an ethyl group or -CH2CH2F.

[0074] In some specific embodiments, ring A is [ka] Selected from R 1 is an ethyl group or -CH2CH2F.

[0075] In some specific embodiments, ring A is [ka] Selected from.

[0076] In some specific embodiments, ring A is [ka] Selected from.

[0077] In some specific embodiments, ring A is [ka] Selected from.

[0078] In some specific embodiments, ring A is [ka] Selected from.

[0079] In some specific embodiments, ring A is [ka] Selected from.

[0080] In some specific embodiments, ring A is [ka] Selected from R 1 is a methyl group or an ethyl group.

[0081] In some specific embodiments, ring A is [ka] Selected from R 1 is a methyl group or an ethyl group.

[0082] In some specific embodiments, R 2 and R 3 are each independently H, halogen, or C 1-4 Alkyl group, C 5-6It is selected from alkyl groups.

[0083] In some specific embodiments, R 2 and R 3 are each independently selected from H, F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group.

[0084] In some specific embodiments, R 2 and R 3 are each independently selected from H, F, Cl, and Br.

[0085] In some specific embodiments, R 2 and R 3 are each independently selected from H and F.

[0086] In some specific embodiments, R 2 and R 3 is also H.

[0087] In some specific embodiments, R 2 and R 3 One of them is H and the other is F.

[0088] In some specific embodiments, R 2 is H and R 3 is F.

[0089] In some specific embodiments, R 2 is F and R 3 is H.

[0090] In some specific embodiments, the compound is [ka] Selected from JPEG2026500760000031.jpg149170.

[0091] As used herein, examples of the term "pharmaceutically acceptable salts of compounds of Formula (I)" are organic acid addition salts formed from organic acids which form pharmaceutically acceptable anions.

[0092] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having certain substituents found in this invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent.

[0093] The term "prodrug" refers to a derivative of a compound of formula (I) having specific substituents found in accordance with the present invention, which may have relatively little or no activity itself, but after administration is converted under physiological conditions (e.g., by metabolism, solvation, or otherwise) to a compound having specific substituents found in accordance with the present invention, which produces the corresponding biological activity in vivo.

[0094] The term "metabolite" refers to a product obtained by in vivo metabolism of a compound of Formula (I) having specific substituents found in accordance with the present invention. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by employing testing methods as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of an administered compound. Correspondingly, the present invention includes metabolites of a compound, including those produced by sufficient contact of a compound of the present invention with a mammal over a period of time.

[0095] The term "deuterated compound" refers to compounds of the invention that contain at least one deuterium atom, specifically, that one or more hydrogen atoms in a compound of the invention can be replaced or substituted by a deuterium atom. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0096] In the event that 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.

[0097] Manufacturing method: Therefore, another aspect of the present invention also provides a method for preparing the compounds according to the present invention described above. The preparation of the compounds represented by general formula (I) of the present invention can be achieved by the following exemplary methods and examples, but these methods and examples should not be construed as limiting the scope of the present invention in any manner. The compounds 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 methods described in the present invention can be used. The products obtained in the reaction of each step can be obtained using 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 generally synthesized according to the literature (e.g., those provided by Scifinder) or purchased.

[0098] The following synthetic routes illustrate methods for preparing compounds of formula (I) of the present invention. All of the raw materials, reagents, catalysts, solvents, etc. used in the synthetic schemes below can be prepared by methods well known to those skilled in the art of organic chemistry or can be obtained commercially. All of the final derivatives of the present invention can be prepared by the methods described in the schemes or by methods analogous thereto, all of which are well known to those skilled in the art of organic chemistry. All variables applied in these schemes are as defined in the context.

[0099] Manufacturing method The definitions of the following variables are as described above, and new variables are defined as described in the contents of this section. Furthermore, the compound represented by general formula (I) and its related intermediates can be purified by common separation methods, such as extraction, recrystallization, and silica gel column chromatography separation. The 200-300 mesh silica gel and thin-layer chromatography silica gel plates used were both manufactured by Qingdao Haiying Chemical Factory. The chemical reagents used were analytically pure or chemically pure commercial products of common reagents, and were not further purified before use.

[0100] The present invention provides a method for preparing a compound of general formula (I), which method comprises the following steps:

[0101] [ka] 1) The compound represented by formula (Ia) is catalyzed by a first base in a first solvent, and then undergoes a nucleophilic substitution reaction with the compound represented by formula (Ib) to obtain the compound represented by formula (Ic). Alternatively, the compounds represented by formula (Ia) and formula (Ib) can be subjected to a Mitsunobu reaction under the action of triphenylphosphine (PPh3) / diethyl azodicarboxylate (DEAD) or triphenylphosphine (PPh3) / diisopropyl azodicarboxylate (DIAD) to obtain the compound represented by formula (Ic).

[0102] 2) The compound represented by formula (Ic) undergoes a nucleophilic substitution reaction with a compound represented by formula (Id) in a second solvent under the action of a second base to give a compound represented by formula (Ie).

[0103] 3) The compound represented by formula (Ie) and the compound represented by formula (If) are subjected to a condensation reaction in a third solvent under the action of a condensing agent and a third base to obtain a compound represented by formula (I).

[0104] Among them, R 1 , R 2 , R 3 , the definition of ring A is as above, X is selected from bromine, iodine, -OMs, -OTf, -OTs, and -OH.

[0105] 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.

[0106] In some embodiments, in step 1), the first base is selected from potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), or a combination thereof.

[0107] 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, dimethyl sulfoxide (DMSO), or a combination thereof.

[0108] In some embodiments, in step 2), the second base is selected from potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), diisopropylethylamine (DIEA), or a combination thereof.

[0109] 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'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), and N-methylimidazole, of which TCFH is particularly suitable for the condensation of relatively sterically hindered amines, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or a combination thereof.

[0110] In some embodiments, in step 3), the third solvent is selected from dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile (MeCN), N,N'-dimethylformamide (DMF), or a combination thereof.

[0111] In some embodiments, the third base is selected from triethylamine (TEA) and diisopropylethylamine (DIEA).

[0112] Pharmaceutical Composition: The present invention also provides pharmaceutical compositions comprising any of the compounds described above, or a stereoisomer, tautomer, crystalline polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

[0113] 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.

[0114] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known or will be apparent to those skilled in the art from the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), methods for preparing such pharmaceutical compositions include incorporating suitable pharmaceutical excipients, carriers, diluents, etc.

[0115] Medicinal Use: Another aspect of the present invention relates to the compound according to the present invention, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, or composition thereof, for treating and / or preventing a disease associated with the biological activity of Aurora B kinase.

[0116] Another aspect of the present invention relates to the use of the compound according to the present invention, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt, or composition thereof, in the manufacture of a medicament for treating and / or preventing a disease associated with the biological activity of Aurora B kinase.

[0117] 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 / prophylactically effective amount of the compound described above, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, pharmaceutically acceptable salt thereof, or the composition described above.

[0118] 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.

[0119] As used herein, "treatment" refers to the administration of a drug or other supportive therapy to a subject to achieve a desired pharmacological and / or physiological effect. The effect may be prophylactic, meaning complete or partial prevention of a disease or its symptoms, and / or therapeutic, meaning partial or complete stabilization or cure of the disease and / or side effects caused by the disease. As used herein, "treatment" covers any treatment of a patient's disease, including (a) preventing a disease or condition from developing in a patient who is susceptible to the disease or condition but has not yet been diagnosed with the disease, (b) inhibiting the symptoms of the disease, i.e., arresting its progression, or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or condition.

[0120] In the present invention, a "subject" refers to a vertebrate. In some embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cows), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, a mammal refers to a human.

[0121] In the present invention, an "effective amount" refers to an amount that effectively achieves the desired therapeutic or preventive effect at the required dosage and for the required time. The "therapeutically effective amount" of a substance / molecule of the present invention can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule to induce a desired response in the individual. A therapeutically effective amount also covers an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or adverse effects. A "prophylactically effective amount" refers to an amount that effectively achieves the desired preventive effect at the required dosage and for the required time. Typically, a prophylactic dose is administered to a subject before the onset of disease or at an early stage of disease, so the prophylactically effective amount will be lower than the therapeutically effective amount, but this is not necessarily the case. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells, shrink tumor volume, inhibit (i.e., delay and preferably stop) the invasion of cancer cells into surrounding organs to some extent, inhibit (i.e., delay and preferably stop) tumor metastasis to some extent, inhibit tumor growth to some extent, and / or alleviate one or more symptoms associated with cancer to some extent.

[0122] Definitions of terms: As per the practice in the field, [ka] is used in structural formulas herein to describe the bond that is the point of attachment of the moiety or substituent to the core or main structure.

[0123] A dash "-" that is not 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.

[0124] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. In particular, it should be noted that the present invention includes each independent subcombination of each member of these group types and ranges. For example, "C 1-6The term "alkyl group" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups, as individually disclosed, or "C 1-4 alkyl group,” or independently disclosed “C 1-3 It refers to an "alkyl group."

[0125] As used herein, the term "alkyl group" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-6 The term "alkyl group" refers to C1, C2, C3, C4, C5, and C6. 1-6 "Alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted, such that one or more of its hydrogens are replaced with another chemical group. Illustrative 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.

[0126] The term "alkoxy group" refers to any of the above alkyl groups (eg, C1-6 alkyl groups, C1-4 alkyl groups, C1-3 alkyl groups, etc.) linked to the remainder of the molecule via an oxygen atom (-O-).

[0127] "Haro C 1-6 Alkyl group" or "Halo C 1-6 The term "alkoxy group" refers to an alkyl group or alkoxy group in which one or more (e.g., two or three) hydrogen atoms are substituted with a halogen atom such as fluorine, chlorine, bromine, or iodine. The alkyl group or alkoxy group is as defined above. In some embodiments, the term "haloC 1-6 The term "alkyl group" is preferably fluorinated or chlorinated, and may be, for example, -CF, -CHF, -CHF, -CHCHF, -CHCHCl, -CHCHF, -CHCF, etc. In some embodiments, "haloC1-6 The term "alkoxy group" is preferably fluorinated and may be, for example, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, and the like.

[0128] As used herein, the term "substituted" refers to the selective replacement of any one or more hydrogens on the designated atom or group with the designated group, provided that the normal valence of the designated atom is not exceeded.

[0129] The term "cycloalkyl group" refers to a cyclized alkyl group, including monocyclic, bicyclic, or polycyclic ring systems. When a cycloalkyl group is bicyclic or polycyclic, each ring must be a saturated carbocyclic ring or carbocyclic residue, and possible connections between the two rings of a bicyclic or polycyclic cycloalkyl group include bridged, fused, or spiro-bonded rings. For example, C 3-10 Cycloalkyl groups include C3, C4, C5, C6, C7, C8, C9, and C 10 It is intended to include cycloalkyl groups. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. [ka] Including, but not limited to, the following:

[0130] The term "carbocycle" or "carbocyclic residue" refers to any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic or polycyclic ring, any one of which may be saturated, partially saturated, unsaturated, or aromatic. Possible connections between the two rings of a bicyclic or polycyclic carbocycle include bridged, fused, or spiro-bonded rings. Illustrative examples of these carbocycles include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptyl, adamantyl, cyclooctyl, phenyl, naphthyl, [2,2,2]bicyclooctane, [ka] Including, but not limited to, the following:

[0131] The terms "heterocycle," "heterocyclic," and "heterocyclic group" may be used interchangeably and refer to substituted and unsubstituted 4- to 8-membered monocyclic or bicyclic groups, 8- to 10-membered bicyclic or tricyclic groups, and 10- to 14-membered tricyclic or polycyclic groups, in which at least one ring contains at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably contains 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, with the proviso that the total number of heteroatoms in each ring is 4 or less, and the further proviso that the ring contains at least 1 carbon atom. In some preferred embodiments, the heteroatoms are exclusively N or O, and the total number is 3 or less, preferably 1 to 2 heteroatoms. Carbon and sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and, where valences permit, ring atoms on heterocycles may be optionally substituted with ═O (oxo) (e.g., [ka] 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. "Heterocycle" as described herein does not include fully aromatic rings.

[0132] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0133] The term "heteroatom" shall include oxygen, sulfur, and nitrogen.

[0134] The term "XXX is unsubstituted or substituted with one or more of the same or different YYY" means that XXX may be unsubstituted or may be substituted with YYY. Substitution with one or more YYY means that substitution with one YYY (i.e., only one substituent YYY) may be present, or that multiple substituents YYY may be present, and each YYY is independent of the others, may be the same or different, may be selected from a corresponding range of substituents, and may be substituted at any substitutable position. In this regard, "multiple" means 2 or more, preferably 2, 3 or 4, and more preferably 2 or 3.

[0135] Throughout this specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds, and compounds that can be used as pharmaceutically acceptable compounds and / or intermediate compounds that can be used in the preparation of pharmaceutically acceptable compounds. [Effects of the Invention]

[0136] The naphthylamide compounds of the specific structure of formula (I) of the present invention have excellent Aurora B kinase inhibitory activity, higher Aurora B kinase inhibitory selectivity than VEGFR2, and have a certain effect on tumor cell cycle, thereby achieving comprehensive benefits of better therapeutic efficacy / safety for related diseases. At the same time, in brain penetration tests, the ratio of compound concentration in brain tissue to plasma concentration of the compounds of the present invention was significantly higher than that of control molecule 01 (Chiauranib) and control molecule 02. This test result indicates that the compounds of the present invention have excellent brain barrier permeability, can cross the blood-brain barrier, and can achieve effective blood concentrations in brain tissue, and can be used for the treatment and prevention of central nervous system-related diseases. In addition, in mouse antitumor efficacy tests, the compounds of the present invention significantly reduced tumor volume and significantly improved tumor volume inhibition rates compared to control molecules 01 and 02. This test result indicates that the compounds of the present invention have excellent in vivo antitumor effect and can significantly inhibit tumor growth. [Brief explanation of the drawings]

[0137] [Figure 1] This shows a graph of changes in subcutaneous tumor volume in mice in each group during treatment with compound I-9 of the present invention, control molecule 01 (Chiauranib), and control molecule 02. The vertical axis represents the average tumor volume (mm), and the horizontal axis represents the number of days of treatment after grouping (days). DETAILED DESCRIPTION OF THE INVENTION

[0138] The examples and preparations provided herein further elucidate and exemplify the compounds described in this invention and the methods for preparing them. It should be understood that the following preparations and examples do not limit the scope of the present invention in any manner.

[0139] It is also to be understood that the terminology employed herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the presently described methods, devices, and materials are the preferred methods, devices, and materials.

[0140] LC-MS analysis method: Mass spectrometry conditions: the instrument was a Thermo ISQ EC, the ion source was ESI (EA+ EA-), the source temperature was 300°C, the sheath gas pressure was 50.0 psi, the auxiliary gas pressure was 5.0 psi, the purge gas pressure was 0.5 psi, and the temperature of the gasification chamber was 300°C.

[0141] Chromatography conditions: The instrument was a Thermo U3000, the detector was a DAD-3000 (RS) (diode array detector), the chromatography column was a Phenomenex Titank C18 3 μm 4.6 × 50 mm, the flow rate was 2.0 mL / min, the column temperature was 35 °C, the mobile phase A was water containing 0.05% formic acid and 5% acetonitrile, and the mobile phase B was acetonitrile containing 0.05% formic acid. The elution method was to linearly increase the A phase from 100% to 5% within 0 to 1.0 min, and then hold at 5% A for 1.2 min.

[0142] HPLC analysis method: The instrument was a Thermo U3000, the detector was a VWD-3x00 (RS) (ultraviolet detector), the wavelength was 254 nm, the chromatography column was a Shimadzu Inertsil 3 μm 4.6 x 150 mm, the flow rate was 0.8 mL / min, the column temperature was 35 °C, the mobile phase A was water containing 0.05% formic acid and 5% acetonitrile, and the mobile phase B was acetonitrile containing 0.05% formic acid. The elution method was to first hold at 100% A phase for 1.0 min, then linearly elute A phase from 100% to 5% within 1.0 to 8.0 min, and finally hold at 5% A phase for 4.0 min.

[0143] 1 H-NMR analysis method: 1 H-NMR was measured at room temperature using a BRUKER AVANCE-400 MHz nuclear magnetic resonance spectrometer in DMSO-d or CDCl using TMS as an internal standard. Signal peaks are represented as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), and dt (triple triplet). Coupling constants (J) are expressed in hertz (Hz).

[0144] According to the above-described method, the present invention has prepared representative compounds I-1 to I-44 (see Table 1), and their purity has been detected and recorded. Among them, five compounds (I-7, I-11, I-12, I-13, and I-14) are used as control compounds.

[0145] [Table 1] JPEG2026500760000038.jpg226170JPEG2026500760000039.jpg60170

[0146] The present invention will be further described below with reference to specific examples, but the scope of the present invention is not limited to these examples. All percentages described in the present invention are by weight unless otherwise specified. The units of measurement, reaction conditions, physical states of compounds, or numerical ranges, such as percentages, described in the specification are intended to provide a clear and unambiguous written reference. Those skilled in the art will appreciate that, when practicing the present invention, desired results can still be achieved even if temperatures, concentrations, amounts, carbon numbers, etc. outside these ranges or different from the individual numerical values ​​are used. Furthermore, unless otherwise specified, all raw materials in the following examples are commercially available and may be purchased from, for example, Shanghai Bitde Pharmaceutical Technology Co., Ltd., Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Shanghai Shaoyuan Reagents Co., Ltd., and Hechun Biotechnology (Shanghai) Co., Ltd.

[0147] [ka] Commercially available I-1a (2.0 g, 11.13 mmol, 1.0 eq) was dissolved in DMF (30 mL), and CsCO (10.88 g, 33.39 mmol, 3.0 eq) and I-1b (3.64 g, 33.39 mmol, 3.0 eq) were added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (150 mL). The precipitated solid was collected by filtration, rinsed three times with water (20 mL), and dried in a fan-air drying box at 50 °C for 8 h to give intermediate I-1c (2.23 g, 96.5% yield) as a yellow solid. LC-MS MS-ESI (m / z) 208.0 [M+H] + .

[0148] [ka] Intermediate I-1c (2.23 g, 10.74 mmol, 1.0 eq) was dissolved in DMSO (30 mL), CsCO (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, and the mixture was heated to 140 °C with stirring for 3 h and then cooled to room temperature. The reaction was quenched with water (150 mL), and the pH was adjusted to 6-7 with 1 N dilute hydrochloric acid. The precipitated solid was collected by filtration, rinsed three times with water (20 mL), and dried in a blast oven at 50 °C for 8 h to give intermediate I-1e (3.49 g, 90.4% yield) as a brown solid. LC-MS MS-ESI (m / z) 360.1 [M+H] + .

[0149] [ka] 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 h. The reaction was quenched with water (200 mL). The precipitated solid was collected by filtration, rinsed three times with water (20 mL), and dried in a blow-dry box at 50 °C for 8 h. The crude product was separated on a silica gel column (200-300 mesh silica gel, eluted with ethyl acetate (EA) / petroleum ether (PE) = 0-1) and then slurried in EA / PE = 1:1 (30 mL) to give a yellow solid I-1 (2.30 g, 52.7% yield). LC-MS MS-ESI (m / z) 450.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.96-7.83 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.58 (dd, J = 9.2, 2.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 9.1, 2.2 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 5.1 Hz, 1H), 5.00 (s, 2H), 4.23 (q, J = 6.9 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H).

[0150] [ka] 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) following the similar steps in Example I-1. (26.0 mg, 9.6% yield). LC-MS MS-ESI (m / z) 484.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.96-7.87 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.62-7.50 (m, 1H), 7.46-7.36 (m, 2H), 7.30 (d, J = 9.1 Hz, 1H), 6.85 (s, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 5.33 (s, 2H), 4.23 (q, J = 6.9 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H).

[0151] [ka] Intermediate I-3c, a yellow solid, was prepared from commercially available I-1a (1.79 g, 10.00 mmol, 1.0 eq), CsCO (4.15 g, 30.00 mmol, 3.0 eq), and I-3b (5.22 g, 30.00 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (1.86 g, 82.4% yield). LC-MS MS-ESI (m / z) 226.0 [M+H] + .

[0152] [ka] The brown solid intermediate I-3e was prepared from intermediate I-3c (1.86 g, 8.24 mmol, 1.0 eq), CsCO (8.86 g, 27.19 mmol, 3.3 eq), and commercially available I-1d (1.55 g, 8.24 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (2.25 g, 72.3% yield). LC-MS MS-ESI (m / z) 378.1 [M+H] + .

[0153] [ka] Yellow solid I-3 was prepared from intermediates 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) following the similar steps in Example I-1. (130.0 mg, 24.9% yield). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.51 (dd, J = 14.2, 6.1 Hz, 2H), 7.36 (dd, J = 9.1, 2.4 Hz, 1H), 6.60 (d, J = 5.2 Hz, 1H), 5.28 (s, 2H), 4.98-4.74 (m, 2H), 4.57- 4.35 (m, 2H).

[0154] [ka] 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) following the similar steps in Example I-1. (120.0 mg, 46.5% yield). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.96-7.81 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.63 (s, 1H), 6.58 (d, J = 4.7 Hz, 1H), 6.46 (d, J = 7.5 Hz, 1H), 4.92 (s, 2H), 4.23 (d, J = 6.8 Hz, 2H), 2.21 (s, 3H), 1.43 (t, J = 6.7 Hz, 3H).

[0155] [ka] 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) following the similar steps in Example I-1. (55.0 mg, 21.0% yield). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.81 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94-7.88 (m, 2H), 7.70-7.62 (m, 1H), 7.57 (dd, J = 9.2, 2.5 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.38-7.26 (m, 2H), 6.64-6.54 (m, 2H), 6.42 (td, J = 8.5, 2.8 Hz, 1H), 5.33 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H).

[0156] [ka] Intermediate I-1e (1.08 g, 3.00 mmol, 1.0 eq) was dissolved in ultra-dry DMF (15 mL). HATU (1.71 g, 4.50 mmol, 1.5 eq), DIEA (1.16 g, 9.00 mmol, 3.0 eq), and I-6f (432.00 mg, 3.00 mmol, 1.0 eq) were added and stirred at room temperature for 18 h. The reaction was quenched with water (150 mL). The precipitated solid was collected by filtration, rinsed three times with water (5 mL), and dried in a fan-air drying box at 50 °C for 8 h. The crude product was separated on a silica gel column (200-300 mesh silica gel, eluted with EA / PE = 0-1) and further slurried in EA / PE = 1:1 (30 mL) to give yellow solid I-6 (682.00 mg, 46.8% yield). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 8.62 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.88 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 9.1 Hz, 1H), 7.20 (s, 1H), 6.70-6.52 (m, 2H), 5.35 (s, 2H), 4.21 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H).

[0157] [ka] Intermediate I-7c, a yellow solid, was prepared from commercially available I-1a (230.00 mg, 1.28 mmol, 1.0 eq), CsCO (1.25 g, 3.84 mmol, 3.0 eq), and I-7b (652.80 mg, 3.84 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (263.00 mg, 92.7% yield). LC-MS MS-ESI (m / z) 222.1 [M+H] + .

[0158] [ka] Intermediate I-7e, a brown solid, was prepared from homemade intermediate I-7c (263.00 mg, 1.19 mmol, 1.0 eq), CsCO (1.28 g, 3.93 mmol, 3.3 eq), and commercially available I-1d (223.96 mg, 1.19 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (392.00 mg, 88.2% yield). LC-MS MS-ESI (m / z) 374.2 [M+H] +.

[0159] [ka] Yellow solid I-7 was prepared from intermediates 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) following the similar steps in Example I-1. (174.0 mg, 35.7% yield). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.89 (s, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 5.0 Hz, 1H), 5.01 (s, 2H), 4.87 (dt, J = 11.7, 5.8 Hz, 1H), 1.37 (d, J = 5.9 Hz, 6H).

[0160] [ka] Intermediate I-8c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), CsCO (9.79 g, 30.06 mmol, 3.0 eq), and I-8b (4.27 g, 30.06 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (1.77 g, 91.2% yield). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0161] [ka] Intermediate I-8e, a brown solid, was prepared from homemade I-8c (1.00 g, 5.16 mmol, 1.0 eq), CsCO (5.55 g, 17.03 mmol, 3.3 eq), and commercially available I-1d (971.11 mg, 5.16 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (1.41 g, 79.2% yield). LC-MS MS-ESI (m / z) 346.1 [M+H] + .

[0162] [ka] 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) following the similar steps in Example I-1. (42.00 mg, 27.67% yield). LC-MS MS-ESI (m / z) 506.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.98 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 6.9 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.69-7.61 (m, 1H), 7.58-7.49 (m, 2H), 7.43 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 9.1, 2.5 Hz, 1H), 6.57 (d, J = 5.2 Hz, 1H), 5.57 (s, 2H), 3.93 (s, 3H).

[0163] [ka] 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) and cooled to 0 °C in an ice bath. NaH (60% in mineral oil, 3.68 g, 0.092 mol, 2.0 eq) was added and the mixture was warmed to room temperature. Di-tert-butyl dicarbonate (BocO, 25.07 g, 0.115 mol, 2.5 eq) was added dropwise and stirred at room temperature for 18 h. The reaction mixture was quenched with ice / water (300 mL) and extracted twice with ethyl acetate (300 mL). 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, eluted with EA / PE=1 / 15) to give a pale yellow solid product I-9f-2 (15.2 g, 88.4% yield). 1 H-NMR (400MHz, CDCl3) δ ppm 7.97-7.93 (m, 1H), 7.35-7.29 (m, 1H), 1.43 (s, 18H).

[0164] [ka] 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 under a hydrogen atmosphere for 20 h. The insoluble material was removed by filtration through diatomaceous earth and rinsed three times with isopropanol (10 mL). The filtrate was concentrated to give the yellow solid product I-9f-3 (13.44 g, 96.1% yield). LC-MS MS-ESI (m / z) 345.1 [M+H] + .

[0165] [ka] 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, and the mixture was heated to 60 °C with stirring for 24 h. The mixture was then cooled to room temperature. The reaction mixture was concentrated, and the residue was diluted with water (200 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were washed once with saturated brine (300 mL), and concentrated. The crude product was separated on a silica gel column (200-300 mesh silica gel, eluted with EA / PE = 1 / 2) to give the pale yellow solid product I-9f (9.41 g, 98.7% yield). LC-MS MS-ESI (m / z) 189.1 [M-55] + . 1 H-NMR (400MHz, CDCl3) δ ppm 8.28 (brs, 1H), 7.02-6.95 (m, 1H), 6.46-6.43 (m, 1H), 4.93 (s, 2H), 1.43 (s, 9H).

[0166] [ka] Intermediate I-8e (200.00 mg, 0.58 mmol, 1.0 eq) was dissolved in ultra-dry THF (10 mL). 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'-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 243.60 mg, 0.87 mmol, 1.5 eq) were added and stirred at room temperature for 24 h. The reaction mixture was concentrated, and the crude product was separated on a silica gel column (200-300 mesh silica gel, eluted with EA / PE = 0-1) to give intermediate I-9g (157.0 mg, 47.3% yield) as a yellow solid. LC-MS MS-ESI (m / z) 572.2 [M+H] + .

[0167] [ka] 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 the mixture was stirred at room temperature for 18 h. 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, eluted with EA / PE = 0-1) to give a yellow solid I-9 (97.00 mg, 76.2% yield). LC-MS MS-ESI (m / z) 472.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.94 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.72-7.60 (m, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.30 (dd, J = 9.1, 2.5 Hz, 1H), 7.26-7.15 (m, 1H), 6.74-6.51 (m, 2H), 5.36 (s, 2H), 3.94 (s, 3H).

[0168] [ka] Yellow solid I-10 was prepared from intermediates 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) following the similar steps in Example I-1. (45.60 mg, 23.29% yield). LC-MS MS-ESI (m / z) 490.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.97-7.85 (m, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.59-7.46 (m, 2H), 7.43 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 9.1, 2.2 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H).

[0169] [ka] Intermediate I-11c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.00 mmol, 1.0 eq), CsCO (4.15 g, 30.00 mmol, 3.0 eq), and I-11b (3.66 g, 30.00 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (1.65 g, 74.3% yield). LC-MS MS-ESI (m / z) 222.0 [M+H] + .

[0170] [ka] The brown solid intermediate I-11e was prepared from 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) following the similar steps as in Example Intermediate I-1e (2.30 g, 82.8% yield). LC-MS MS-ESI (m / z) 374.1 [M+H] + .

[0171] [ka] Yellow solid I-11 was prepared from intermediates 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) following the similar steps in Example I-1. (590.00 mg, 36.6% yield). LC-MS MS-ESI (m / z) 464.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.91-7.86 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.57 (dd, J = 9.2, 2.4 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.31 (dd, J = 9.1, 2.4 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 5.2 Hz, 1H), 5.00 (s, 2H), 4.13 (t, J = 6.5 Hz, 2H), 1.90-1.77 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H).

[0172] [ka] Yellow solid I-12 was prepared from intermediates 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) following the similar steps in Example I-1. (100.00 mg, 38.5% yield). LC-MS MS-ESI (m / z) 482.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.93-7.88 (m, 2H), 7.71-7.60 (m, 1H), 7.57 (dd, J = 9.2, 2.5 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37-7.26 (m, 2H), 6.62-6.56 (m, 2H), 6.42 (td, J = 8.5, 2.8 Hz, 1H), 5.32 (s, 2H), 4.13 (t, J = 6.5 Hz, 2H), 1.90-1.76 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).

[0173] [ka] Intermediate I-13c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.00 mmol, 1.0 eq), CsCO (4.15 g, 30.00 mmol, 3.0 eq), and I-13b (4.11 g, 30.00 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (1.72 g, 73.0% yield). LC-MS MS-ESI (m / z) 236.1 [M+H] + .

[0174] [ka] The brown solid intermediate I-13e was prepared from the self-made 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) following the similar steps as in Example Intermediate I-1e (850.00 mg, 73.1% yield). LC-MS MS-ESI (m / z) 388.2 [M+H] + .

[0175] [ka] Yellow solid I-13 was prepared from intermediates 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) following the similar steps in Example I-1. (37.00 mg, 27.7% yield). LC-MS MS-ESI (m / z) 478.3 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91-7.86 (m, 2H), 7.70-7.63 (m, 1H), 7.57 (dd, J = 9.2, 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 9.1, 2.4 Hz, 1H), 7.00 (t, J = 7.1 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.64 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 5.2 Hz, 1H), 5.00 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 1.88-1.73 (m, 2H), 1.51 (dq, J = 14.7, 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0176] [ka] 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) following the similar steps in Example I-1. (1015.00 mg, 56.7% yield). LC-MS MS-ESI (m / z) 496.3 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.92-7.87 (m, 2H), 7.69-7.62 (m, 1H), 7.56 (dd, J = 9.2, 2.5 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37-7.25 (m, 2H), 6.67-6.51 (m, 2H), 6.41 (td, J = 8.5, 2.9 Hz, 1H), 5.32 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 1.87-1.71 (m, 2H), 1.61-1.44 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0177] [ka] Intermediate I-15g, a yellow solid, 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) following the same steps as in Example I-9g. (100.0 mg, 31.5% yield). LC-MS MS-ESI (m / z) 568.2 [M+H] + .

[0178] [ka] 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) following the similar steps in Example I-9. (60.00 mg, 71.3% yield). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.92-7.82 (m, 2H), 7.64 (t, J = 7.7 Hz, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.42-7.35 (m, 2H), 7.28 (dd, J = 9.1, 2.4 Hz, 1H), 6.88-6.76 (m, 2H), 6.56 (d, J = 5.2 Hz, 1H), 4.91 (s, 2H), 4.20 (q, J = 6.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H).

[0179] [ka] Intermediate I-16g, a yellow solid, 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) following the same steps as in Example Intermediate I-9g. (100.00 mg, 31.5% yield). LC-MS MS-ESI (m / z) 568.2 [M+H] + .

[0180] [ka] Yellow solid I-16 was prepared from intermediate I-16g (100.00 mg, 0.18 mmol, 1.0 eq) and TFA (1.5 mL) following the similar steps in Example I-9. (60.00 mg, 71.3% yield). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.94-7.88 (m, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.34-7.26 (m, 2H), 7.07-6.91 (m, 1H), 6.65 (dd, J = 14.0, 8.0 Hz, 1H), 6.59 (d, J = 5.2 Hz, 1H), 4.99 (s, 2H), 4.23 (q, J = 6.9 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H).

[0181] [ka] Commercially available I-17a-2 (51.10 g, 354.60 mmol, 1.0 eq) was dissolved in trimethyl orthoformate (300.0 mL), purged with nitrogen three times, heated to 105 °C, and stirred for 1 h. I-17a-1 (50.00 g, 354.60 mmol) was then added, and the mixture was stirred at the same temperature for 1 h and cooled to room temperature. n-Pentane (300 mL) was added, and the precipitated solid was collected by filtration, rinsed three times with n-pentane (30 mL), and dried in a fan-air drying box at 50 °C for 8 h to give intermediate I-17a-3 as a yellow solid (86.00 g, 82.2% yield). LC-MS MS-ESI (m / z) 296.1 [M+H]+ .

[0182] [ka] A mixture of I-17a-3 (60.00 g, 203.30 mmol, 1.0 eq) and diphenyl ether (500 mL) was heated to 220 °C, stirred for 1 h, and cooled to room temperature. Petroleum ether (500 mL) was added, and the precipitated solid was collected by filtration, rinsed three times with petroleum ether (50 mL), and dried. The crude product was separated using a reverse-phase C18 chromatography column (acetonitrile / water / 0.1% TFA, 12-13%) to give white solid I-17a-4 (18.00 g, 46.0% yield). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0183] [ka] 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 h, and cooled to room temperature. The reaction mixture was quenched by slowly adding ice / water, and the pH was adjusted to 6-7 with 10% NaOH solution. The precipitated solid was collected by filtration, rinsed three times with water (10 mL), and dried. The crude product was separated on a silica gel column (200-300 mesh silica gel, eluted with EA / PE = 1:1) to give intermediate I-17a-5 (16.10 g, 81.8% yield) as a yellow solid. LC-MS MS-ESI (m / z) 212.0 [M+H] + .

[0184] [ka] Intermediate I-17a-5 (12.00 g, 87.60 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (DCE, 100.0 mL) and cooled to 0 °C. A 1.0 M solution of boron tribromide in dichloromethane (198.80 mL, 198.80 mmol, 2.27 eq) was added dropwise. After the addition was complete, the mixture was heated to 100 °C, stirred for 8 h, and cooled to room temperature. The reaction was quenched by the slow addition of methanol (100 mL), water (300 mL), and the pH was adjusted to 12-13 with 10% NaOH solution. The organic and aqueous phases were separated, and the aqueous phase was adjusted to pH 5-6 with 2 M dilute hydrochloric acid. The precipitated solid was collected by filtration, rinsed three times with water (10.0 mL), and dried in a blast oven at 50 °C for 8 h to give intermediate I-17a as a yellow solid (9.10 g, 80.2% yield). LC-MS MS-ESI (m / z) 198.0 [M+H] + . 1 H-NMR(400 MHz, DMSO-d6)δ ppm 10.82 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.19 (s, 1H), 7.08 (dd, J = 14.0, 2.3 Hz, 1H).

[0185] [ka] Pale yellow solid intermediate I-17c was prepared from intermediate I-17a (800.00 mg, 4.05 mmol, 1.0 eq), CsCO (3.96 g, 12.15 mmol, 3.0 eq) and I-1b (1.32 g, 12.15 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (810.00 mg, 88.7% yield). LC-MS MS-ESI (m / z) 226.0 [M+H] + .

[0186] [ka] Intermediate I-17e, a brown solid, was prepared from intermediate I-17c (450.00 mg, 2.00 mmol, 1.0 eq), CsCO (2.15 g, 6.60 mmol, 3.3 eq), and commercially available I-1d (376.40 mg, 2.00 mmol, 1.0 eq) following the same steps as in Example Intermediate I-1e (640.00 mg, 84.8% yield). LC-MS MS-ESI (m / z) 378.2 [M+H] + .

[0187] [ka] Yellow solid I-17 was prepared from intermediates 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) following the similar steps in Example I-1. (99.00 mg, 23.5% yield). LC-MS MS-ESI (m / z) 467.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 6.7 Hz, 1H), 7.81 (s, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.29 (s, 1H), 7.12 (d, J = 13.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.71-6.52 (m, 2H), 4.98 (s, 2H), 4.33-4.12 (m, 2H), 1.40 (t, J = 6.7 Hz, 3H).

[0188] [ka] Yellow solid I-18 was prepared from intermediates 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) following the similar steps in Example I-1. (282.00 mg, 64.5% yield). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.03 (s, 1H), 8.65 (d, J = 5.0 Hz, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 6.6 Hz, 1H), 7.83 (s, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.38-7.23 (m, 2H), 7.14 (d, J = 13.3 Hz, 1H), 7.06-6.91 (m, 1H), 6.65 (d, J = 4.9 Hz, 2H), 4.99 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 1.42 (t, J = 6.7 Hz, 3H).

[0189] [ka] Yellow solid I-19 was prepared from intermediates 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) following the similar steps in Example I-1. (164.00 mg, 36.2% yield). LC-MS MS-ESI (m / z) 504.2 [M+H]+ . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.0 Hz, 1H), 7.83 (s, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.55 (dd, J = 9.2, 2.0 Hz, 1H), 7.31 (s, 1H), 7.28-7.18 (m, 1H), 7.14 (dd, J = 13.4, 1.9 Hz, 1H), 6.69-6.58 (m, 2H), 5.37 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 1.42 (t, J = 6.9 Hz, 3H).

[0190] [ka] Intermediate I-20g, a yellow solid, 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) following the same steps as in Example I-9g. (152.00 mg, 28.8% yield). LC-MS MS-ESI (m / z) 586.2 [M+H] + .

[0191] [ka] Yellow solid I-20 was prepared from intermediate I-20g (152.0 mg, 0.26 mmol, 1.0 eq) and TFA (1.5 mL) following the similar steps in Example I-9. (32.00 mg, 25.3% yield). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.83 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.60-7.51 (m, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.20-7.08 (m, 1H), 6.92-6.75 (m, 2H), 6.66 (d, J = 5.2 Hz, 1H), 4.93 (s, 2H), 4.24 (q, J = 6.9 Hz, 2H), 1.42 (t, J = 6.9 Hz, 3H).

[0192] [ka] Commercially available I-21b-1 (3.0 g, 24.01 mmol, 1.0 eq) was dissolved in DCM / HO (30 mL / 30 mL), KOAc (14.50 g, 148.00 mmol, 6.16 eq) was added, and the mixture was cooled to 0 °C in 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 h. The reaction was quenched with saturated NaHCO solution (100 mL) and extracted twice with DCM (50 mL). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure below 5 °C to give intermediate I-21b (1.10 g, 26.2% yield). LC-MS MS-ESI (m / z) 175.0 [M+H] + .

[0193] [ka] Intermediate I-21c, a yellow solid, was prepared from commercially available I-1a (2.0 g, 11.13 mmol, 1.0 eq), CsCO (10.88 g, 33.39 mmol, 3.0 eq), and homemade intermediate I-21b (2.92 g, 16.69 mmol, 1.5 eq) following the similar steps in Example Intermediate I-1c. (2.46 g, 80.7% yield). LC-MS MS-ESI (m / z) 274.0 [M+H] + .

[0194] [ka] Intermediate I-21e, a brown solid, was prepared from intermediate I-21c (2.46 g, 8.99 mmol, 1.0 eq), CsCO (9.67 g, 29.67 mmol, 3.3 eq), and commercially available I-1d (1.69 g, 8.99 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e. (3.42 g, 89.4% yield). LC-MS MS-ESI (m / z) 426.1 [M+H] + .

[0195] [ka] Yellow solid I-21 was prepared from intermediates 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) following the similar steps in Example I-1. (514.00 mg, 33.4% yield). LC-MS MS-ESI (m / z) 515.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.05 (d, J = 6.5 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.23 ​​(d, J = 9.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 6.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.53 (dd, J = 9.2, 2.5 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 9.1, 2.4 Hz, 1H), 6.78 (t, 2 J F-H = 75.7 Hz, 1H), 6.57 (d, J = 5.2 Hz, 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).

[0196] [ka] 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) following the similar steps in Example I-1. (596.00 mg, 36.3% yield). LC-MS MS-ESI (m / z) 552.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.75-7.63 (m, 1H), 7.58 (dd, J = 9.2, 2.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 9.2, 2.5 Hz, 1H), 7.30-7.16 (m, 1H), 6.81 (t, 2 J F-H = 75.7 Hz, 1H), 6.70-6.55 (m, 2H), 5.38 (s, 2H), 4.40 (dd, J = 5.4, 2.9 Hz, 2H), 4.27 (dd, J = 5.2, 3.0 Hz, 2H).

[0197] [ka] The 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) following the similar steps as in Example Intermediate I-1c (2.10 g, 79.4% yield). LC-MS MS-ESI (m / z) 238.1 [M+H] + .

[0198] [ka] Intermediate I-23e, a brown solid, was prepared from intermediate I-23c (2.10 g, 8.83 mmol, 1.0 eq), CsCO (9.50 g, 29.14 mmol, 3.3 eq), and commercially available I-1d (1.66 g, 8.83 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (3.12 g, 90.7% yield). LC-MS MS-ESI (m / z) 390.1 [M+H] + .

[0199] [ka] Yellow solid I-23 was prepared from intermediates 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) following the similar steps in Example I-1. (385.00 mg, 20.9% yield). LC-MS MS-ESI (m / z) 479.2 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ ppm 8.62 (d, J = 5.2 Hz, 1H), 8.47 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.67-7.61 (m, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.48-7.41 (m, 2H), 7.33 (d, J = 9.2 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 6.31 (d, J = 6.8 Hz, 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).

[0200] [ka] 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) following the similar steps in Example I-1. (85.00 mg, 43.8% yield). LC-MS MS-ESI (m / z) 485.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J = 7.3 Hz, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.05-8.00 (m, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.63-7.59 (m, 2H), 7.55 (dd, J = 9.2, 2.5 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 9.1, 2.4 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 4.67 (s, 2H), 4.53 (s, 2H), 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).

[0201] [ka] 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) following the similar steps in Example I-1. (93.00 mg, 48.2% yield). LC-MS MS-ESI (m / z) 483.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J = 6.8 Hz, 1H), 8.64 (d, J = 4.5 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.66-7.50 (m, 3H), 7.46 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 4.5 Hz, 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).

[0202] [ka] Yellow solid I-26 was prepared from intermediates 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) following the similar steps in Example I-1. (40.00 mg, 21.8% yield). LC-MS MS-ESI (m / z) 471.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.01 (d, J = 6.9 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.64-7.51 (m, 3H), 7.47 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 9.1, 2.1 Hz, 1H), 6.58 (d, J = 5.1 Hz, 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 = 12.1 Hz, 1H), 1.45-1.26 (m, 4H), 1.23-1.09 (s, 1H).

[0203] [ka] Yellow solid I-27 was prepared from intermediate I-23e (150.00 mg, 0.39 mmol, 1.0 eq), HATU (220.40 g, 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) following the similar steps in Example I-1. (40.00 mg, 22.3% yield). LC-MS MS-ESI (m / z) 461.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, J = 6.9 Hz, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.69-7.58 (m, 2H), 7.54 (dd, J = 9.2, 2.4 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 9.1, 2.4 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 5.41-5.15 (m, 1H), 4.64 (d, J = 3.7 Hz, 1H), 4.36-4.25 (m, 2H), 3.80-3.71 (m, 2H), 3.35 (s, 3H), 2.64-2.43 (m, 4H).

[0204] [ka] Pale 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) following the similar steps in Example Intermediate I-1c. (541.00 mg, 92.8% yield). LC-MS MS-ESI (m / z) 292.0 [M+H] + .

[0205] [ka] Intermediate I-28e, a brown solid, was prepared from intermediate I-28c (541.00 mg, 1.86 mmol, 1.0 eq), CsCO (2.00 g, 6.14 mmol, 3.3 eq), and commercially available I-1d (349.68 mg, 1.86 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (702.00 mg, 85.1% yield). LC-MS MS-ESI (m / z) 444.1 [M+H] + .

[0206] [ka] Yellow solid I-28 was prepared from intermediates 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) following the similar steps in Example I-1. (259.00 mg, 32.6% yield). LC-MS MS-ESI (m / z) 552.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 6.7 Hz, 1H), 7.85 (s, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 13.0 Hz, 1H), 7.02-6.94 (m, 1H), 6.80 (t, 2 J F-H = 72.0 Hz, 1H), 6.73-6.63 (m, 2H), 5.00 (s, 2H), 4.48-4.38 (m, 2H), 4.31-4.22 (m, 2H).

[0207] [ka] Yellow solid I-29 was prepared from intermediates 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) following the similar steps in Example I-1. (182.00 mg, 34.2% yield). LC-MS MS-ESI (m / z) 533.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, J = 6.4 Hz, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.64-7.57 (m, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 7.20 (d, J = 13.2 Hz, 1H), 6.79 (t, 2 J F-H = 75.7 Hz, 1H), 6.65 (d, J = 5.1 Hz, 1H), 4.52-4.31 (m, 3H), 4.25 (s, 2H), 3.15-2.95 (m, 2H), 2.90-2.67 (m, 2H).

[0208] [ka] Yellow solid I-30 was prepared from intermediates 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) following the similar steps in Example I-1. (1.20 g, 60.5% yield). LC-MS MS-ESI (m / z) 468.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.89 (t, J = 4.5 Hz, 2H), 7.71-7.62 (m, 1H), 7.58 (dd, J = 9.2, 2.5 Hz, 1H), 7.48 (t, J = 9.4 Hz, 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 = 5.2 Hz, 1H),5.00 (s, 2H), 4.94-4.87 (m, 1H), 4.79 (dd, J = 4.5, 2.9 Hz, 1H), 4.52-4.46 (m, 1H), 4.47-4.37 (m, 1H).

[0209] [ka] 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) following the similar steps in Example I-1. (187.00 mg, 58.1% yield). LC-MS MS-ESI (m / z) 486.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.95-7.87 (m, 2H), 7.73-7.62 (m, 1H), 7.59 (dd, J = 9.2, 2.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 9.1, 2.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.05- 6.95 (m, 1H), 6.70-6.63 (m, 1H), 6.61 (d, J = 5.2 Hz, 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).

[0210] [ka] Yellow solid I-32 was prepared from intermediates 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) following the similar steps in Example I-1. (80.00 mg, 30.0% yield). LC-MS MS-ESI (m / z) 504.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.69-7.62 (m, 1H), 7.56 (dd, J = 9.2, 2.4 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 9.1, 2.5 Hz, 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).

[0211] [ka] Yellow solid I-33 was prepared from intermediates 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) following the similar steps in Example I-1. (66.00 mg, 35.3% yield). LC-MS MS-ESI (m / z) 467.2 [M+H] +. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.09 (d, J = 6.6 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.66-7.60 (m, 1H), 7.57 (dd, J = 9.2, 2.5 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 9.2, 2.5 Hz, 1H), 6.60 (d, J = 5.2 Hz, 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).

[0212] [ka] 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) following the similar steps in Example I-1. (57.00 mg, 31.2% yield). LC-MS MS-ESI (m / z) 457.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (d, J = 7.2 Hz, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 9.1 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.69-7.58 (m, 2H), 7.56 (dd, J = 9.2, 2.2 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 9.1, 2.2 Hz, 1H), 6.60 (d, J = 5.2 Hz, 1H), 4.86 (d, J = 47.8 Hz, 2H), 4.75-4.65 (m, 1H), 4.47 (d, J = 30.3 Hz, 2H), 2.46-2.28 (m, 4H), 0.57-0.40 (m, 4H).

[0213] [ka] Yellow solid I-35 was prepared from intermediates 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) following the similar steps in Example I-1. (40.00 mg, 21.8% yield). LC-MS MS-ESI (m / z) 459.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J = 5.1 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.29 (dd, J = 19.6, 9.2 Hz, 2H), 8.00 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.63 -7.51 (m, 3H), 7.48 (s, 1H), 7.35 (dd, J = 9.1, 1.9 Hz, 1H), 6.57 (d, J = 5.1 Hz, 1H), 4.85 (d, J = 47.9 Hz, 2H), 4.46 (d, J = 30.2 Hz, 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).

[0214] [ka] Intermediate I-36e, a brown solid, was prepared from intermediate I-17a-5 (800.00 mg, 3.78 mmol, 1.0 eq), CsCO (4.07 g, 12.47 mmol, 3.3 eq), and commercially available I-1d (710.64 mg, 3.78 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (1.00 g, 72.8% yield). LC-MS MS-ESI (m / z) 364.1 [M+H] + .

[0215] [ka] 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) following the similar steps in Example I-1. (120.00 mg, 43.1% yield). LC-MS MS-ESI (m / z) 506.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 8.66 (d, J = 4.7 Hz, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 6.6 Hz, 1H), 7.83 (s, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.45-7.30 (m, 2H), 7.16 (d, J = 13.2 Hz, 1H), 6.72-6.60 (m, 2H), 5.55 (s, 2H), 3.96 (s, 3H).

[0216] [ka] Intermediate I-37g, a yellow solid, 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) following the same steps as in Example I-9g. (462.00 mg, 40.6% yield). LC-MS MS-ESI (m / z) 590.2 [M+H] + .

[0217] [ka] 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) following the similar steps in Example I-9. (263.0 mg, 68.9% yield). LC-MS MS-ESI (m / z) 490.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.67 (d, J = 5.3 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.76-7.60 (m, 1H), 7.56 (dd, J = 9.2, 2.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.27-7.19 (m, 1H), 7.17 (dd, J = 13.4, 2.4 Hz, 1H), 6.77-6.51 (m, 2H), 5.37 (s, 2H), 3.96 (s, 3H).

[0218] [ka] Pale yellow solid intermediate I-38c was prepared from intermediate I-17a (396.00 mg, 2.00 mmol, 1.0 eq), CsCO (1.95 g, 6.00 mmol, 3.0 eq) and I-30b (1.04 g, 6.00 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (460.00 mg, 94.4% yield). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0219] [ka] Intermediate I-38e, a brown solid, was prepared from intermediate I-38c (460.00 mg, 1.89 mmol, 1.0 eq), CsCO (2.03 g, 6.24 mmol, 3.3 eq), and commercially available I-1d (355.70 mg, 1.89 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e. (680.00 mg, 91.0% yield). LC-MS MS-ESI (m / z) 396.1 [M+H] + .

[0220] [ka] 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) following the similar steps in Example I-1. (396.00 mg, 44.1% yield). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.71 -7.62 (m, 1H), 7.56 (dd, J = 9.2, 2.5 Hz, 1H), 7.38 (d, J = 2.1 Hz, 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).

[0221] [ka] I-39a-1 (10.00 g, 70.85 mmol, 1.0 eq) was dissolved in isopropanol (200 mL), I-39a-2 (15.80 g, 84.87 mmol, 1.2 eq) was added, and the resulting mixture was heated to 70 °C and stirred for 2 h. After cooling to room temperature, n-pentane (200 mL) was added, and the precipitated solid was collected by filtration, rinsed three times with isopropanol / n-pentane (1:1, 10 mL), and dried in a blow-drying oven at 50 °C for 8 h to give intermediate I-39a-3 as a white solid (17.0 g, 81.2% yield). LC-MS MS-ESI (m / z) 296.1 [M+H] + .

[0222] [ka] Intermediate I-39a-4, a white solid, was prepared from intermediate I-39a-3 (12.00 g, 40.64 mmol, 1.0 eq) and diphenylether (300 mL) following the similar steps in Example I-17a-4 (5.50 g, 70.0% yield). LC-MS MS-ESI (m / z) 194.0 [M+H] + .

[0223] [ka] Intermediate I-39a-5, a white solid, was prepared from intermediate I-39a-4 (5.50 g, 28.47 mmol, 1.0 eq) and phosphorus oxychloride (30.0 mL) following the similar steps in Example I-17a-5 (4.50 g, 74.7% yield). LC-MS MS-ESI (m / z) 212.0 [M+H] + .

[0224] [ka] Intermediate I-39a, a yellow solid, was prepared from intermediate I-39a-5 (4.50 g, 21.27 mmol, 1.0 eq), a 1.0 M solution of boron tribromide in dichloromethane (75 mL, 75.00 mmol, 3.53 eq), and 1,2-dichloroethane (DCE, 210 mL) following the same procedure as in Example I-17a (2.10 g, 50.0% yield). LC-MS MS-ESI (m / z) 198.0 [M+H] + . 1 H-NMR(400 MHz, DMSO-d6)δ ppm 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).

[0225] [ka] The pale yellow solid intermediate I-39c was prepared from intermediate I-39a (396.00 mg, 2.00 mmol, 1.0 eq), CsCO (1.95 g, 6.00 mmol, 3.0 eq) and I-30b (1.04 g, 6.00 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (480.00 mg, 98.5% yield). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0226] [ka] Intermediate I-39e, a brown solid, was prepared from intermediate I-39c (480.00 mg, 1.97 mmol, 1.0 eq), CsCO (2.12 g, 6.50 mmol, 3.3 eq), and commercially available I-1d (370.75 mg, 1.97 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (710.00 mg, 91.1% yield). LC-MS MS-ESI (m / z) 396.1 [M+H] + .

[0227] [ka] 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) following the similar steps in Example I-1. (54.00 mg, 5.8% yield). LC-MS MS-ESI (m / z) 522.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.65 (d, J = 5.1 Hz, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.09 (t, J = 10.8 Hz, 2H), 8.02-7.87 (m, 2H), 7.79-7.62 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.29-7.17 (m, 1H), 6.76-6.53 (m, 2H), 5.37 (s, 2H), 4.88 (d, J = 47.8 Hz, 2H), 4.56 (d, J = 29.7 Hz, 2H).

[0228] [ka] Pale 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) following the similar steps as in Example Intermediate I-1c. (2.25 g, 92.9% yield). LC-MS MS-ESI (m / z) 242.0 [M+H] + .

[0229] [ka] Intermediate I-40e, a brown solid, was prepared from intermediate I-40c (2.25 g, 9.29 mmol, 1.0 eq), CsCO (9.98 g, 30.65 mmol, 3.3 eq), and commercially available I-1d (1.75 g, 9.29 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (3.20 g, 87.46% yield). LC-MS MS-ESI (m / z) 394.1 [M+H] + .

[0230] [ka] Yellow solid I-40 was prepared from intermediates 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) following the similar steps in Example I-1. (42.00 mg, 23.5% yield). LC-MS MS-ESI (m / z) 447.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (d, J = 7.6 Hz, 1H), 8.66 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 9.1, 2.3 Hz, 1H), 6.60 (d, J = 5.2 Hz, 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).

[0231] [ka] Intermediate I-41c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), CsCO (9.79 g, 30.06 mmol, 3.0 eq), and I-41b (4.36 g, 30.06 mmol, 3.0 eq) following the similar steps as in Example Intermediate I-1c. (1.70 g, 69.6% yield). LC-MS MS-ESI (m / z) 244.0 [M+H] + .

[0232] [ka] Intermediate I-41e, a brown solid, was prepared from homemade intermediate I-41c (731.00 mg, 3.00 mmol, 1.0 eq), CsCO (3.22 g, 9.90 mmol, 3.3 eq), and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (800.00 mg, 67.4% yield). LC-MS MS-ESI (m / z) 396.1 [M+H] + .

[0233] [ka] Yellow solid I-41 was prepared from intermediates 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-41f (40.20 mg, 0.28 mmol, 1.0 eq) following the similar steps in Example I-1. (40.00 mg, 29.5% yield). LC-MS MS-ESI (m / z) 485.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.09 (d, J = 6.5 Hz, 1H), 8.68 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 6.7 Hz, 1H), 7.67-7.60 (m, 1H), 7.59-7.53 (m, 2H), 7.40 (dd, J = 9.2, 2.3 Hz, 1H), 6.62 (d, J = 5.2 Hz, 1H), 6.52 (tt, J = 56.0, 3.2 Hz, 1H),4.57 (td, J = 14.7, 3.2 Hz, 2H), 4.45-4.30 (m, 1H), 3.13 -2.96 (m, 2H), 2.88-2.70 (m, 2H).

[0234] [ka] Intermediate I-42c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), CsCO (9.79 g, 30.06 mmol, 3.0 eq), and I-42b (2.33 g, 10.02 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1c. (1.60 g, 63.7% yield). LC-MS MS-ESI (m / z) 251.1 [M+H] + .

[0235] [ka] Intermediate I-42e, a brown solid, was prepared from homemade intermediate I-42c (752.10 mg, 3.00 mmol, 1.0 eq), CsCO (3.22 g, 9.90 mmol, 3.3 eq), and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (800.00 mg, 66.2% yield). LC-MS MS-ESI (m / z) 403.2 [M+H] + .

[0236] [ka] Yellow solid I-42 was prepared from intermediates 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) following the similar steps in Example I-1. (40.00 mg, 29.1% yield). LC-MS MS-ESI (m / z) 492.2 [M+H] + .

[0237] [ka] Intermediate I-43c, a yellow solid, was prepared from commercially available I-1a (1.80 g, 10.02 mmol, 1.0 eq), CsCO (9.79 g, 30.06 mmol, 3.0 eq), and I-43b (1.78 g, 10.02 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1c. (1.60 g, 57.7% yield). LC-MS MS-ESI (m / z) 277.1 [M+H] + .

[0238] [ka] Intermediate I-43e, a brown solid, was prepared from homemade intermediate I-43c (830.40 mg, 3.00 mmol, 1.0 eq), CsCO (3.22 g, 9.90 mmol, 3.3 eq), and commercially available I-1d (564.60 mg, 3.00 mmol, 1.0 eq) following the similar steps as in Example Intermediate I-1e (850.00 mg, 66.1% yield). LC-MS MS-ESI (m / z) 429.2 [M+H] + .

[0239] [ka] 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) following the similar steps in Example I-1. (40.00 mg, 25.7% yield). LC-MS MS-ESI (m / z) 555.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.71-7.63 (m, 1H), 7.57 (dd, J = 9.2, 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 9.1, 2.5 Hz, 1H), 7.27 -7.19 (m, 1H), 6.72-6.56 (m, 2H), 5.38 (s, 2H), 4.27 (t, J = 5.8 Hz, 2H), 2.89 (t, J = 5.7 Hz, 2H), 2.65-2.52 (m, 4H), 1.83-1.58 (mm, 4H).

[0240] [ka] Yellow solid I-44 was prepared from intermediates 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) following the similar steps in Example I-1. (65.00 mg, 22.65% yield). LC-MS MS-ESI (m / z) 504.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.03 (s, 1H), 8.64 (d, J = 4.9 Hz, 1H), 8.43 (d, J = 9.1 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.98-7.87 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.60-7.46 (m, 2H), 7.42 (s, 1H), 7.30 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 4.9 Hz, 1H), 5.27 (s, 2H), 4.23 (d, J = 6.9 Hz, 2H), 1.43 (t, J = 6.7 Hz, 3H).

[0241] Other compounds of the present invention may also be prepared by following analogous steps in the above examples.

[0242] In vitro biological evaluation Example A: Inhibitory activity and relative selectivity test of the compounds of the present invention against Aurora B and VEGFR2 kinase Preparation of DMSO working solutions of gradient concentrations of compounds: Compounds were prepared in 0.2 mM DMSO solutions and diluted in DMSO to 10 gradient concentrations (corresponding to final compound concentrations 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 in the reaction system).

[0243] Aurora B kinase and VEGFR2 inhibitory activity test: The half inhibitory concentration (IC) of compounds against Aurora B kinase and VEGFR2 was measured using the HTRF KinEASE-TK kit (Cisbio, Catalog No. 62TK0PEC) and the HTRF KinEASE-STK kit (Cisbio, Catalog No. 61ST2BLE). 50) were tested. 2x kinase & metal solution (Aurora B / catalog number 05-102 and VEGFR2 / catalog number 08-191 were both purchased from Carna) and 2x substrate & ATP solution (substrates S2 and TK were used for Aurora B and VEGFR2, respectively) were prepared according to the reagent kit instructions. 25 nL of each concentration gradient working solution of the compound to be measured and 2.5 μL of 2x kinase & metal solution were added to each well of a 384-well plate. The plate was blocked with blocking film, mixed uniformly, centrifuged, and then incubated at 25°C for 10 minutes. Next, 2.5 μL of 2x substrate & ATP solution was added to each well, and the plate was again incubated at 25°C for 30 minutes. Finally, 5 μL of 2×XL665 & Antibody kinase detection reaction solution was added to each well, and after incubation at 25° C. for 60 minutes, the fluorescent signals of each well were read at wavelengths of 665 nm and 620 nm using a microplate reader.

[0244] The 665 nm / 620 nm fluorescence signal ratio (X) of each well was calculated. The compound-free wells were used as negative references (Y) and enzyme-free wells as positive references (Z). The inhibitory rate of the compound against the corresponding kinase in each test well was calculated using the formula: Inhibition (%) = 100% - (XZ) / (YZ) × 100%. The half inhibitory concentration (IC) of each compound against the corresponding kinase was calculated using GraphPad 7.0 software. 50 ) was calculated.

[0245] The relative selectivity of inhibitory potency against Aurora B kinase was determined by the IC 50 and IC for Aurora B 50 The ratio of IC 50-VEGFR2 / I C 50-Aurora B The larger the ratio, the stronger the inhibitory potency of the compound against Aurora B kinase compared to VEGFR2. Specific data are shown in Table 2 below.

[0246] [Table 2]

[0247] Compounds No. 31 (Chiauranib) and No. 32 are examples disclosed in Patent CN101906076A, and the present inventors have synthesized these two compounds by referring to the synthetic methods therein for use as control molecules. The structural formulas of these two compounds are as follows:

[0248] [ka] The results in Table 2 show that the compounds of the present invention have excellent Aurora B kinase inhibitory activity and, at the same time, extremely high Aurora B kinase selectivity compared to VEGFR2. Specifically, compared with control molecule 01 (Chiauranib), control molecule 02, and control examples I-7, I-11, I-12, I-13, and I-14, the compounds of the present invention not only have stronger inhibitory effects on Aurora B kinase, but also have Aurora B IC50s of 10 nM or less. At the same time, the compounds of the present invention have extremely high Aurora B kinase selectivity compared to VEGFR2, with IC50-VEGFR2 / IC50-Aurora B being 7 or greater, achieving an unexpected technical effect.

[0249] Example B: Testing the effect of compounds of the invention on tumor cell cycle Inhibition of Aurora B kinase activity in tumor cells leads to the failure of cytokinesis due to the disruption of chromosome alignment and segregation, resulting in the formation of tetraploids or polyploids, and severe genomic instability and mitotic catastrophe, leading to apoptosis. The fluorescent dye propidium iodide (PI), which specifically binds to nucleic acids, can be used to measure intracellular DNA content, which can then be classified into sub-G0 / G1 (apoptosis), G0 / G1, S, G2 / M (tetraploid), and polyploid states. Sub-G0 / G1 is a state in which the DNA content is less than 2N and is generally considered to be a state in which cells are undergoing apoptosis (random DNA degradation, cell membrane permeation), while polyploid is a state in which the DNA content is greater than 4N.

[0250] Testing Procedure: Human acute lymphoblastic leukemia cells Molt-4 (CRL-1582) were purchased from the American Type Culture Collection (ATCC). Molt-4 cells were cultured in suspension and counted during logarithmic growth. 6 Cells were seeded into 6-well plates at 100 cells / well and cultured overnight as usual. Test compounds were prepared in 1 mM and 3 mM DMSO solutions, which were then further diluted 50-fold with culture medium. Finally, the above solutions were added to the culture system at a volume ratio of 1:19 so that the final compound concentration in each well reached 1 μM or 3 μM, respectively. After 48 hours of culture, the cells were collected by centrifugation. Each cell sample was resuspended in 300 μl of PBS and added dropwise to 700 μl of pre-chilled absolute ethanol. The mixture was then gently inverted several times to mix evenly. Cell collection and fixation were completed, and the samples were then left at 4°C for at least 12 hours before flow cytometry analysis.

[0251] PBS was mixed uniformly with 10 mg / mL PI stock solution and 10 mg / mL RNase A solution at a ratio of 1000:5:2 to prepare the working solution. The fixed cell samples were centrifuged at 1000 rpm at 4°C for 10 minutes, the supernatant was removed by aspiration, and the cells were washed twice with PBS and resuspended in the working solution at 300 μL per tube. After incubation at 37°C for 30 minutes in the dark, the cells were filtered through a 200-mesh stainless steel mesh, and the filtrate was subjected to flow cytometric cell cycle analysis (10,000 cells were counted per sample).

[0252] Histograms showing DNA content were obtained by flow cytometry, and the cycle distribution in each sample was analyzed using the flow data analysis software FlowJo. The mean (X) and standard deviation (SD) were calculated, and the data were expressed as X ± SD. After treating Molt-4 with different doses of the test compounds, the proportions of apoptotic cells, tetraploids, and polyploids were shown in Table 3 below.

[0253] [Table 3]

[0254] The results in Table 3 show that, at both the 1 μM and 3 μM doses, the compounds of the present invention have significantly improved effects on inducing tetraploidy, polyploidy, and apoptosis in Molt-4 cells compared with the control molecule 01 (Chiauranib) and the control molecule 02. This demonstrates that the compounds of the present invention have a stronger inhibitory effect on Aurora B kinase activity in tumor cells, thereby affecting the cell cycle of tumor cells and achieving overall benefits of better therapeutic efficacy / safety against related diseases.

[0255] Example C Brain penetration test of compounds of the present invention To test whether the compounds of the present invention can cross the blood-brain barrier (BBB), 6-week-old B / C female mice (purchased from the Guangdong Provincial Medical Animal Experimental Center) were used. The compounds of the present invention were prepared in a solvent containing 5% dimethyl sulfoxide, 60% 1,3-propanediol, and 35% purified water. 5 mg / kg of the compounds were administered intragastrically. Four hours after administration, the animals were sacrificed and blood and brain tissue were collected. Blood was anticoagulated with K2-EDTA and centrifuged at 5000 rpm for 5 minutes to separate the plasma. Brain tissue was accurately weighed and homogenized in a fixed amount of phosphate buffered saline (PBS). The biological samples were frozen and stored at -80°C for analysis. After sample extraction, the compound concentrations were measured using a liquid chromatography-mass spectrometer (LC-MS / MS). Brain penetration is defined as the ratio of the compound concentration in brain tissue to that in plasma.

[0256] [Table 4]

[0257] As shown by the results in Table 4, in the brain penetration detection, 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 achieve effective blood concentrations in brain tissue, and can be used for the treatment and prevention of central nervous system-related diseases.

[0258] Example D Antitumor effect experiment of the compound of the present invention in PANC02 mouse pancreatic cancer model A mouse PANC02 pancreatic cancer transplantation model was established using C57BL / 6 mice (female, 6 weeks old), PANC02 (mouse pancreatic cancer cells), and the cell culture medium was DMEM containing 1% double antibody and 10% fetal bovine serum. PANC02 cells in the logarithmic growth phase and proliferating well were collected and cultured at a concentration of 0.9 × 10 6 The tumor was subcutaneously inoculated into the left side of a C57BL / 6 mouse at a concentration of 0.2 ml / cell. The major axis (a, mm) and minor axis (b, mm) of the tumor were measured using a caliper, and the tumor volume (V, mm) was calculated.3 ) is calculated as V=1 / 2a*b 2 Tumor volumes were measured 2-3 times a week using calipers. The average tumor volume in mice was 190 mm 3 Once the animals reached this level, they were divided into groups of 8 animals each. The day of grouping was Day 0 (i.e., Day 0). They were divided into a total of 4 groups: the solvent control group (0.2% CMC-Na aqueous solution), compound I-9 group (10 mg / kg / day), control molecule 01 group (Chiauranib) (10 mg / kg / day), and control molecule 02 group (10 mg / kg / day). All 4 groups were intragastrically administered once daily, and the experiment was terminated on the day of the final administration.

[0259] The tumor volume results were expressed as the mean and standard deviation (Mean ± SEM). Comparisons between two groups were detected using the Mann-Whitney test. A p<0.05 was considered statistically significant. The tumor volume inhibition rate (TGI) was calculated as follows: TGI (%) = [1-(Ti-T0) / (Vi-V0)] × 100%. (Ti: mean tumor volume of the treatment group on day i of administration; T0: mean tumor volume of the treatment group on day 0 of administration; Vi: mean tumor volume of the vehicle control group on day i of administration; and V0: mean tumor volume of the vehicle control group on day 0 of administration.) The average tumor volume and tumor volume inhibition rate of mice in each group on different days of administration are shown in Table 5, and the statistical results of the average tumor volume are shown in Figure 1.

[0260] [Table 5]

[0261] As can be seen from Figure 1, on the 9th day of group administration, the tumor volume of mice in the compound I-9 group was significantly reduced compared to the control molecule 01 (Chiauranib) group (p<0.01). Compared to the control molecule 02 group, the tumor volume of mice in the compound I-9 group was significantly reduced (p<0.05). Compared to the solvent control group, the tumor volume of mice in the compound I-9 group was significantly reduced (p<0.001).

[0262] As can be seen from Table 5, the tumor volume inhibition rate of the representative compound I-9 group (TGI 114.0%) was significantly superior to that of the control molecule 01 (Chiauranib) group (TGI 74.6%) and the control molecule 02 group (TGI 68.9%).

[0263] In summary, the compounds of the present invention have excellent in vivo antitumor effects and can clearly inhibit tumor growth.

[0264] It should be noted that the above-described embodiments are merely preferred embodiments of the present invention, and that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of the claims of the present invention.

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer, crystalline polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 Among them, R １ is selected from a methyl group or an ethyl group, and said methyl group or ethyl group is unsubstituted or has one or more of the same or different R ａ is replaced by Each R ａ are each independently a halogen, C １－６ Alkoxy group, —NR′R″, haloC １－６ alkoxy groups, wherein R′ and R″ are each independently selected from H, C １－６ Alkyl group, C ３－６ or R' and R" together with the N atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; R ２ and R ３ are each independently H, halogen, or C １－６ alkyl groups, Ring A is C ４－１０ a cycloalkyl group or a 4- to 10-membered heterocyclic group, the 4- to 10-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, O, and S; ４－１０ The cycloalkyl group or the 4- to 10-membered heterocyclic group may be unsubstituted or may have one or more of the same or different R ｂ is replaced by Each R ｂ are each independently a halogen, C １－６ Alkyl group, halo C １－６ selected from alkyl groups, Alternatively, ring A is a group 【Chemistry 2】 Selected from, among which: In A1, R ４ are F, Cl, C １－６ Alkyl group, halo C １－６ selected from alkyl groups, In A2, R ５ is a halogen, C １－６ Alkyl group, halo C １－６ selected from alkyl groups, In A3, R ４ and R ５ are each independently a halogen, C １－６ Alkyl group, halo C １－６ selected from alkyl groups, In A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently a halogen, C １－６ Alkyl group, halo C １－６ alkyl groups, R ６ When is Cl, R １ is a methyl group or an ethyl group, In A5, R ５ and R ６ are each independently a halogen, C １－６ Alkyl group, halo C １－６ selected from alkyl groups, Ring A is 【Transformation 3】 If R １ is an ethyl group or one or more R ａ is a methyl group or an ethyl group substituted with A compound, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

2. R １ is selected from a methyl group and an ethyl group, and the methyl group and the ethyl group are unsubstituted or have one, two or three identical or different R ａ is replaced by Preferably, each R ａ are each independently a halogen, C １－４ Alkoxy group, —NR′R″, haloC １－４ alkoxy groups, wherein R′ and R″ are each independently selected from H, C １－４ Alkyl group, C ３－５ or R' and R" together with the N atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; Preferably, each R ａ are each independently a halogen, C ５－６ Alkoxy group, —NR′R″, haloC ５－６ alkoxy groups, wherein R′ and R″ are each independently selected from H, C ５－６ Alkyl group, C ５－６ cycloalkyl groups, or R' and R" together with the N atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; Preferably, each R ａ are each independently a halogen, C １－３ Alkoxy group, —NR′R″, haloC １－３ alkoxy groups, wherein R′ and R″ are each independently selected from H, C １－３ Alkyl group, C ３－４ or R' and R" together with the N atom to which they are attached form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; Preferably, each R ａ are each independently selected from halogen, a methoxy group, an ethoxy group, a propoxy group, —NR′R″, a halomethoxy group, a haloethoxy group, and a halopropoxy group, wherein R′ and R″ are each independently selected from H, a methyl group, and an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 8-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O, and S; Preferably, each R ａ are each independently selected from F, Cl, Br, a methoxy group, an ethoxy group, a propoxy group, —NR′R″, a halomethoxy group, a haloethoxy group, and a halopropoxy group, wherein R′ and R″ are each independently selected from H, a methyl group, and an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 7-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O, and S; Preferably, each R ａ are each independently selected from F, Cl, Br, a methoxy group, an ethoxy group, —NR′R″, a methoxy group or an ethoxy group substituted with 1 to 3 F or Cl groups, wherein R′ and R″ are each independently selected from a methyl group or an ethyl group, or R′ and R″ together with the N atom to which they are linked form a 4- to 7-membered nitrogen-containing heterocyclic group, which may further contain 1 to 2 heteroatoms selected from N, O and S; Preferably, each R ａ are each independently F, Cl, a methoxy group, an ethoxy group, —NR′R″, —OCH ２ F, -OCHF ２ , -OCF ３ , -OCH ２ CH ２ F, -OCH ２ CHF ２ , -OCH ２ CF ３ wherein R′ and R″ are each independently selected from a methyl group, an ethyl group, or R′ and R″ together with the N atom to which they are attached are selected from 【Chemistry 4】 Forming Preferably, each R ａ each independently represents F, Cl, a methoxy group, an N,N-dimethylamino group, an N-methylamino group, or —OCHF ２ , 【Transformation 5】 Selected from Preferably, R １ is a methyl group, an ethyl group, -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CH ２ Cl, methoxyethyl group, 【Transformation 6】 Selected from Preferably, ring A is 【Transformation 7】 If R １ is an ethyl group or -CH ２ CH ２ F, Preferably, R １ is selected from a methyl group and an ethyl group, and the methyl group and the ethyl group are unsubstituted; 2. The compound according to claim 1, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

3. Ring A is C ４－７ Monocycloalkyl group, C ５－１０ The 4- to 7-membered monoheterocyclic group or the 6- to 10-membered spirobiheterocyclic group contains 1 to 4 heteroatoms selected from N, O, and S, and the C ４－７ Monocycloalkyl group, C ５－１０ The spirobicycloalkyl group, the 4- to 7-membered monoheterocyclic group, and the 6- to 10-membered spirobiheterocyclic group may be unsubstituted or may have one, two, or three identical or different R ｂ is replaced by Ring A is C ４－６ Monocycloalkyl group, C ６－８ a spirobicycloalkyl group, a 4- to 7-membered monoheterocyclic group, or a 6- to 8-membered spirobiheterocyclic group, wherein the 4- to 7-membered monoheterocyclic group or the 6- to 8-membered spirobiheterocyclic group contains 1 to 2 heteroatoms selected from N, O, and S; and ４－６ Monocycloalkyl group, C ６－８ The spirobicycloalkyl group, the 4- to 7-membered monoheterocyclic group, and the 6- to 8-membered spirobiheterocyclic group may be unsubstituted or may have one, two, or three identical or different R ｂ is replaced by Preferably, ring A is 【Transformation 8】 and 【Chemistry 9】 is unsubstituted or is substituted with one, two or three of the same or different R ｂ is replaced by Preferably, each R ｂ are each independently a halogen, C １－６ selected from alkyl groups, Preferably, each R ｂ are each independently F, Cl, Br, C １－４ Alkyl group, C ５－６ selected from alkyl groups, Preferably, each R ｂ are each independently F, Cl, Br, a methyl group, an ethyl group, or C ３ Alkyl group, C ４ Alkyl group, C ５ Alkyl group, C ６ selected from alkyl groups, Preferably, each R ｂ are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a sec-butyl group; Preferably, each R ｂ are each independently selected from F, Cl, Br, and a methyl group; Preferably, each R ｂ are each independently selected from F; Preferably, ring A is 【Chemistry 10】 Selected from 2. The compound according to claim 1, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

4. In A1, R ４ are F, Cl, C １－４ Alkyl group, C ５－６ Alkyl group, halo C １－４ Alkyl group, halo C ５－６ selected from alkyl groups, Preferably, in A1, R ４ are F, Cl, C １－４ Alkyl group, halo C １－４ selected from alkyl groups, Preferably, in A1, R ４ is F, Cl, methyl group, ethyl group, propyl group, isopropyl group, C １－４ Alkyl group, halomethyl group, haloethyl group, halopropyl group, haloisopropyl group, haloC ４ selected from alkyl groups, Preferably, in A1, R ４ is selected from F, Cl, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; Preferably, in A1, R ４ is selected from F, Cl, and a methyl group; Or, In A2, R ５ are F, Cl, Br, C １－４ Alkyl group, C ５－６ Alkyl group, halo C １－４ Alkyl group, halo C ５－６ alkyl groups, Preferably, in A2, R ５ are F, Cl, Br, C １－４ Alkyl group, halo C １－４ selected from alkyl groups, Preferably, in A2, R ５ are F, Cl, Br, C ５－６ Alkyl group, halo C ５－６ selected from alkyl groups, Preferably, in A2, R ５ is F, Cl, Br, methyl group, ethyl group, propyl group, isopropyl group, C ４ Alkyl group, halomethyl group, haloethyl group, halopropyl group, haloisopropyl group, haloC ４ selected from alkyl groups, Preferably, in A2, R ５ is selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; Preferably, in A2, R ５ is selected from F, Cl, Br, and a methyl group; Preferably, in A2, R ５ is selected from F, Or, In A3, R ４ and R ５ are each independently a halogen, C １－４ Alkyl group, C ５－６ Alkyl group, halo C １－４ Alkyl group, halo C ５－６ selected from alkyl groups, Preferably, in A3, R ４ and R ５ are each independently F, Cl, Br, C １－４ Alkyl group, halo C １－４ selected from alkyl groups, Preferably, in A3, R ４ and R ５ are each independently F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, or C ４ Alkyl group, halomethyl group, haloethyl group, halopropyl group, haloisopropyl group, haloC ４ selected from alkyl groups, Preferably, in A3, R ４ and R ５ are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; Preferably, in A3, R ４ and R ５ are each independently selected from F or Cl; Preferably, in A3, R ４ is F and R ５ is F or Cl, Or, In A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently a halogen, C １－４ Alkyl group, C ５－６ Alkyl group, halo C １－４ Alkyl group, halo C ５－６ alkyl groups, R ６ When is Cl, R １ is a methyl group or an ethyl group, Preferably, in A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently F, Cl, Br, C １－４ Alkyl group, halo C １－４ alkyl groups, R ６ When is Cl, R １ is a methyl group or an ethyl group, Preferably, in A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, or C ４ Alkyl group, halomethyl group, haloethyl group, halopropyl group, haloisopropyl group, haloC ４ alkyl groups, R ６ When is Cl, R １ is a methyl group or an ethyl group, Preferably, in A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; R ６ When is Cl, R １ is a methyl group or an ethyl group, Preferably, in A4, R ６ is selected from F or Cl, R ４ and R ５ are each independently selected from F or Cl, R ６ When is Cl, R １ is a methyl group or an ethyl group, Or, In A5, R ５ and R ６ are each independently a halogen, C １－４ Alkyl group, C ５－６ Alkyl group, halo C １－４ Alkyl group, halo C ５－６ selected from alkyl groups, Preferably, in A5, R ５ and R ６ are each independently F, Cl, Br, C １－４ Alkyl group, halo C １－４ selected from alkyl groups, Preferably, in A5, R ５ and R ６ are each independently F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, or C ４ Alkyl group, halomethyl group, haloethyl group, halopropyl group, haloisopropyl group, haloC ４ selected from alkyl groups, Preferably, in A5, R ５ and R ６ are each independently selected from F, Cl, Br, a methyl group, an ethyl group, a fluorine- or chlorine-substituted methyl group, and a fluorine- or chlorine-substituted ethyl group; Preferably, in A5, R ５ and R ６ are each independently selected from F or Cl; Preferably, ring A is 【Chemistry 11】 Selected from Ring A is 【Chemistry 12】 When selected from １ is a methyl group or an ethyl group, Preferably, ring A is 【Chemistry 13】 Selected from 2. The compound according to claim 1, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

5. R ２ and R ３ are each independently H, halogen, or C １－４ Alkyl group, C ５－６ alkyl groups, Preferably, R ２ and R ３ are each independently selected from H, F, Cl, Br, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group; Preferably, R ２ and R ３ are each independently selected from H, F, Cl, and Br; Preferably, R ２ and R ３ are each independently selected from H and F; Preferably, R ２ and R ３ is simultaneously H, Alternatively, preferably, R ２ and R ３ one of which is H and the other is F, Preferably, R ２ is H and R ３ is F, Alternatively, preferably, R ２ is F and R ３ is H, 2. The compound according to claim 1, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

6. The compound is 【Chemistry 14】 【change】 Selected from The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, crystalline polymorph, co-crystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or adjuvant and / or diluent.

8. Use of the compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, in the manufacture of a medicament for treating and / or preventing a disease associated with Aurora B kinase, Preferably, the disease associated with Aurora B kinase is selected from tumors or hyperproliferative diseases. use.

9. A method for treating and / or preventing a disease associated with Aurora B kinase, comprising administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7; Preferably, the disease associated with Aurora B kinase is selected from tumors or hyperproliferative diseases. method.

10. It is used for the treatment and / or prevention of diseases associated with Aurora B kinase, Preferably, the disease associated with Aurora B kinase is selected from tumors or hyperproliferative diseases. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, crystalline polymorph, cocrystal, solvate, metabolite, prodrug, deuterated compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7.

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