TW202300485A - Plk4 inhibitors and use thereof - Google Patents

Abstract

The invention relates to the technical field of medicine, and specifically relates to a polo-like kinase 4 ("PLK4" for short) inhibitor compound and its pharmaceutically acceptable salt, ester, solvate and isomer, and a pharmaceutical composition and a formulation containing the compound, the pharmaceutically acceptable salt, the ester, the solvate, and the isomer thereof, and a method of preparing the compound, the pharmaceutically acceptable salt, the ester, the solvate, and the isomer thereof, and use of the compound, the pharmaceutically acceptable salt, the ester, the solvate, and the isomer thereof.

Description

PLK4 inhibitors and uses thereof

The present invention belongs to the technical field of medicine, and specifically relates to polo-like kinase 4 (hereinafter referred to as "PLK4") inhibitor compound and its application.

Polo-like kinases (polo-like kinases, PLKs) are a class of highly conserved serine/threonine protein kinases, with a highly homologous serine/threonine kinase domain at the N-terminal and a highly homologous serine/threonine kinase domain at the C-terminal It has a polo-box domain (polo-box domain, PBD), which can regulate the kinase activity of PLKs and is related to the subcellular dynamic localization of the protein. There are many members of the PLKs family, and there are four subtypes in the human body, namely PLK1, PLK2, PLK3 and PLK4, which play a vital role in the regulation of each phase of the cell cycle.

Among them, PLK4 was discovered in 1994 and widely exists in eukaryotes. Mouse PLK4 is located on chromosome 13 and is divided into two subtypes, a and b. Human PLK4 is located on chromosome 4q28. There is only one PLK4 protein, and the whole process is 970 Amino acids, which are highly homologous to mouse PLK4-a. The amino acid sequence of PLK4 is quite different from other PLKs. The PBDs of other PLKs have two polo boxes arranged in series, while PLK4 has only one polo box.

Studies have found that PLK4 is mainly expressed in actively dividing tissues and cells, and the mRNA of PLK4 protein is expressed at the highest level in the testis, and is also expressed in tumor cell lines such as Hela, SKOV-3, Saos-2, A-431, etc. . In normal cycle cells, the mRNA level of PLK4 protein was not expressed in G0 phase cells, increased at the end of G1 phase, and continued to rise in S phase and M phase; after the end of mitosis, it gradually decreased in early G1 phase. Studies have shown that this precise regulation is necessary to maintain the integrity of the nucleus during cell growth and cell division.

PLK4 is one of the main regulators of centriole replication. During the replication process, its activation can promote the recruitment of tubulin to centrioles, thereby promoting the gradual maturation of centrioles. Habedanck ¹ first discovered that overexpression of wild-type PLK4 can lead to an increase in the number of centrioles in cells, while underexpression of PLk4 can also lead to a decrease in the number of centrioles and abnormal structure of centrosomes in cells. In tumor cells, abnormalities in the structure and number of centrosomes often occur, and the abnormalities are accompanied by defects in cell division and genome instability. It has been found that PLK4 is abnormally expressed in some tumor tissues and cell lines, and is regulated by P53, which may be involved in the occurrence and development of tumors. Therefore, PLK4 is a potential target for tumor-targeted therapy.

Currently, there is no PLK4 kinase inhibitor drug on the market. Among them, CFI-400945, developed by The University Health Network, is a selective PLK4 kinase inhibitor that has shown good anti-tumor activity ² and is still in clinical trials. Therefore, the development of new PLK4 kinase inhibitors, the enrichment of clinical drug types, and the improvement of drug availability have important medical value and social significance.

The technical problem to be solved by the present invention is to provide a compound with novel structure and PLK4 kinase inhibitory activity. Further, the present invention provides a compound with novel structure and PLK4 kinase inhibitory activity with better pharmacodynamic activity.

The technical problem that the present invention can solve also includes that the compound of the present invention can be used to treat cancer diseases mediated by PLK4.

式（I） 其中， X選自N或C(R ⁷)； 環A選自5-6元環烷基、5-6元雜環基、8-14元稠雜環基、7-11元螺雜環基，其中所述的各雜環中獨立地包含一個或多個C(O)、N(R ⁵)x、O和/或S(O)y； 環B選自苯基或5-6元雜芳基； L ¹選自任選被一個或多個S1取代的C _1-6亞烷基、C _2-6亞烯基、C _2-6亞炔基；其中，所述的S1獨立地選自鹵素、C _1-6烷基、C _1-6烷氧基或鹵代C _1-6烷基； R ¹選自氫、鹵素、羥基或C _1-6烷基； 每個R ²分別獨立地選自氫、鹵素、氰基、羥基或任選被一個或多個S2取代的如下基團：C _1-6烷基、C _1-6烷基-C(O)-、C _1-6烷基-S(O) ₂-、C _1-6烷氧基、苯基、5-6元雜芳基；其中，所述的S2獨立地選自鹵素、羥基、C _1-6烷基或C _1-6烷氧基； 每個R ³分別獨立地選自氫、鹵素、氰基、羥基、C _1-6烷基、鹵代C _1-6烷基或C _1-6烷氧基； 每個R ⁴分別獨立地選自R ^4a和/或R ^4b； 每個R ^4a獨立地選自氫、鹵素、氰基、羥基、或任選被一個或多個S3取代的如下基團：C _1-6烷基、C _1-6烷基羰基、(R ⁵)(R ⁶)N-、C _1-6烷氧基、C _1-6烷氧基羰基、(C _1-6烷基)-S(O)-、(C _1-6烷基)-S(O) ₂-； 每個R ^4b獨立地選自

，其中環C選自任選被一個或多個S3取代的如下基團：3-6元環烷基、 3-6元雜環基、6-10元稠雜環基、7-12元螺雜環基或6-8元橋雜環基；所述的6-10元稠雜環基優選6-8元稠雜環基； 其中，所述的S3獨立地選自鹵素、羥基、氰基、羧基、C _1-6烷基、鹵代C _1-6烷基、羥基C _1-6烷基、 (R ⁵)(R ⁶) N-、(R ⁵)(R ⁶)NC(O)-、C _1-6烷氧基、C _1-6烷氧基-C _1-6烷基-、(R ⁵)(R ⁶)N-C _1-6烷基-或3-6元環烷基； L ²選自化學鍵、或任選被一個或多個S4取代的C _1-6亞烷基，其中C _1-6亞烷基中的一個或多個碳原子任選被C(O)、NR ⁵、S(O)y和/或O取代；其中，所述的S4獨立地選自鹵素、氰基、羥基、胺基、C _1-6烷基、或者任意兩個S4與其所相連的被取代原子共同形成3-6元環烷基或3-6元雜環基；並且，所述的S4可以位於相同或不同的取代原子上； 每個R ⁵、R ⁶、R ⁷分別獨立地選自氫、氰基、羧基、羥基、C _1-6烷基； x選自0或1； y選自0、1或2； m、n、p分別獨立地選自0、1、2、3、4或5。 The technical scheme of the present invention is as follows: In one aspect, the present application provides a compound represented by the following general formula (I), its pharmaceutically acceptable salt, its ester, its solvate or its isomer,

Formula (I) wherein, X is selected from N or C(R ⁷ ); ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, 8-14 membered condensed heterocyclic group, Spiroheterocyclyl, wherein each heterocycle independently contains one or more C(O), N(R ⁵ )x, O and/or S(O)y; ring B is selected from phenyl or 5 -6-membered heteroaryl; L ^is selected from C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene optionally substituted by one or more S1; wherein, the S1 is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl; R ^is selected from hydrogen, halogen, hydroxyl or C _1-6 alkyl; each R ² are independently selected from hydrogen, halogen, cyano, hydroxyl, or the following groups optionally substituted by one or more S2: C _1-6 alkyl, C _1-6 alkyl-C(O)-, C _1-6 alkyl-S(O) ₂ -, C _1-6 alkoxy, phenyl, 5-6 membered heteroaryl; wherein, said S2 is independently selected from halogen, hydroxyl, C _{1- 6} alkyl or C _1-6 alkoxy; each R ³ is independently selected from hydrogen, halogen, cyano, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 Alkoxy; Each R ⁴ is independently selected from R ^4a and/or R ^4b ; Each R ^4a is independently selected from hydrogen, halogen, cyano, hydroxyl, or optionally substituted by one or more S3 as follows Group: C _1-6 alkyl, C _1-6 alkylcarbonyl, (R ⁵ )(R ⁶ )N-, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, (C _{1- 6} alkyl)-S(O)-, (C _1-6 alkyl)-S(O) _2- ; each R ^4b is independently selected from

, wherein ring C is selected from the following groups optionally substituted by one or more S3: 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 6-10 membered fused heterocyclic group, 7-12 membered spiro Heterocyclic group or 6-8 member bridged heterocyclic group; said 6-10 membered fused heterocyclic group is preferably 6-8 membered fused heterocyclic group; wherein, said S3 is independently selected from halogen, hydroxyl, cyano , carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, (R ⁵ )(R ⁶ ) N-, (R ⁵ )(R ⁶ )NC(O) -, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl-, (R ⁵ )(R ⁶ )NC _1-6 alkyl- or 3-6 membered cycloalkyl; L ² is selected from a chemical bond, or a C _1-6 alkylene group optionally substituted by one or more S4, wherein one or more carbon atoms in the C _1-6 alkylene group are optionally replaced by C(O), NR ^5. Substituted by S(O)y and/or O; wherein, said S4 is independently selected from halogen, cyano, hydroxyl, amino, C _1-6 alkyl, or any two S4s connected to it by The substituting atoms together form a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; and, the S4 can be located on the same or different substituting atoms; each R ⁵ , R ⁶ , and R ⁷ are independently selected from From hydrogen, cyano, carboxyl, hydroxyl, C _1-6 alkyl; x is selected from 0 or 1; y is selected from 0, 1 or 2; m, n, p are independently selected from 0, 1, 2, 3 , 4 or 5.

時，n為1； 和/或，優選地，環A為

時，R ¹不為氫； 和/或，優選地，環A為

時，

不為

。 In another preferred technical solution, ring A is selected as

When, n is 1; and/or, preferably, ring A is

When, R ¹ is not hydrogen; and/or, preferably, Ring A is

hour,

not for

.

，其中環C選自任選被1-3個S3取代的如下基團：4-6元環烷基、 4-6元雜環基、6-8元稠雜環基、7-11元螺雜環基或6-8元橋雜環基； 其中，所述的S3獨立地選自鹵素、羥基、氰基、羧基、C _1-4烷基、鹵代C _1-4烷基、羥基C _1-4烷基、(R ⁵)(R ⁶)N-、(R ⁵)(R ⁶)NC(O)-、C _1-4烷氧基、C _1-4烷氧基-C _1-4烷基-、(R ⁵)(R ⁶)N-C _1-4烷基-或3-6元環烷基； L ²選自化學鍵、或任選被1-3個S4取代的C _1-4亞烷基，其中，C _1-4亞烷基中的碳原子任選被1-3個C(O)、NR ⁵、S、S(O)、S(O) ₂和/或O取代；其中，所述的S4獨立地選自氟、羥基、甲基、乙基、或者任意兩個位於同一原子上的S4與其所相連的被取代原子共同形成3-4元環烷基或3-4元雜環基； 每個R ⁵、R ⁶分別獨立地選自氫或C _1-4烷基； x選自0或1； y選自0、1或2； m、n、p分別獨立地選自0、1、2、3。 In a preferred embodiment of formula (I), X is selected from N; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, 8-14 membered fused heterocyclic group, 7-10 membered Spiroheterocyclyl, wherein each heterocycle independently contains 1-3 C(O), N(R ⁵ )x, S(O)y and/or O; ring B is selected from phenyl or 5 -6-membered heteroaryl; L ¹ is selected from C _2-4 alkenylene optionally substituted by 1-3 S 1 , said S 1 is independently selected from fluorine, methyl or ethyl; R ¹ is selected from hydrogen , hydroxyl or methyl; each R ² is independently selected from hydrogen, halogen, cyano, hydroxyl or the following groups optionally substituted by 1-3 S2: C _1-4 alkyl, C _1-4 alkane Oxygen, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S(O) ₂ -, phenyl, pyridyl, pyrimidinyl; wherein, the S2 is independently selected from halogen , hydroxyl, C _1-4 alkyl or C _1-4 alkoxy; each R ³ is independently selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; each R ⁴ are independently selected from R ^4a and/or R ^4b ; each R ^4a is independently selected from hydrogen, halogen, cyano, hydroxyl, or the following groups optionally substituted by 1-3 S3: C _1-4 alkane radical, (R ⁵ )(R ⁶ )N- or C _1-4 alkoxy; each R ^4b is independently selected from

, wherein ring C is selected from the following groups optionally substituted by 1-3 S3: 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 6-8 membered fused heterocyclyl, 7-11 membered spiro Heterocyclyl or 6-8 member bridged heterocyclyl; Wherein, said S3 is independently selected from halogen, hydroxyl, cyano, carboxyl, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxyl C _1-4 alkyl, (R ⁵ )(R ⁶ )N-, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 alkoxy, C _1-4 alkoxy-C _{1- 4} alkyl-, (R ⁵ )(R ⁶ )NC _1-4 alkyl- or 3-6 membered cycloalkyl; L ² is selected from chemical bonds, or C _1-4 optionally substituted by 1-3 S4 Alkylene, wherein, the carbon atoms in the C _1-4 alkylene are optionally substituted by 1-3 C(O), NR ⁵ , S, S(O), S(O) ₂ and/or O; Wherein, said S4 is independently selected from fluorine, hydroxyl, methyl, ethyl, or any two S4 located on the same atom and the substituted atom to which it is connected together form a 3-4 membered cycloalkyl group or a 3-4 membered heterocyclic group; each R ⁵ , R ⁶ are independently selected from hydrogen or C _1-4 alkyl; x is selected from 0 or 1; y is selected from 0, 1 or 2; m, n, p are independently selected Choose from 0, 1, 2, 3.

，其中環C選自任選被1-3個S3取代的如下基團：4-6元環烷基、 4-6元雜環基、6-8元稠雜環基、7-11元螺雜環基或6-8元橋雜環基； 其中，所述的S3獨立地選自鹵素、羥基、氰基、羧基、C _1-4烷基、鹵代C _1-4烷基、(R ⁵)(R ⁶)N-、(R ⁵)(R ⁶)NC(O)-、C _1-4烷氧基、C _1-4烷氧基-C _1-4烷基-、(R ⁵)(R ⁶)N-C _1-4烷基-或3-6元環烷基； L ²選自化學鍵、或任選被1-3個S4取代地的C _1-4亞烷基，其中C _1-4亞烷基中的碳原子任選被1-3個C(O)、NR ⁵、S、S(O)、S(O) ₂和/或O取代；其中，所述的S4獨立地選自氟、羥基、甲基、乙基、或者任意兩個位於同一原子上的S4與其所相連的被取代原子共同形成3-4元環烷基或3-4元雜環基； 每個R ⁵、R ⁶分別獨立地選自氫或C _1-4烷基； x選自0或1； y選自0、1或2； m、n、p分別獨立地選自0、1、2、3。 In a preferred embodiment of formula (I), X is selected from N; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, 8-14 membered fused heterocyclic group, 7-10 membered Spiral heterocyclyl; wherein, each of the heterocycles independently contains 1-3 C(O), N(R ⁵ )x, S(O)y and/or O; Ring B is selected from phenyl or 5-6 membered heteroaryl; L ¹ is selected from C _2-4 alkenylene optionally substituted by 1-3 S1, said S1 is independently selected from fluorine, methyl or ethyl; R ¹ is selected from Hydrogen, hydroxyl or methyl; Each ^R2 is independently selected from hydrogen, halogen, cyano, hydroxyl or the following groups optionally substituted by 1-3 S2: C _1-4 alkyl, C _1-4 Alkoxy, phenyl; wherein, said S2 is independently selected from halogen, C _1-4 alkyl or C _1-4 alkoxy; each R ³ is independently selected from hydrogen, halogen, C _{1- 4} Alkyl or C _1-4 alkoxy; Each R ⁴ is independently selected from R ^4a and/or R ^4b ; Each R ^4a is independently selected from hydrogen, halogen, cyano, hydroxyl, or optionally 1-3 S3 substituted following groups: C _1-4 alkyl, (R ⁵ )(R ⁶ )N- or C _1-4 alkoxy; each R ^4b is independently selected from

, wherein ring C is selected from the following groups optionally substituted by 1-3 S3: 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 6-8 membered fused heterocyclyl, 7-11 membered spiro Heterocyclyl or 6-8 member bridged heterocyclyl; Wherein, said S3 is independently selected from halogen, hydroxyl, cyano, carboxyl, C _1-4 alkyl, halogenated C _1-4 alkyl, (R ⁵ ) (R ⁶ )N-, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl-, (R ⁵ )(R ⁶ )NC _1-4 alkyl-or 3-6 membered cycloalkyl; L ² is selected from chemical bonds, or C _1-4 alkylene optionally substituted by 1-3 S4, wherein C ₁ The carbon atoms in the _-4 alkylene group are optionally substituted by 1-3 C(O), NR ⁵ , S, S(O), S(O) ₂ and/or O; wherein, the S4 is independently Selected from fluorine, hydroxyl, methyl, ethyl, or any two S4 located on the same atom and the substituted atom to which it is connected together form a 3-4 membered cycloalkyl or a 3-4 membered heterocyclic group; each R ⁵ , R ⁶ are independently selected from hydrogen or C _1-4 alkyl; x is selected from 0 or 1; y is selected from 0, 1 or 2; m, n, p are independently selected from 0, 1, 2, 3.

In a preferred embodiment of formula (I), ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl.

In a preferred embodiment of formula (I), ring B is selected from pyrazolyl and imidazolyl.

In a preferred embodiment of formula (I), ring B is selected from phenyl.

In a preferred embodiment of formula (I), ring B is selected from pyridyl.

In a preferred technical solution of formula (I), L ¹ is selected from -CH ₂ -CH ₂ - or -CH ₂ ═CH ₂ -.

In a preferred technical solution of formula (I), L ¹ is selected from -CH ₂ =CH ₂ -.

In a preferred technical solution of formula (I), R ¹ is selected from hydrogen, fluorine, hydroxyl or methyl.

In a preferred technical solution of formula (I), R ¹ is selected from hydrogen or hydroxyl.

In a preferred technical solution of formula (I), each R ³ is independently selected from hydrogen, fluorine, chlorine, methyl or methoxy.

In a preferred technical solution of formula (I), each R ³ is independently selected from hydrogen, fluorine, methyl or methoxy.

In a preferred technical solution of formula (I), each R ⁵ and R ⁶ is independently selected from hydrogen, methyl and ethyl.

選自

或

，Y選自CH或N，pa選自0、1或2。 In a preferred technical solution of formula (I), the structural unit

selected from

or

, Y is selected from CH or N, pa is selected from 0, 1 or 2.

，環C選自任選被1-3個S3取代的如下基團：5-6元飽和含氮雜環基、8-10元飽和含氮稠雜環基、7-10元飽和含氮螺雜環基、6-8元飽和含氮橋雜環基。 In a preferred embodiment of formula (I), each R ^4b is independently selected from

, Ring C is selected from the following groups optionally substituted by 1-3 S3: 5-6 membered saturated nitrogen-containing heterocyclic group, 8-10 membered saturated nitrogen-containing condensed heterocyclic group, 7-10 membered saturated nitrogen-containing spiro Heterocyclic group, 6-8 membered saturated nitrogen-containing bridged heterocyclic group.

In a preferred technical scheme of formula (I), the nitrogen-containing heterocyclic group, nitrogen-containing condensed heterocyclic group, nitrogen-containing spiroheterocyclic group, and nitrogen-containing bridging heterocyclic group described in R ⁴ are combined with L through a nitrogen atom. ² connected.

，結構單元

選自環丙烷基-L ²-、環丁烷基-L ²-、環戊基-L ²-、環己基-L ²-、氮雜環丙烷基-L ²-、氧雜環丙烷基-L ²-、氮雜環丁烷基-L ²-、氧雜環丁烷基-L ²-、吡咯烷基-L ²-、咪唑烷基-L ²-、四氫呋喃基-L ²-、哌啶基-L ²-、哌𠯤基-L ²-、嗎福林基-L ²-、四氫吡喃基-L ²-、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

；其中，K ¹、K ²分別獨立的選自CH ₂、O、或NH； 每個S3獨立地選自氟、羥基、氰基、羧基、甲基、乙基、甲氧基、乙氧基、異丙氧基、CF ₃CH ₂-、環丙基、H ₂NC(O)-、N,N-二甲基胺基、N,N-二甲基胺基甲基、甲氧基甲基、ClCH ₂-、HOCH ₂-；w選自0、1、或2。 In a preferred technical scheme of formula (I), each R ⁴ is independently selected from R ^4a or R ^4b ; each R ^4a is independently selected from hydrogen, chlorine, fluorine, methyl, methoxy, ethyl Oxygen, isopropoxy, trifluoromethyl, dimethylaminomethyl; each R ^4b is independently selected from

,Structural units

Selected from cyclopropyl-L ² -, cyclobutanyl-L ^2- , cyclopentyl-L ^2- , cyclohexyl-L ^2- , aziridine-L ^2- , oxirane- L ² -, azetidinyl-L ² -, oxetanyl-L ² -, pyrrolidinyl-L ² -, imidazolidinyl-L ² -, tetrahydrofuranyl-L ² -, piperidine Pyridyl-L ² -, piperyl-L ² -, morpholinyl-L ² -, tetrahydropyranyl-L ² -,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

; wherein, K ¹ and K ² are independently selected from CH ₂ , O, or NH; each S3 is independently selected from fluorine, hydroxyl, cyano, carboxyl, methyl, ethyl, methoxy, ethoxy , Isopropoxy, CF ₃ CH ₂ -, Cyclopropyl, H ₂ NC(O)-, N,N-Dimethylamino, N,N-Dimethylaminomethyl, Methoxymethyl group, ClCH ₂ -, HOCH ₂ -; w is selected from 0, 1, or 2.

，其中，結構單元

選自氮雜環丁烷基-L ²-、吡咯烷基-L ²-、哌啶基-L ²-、嗎福林基-L ²-； 每個S3獨立地選自甲基；w選自0、1、或2。 In a preferred technical scheme of formula (I), R ^4a is selected from hydrogen; R ^4b is independently selected from

, where the structural unit

selected from azetidinyl-L ² -, pyrrolidinyl-L ² -, piperidinyl-L ² -, morpholinyl-L ² -; each S3 is independently selected from methyl; w is selected from from 0, 1, or 2.

、

、

、

、-CH ₂-CH ₂-、-CH ₂-O-、-CH ₂-C(O)-、-CH ₂-NR ⁵-、-C(O)-NR ⁵-、-C(O)-O-、-C(O)-、-S(O)-、-S(O) ₂-、-CH ₂-CH ₂-CH ₂-、-CH ₂-NH-CH ₂-、-CH ₂-CH ₂-CH ₂-CH ₂-、

、

、

、

、

或

。 In a preferred technical scheme of formula (I), L ² is selected from chemical bonds, -CH ₂ -, -CF ₂ -,

,

,

,

, -CH ₂ -CH ₂ -, -CH ₂ -O-, -CH ₂ -C(O)-, -CH ₂ -NR ⁵ -, -C(O)-NR ⁵ -, -C(O)- O-, -C(O)-, -S(O)-, -S(O) ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -NH-CH ₂ -, -CH ₂ - _CH2 - _CH2 - _CH2- ,

,

,

,

,

or

.

In a preferred technical solution of formula (I), L ² is selected from -CH ₂ -.

、

、

、

、

、

、

、

、

、

、

、

、

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； p選自1、2或3。 In a preferred technical solution of formula (I), R ⁴ is selected from R ^4a and/or R ^4b ; R ^4a is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, ethoxy , N,N-dimethylaminomethyl; R ^4b is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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,

,

,

,

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,

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,

,

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,

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,

,

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,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

p is selected from 1, 2 or 3.

、

、

、

、

、

、

； p選自1或2。 In a preferred version of formula (I), R ^4a is selected from methyl, methoxy, fluorine, trifluoromethyl; R ^4b is selected from

,

,

,

,

,

,

; p is selected from 1 or 2.

、

、

、

、

、

。 In a preferred embodiment of formula (I), R ^4a is selected from hydrogen, R ^4b is selected from

,

,

,

,

,

.

式（I） X為N； 環A選自5-6元雜環基，其中所述的雜環中獨立地包含1個C(O)和/或1個N(R ⁵)x； 每個R ²分別獨立地選自氫、鹵素、C _1-4烷基、C _1-4烷氧基-C _1-4烷基-、羥基C _1-4烷基、

、

、

；其中，S2選自甲基、甲氧基、氟、溴；m選自1或2，t選自0或1； R ¹、R ³、R ⁴、R ⁵、R ⁶、L ¹、環B、m、n、p、x如前文任一方案所述。 In a preferred embodiment of formula (I), the compound represented by formula (I), its pharmaceutically acceptable salt, its ester, its isomer, solvate, wherein

Formula (I) X is N; Ring A is selected from 5-6 membered heterocyclic groups, wherein the heterocyclic rings independently contain 1 C(O) and/or 1 N(R ⁵ )x; each R ² are independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl-, hydroxy C _1-4 alkyl,

,

,

; Wherein, S2 is selected from methyl, methoxy, fluorine, bromine; m is selected from 1 or 2, t is selected from 0 or 1; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , L ¹ , ring B, m, n, p, x are as described in any scheme above.

；其中，S2選自甲基、甲氧基、氟； t選自0或1； m選自1或2。 In a preferred technical solution of formula (I), each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl,

; Wherein, S2 is selected from methyl, methoxy, fluorine; t is selected from 0 or 1; m is selected from 1 or 2.

In a preferred technical solution of formula (I), ring A is selected from 5-6 membered saturated heterocyclic groups; wherein, the heterocyclic rings independently contain 1 C(O) and/or 1 N( R ⁵ )x.

In a preferred technical solution of formula (I), ring A is selected from 5-6 membered partially saturated heterocyclic groups; wherein, the heterocyclic ring contains a lactam structure.

、

。 In a preferred technical solution of formula (I), ring A is selected from

,

.

、

；每個R ²分別獨立地選自氟、氯、甲基、CH ₃OCH ₂-、HOCH ₂-、

、

；其中，S2選自甲基、甲氧基、氟、溴； t選自0或1；m選自1或2。 In a preferred technical solution of formula (I), ring A is selected from

,

; Each R ² is independently selected from fluorine, chlorine, methyl, CH ₃ OCH ₂ -, HOCH ₂ -,

,

; Wherein, S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1; m is selected from 1 or 2.

選自

、

、

、

、

或

； 每個R ²分別獨立地選自氫、氟、氯、甲基、CH ₃OCH ₂-、HOCH ₂-、

、

；其中，S2選自甲基、甲氧基、氟、溴； t選自0或1。 In a preferred technical solution of formula (I),

selected from

,

,

,

,

or

; each R ² is independently selected from hydrogen, fluorine, chlorine, methyl, CH ₃ OCH ₂ -, HOCH ₂ -,

,

; Wherein, S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1.

選自

，R ²選自

，S2選自甲基、甲氧基、氟、溴；t選自0或1。 In a preferred technical solution of formula (I),

selected from

, ^R2 is selected from

, S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1.

式（I） 環A選自7-10元螺雜環基，其中所述的螺雜環中獨立地包含1-3個C(O)、N(R ⁵)x、S(O)y和/或O； 每個R ²分別獨立地選自鹵素、氰基、羥基或任選被1-2個S2取代的如下基團：C _1-4烷基、(R ⁵)(R ⁶)N-、C _1-4烷氧基、C _1-4烷基-C(O)-、C _1-4烷基-S(O) ₂-；其中，所述的S2獨立地選自鹵素、羥基、C _1-4烷基、(R ⁵)(R ⁶)N-或C _1-4烷氧基； X、R ¹、R ³、R ⁴、R ⁵、R ⁶、L ¹、環B、m、n、p、x、y如前文任一方案所述。 In a preferred embodiment of formula (I), the compound represented by formula (I), its pharmaceutically acceptable salt, its ester, its isomer, solvate, wherein

Formula (I) Ring A is selected from 7-10 membered spiro heterocyclic groups, wherein the spiro heterocyclic ring independently contains 1-3 C(O), N(R ⁵ )x, S(O)y and /or O; Each R ² is independently selected from halogen, cyano, hydroxyl, or the following groups optionally substituted by 1-2 S2: C _1-4 alkyl, (R ⁵ )(R ⁶ )N -, C _1-4 alkoxy, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S(O) ₂ -; wherein, the S2 is independently selected from halogen, hydroxyl , C _1-4 alkyl, (R ⁵ )(R ⁶ )N- or C _1-4 alkoxy; X, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , L ¹ , Ring B, m, n, p, x, y are as described in any scheme above.

In a preferred technical solution of formula (I), each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl-, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S(O) ₂ -.

In a preferred technical solution of formula (I), ring A is selected from 8-10 membered spiroheterocyclyls, wherein the spiroheterocycles independently contain 1 C(O) and/or 1 NR ⁵ .

In a preferred technical solution of formula (I), ring A is selected from 8-10 membered saturated spiroheterocyclic groups, wherein the spiroheterocycle contains a lactam structure and 0-1 C(O), NR ⁵ , S(O)y and/or O.

、

、

、

、

、

、

或

，其中，Z ²選自CH ₂、C(O)、NR ⁵、S、S(O)、S(O) ₂或O。 In a preferred technical solution of formula (I), ring A is selected from

,

,

,

,

,

,

or

, wherein Z ² is selected from CH ₂ , C(O), NR ⁵ , S, S(O), S(O) ₂ or O.

In a preferred technical scheme of formula (I), R ^is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methoxymethyl, acetyl, methylsulfonyl; m is selected from 0 or 1.

In a preferred embodiment of formula (I), R ² is selected from fluorine, methyl, methoxy or methoxymethyl; m is selected from 0 or 1.

；Z ²選自CH ₂、O、NH。 In a preferred technical solution of formula (I), ring A is selected from

; Z ² is selected from CH ₂ , O, NH.

其中，pa選自0、1或2； w選自0、1或2；Y選自N或CH； R ²、R ³、R ⁴、L ²、S3、R ^4a、環B、環C、m、n、p如前文任一方案所定義。 In a preferred embodiment of formula (I), the compound, its pharmaceutically acceptable salt, its ester, solvate or its isomer has the structure shown in the following general formula:

Wherein, pa is selected from 0, 1 or 2; w is selected from 0, 1 or 2; Y is selected from N or CH; R ² , R ³ , R ⁴ , L ² , S3, R ^4a , ring B, ring C, m, n, p are as defined in any scheme above.

其中，w選自0、1或2；t選自0或1；pa選自0、1或2；n選自0或1； m選自0、1或2；K ¹選自N或CH；K ²選自N-S3、NH、O或CH ₂； R ²、R ³、R ⁴、R ^4a、環C、S2、S3、L ²、Z ²如前文任一方案所定義。 In a preferred embodiment of formula (I), the compound, its pharmaceutically acceptable salt, its ester, its isomer, and its solvate have the structure shown in the following general formula,

Wherein, w is selected from 0, 1 or 2; t is selected from 0 or 1; pa is selected from 0, 1 or 2; n is selected from 0 or 1; m is selected from 0, 1 or 2; K ^is selected from N or CH ; K ² is selected from N-S3, NH, O or CH ₂ ; R ² , R ³ , R ⁴ , R ^4a , ring C, S2, S3, L ² , Z ² are as defined in any scheme above.

式（I） 其中，X選自N或C(R ⁷)； 環A選自9-13元稠雜環基，其中所述的稠雜環中獨立地包含1-3個C(O)、O和/或N(R ⁵)x。 每個R ²分別選自氫、鹵素、C _1-4烷基、C _1-4烷氧基； 環B、R ¹、R ³、R ⁴、R ⁵、環B、R ⁷、L ¹、m、n、p如前文任一方案所定義。 In a preferred embodiment of formula (I), the compound represented by formula (I), its pharmaceutically acceptable salt, its ester, its isomer, solvate,

Formula (I) wherein, X is selected from N or C(R ⁷ ); ring A is selected from 9-13 membered fused heterocyclic groups, wherein the fused heterocyclic rings independently contain 1-3 C(O), O and/or N(R ⁵ )x. Each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; Ring B, R ¹ , R ³ , R ⁴ , R ⁵ , Ring B, R ⁷ , L ¹ , m, n, p are as defined in any scheme above.

時，n為1。 In a preferred technical solution of formula (I), ring A is selected as

, n is 1.

時，R ¹不為氫。 In a preferred technical solution of formula (I), ring A is

, R ¹ is not hydrogen.

時，

不為

。 In a preferred technical solution of formula (I), ring A is

hour,

not for

.

In a preferred technical solution of formula (I), ring A is selected from 9-12 membered condensed heterocyclic groups.

In a preferred technical solution of formula (I), ring A is selected from 9-10 membered condensed heterocyclic groups.

In a preferred technical solution of formula (I), the condensed heterocyclic ring contains a lactam structure and 0-1 N or O atoms.

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In a preferred technical solution of formula (I), ring A is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

式（IV-1） 其中，環A選自

、

、

、

、

或

； R ¹、R ²、R ³、m、n如前文任一方案所定義； 在式（IV-1）的一個優選的技術方案中，環A選自

時，n為1。 In a preferred technical solution of formula (I), the compound, its pharmaceutically acceptable salt, its ester, its isomer, and solvate have the structure shown in the following general formula,

Formula (IV-1) wherein, ring A is selected from

,

,

,

,

or

; R ¹ , R ² , R ³ , m, n are as defined in any scheme above; In a preferred technical scheme of formula (IV-1), ring A is selected from

, n is 1.

時，R ¹不為氫。 In a preferred technical solution of formula (IV-1), ring A is

, R ¹ is not hydrogen.

、

其中，環C選自如前文任一方案中R ^4b所定義的螺雜環基； 環B如選自如前文任一方案中環B的定義； w選自0、1或2； pa選自0、1或2； K ¹選自N或CH；K ²選自N-S3、NH、O或CH ₂； R ^4a、L ²、S3、R ²和m如前文任一方案所定義。 In a preferred technical scheme of formula (I), the compound, its pharmaceutically acceptable salt, its ester, its isomer, and its solvate have the structure shown in the following general formula,

,

Wherein, ring C is selected from the spiroheterocyclyl as defined by R ^4b in any scheme above; Ring B is selected from the definition of ring B in any scheme above; w is selected from 0, 1 or 2; pa is selected from 0, 1 or 2; K ¹ is selected from N or CH; K ² is selected from N-S3, NH, O or CH ₂ ; R ^4a , L ² , S3, R ² and m are as defined in any scheme above.

、

環A選自

、

、

或

； R ²選自氫、氟、甲基、甲氧基； 其中，環C選自如前文任一方案中R ⁴所定義的雜環基； R ^4a選自甲基、甲氧基、氟、三氟甲基、氰基； K ¹選自N或CH；K ²選自N-S3、NH、O或CH ₂； pa選自0、1或2； w選自0、1或2； L ²、S3、m如前文任一方案所定義。 In a preferred embodiment of formula (I), the compound, its pharmaceutically acceptable salt, its ester, its isomer, and its solvate have the structure shown in the following general formula,

,

Ring A is selected from

,

,

or

; R ² is selected from hydrogen, fluorine, methyl, methoxy; Wherein, ring C is selected from heterocyclic groups as defined by R ⁴ in any of the preceding schemes; R ^4a is selected from methyl, methoxy, fluorine, tri Fluoromethyl, cyano; ^K1 is selected from N or CH; ^K2 is selected from N-S3, NH, O or _CH2 ; pa is selected from 0, 1 or 2; w is selected from 0, 1 or 2; ^L2 , S3, m are as defined in any scheme above.

Each of the substituents and each of the optional groups in the aforementioned technical solutions of the present application can be combined with each other to form a new complete technical solution, and the new technical solution formed has the same technical effect as the previous solution of the present application. All of them are included in the scope of the present invention.

。 In one embodiment of formula (I), the compound described in formula (I), its pharmaceutically acceptable salt, its ester, its isomer, and solvate are selected from the following compounds:

.

In another aspect, the present application also provides a pharmaceutical preparation, containing the compound described in any of the preceding schemes, its pharmaceutically acceptable salt, its ester, its solvate or its isomer, and one or more pharmaceutically acceptable Adjuvant; the pharmaceutical preparation can be any pharmaceutically acceptable dosage form. A pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or disease type and state being used to treat a particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, Stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. Flavoring agents, preservatives and sweeteners, etc. can also be added to the pharmaceutical compositions when necessary.

In certain embodiments, the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. For parenteral administration, the above pharmaceutical preparations can also be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used to produce. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine. For rectal administration, the pharmaceutical composition can be made into suppositories and the like. For pulmonary administration, the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.

In another aspect, the present application also provides a pharmaceutical composition, which contains the compound described in any of the preceding schemes, its pharmaceutically acceptable salt, its ester, solvate or its isomer, and one or more second therapeutic agents Active agent, the second therapeutically active agent can be used in combination with the PLK4 kinase inhibitor compound of the present application for the treatment and/or prevention of related diseases mediated by it. In another preferred example, the second therapeutically active agent includes anti-tumor agents (including chemical agents, biological agents, CAR-T therapy, immunomodulators), agents for reducing adverse reactions (such as antiemetics, chemotherapy Poisons, blood-increasing drugs), antibacterial drugs, analgesics, radiation sensitizers, nutritional drugs. In another preferred example, the second therapeutically active agent is selected from anti-tumor agents, such as antibody drugs, cytotoxic drugs, hormone drugs, biological response modifiers (such as enhancing immune function), cell differentiation inducers , apoptosis inducers, angiogenesis inhibitors, epidermal growth factor receptor inhibitors, etc.

In another aspect, the present application also provides the use of the compound described in any of the preceding schemes, its pharmaceutically acceptable salt, its ester, solvate or its isomer in the preparation of medicines for the prevention and treatment of /or treat a subject's related disease mediated by PLK4; preferably, the related disease mediated by PLK4 is a cell abnormal proliferation disease. In another embodiment, the cell dysproliferative disease is cancer selected from the group consisting of lung cancer, breast cancer, colon cancer, brain cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, head and neck cancer, neurogenic Cytoma, prostate cancer, melanoma, glioblastoma multiforme, ovarian cancer, cervical cancer, lymphoma, leukemia, sarcoma, with tumor effector, osteosarcoma, germ cell tumor, glioma, or mesothelioma. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In another embodiment, the cancer is a breast cancer. In another embodiment, the cancer is a basal subtype breast cancer or a luminal B subtype breast cancer. In another specific embodiment, the cancer is a soft tissue cancer, including tumors originating from any soft tissue of the body. These soft tissues connect, support, and surround different structures and organs of the body, including but not limited to: smooth muscle, skeletal muscle, tendon, fibrous tissue, adipose tissue, blood vessels and lymphatic vessels, perivascular tissue, nerves, mesenchymal cells, synovial tissue . Thus, soft tissue cancers may be cancers of adipose tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymphatic vessels, and fibrous tissue. Soft tissue cancers can be benign or malignant. In another embodiment, the soft tissue cancer is selected from the group consisting of fibrosarcoma, gastrointestinal sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, synovial sarcoma. In another embodiment, the abnormal cell proliferation disorder is cancer, such as human breast cancer.

In another aspect, the present application also provides a method for treating cancer, comprising administering an effective amount of the compound or pharmaceutical composition or pharmaceutical preparation described in any of the aforementioned schemes. In one embodiment, the compounds of the invention inhibit the growth of tumors. In another embodiment, compounds of the invention inhibit the growth of tumors that overexpress PLK4. In another embodiment, the compounds of the invention inhibit tumor growth by inducing apoptosis of tumor cells or by inhibiting proliferation of tumor cells. The cancer is as described above.

In another embodiment, the methods of the invention may be combination therapy in combination with other therapies known in the art for the treatment of the desired disease or indication. In one embodiment, one or more other antiproliferative or anticancer therapies are combined with a compound of the invention or a pharmaceutical composition or pharmaceutical formulation comprising it. In one embodiment, the compounds of the present invention are used in combination with other anticancer agents (ie, second therapeutically active agents) as previously described for the treatment of cancer. In one embodiment, anticancer therapies used in combination with the compounds of the invention include surgery, radiation therapy, endocrine therapy.

Description and Definition

In this application, unless otherwise specified, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art to which the present invention belongs. However, for a better understanding of the present invention, some terms are provided below definition. When the definitions of the terms provided in the present application are inconsistent with the meanings generally understood by those skilled in the art to which the present invention belongs, the definitions and explanations of the terms provided in the present application shall prevail.

The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit/risk ratio Comparable to those compounds, materials, compositions and/or dosage forms.

The "pharmaceutically acceptable salt" in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as _-NH2 , etc.) present in compounds with suitable inorganic or organic anions (acids) , including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.). These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base.

The compounds of the present invention can exist in unsolvated as well as solvated forms, solvated including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of this invention.

The "ester" in the present invention refers to the product formed by dehydration of acid and alcohol; when there is a -COOH group in the structure of the compound of the present invention, it can be dehydrated with a pharmaceutically acceptable alcohol compound to form an ester; when the present invention There is -OH in the compound structure, which can be dehydrated with a pharmaceutically acceptable organic acid or inorganic acid compound to form an ester. The ester compound can produce the active compound of the present invention through metabolism or hydrolysis in an organism, and the ester in vitro may have similar biological activity to the free body, or may have no or weak biological activity.

The compounds of the present invention have geometric isomers and stereoisomers. Specific examples of "isomers" according to the present invention are cis-trans isomers, enantiomers, diastereoisomers, mutual The isomers, and their racemic and other mixtures, all such mixtures are within the scope of the invention.

The term "enantiomer" refers to stereoisomers that are mirror images of each other.

The term "tautomer" refers to one of functional isomers having different points of attachment by displacement of one or more double bonds, for example, a ketone and its enol form are keto-enol tautomers .

The term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and which are in a non-mirror-image relationship.

The term "cis-trans isomers" refers to different configurations formed by different spatial arrangements of double bonds or single bonds of ring-forming carbon atoms in molecules that cannot freely rotate.

The compounds of the present invention may be prepared by enantiospecific synthesis or by resolution from enantiomeric mixtures to prepare individual enantiomeric forms. Conventional resolution techniques include the use of optically active acids to form the base form salts of each isomer of the enantiomeric pair (followed by fractional crystallization and regeneration of the free base), the use of optically active amines to form the Salts of the acid forms of each enantiomer (followed by fractional crystallization and regeneration of the free acid), formation of each of each enantiomer of the enantiomeric pair using optically pure acids, amines, or alcohols esters or amides (followed by chromatographic separation and removal of chiral auxiliaries) or by resolution of enantiomeric mixtures of starting materials or final products using various well-known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by a structure, the named or depicted stereoisomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight relative to the other stereoisomers Or 99.9% pure by weight. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% optically pure . Optical purity (commonly expressed as ee value) is the difference between the weight of a single enantiomer (such as the R-type isomer) minus the weight of its corresponding isomer (such as the S-type) and the sum of the weight of the corresponding isomers (eg R+S) ratio.

When a disclosed compound is named or depicted by a structure where no stereochemistry is indicated and the compound has at least one isomerizing element (e.g., a chiral center, a double bond, a ring-forming carbon atom that cannot rotate freely), the A name or structure encompasses a mixture of individual isomers of the compound or a mixture enriched in one enantiomer relative to the other.

The terms "therapeutically effective amount" and "effective amount" mean that when the compound of the present invention is administered to a subject, it is sufficient to produce a beneficial or desired effect; the effect may be to prevent the occurrence of tumors, and/or to inhibit the growth of tumors , and/or limit tumor spread, and/or reduce tumor volume, and/or improve clinical symptoms or indicators associated with cancer. It should be recognized, however, that the total daily dosage of the compounds of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition or dosage form employed. ; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound employed; duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical field. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.

The term "optionally substituted" in the present invention refers to two situations in which one or more hydrogen atoms on the substituted group can be "substituted" or "not substituted" by one or more substituents.

In the present invention, when any variable occurs more than once in the composition or structure of a compound, its definition in each case is independent, and the substituents may be the same or different. For example, when m in general formula (I) is 2, ring A is substituted by two R ² groups, wherein each R ² is independent of each other; for example, said R ² is substituted by one or more S2, Wherein, each S2 is also mutually independent; for example, when R ² is selected from -N(R ⁵ )(R ⁶ ), and R ⁴ is selected from -N(R ⁵ )(R ⁶ ), wherein each of R ⁵ , R The definition of ⁶ in each substituent is independent.

The substituents described in the present invention "(3-8 membered cycloalkyl)-L ² -, (3-8 membered heterocyclic group)-L ² -, (6-14 membered condensed heterocyclic group)-L ² - , (5-12 membered spiro heterocyclic group)-L ² -, (6-12 membered bridged heterocyclic group)-L ² -”, when L ² is selected from a chemical bond, it refers to the cycloalkyl, hetero Cyclic group, condensed heterocyclic group, spiro heterocyclic group and bridging heterocyclic group are directly connected to ring B through a chemical bond. This definition also applies to the subordinate concepts of the respective ring structures.

、

、

。 "C(O)", "S(O)", "S(O) ₂ " appearing in the substituent means

,

,

.

表示取代基R ₁可以在苯環上的任意一個位置發生取代。 When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, the structural unit

Indicates that the substituent R ₁ can be substituted at any position on the benzene ring.

表示該原子為鍵合原子，例如

，表示該環羰基鄰位上的C原子為鍵合原子。 When the specific atom connected to the general structure is not specified in the substituent, it means that the substituent can be bonded to the general structure through any atom, for example, pyrazole as a substituent refers to the Any ring atom can be connected to the substituted group; when the substituent structure appears

Indicates that the atom is a bonded atom, e.g.

, indicating that the C atom at the ortho position of the ring carbonyl is a bonding atom.

”表示該化學鍵可以為單鍵或雙鍵。 In the compound structure, "

" indicates that the chemical bond can be a single bond or a double bond.

”為共價單鍵，代表其所連接的取代基在雙鍵一側位置並不固定，即所連接的具體化學基團可以存在順反異構，即該化合物可以包括Z型和E型結構。“

”和“

”表示一個立體中心的絕對構型。“

”或“

”表示Z型和E型，雙實鍵或雙虛鍵均表示順式構型Z，一實一虛表示反式構型E。 In general structure or specific compound structure, "

"is a covalent single bond, which means that the substituent connected to it is not fixed on one side of the double bond, that is, the specific chemical group connected can have cis-trans isomerism, that is, the compound can include Z-type and E-type structures .”

"and"

"Denotes the absolute configuration of a stereocenter."

"or"

"Represents Z type and E type, double real bond or double imaginary bond all represent cis configuration Z, one real and one imaginary represent trans configuration E.

The "halogen" in the present invention refers to fluorine atom, chlorine atom, bromine atom or iodine atom.

The "C _1-6 alkyl" in the present invention means a linear or branched alkyl group containing 1-6 carbon atoms, including, for example, "C _1-5 alkyl", "C _1-4 alkyl" , "C _1-3 alkyl", "C _1-2 alkyl", "C _{2-6 alkyl", "C 2-5 alkyl} ", "C _2-4 alkyl", "C _{2- 3} alkyl", "C _3-6 alkyl", "C _3-5 alkyl", "C _3-4 alkyl", "C _4-6 alkyl", "C _4-5 alkyl", "C _5-6 alkyl", etc., specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl , 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl , 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C _1-4 alkyl" in the present invention refers to specific examples of C _1-6 alkyl containing 1-4 carbon atoms.

The "halogenated C _1-6 alkyl" in the present invention means that the hydrogens in the C _1-6 alkyl are respectively replaced by one or more halogens, such as "fluoromethyl" includes monofluoromethyl, Difluoromethyl, trifluoromethyl; C _1-6 alkyl is as defined above.

The "C _1-6 alkylene" mentioned in the present invention refers to the group derived from a linear or branched alkane containing 1-6 carbon atoms by removing two hydrogens, including "C _1-5 alkylene ", "C _1-4 alkylene", "C _1-3 alkylene", "C _1-2 alkylene", specific examples include but not limited to: -CH ₂ -, -CH ₂ CH ₂ - , -CH ₂ CH ₂ CH ₂ -, -CH(CH ₂ )CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH(CH ₂ )CH ₂ CH ₂ -, -CH(CH ₂ CH ₂ )CH ₂ -, -C(CH ₂ )(CH ₂ )CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -, etc.; preferably, the C _1-6 alkylene group is a linear group.

The "C _2-6 alkenylene" in the present invention refers to a group derived from a linear or branched alkene containing at least one double bond and having 2-6 carbon atoms by removing two hydrogens, including "C _2-5 alkenylene", "C _2-4 alkenylene", "C _2-3 alkenylene", specific examples include but not limited to: -CH=CH-, -CH=CHCH ₂ -, -C (CH2)=CH-, -CH=CHCH ₂ CH ₂ -, -CH ₂ CH=CHCH ₂ -, -C(CH ₂ )=C(CH ₂ )-, etc.; preferably, C _2-6 alkenylene is a straight-chain group.

、

、

。 The " _C2-6 alkynylene group" mentioned in the present invention refers to a straight-chain or branched alkyne containing at least one triple bond and a carbon number of 2-6 derived by removing two hydrogens that are not on the same carbon atom. Groups, including "C _2-5 alkynylene", "C _2-4 alkynylene", "C _2-3 alkynylene", specific examples include but are not limited to:

,

,

.

In the present invention, when ^L1 is a specific "C _1-6 alkylene group", "C _2-6 alkylene group" or "C _2-6 alkynylene group", the writing method of the specific group does not limit it to the two The direction of attachment of the side substituents. For example, L ¹ is -CH=CHCH ₂ -, and the compound structure includes the following two types: core core -CH=CHCH ₂ -ring B, ring B-CH=CHCH ₂ -core core.

The "C _1-6 alkoxy" in the present invention refers to the group that the term "C _1-6 alkyl" is connected to other structures through an oxygen atom, such as methoxy, ethoxy, propoxy, 1- Methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferred C _1-4 alkoxy, more preferably C _1-3 alkoxy; wherein "C _1-6 alkyl" is as defined above.

"C _1-6 alkylcarbonyl" and "C _1-6 alkoxycarbonyl" in the present invention refer to "C _1-6 alkyl" and "C _1-6 alkoxy" connected to other structures through carbonyl A group, wherein "C _1-6 alkyl" and "C _1-6 alkoxy" are as defined above.

The "cycloalkyl" in the present invention refers to a cyclic alkyl group derived from cycloalkane moiety by removing one hydrogen atom, including saturated monocyclic or polycyclic hydrocarbon groups; A polycyclic group formed by connecting the above cyclic structures through spiro, bridge, fused, etc. methods. The cycloalkyl group of the present invention is preferably a 3-8 membered cycloalkyl group, preferably a 3-8 membered monocycloalkyl group, more preferably a 3-6 membered monocycloalkyl group; examples include but are not limited to cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, cycloheptyl, cyclooctyl.

。所述雜環基類型包括 “3-8元雜環基”“3-8元飽和雜環基”和“3-8元部分飽和雜環基”，優選3-6元雜環基、5-6元雜環基，進一步優選為3-6元飽和雜環基、4-6元飽和雜環基、5-6元飽和雜環基、5-6元部分飽和雜環基，更具體的例子包括4-6元飽和含氮雜環基、5-6元飽和含氮雜環基、5-6元部分飽和含氮雜環基等。其中所述的“含氮雜環基”是指環狀基團中至少含有一個氮原子，還可以包含其它結構的雜原子，例如，僅包含1個或2個氮原子，或者，包含1個氮原子和其他的1個或2個雜原子（例如C(O)和/或O原子），或者，包含2個氮原子和其他的1個或2個雜原子。所述雜環基的具體實例包括但不限於：吡咯烷基、咪唑烷基、呋喃烷基、㗁唑烷基、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

。 The "certain-membered heterocyclic group" in the present invention refers to a saturated or partially saturated but non-aromatic monocyclic group containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from N, O, and S; The ring carbon atoms and heteroatoms in the heterocycle can be further oxo-substituted to form ring groups containing C(O), NO, SO, S(O) ₂ groups, which are also included in the heterocycles of the present invention. Within the definition of ring group. The "non-aromatic" mentioned in this definition means that the group does not have aromaticity when it exists independently. The present invention does not limit the group to be connected to other structures through internal or external unsaturated bonds, or to be connected to other unsaturated structures through single bonds, or to make it aromatic under certain conditions (such as in special solvents) . Preferably, the heterocyclic group independently includes 1-3 CO, N and/or O, preferably 1 C(O) and/or 1 N, preferably the heteroatoms form a lactamide structure, namely structured as

. The heterocyclic group type includes "3-8 membered heterocyclic group", "3-8 membered saturated heterocyclic group" and "3-8 membered partially saturated heterocyclic group", preferably 3-6 membered heterocyclic group, 5- 6-membered heterocyclic group, more preferably 3-6 membered saturated heterocyclic group, 4-6 membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group, 5-6 membered partially saturated heterocyclic group, more specific examples Including 4-6 membered saturated nitrogen-containing heterocyclic group, 5-6 membered saturated nitrogen-containing heterocyclic group, 5-6 membered partially saturated nitrogen-containing heterocyclic group and the like. The "nitrogen-containing heterocyclic group" mentioned therein means that the cyclic group contains at least one nitrogen atom, and may also contain heteroatoms of other structures, for example, containing only 1 or 2 nitrogen atoms, or containing 1 Nitrogen atom and 1 or 2 other heteroatoms (such as C(O) and/or O atoms), or, 2 nitrogen atoms and 1 or 2 other heteroatoms. Specific examples of the heterocyclic group include, but are not limited to: pyrrolidinyl, imidazolidinyl, furanyl, oxazolidinyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

.

。本發明所述的 “8-14元稠雜環基”包括“8-14元飽和稠雜環基”和“8-14元部分飽和稠雜環基”，優選6-10元稠雜環基、6-8元稠雜環基、8-12元稠雜環基、9-13元稠雜環基、9-12元稠雜環基、9-10元稠雜環基，優選雙環稠雜環基、三環稠雜環基，進一步優選9-13元含氮稠雜環基、9-12元含氮稠雜環基等；稠和方式可以為5-6元雜環基并5-6元雜環基、5-6元雜環基并5-6元環烷基、苯并5-6元雜環基、苯并5-6元飽和雜環基、5-6元雜芳基并5-6元雜環基、5-6元雜芳基并5-6元飽和雜環基、苯并5-6元雜環基并5-6元雜環基、5-6元雜芳基并5-6元雜環基并5-6元雜環基、苯并5-6元環烷基并5-6元雜環基、5-6元雜芳基并5-6元環烷基并5-6元雜環基；所述的“含氮雜稠雜環基”是指稠環基團中至少含有一個氮原子，還可以包含其它結構的雜原子，例如，僅包含1個或2個氮原子，或者，包含一個氮原子和其他的1個或2個雜原子（例如C(O)和/或O原子），或者，包含2個氮原子和其他的1個或2個雜原子。所述的稠雜環基的具體實例包括但不限於：

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 The "fused heterocyclic group" mentioned in the present invention refers to a saturated or partially saturated ring structure formed by two or more ring structures sharing two adjacent atoms, containing at least one ring atom as a heteroatom Non-aromatic cyclic group; the heteroatoms are generally selected from N, O, S; the ring carbon atoms and heteroatoms in the condensed heterocycle can be further oxo-substituted to form a group containing C(O), NO, SO , S(O) ₂ The cyclic group of the group is also included in the definition of the heterocyclic group in the present invention. The "non-aromatic" mentioned in this definition means that the group does not have aromaticity when it exists independently. The present invention does not limit the group to be connected to other structures through internal or external unsaturated bonds, or to be connected to other unsaturated structures through single bonds, or to make it aromatic under certain conditions (such as in special solvents) . The fused heterocyclic group preferably contains 1-3 C(O) and/or N, preferably 1 C(O) and/or 1 N, preferably the heteroatoms form a lactamide structure, that is, the structure is

. The "8-14 membered fused heterocyclic group" in the present invention includes "8-14 membered saturated fused heterocyclic group" and "8-14 membered partially saturated fused heterocyclic group", preferably 6-10 membered condensed heterocyclic group , 6-8 membered fused heterocyclic group, 8-12 membered fused heterocyclic group, 9-13 membered fused heterocyclic group, 9-12 membered fused heterocyclic group, 9-10 membered fused heterocyclic group, preferably bicyclic fused heterocyclic group Cyclic group, tricyclic fused heterocyclic group, more preferably 9-13 membered nitrogen-containing fused heterocyclic group, 9-12 membered nitrogen-containing fused heterocyclic group, etc.; the condensed method can be 5-6 membered heterocyclic group and 5- 6-membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, benzo 5-6 membered saturated heterocyclyl, 5-6 membered heteroaryl And 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group, benzo 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heteroaryl Base and 5-6 membered heterocyclyl and 5-6 membered heterocyclyl, benzo 5-6 membered cycloalkyl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered cycloalkane The base is a 5-6 membered heterocyclic group; the "nitrogen-containing heterocondensed heterocyclic group" means that the condensed ring group contains at least one nitrogen atom, and may also contain heteroatoms of other structures, for example, only one or 2 nitrogen atoms, or, contain 1 nitrogen atom and 1 or 2 other heteroatoms (such as C(O) and/or O atoms), or, contain 2 nitrogen atoms and 1 or 2 other heteroatoms heteroatoms. Specific examples of the fused heterocyclic group include, but are not limited to:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

The "heteroaryl" mentioned in the present invention refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from CO, N, O, S, NO, SO, S(O) ₂ . The heteroaryl independently contains 1-3 CO, N and/or O. The heteroaryl group of the present invention is preferably a monoheteroaryl group, preferably "5-6 yuan monoheteroaryl", "5-6 nitrogen-containing monoheteroaryl", "6 nitrogen-containing monoheteroaryl", so The heteroatoms in the above "nitrogen-containing heteroaryl" contain at least one nitrogen atom, for example, contain only 1 or 2 nitrogen atoms, or contain a nitrogen atom and other 1 or 2 heteroatoms (such as S and/or O atoms), or, contain 2 nitrogen atoms and 1 or 2 other heteroatoms. Specific examples of such heteroaryl groups include, but are not limited to: furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl , pyrazolyl, etc.

、

、

、

、

、

、

、

、

、

、

、

、

、、

、

、

、

、

、

或

等。 The "spiroheterocyclic group" mentioned in the present invention refers to a saturated or partially saturated ring structure formed by two or more ring structures sharing one ring atom with each other, containing at least one ring atom as a heteroatom . The heteroatoms are generally selected from CO, N, O, S, NO, SO, S(O) ₂ , the heteroatoms are independently preferably 1-3 CO, N and/or O, and the heteroatoms are independently 1 CO and 1 N are preferred, and the heteroatoms preferably form a lactam structure. The spiroheterocyclyl of the present invention includes "5-12 membered spiroheterocyclyl", "5-15 membered saturated spiroheterocyclyl" and "5-15 membered partially saturated spiroheterocyclyl", preferably 7-12 membered Spiroheterocyclyl, 7-11 membered spiroheterocyclyl, 8-11 membered spiroheterocyclyl, 8-11 membered saturated spiroheterocyclyl, 9-11 membered saturated spiroheterocyclyl, 9-11 membered saturated spiroheterocyclyl Cyclic group, 9-11 membered nitrogen-containing spiroheterocyclic group, 9-11 membered nitrogen-containing saturated spiroheterocyclic group. Specific examples include but are not limited to:

,

,

,

,

,

,

,

,

,

,

,

,

,,

,

,

,

,

,

or

wait.

、

、

、

、

等。 The "bridged heterocyclic group" in the present invention refers to a saturated or partially saturated ring structure formed by two or more ring structures sharing two non-adjacent carbon atoms, containing at least one ring atom as a heteroatom ring structure. The bridging heterocyclic group generally contains CO, N, O, S, NO, SO, S(O) ₂ , preferably independently contains 1-3 CO, N and/or O, more preferably independently contains 1 O and/or 1 N. The bridging heterocyclic group in the present invention includes "6-12 membered spiroheterocyclic group", "6-12 membered saturated spiroheterocyclic group" and "6-12 membered partially saturated spiroheterocyclic group", preferably 6-10 membered Bridged heterocyclic group, 6-8 membered bridged heterocyclic group, 7-8 membered bridged heterocyclic group, 6-8 membered bridged heterocyclic group, 6-8 membered nitrogen-containing bridged heterocyclic group, 6-8 membered saturated Nitrogen-bridged heterocyclyl. Specific examples include but are not limited to

,

,

,

,

wait.

結構，其碳氧雙鍵是在環外、並且不參與成環，其被認為是飽和結構。所述“部分飽和環”是指不飽和鍵在環內、部分成環化學鍵為雙鍵或三鍵、部分為單鍵的環，比如

結構，因環內含有一個雙鍵，可被認為部分飽和結構。 Unless otherwise specified, the "saturated ring" mentioned in the present invention refers to a ring that does not contain double bonds (tautomerism is not considered) and the chemical bonds forming the ring are all saturated bonds. for example

A structure whose carbon-oxygen double bond is outside the ring and does not participate in ring formation is considered a saturated structure. The "partially saturated ring" refers to a ring in which the unsaturated bond is in the ring, part of the ring-forming chemical bond is a double bond or a triple bond, and part of it is a single bond, such as

The structure, because the ring contains a double bond, can be considered a partially saturated structure.

In the examples of the present invention, the name of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the name of the compound and the structure of the compound, it can be determined by comprehensively related information and reaction routes; if it cannot be confirmed by other methods, the structural formula of the given compound shall prevail.

The compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and those skilled in the art Known equivalents, preferred embodiments include but are not limited to the examples of the present invention.

The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be adjusted appropriately according to different reactants.

1. Summary of experimental equipment:

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS), or ultra-high performance liquid chromatography-mass chromatography (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is carried out with Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instruments, and the determination solvents are deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD ) and deuterated chloroform (CDCl ₃ ), heavy water (D ₂ O), the internal standard is tetramethylsilane (TMS).

Agilent 1260-6125B single quadrupole mass spectrometer was used for liquid chromatography-mass chromatography LC-MS, and the column was Welch Biomate column (C18, 2.7 um, 4.6*50 mm) or waters H-Class SQD2, and the column was Welch Ultimate column (XB -C18, 1.8 um, 2.1*50 mm) mass spectrometer (ion source is electrospray ionization).

Waters UPLC H-class SQD mass spectrometer (ion source is electrospray ionization) was used for the determination of ultra-high performance liquid chromatography-mass chromatography UPLC-MS.

The determination of HPLC uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

Preparative HPLC uses Waters 2555-2489 (10 µm, ODS 250cm × 5cm) or GILSON Trilution LC, and the column is Welch XB-C18 column (5um, 21.2*150 mm).

Chiral HPLC uses waters aquity UPC2; the column is Daicel chiralpak AD-H (5 um, 4.6*250 mm), Daicel chiralpak OD-H (5 um, 4.6*250 mm), Daicel chiralpak IG-3 (3 um, 4.6*150 mm), Chiral Technologies Europe AD-3 (3 um, 3.0*150 mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5 um, 3.0*150 mm).

Supercritical fluid chromatography (SFC) uses waters SFC 80Q, the column is Daicel Chiralcel OD/OJ/OZ (20 x 250 mm, 10 um) or Daicel Chiralpak IC/IG/IH/AD/AS (20 x 250 mm, 10 um ).

Thin-layer chromatography silica gel plates use GF254 silica gel plates from Yantai Jiangyou Silicone Rubber Development Co., Ltd. or Rushan Shangbang New Materials Co., Ltd. GF254 silica gel plates. The specifications used by TLC are 0.15 mm to 0.20 mm. Analysis is generally used in 200~300 mesh silica gel as a carrier in Chenghua Chemical Industry.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.

Unless otherwise specified, all reactions in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of reaction temperature is Celsius.

Unless otherwise specified, the mixed solvent ratio used in the examples of the present invention is a volume ratio, and specific expressions include but are not limited to: petroleum ether/ethyl acetate=3/1.

In the embodiments of the present invention, when "M" appears, it means "mol/L", which is the reagent concentration; "nM" means nmol/L.

In the embodiments of the present invention, the "room temperature" generally refers to 25±5°C.

The purification reagent or mobile phase used in the purification process of some compounds in this application contains trifluoroacetic acid, so the final product form of some compounds obtained is its trifluoroacetic acid salt. Those with ordinary knowledge in the field of the present invention can understand that the applicant has obtained the free base compound in the preparation process, and adding trifluoroacetic acid is only used as a purification step; trifluoroacetic acid may not be added in the purification step, and what is obtained is the corresponding The pure "free base" compound. In addition, the preparation of free base compounds by trifluoroacetic acid salts, or the preparation of trifluoroacetic acid salts by compounds are relatively conventional means, and the structure of the compound trifluoroacetic acid salts disclosed in this application or its preparation can be regarded as equivalently disclosed free base compound structures and its preparation.

反應路線:

Example 1: (E)-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-4-phenyl pyrrolidin-2-one

Reaction route:

Operation steps: Step A: Dissolve 4-phenylpyrrolidone-2-one (10.0 g, 62.0 mmol) in acetic anhydride (100 ml), and reflux at 145°C for two hours. TLC monitors that the raw materials have reacted, concentrated most of the acetic anhydride, added the reaction solution to aqueous sodium bicarbonate (100 ml), extracted twice with ethyl acetate, combined the organic phases, and washed the organic phase with aqueous sodium bicarbonate. Wash with saturated brine, dry the organic phase with sodium sulfate, filter, concentrate the filtrate, beat with petroleum ether after solidification, and filter to obtain 1-acetyl-4-phenylpyrrolidone-2-one (11.5 g, yield 91.2 %) Step B: Dissolve 1H-indazole-6-carbaldehyde (25.0 g, 171.0 mmol) in N,N-dimethylformamide (150 mL) potassium carbonate (47.3 g, 342 mmol), subsequently, iodine (73.8 g, 291.0 mmol) dissolved in N,N-dimethylformamide (150 ml) was added to the reaction solution, and stirred for two hours. TLC detects that the reaction of the raw materials is complete, and the mixed solution of sodium thiosulfate/potassium carbonate/water is added to the reaction system, stirred for one hour, and one liter of ice water is added, solids are precipitated, filtered and dried to obtain 3-iodo-1H- Indazole-6-carbaldehyde (36.5 g, 78.5% yield). Step C: 3-Iodo-1H-indazole-6-carbaldehyde (30.0 g, 110.0 mmol) was dissolved in dichloromethane (600.0 ml). Subsequently, p-toluenesulfonic acid (4.2 g, 22.1 mmol), 3.4-dihydro-2Hpyran, and magnesium sulfate (22.8 g, 189 mmol) were added thereto and stirred at 35°C for two hours. After the reaction of the raw materials was detected by TLC, and LCMS monitoring showed that it was the product, the reaction solution was filtered, and aqueous sodium bicarbonate (200 ml) was added to the reaction solution to quench it, and the mixture was extracted with dichloromethane (300 ml × 3 times), and combined The organic phase was washed with saturated brine (100 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. Slurry with petroleum ether/ethyl acetate 15/1, filter to obtain 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (26.8 grams, yield 67 %). MS (ESI) M/Z: 357.1 [M+H] ⁺ . Step D: Dissolve NaH (4.2 g, 139.7 mmol) in THF (40.0 mL), add 1-acetyl-4-benzene in ice-water bath ylpyrrolidinone-2-one (11.4 g, 55.8 mmol) and (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (16.5 g, 46.6 mmol Mole, raw material 1) tetrahydrofuran (160 ml) mixed solution, stirred in an ice-water bath for 1 hour. TLC monitoring raw material 1 basically reacted, LCMS monitoring showed product, the reaction solution was added to ammonium chloride aqueous solution (50 ml) to quench The mixture was extracted with ethyl acetate (200 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (100 ml), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was used Purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to obtain (E)-3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H -Indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one mixture (10.6 g, 46.1% yield) was used directly in the next step without further purification. MS (ESI) M/Z : 500.5 [M+H] ⁺ .

反應路線:

Example 2: (E)-1-(4-methoxybenzyl)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde

Reaction route:

Operation steps: Step A: The raw material 3-iodo-1H-indazole-6-carbaldehyde (5 g, 18.4 mmol) was dissolved in N,N dimethylformamide (30 ml) and cooled to 0°C in an ice-water bath. Then potassium carbonate (7.6 g, 55.1 mmol) and p-methoxybenzyl chloride (referred to as PMBCl, 5.8 g, 36.8 mmol) were added, and the mixture was raised to room temperature and stirred for 2 hours. After LCMS monitoring showed disappearance of starting material, water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue, crude 3-iodo-1-(4-methoxybenzyl)-1H-indazole-6-carbaldehyde, was used directly in the next step. MS (ESI) M/Z: 393.2 [M+H] ⁺ . Step B: The above crude 3-iodo-1-(4-methoxybenzyl)-1H-indazole-6-carbaldehyde (18.4 mmol ear), 4-vinylpyridine (3.9 g, 36.8 mmol), diisopropylethylamine (4.7 g, 36.8 mmol), palladium acetate (1.1 g, 5 mmol) and 3 (o Tolyl)phosphine (4.6 g, 15 mmol) was added into NN-dimethylformamide (60 ml), nitrogen was replaced 3 times, and then the temperature was raised to 100°C for overnight reaction. After LCMS monitoring showed that the starting material (3-iodo-1-(4-methoxybenzyl)-1H-indazole-6-carbaldehyde) disappeared, water (200 ml) was added to the reaction system. The mixture was extracted with ethyl acetate (100 ml x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (E)-1-(4-methoxybenzyl)-3-(2-(pyridine- 4-yl)vinyl)-1H-indazole-6-carbaldehyde (4.2 g, 62.0% yield over two steps). MS (ESI) M/Z: 370.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.15 (s, 1H), 8.58 (d, J = 6.0 Hz, 2H), 8.49 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 16.8 Hz, 1H), 7.77-7.72 (m, 3H), 7.56 (d, J = 16.8 Hz, 1H) , 7.30 (d, J = 8.8 Hz, 2H), 6.91-6.89 (m, 2H), 5.75 (s, 2H), 3.70 (s, 3H).

反應路線:

Example 3: 4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene))methyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-3-yl)vinyl)benzaldehyde

Reaction route:

Operation steps: Step A: Dissolve p-bromobenzaldehyde (4.0 g, 21.6 mmol) and vinyl borate pinacol ester (3.7 g, 23.8 mmol) in toluene (100 ml), add tri(di benzylideneacetone) dipalladium (620.5 mg, 1.1 mmol), N,N-diisopropylethylamine (5.6 g, 43.3 mmol) and tri-tert-butylphosphine tetrafluoroborate (624.8 mg , 2.2 mmol). Vacuum the air to replace the nitrogen for 3-4 times, and the reaction temperature was raised to 90 degrees Celsius for 3 hours. After LC-MS monitoring showed that the starting material disappeared, the toluene was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in ethyl acetate, filtered, and water (50 ml) was added to the filtrate. The mixture was extracted with ethyl acetate (70 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 40/1) to obtain (E)-4-(2-(4,4,5,5-tetramethyl-1, 3,2-dioxolan-2-yl)vinyl)benzaldehyde (4.5 g, yield 80.6%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.00 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 18.4 Hz, 1H), 6.33 (d, J = 18.4 Hz, 1H), 1.33 (s, 12H). Step B: (E)-3-((3-iodo-1-(tetrahydro-2H-pyran -2-yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one (3.0 g, 6.0 mmol) and (E)-4-(2-( 4,4,5,5-Tetramethyl-1,3,2-dioxolan-2-yl)vinyl)benzaldehyde (2.2 g, 8.4 mmol) dissolved in 1,4-di oxane (100ml) and water (25ml). Potassium carbonate (2.1 g, 15.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (440 mg, 0.6 mmol) were added. The nitrogen was evacuated for 3-4 times by vacuum pumping, and the reaction system was heated to 105 degrees Celsius under reflux and stirred for 3 hours. After LC-MS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench it. Celite was filtered, the filtrate was extracted with ethyl acetate (100 ml × 2 times), the organic phase was combined, the organic phase was first washed with saturated brine (50 ml × 2 times), then dried with anhydrous sodium sulfate, filtered, and finally Concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 40/1) to obtain 4-((E)-2-(6-((E)-(2-oxo-4- Phenylpyrrolidin-3-ylidene))methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)vinyl)benzaldehyde (2.6 g, yield Yield 85.1%) can be directly used in the next step without further purification. MS (ESI) M/Z: 504.2 [M+H] ⁺ .

反應路線:

Example 4: (E)-4-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene-1,2-di Hydroisoquinolin-3(4H)-one trifluoroacetate

Reaction route:

Operation steps: Step A: 1,4-Dihydroisoquinolin-3(2H)-one (181.3 mg, 1.3 mmol) was dissolved in tert-butanol (6 mL). Then add (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole- 6-Formaldehyde (493.4 mg, 1.3 mmol) and potassium tert-butoxide (325.4 mg, 2.9 mmol). The reaction system was heated to 80 degrees Celsius and refluxed for 4 hours. After LCMS monitoring showed that the starting material disappeared, water (80 mL) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (40 mL x 1 time), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain (E)-4-((3-((E)-2-(pyridin-4-yl)ethylene Base)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)-1,4-dihydroisoquinoline-3 (2H)-Kone (317.4 mg, 48% yield). MS (ESI) M/Z: 509.2 [M+H] ⁺ . Step B: (E)-4-((3-((E)-2-(pyridin-4-yl)ethylene Base)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)-1,4-dihydroisoquinoline-3 (2H)-Kone (203.5 mg, 0.4 mmol) was dissolved in 1,4-dioxane (10 mL). Subsequently, concentrated sulfuric acid (0.5 g) was added. The reaction solution was stirred at 60°C for 30 minutes, then filtered, and the filter cake was dissolved in ethanol (12 ml). Then 2M sulfuric acid aqueous solution (7 ml) was added, and the reaction solution was refluxed at 80° C. for 3 hours. After LCMS monitoring showed that the starting material disappeared, aqueous sodium bicarbonate solution (50 ml) was added to the reaction system to quench it. The mixture was extracted with dichloromethane/methanol = 10:1 (30 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml), then dried with anhydrous sodium sulfate, filtered, and finally depressurized concentrate. The resulting residue was purified by prep (trifluoroacetic acid was included in the purification reagent) to give (E)-4-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazole-6 -yl)methylene-1,2-dihydroisoquinolin-3(4H)-one trifluoroacetate (5.6 mg, 2.9% yield). MS (ESI) M/Z: 379.3 [M+H ] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.37 (s, 1H), 8.89 - 8.73 (m, 4H), 8.31 - 8.11 (m, 4H), 7.93 (dd, J = 15.9, 8.5 Hz, 2H), 7.65 (d, J = 16.8 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.37 - 7.25 (m, 3H), 4.45 (s, 2H).

反應路線:

Example 5: (E)-4-phenyl-3-(((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene ) pyrrolidin-2-one trifluoroacetate

Reaction route:

Operation steps: Step A: 4-phenylpyrrolidone-2-one (10.0 g, 62.1 mmol) was dissolved in acetic anhydride (100.0 ml), and refluxed at 145°C for two hours. TLC monitors the completion of the reaction of the raw materials, concentrates most of the acetic anhydride, adds the reaction solution to aqueous sodium bicarbonate (50 ml), extracts twice with ethyl acetate, combines the organic phases, washes the organic phase with saturated brine, and washes the organic phase with anhydrous Sodium sulfate was dried, filtered, and the filtrate was concentrated. After solidification, it was beaten with petroleum ether and filtered to obtain 1-acetyl-4-phenylpyrrolidone-2-one (11.5 g, yield 91.2%). Step B: NaH ( 60.9 mg, 2.0 mmol) was dissolved in tetrahydrofuran (2.0 ml), and 1-acetyl-4-phenylpyrrolidone-2-one (162.4 mg, 0.8 mmol) and (E)-1- (4-Methoxybenzyl)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (258.6 mg, 0.7 mmol, starting material 1) in THF (4 milliliters) mixed solution, stirred in an ice-water bath for 1 hour, TLC monitoring of the raw materials—after the basic reaction was complete, and LCMS monitoring showed that the raw materials disappeared, and quenched by adding ammonium chloride aqueous solution (20 milliliters) to the reaction system. The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) (4-methoxybenzyl)-6-(((E)-(4-phenylpyrrolidine- 3-Ylidene)methyl]-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazole (283.5 mg, yield 79.0%). MS (ESI) M/Z :514.0 [M+H] ⁺ . Step C: Add 1-(4-methoxybenzyl)-6-(((E)-(4-phenylpyrrolidin-3-ylidene)methyl]- 3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazole (153.8 mg, 0.3 mmol) was dissolved in trifluoroacetic acid (4.5 ml) and reacted at 100°C for 3 hours by TLC Monitoring raw material reaction is finished, in reaction system, add sodium bicarbonate aqueous solution (10 milliliters) to quench.Mixed solution is extracted with dichloromethane+methanol (20 milliliters * 3 times), merges organic phase, and organic phase is washed with sodium bicarbonate, The organic phase was washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was prepared and purified (purification reagent contained trifluoroacetic acid) to obtain (E)-4-phenyl- 3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (9.2 mg , yield 5.8%). MS (ESI) M/Z: 393.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.69 (d, J = 6.3 Hz, 2H), 8.21 ( d, J = 6.3 Hz, 2H), 8.15 - 8.02 (m, 2H), 7.69 - 7.56 (m, 3H), 7.37 - 7.15 (m, 7H), 4.79 (d, J = 8.1 Hz, 1H), 4.02 (dd, J = 10.1, 8.0 Hz, 1H).

參考實施例5的製備方法得到(E)-5-苯基-3-((3-((E)-2-(吡啶-4-基)乙烯基)-1H-吲唑-6-基)亞甲基)-1H-吡咯-2(3H) -酮三氟乙酸鹽（4毫克，收率5%）。 MS (ESI) M/Z: 391.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.72 (d, J= 6.8 Hz, 2H), 8.30-8.20 (m, 4H), 7.96 (s, 1H), 7.79 - 7.72 (m, 4H), 7.49 - 7.44 (m, 4H), 6.79 (s, 1H). Example 6: (E)-5-Phenyl-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene) -1H-pyrrol-2(3H)-one trifluoroacetate

The preparation method of reference example 5 obtained (E)-5-phenyl-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl) Methylene)-1H-pyrrole-2(3H)-one trifluoroacetate (4 mg, yield 5%). MS (ESI) M/Z: 391.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.72 (d, J = 6.8 Hz, 2H), 8.30-8.20 (m, 4H), 7.96 (s, 1H), 7.79 - 7.72 (m, 4H), 7.49 - 7.44 (m, 4H), 6.79 (s, 1H).

參考實施例4的製備方法得到4-((3-((E)-2-(吡啶-4-基乙烯基)-1H-吲唑-6-基)亞甲基)異喹啉-1,3(2H，4H)-二酮三氟乙酸鹽（10.8毫克，收率7%）。 MS (ESI) M/Z: 393.4 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.70 (d, J= 6.1 Hz, 2H), 8.33 (d, J= 3.3 Hz, 1H), 8.28 - 8.10 (m, 6H), 7.74 (d, J= 1.5 Hz, 1H), 7.57 (dd, J= 23.6, 8.9 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.39 - 7.30 (m, 2H). Example 7: 4-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)isoquinoline-1,3(2H , 4H)-Diketone trifluoroacetate

The preparation method of reference example 4 obtains 4-((3-((E)-2-(pyridin-4-ylvinyl)-1H-indazol-6-yl)methylene)isoquinoline-1, 3(2H,4H)-Diketone trifluoroacetate (10.8 mg, 7% yield). MS (ESI) M/Z: 393.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) : δ 8.70 (d, J = 6.1 Hz, 2H), 8.33 (d, J = 3.3 Hz, 1H), 8.28 - 8.10 (m, 6H), 7.74 (d, J = 1.5 Hz, 1H), 7.57 (dd , J = 23.6, 8.9 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.39 - 7.30 (m, 2H).

參考實施例5的製備方法得到(E)-5-苯基-3-((3-((E)-2-(吡啶-4-基)乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽（13.6毫克，收率11.6%）。 MS (ESI) M/Z: 393.1[M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.69 (d, J= 5.9 Hz, 2H), 8.30 - 8.11 (m, 4H), 7.75 - 7.66 (m, 2H), 7.54 - 7.26 (m, 7H), 4.96 (dd, J= 8.1, 3.9 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.07 - 2.97 (m, 1H). Example 8: (E)-5-Phenyl-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene) Pyrrolidin-2-one trifluoroacetate

The preparation method of reference example 5 obtained (E)-5-phenyl-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl) Methylene)pyrrolidin-2-one trifluoroacetate (13.6 mg, 11.6% yield). MS (ESI) M/Z: 393.1[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.69 (d, J = 5.9 Hz, 2H), 8.30 - 8.11 (m, 4H), 7.75 - 7.66 (m, 2H), 7.54 - 7.26 (m, 7H), 4.96 (dd, J = 8.1, 3.9 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.07 - 2.97 (m, 1H).

參考實施例4的製備方法得到4-((1-(2-(吡啶-4-基)乙基)-1H-苯并[d] [1,2,3]三唑-5-基)亞甲基)異喹啉-1,3(2H，4H) -二酮（160毫克，收率50.6%）。 MS (ESI) M/Z: 396.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.66-11.49 (m, 1H), 8.54 -8.33 (m, 2H), 8.24 - 8.17 (m, 2H), 8.09 (td, J= 7.9, 1.5 Hz, 1H), 7.91 - 7.71 (m, 2H), 7.65 - 7.27 (m, 3H), 7.27 - 7.16 (m, 2H), 5.05 (td, J= 7.0, 1.8 Hz, 2H), 3.31 (t, J= 7.0 Hz, 2H). Example 9: 4-((1-(2-(pyridin-4-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)methylene)iso Quinoline-1,3(2H, 4H)-dione

The preparation method of reference example 4 obtains 4-((1-(2-(pyridin-4-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl)ylidene Methyl)isoquinoline-1,3(2H,4H)-dione (160 mg, 50.6% yield). MS (ESI) M/Z: 396.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.66-11.49 (m, 1H), 8.54 -8.33 (m, 2H), 8.24 - 8.17 (m, 2H), 8.09 (td, J = 7.9, 1.5 Hz, 1H), 7.91 - 7.71 (m, 2H), 7.65 - 7.27 (m, 3H), 7.27 - 7.16 (m, 2H), 5.05 ( td, J = 7.0, 1.8 Hz, 2H), 3.31 (t, J = 7.0 Hz, 2H).

參考實施例4的製備方法得到 (E)-4-(((1-(2-(吡啶-4-基)乙基)-1H-苯并[d] [1,2,3]三唑-5-基)亞甲基)-1,4-二氫異喹啉-3(2H)-酮（27.1毫克，收率7.9%）。 MS (ESI) M/Z: 382.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.22 (s, 1H), 8.83 (s, 1H), 8.42 - 8.31 (m, 2H), 7.93 (d, J= 8.5 Hz, 2H), 7.77 (s, 1H), 7.73 - 7.67 (m, 1H), 7.55-7.57 (m, 1H), 7.48 (dd, J= 8.7, 1.4 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.22 - 7.14 (m, 2H), 4.94 (t, J= 7.2 Hz, 2H), 4.41 (s, 2H), 3.24 (t, J= 7.2 Hz, 2H). Example 10: (E)-4-(((1-(2-(pyridin-4-yl)ethyl)-1H-benzo[d][1,2,3]triazol-5-yl) Methylene)-1,2-dihydroisoquinolin-3(4H)-one

The preparation method of reference example 4 obtains (E)-4-(((1-(2-(pyridin-4-yl) ethyl)-1H-benzo[d][1,2,3]triazole- 5-yl)methylene)-1,4-dihydroisoquinolin-3(2H)-one (27.1 mg, 7.9% yield). MS (ESI) M/Z: 382.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.22 (s, 1H), 8.83 (s, 1H), 8.42 - 8.31 (m, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.77 (s, 1H), 7.73 - 7.67 (m, 1H), 7.55-7.57 (m, 1H), 7.48 (dd, J = 8.7, 1.4 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.22 - 7.14 (m, 2H), 4.94 (t, J = 7.2 Hz, 2H), 4.41 (s, 2H), 3.24 (t, J = 7.2 Hz, 2H).

反應路線:

Example 11: ((E)-3-((4-fluoro-3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl) Methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

Reaction route:

Procedure: Step A: 4-Bromo-2,6-difluorobenzaldehyde (5.0 g, 22.6 mmol) and 80% hydrazine hydrate (10 mL) in 1,4-dioxane (10 mL) The mixture in was heated to 95°C and stirred at this temperature for 2 hours. After TLC plate monitoring showed that the raw materials disappeared, the mixture was cooled to room temperature, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 6-bromo-4-fluoro-1H-indazole (4 g, yield 82.3%). MS (ESI) M/Z: 214.9 [M+H] ⁺ . Step B: 6-Bromo-4-fluoro-1H-indazole (1 g, 4.7 mmol) and p-toluenesulfonic acid monohydrate (178.6 mg, 0.9 mmol) was dissolved in dichloromethane (25 mL), and magnesium sulfate (962.9 mg, 8.0 mmol), 3,4-dihydro-2H-pyran (789.6 mg, 9.4 mmol ) The reaction system was heated to 40°C and stirred for 2 hours. After TLC plate monitoring showed disappearance of starting material, water (80 ml) was added to the reaction solution. The mixture was extracted with dichloromethane (50 ml x 2 times), and the organic phase was combined. The organic phase was first combined with aqueous sodium bicarbonate solution (30 ml x 2), and then washed with saturated brine (30 ml x 3 times). , then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 40/1) to obtain 6-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole (1.15 g, 81.9% yield). Step C: Mix 6-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.1 g, 3.8 mmol) and (E)-styrylboronic acid (680.7 mg, 4.6 mmol) dissolved in 1,4-dioxane (40 ml) and water (10 ml). Subsequently, sodium carbonate (1.0 g, 9.6 mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (139.0 mg, 0.19 mmol) were added. Under the protection of nitrogen, the reaction was stirred overnight at 80°C. After LC-MS monitoring showed that the raw materials disappeared, the diatomaceous earth was filtered, and the filtrate was added to water (20 ml) and extracted with ethyl acetate (30 ml × 3 times), and the organic phase was combined, and the organic phase was first washed with saturated brine (30 ml × 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30/1) to obtain (E)-4-fluoro-6-styryl-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole (820.0 mg, yield 67.0%). MS (ESI) M/Z: 323.2 [M+H] ⁺ . Step D: Add (E)-4-fluoro-6-styryl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole (805.0 mg, 2.5 mmol) was dissolved in THF (20 mL) and water (10 mL), and sodium periodate (3.3 g, 15.3 mmol), potassium osmate dihydrate (22.1 mg, 0.06 mmol) and 2,3-lutidine (546.5 mg, 5.1 mmol). The reaction was stirred overnight at room temperature. After LC-MS monitoring showed disappearance of starting material, water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 ml x 2 times), the organic phase was combined, and the organic phase was first washed with 0.3M hydrochloric acid (40 ml x 2) to combine the organic phase, and then washed with saturated brine (30 ml x 3 times) , then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (600 mg, yield 96.6 %). MS (ESI) M/Z: 248.9 [M+H] ⁺ . Step E: 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (595.8 mg , 2.4 mmol) was dissolved in absolute ethanol (12 ml). Subsequently, 3M hydrochloric acid (12 ml, 36 mmol) was added thereto. Stir for 1 hour at 60 °C. After TLC plate monitoring showed that the raw materials disappeared, aqueous sodium bicarbonate solution (50 ml) was added to the reaction solution to quench, the mixture was extracted with ethyl acetate (50 ml × 3 times), and the organic phases were combined. ), washed with saturated brine (30 ml × 3 times), then dried and filtered with anhydrous sodium sulfate, and finally concentrated under reduced pressure, the dried solid was beaten with petroleum ether/ethyl acetate=10/1, filtered, and dried to obtain 4-Fluoro-1H-indazole-6-carbaldehyde (196.0 mg, 49.7% yield). Step F: Dissolve 4-fluoro-1H-indazole-6-carbaldehyde (197.0 mg, 1.2 mmol) in N,N-dimethylformamide (5 mL), and add potassium carbonate (326.4 mg, 2.4 mmol), dissolved iodine (507.6 mg, 2.0 mmol) in N,N-dimethyldiamide (6 ml). Stir at room temperature for 2 hours. After LC-MS monitoring showed that the raw materials disappeared, a mixed solution (sodium thiosulfate (371.0 mg), potassium carbonate (16.2 mg), water (12 ml)) was added to the reaction solution. After stirring for 30 minutes water (100 ml) was added and stirred for 1 hour. A solid precipitated and was filtered. The product in the filtrate was extracted with ethyl acetate (50 ml × 3 times), and the organic phase was combined. The organic phase was first washed with water (40 × 2) and the combined organic phase was washed with saturated brine (30 ml × 3 times), and then washed with Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure to give crude 4-fluoro-3-iodo-1H-indazole-6-carbaldehyde (300 mg). MS (ESI) M/Z: 291.1 [M+H] ⁺ . Step G: Crude 4-fluoro-3-iodo-1H-indazole-6-carbaldehyde (300 mg) and p-toluenesulfonic acid monohydrate (38.0 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and magnesium sulfate (252.8 mg, 2.1 mmol), 3,4-dihydro-2H-pyran (201.6 mg, 2.4 mmol ) The reaction system was heated to 40°C and stirred for 2 hours. After TLC plate monitoring showed disappearance of starting material, water (30 ml) was added to the reaction solution. The mixture was extracted with dichloromethane (40 ml x 2 times), and the organic phase was combined. The organic phase was first combined with aqueous sodium bicarbonate solution (30 ml x 2), and then washed with saturated brine (30 ml x 3 times). , then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 40/1) to obtain 4-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole-6-carbaldehyde (370 mg, 82.4% yield over two steps). Step H: Sodium hydride (120 mg, 3.0 mmol, 60% in mineral oil) was dissolved in THF (5 mL). After the reaction solution was stirred at room temperature for 30 minutes, 4-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (374.2 mg , 1.0 mmol) in tetrahydrofuran (6 ml) and 1-acetyl-5-phenylpyrrolidone-2-one (272.7 mg, 1.2 mmol) in tetrahydrofuran (6 ml). React at 0°C for 1 hour. The TCL plate showed no reaction, and the reaction was raised to room temperature for 2 hours. After LC-MS monitoring showed that the starting material disappeared, aqueous ammonium chloride solution (30 ml) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain (E)-3-((4-fluoro-3-iodo-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone (190 mg, yield 36.8%). MS (ESI) M/Z: 518.1 [M+H] ⁺ . Step I: Add (E)-3-((4-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl )-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone (206.9 mg, 0.4 mmol) and (E)-1-(4-(2-(4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl)piperidine (196.4 mg, 0.6 mmol) dissolved in 1,4-diox Hexacyclone (16 mL) and water (4 mL). Potassium carbonate (122.4 mg, 0.9 mmol) and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (29.3 mg, 0.04 Millimoles). Vacuum pumping air to replace nitrogen 3-4 times, the reaction system was heated to 105 degrees Celsius under reflux and stirred for 3 hours. After LC-MS monitoring showed that the raw material disappeared, water (20 milliliters) was added to the reaction solution to quench. Mix The solution was extracted with ethyl acetate (30 ml × 2 times), the organic phases were combined, and the organic phase was washed with saturated brine (50 ml × 2 times), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue The compound was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain (E)-3-((4-fluoro-3-((E)-4-(piperidine-1- ylmethyl)styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one (100 mg, yield 42.4%)). MS (ESI) M/Z: 591.1 [M+H] ⁺ . Step J: (E)-3-((4-fluoro-3-((E)-4-(piper Pyridin-1-ylmethyl)styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2 - Ketone, (118.1 mg, 0.2 mmol) was dissolved in methanol (6 mL) and methanesulfonic acid (163.4 mg, 1.7 mmol) was added. The reaction temperature was raised to 60 °C for 2 hours. LC-MS monitoring After the disappearance of raw materials was shown, aqueous sodium bicarbonate solution (20 ml) was added to the reaction system to quench. The mixture was extracted with ethyl acetate (20 ml × 2 times), and the organic phases were combined, and the organic phase was first washed with saturated brine (10 ml ×3 times), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was prepared by reverse phase chromatography (containing trifluoroacetic acid in the mobile phase) to obtain (E)-3-((4-fluoro-3-( (E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate (8.2 mg, yield 8.1%). MS (ESI) M/Z: 507.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.69 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 2.5 Hz, 1H), 7.54 - 7.43 (m, 4H), 7.33 (s, 1H), 7.29 (d, J = 5.2 Hz, 4H), 7.24 - 7.17 (m, 1H), 6.90 (d, J = 12.4 Hz, 1H), 4.77 (d, J = 8.0 Hz, 1H), 4.29 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H) , 3.53 - 3.38 (m, 2H), 3.30 (m, 1H), 2.97 (t, J = 12.4 Hz, 2H), 1.96 (d, J = 14.6 Hz, 2H), 1.84 (d, J = 13.4 Hz, 1H), 1.72 (q, J = 13.4 Hz, 2H), 1.51 (q, J = 12.6 Hz, 1H).

參考實施例11的製備方法得到(E)-3-((7-氟-3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮三氟乙酸鹽（11.3毫克，收率11.2%）。 MS (ESI) M/Z: 507.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.73 (m, 3H), 7.67 - 7.58 (m, 2H), 7.54 - 7.38 (m, 3H), 7.25 - 7.16 (m, 4H), 7.15 - 7.06 (m, 2H), 4.78 - 4.64 (m, 1H), 4.30 (s, 2H), 4.01 (dd, J= 10.2, 8.3 Hz, 1H), 3.47 (d, J= 12.2 Hz, 2H), 3.28 (d, J= 3.0 Hz, 1H), 2.98 (t, J= 12.3 Hz, 2H), 1.96 (m, 2H), 1.79 (m, 3H), 1.52 (m, 1H). Example 12: (E)-3-((7-fluoro-3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)ylidene Methyl)-4-phenylpyrrolidinone-2-one trifluoroacetate

The preparation method of reference example 11 obtained (E)-3-((7-fluoro-3-((E)-4-(piperidin-1-ylmethyl) styryl)-1H-indazole-6 -yl)methylene)-4-phenylpyrrolidon-2-one trifluoroacetate (11.3 mg, yield 11.2%). MS (ESI) M/Z: 507.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.73 (m, 3H), 7.67 - 7.58 (m, 2H), 7.54 - 7.38 (m , 3H), 7.25 - 7.16 (m, 4H), 7.15 - 7.06 (m, 2H), 4.78 - 4.64 (m, 1H), 4.30 (s, 2H), 4.01 (dd, J = 10.2, 8.3 Hz, 1H ), 3.47 (d, J = 12.2 Hz, 2H), 3.28 (d, J = 3.0 Hz, 1H), 2.98 (t, J = 12.3 Hz, 2H), 1.96 (m, 2H), 1.79 (m, 3H ), 1.52 (m, 1H).

參考實施例4的製備方法得到(E)-4-(3-(2-(吡啶-4-基)乙烯基)-1H-吲唑-6-羰基)-3,4-二氫喹喔啉-2(1H)-酮三氟乙酸鹽（50毫克，收率 42.4%）。 MS (ESI) M/Z: 396.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.69 (m, 2H), 8.20-8.13 (m, 4H), 7.71-7.67 (m, 2H), 7.28-7.26 (d, J= 9.2 Hz, 1H), 7.11-7.04 (m, 2H), 6.71 (s, 2H), 4.57 (s, 2H). Example 13: (E)-4-(3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonyl)-3,4-dihydroquinoxaline-2(1H )-keto trifluoroacetate

The preparation method of reference example 4 obtains (E)-4-(3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonyl)-3,4-dihydroquinoxaline -2(1H)-Kone trifluoroacetate (50 mg, yield 42.4%). MS (ESI) M/Z: 396.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.69 (m, 2H), 8.20-8.13 (m, 4H), 7.71-7.67 (m , 2H), 7.28-7.26 (d, J = 9.2 Hz, 1H), 7.11-7.04 (m, 2H), 6.71 (s, 2H), 4.57 (s, 2H).

參考實施例5的製備方法得到(E)-4-(4-甲氧基苯基)-3-((3-((E)-2-(吡啶-4-基)乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽（6.7毫克，收率7.9%）。 MS (ESI) M/Z: 423.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.67 (d, J= 6.8 Hz , 2H), 8.17 (d, J= 6.8 Hz , 2H), 8.06 (d, J= 7.6 Hz , 2H), 7.66-7.62 (m, 2H), 7.59 (s, 1H), 7.35 (d, J= 7.6 Hz ,1H), 7.21 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.71 (m, 1H), 4.00 (m, 1H), 3.70 (s, 3H), 3.3 (m, 1H). Example 14: (E)-4-(4-methoxyphenyl)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method of reference example 5 obtained (E)-4-(4-methoxyphenyl)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H- Indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (6.7 mg, yield 7.9%). MS (ESI) M/Z: 423.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.67 (d, J = 6.8 Hz , 2H), 8.17 (d, J = 6.8 Hz , 2H), 8.06 (d, J = 7.6 Hz , 2H), 7.66-7.62 (m, 2H), 7.59 (s, 1H), 7.35 (d, J = 7.6 Hz ,1H), 7.21 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.71 (m, 1H), 4.00 (m, 1H), 3.70 (s, 3H), 3.3 (m, 1H).

參考實施例11的製備方法得到 (E)-3-((3-((E)-4-(((2S, 6R)-2,6-二甲基嗎福林代)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮（120.0毫克，收率57.8%）。 MS (ESI) M/Z: 519.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.65-7.52 (m, 4H), 7.45 (s, 2H), 7.32-7.19 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.89 (m, 1H), 3.57 (m, 2H), 3.44 (s, 2H), 3.13 (m, 1H), 2.68 (d, J= 10.4 Hz, 2H), 1.67 (m, 2H), 1.02 (m, 6H). Example 15: (E)-3-((3-((E)-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl)-1H -Indazol-6-yl)methylene)-4-phenylpyrrolidone

The preparation method of reference example 11 obtains (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methyl)styrene yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone (120.0 mg, yield 57.8%). MS (ESI) M/Z: 519.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.65-7.52 (m, 4H), 7.45 (s, 2H), 7.32-7.19 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.89 (m, 1H), 3.57 (m, 2H), 3.44 (s, 2H), 3.13 (m, 1H), 2.68 (d, J = 10.4 Hz, 2H), 1.67 (m, 2H), 1.02 (m, 6H).

參考實施例11的製備方法得到(E)-3-((3-((E)-4-((4-甲基哌𠯤-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮（42.4毫克，收率26.2%）。 MS (ESI) M/Z: 504.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.4 Hz 1H), 7.63 (d, J= 8.0 Hz 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.45 (s, 2H), 7.32 - 7.17 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.89 (t, 1H), 3.45 (s, 2H), 3.12 (d, J= 9.6 Hz, 1H), 2.33 (br, 8H), 2.15 (s, 3H). Example 16: (E)-3-((3-((E)-4-((4-methylpiperone-1-yl)methyl)styryl)-1H-indazol-6-yl )methylene)-4-phenylpyrrolidin-2-one

The preparation method of reference example 11 obtains (E)-3-((3-((E)-4-((4-methylpiper-1-yl)methyl)styryl)-1H-indazole -6-yl)methylene)-4-phenylpyrrolidin-2-one (42.4 mg, yield 26.2%). MS (ESI) M/Z: 504.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.4 Hz 1H), 7.63 (d, J = 8.0 Hz 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.45 (s, 2H), 7.32 - 7.17 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.89 (t, 1H), 3.45 (s, 2H), 3.12 (d, J = 9.6 Hz, 1H), 2.33 (br, 8H), 2.15 (s, 3H).

製備方法參考實施例16，最後得到目標產物 (E)-4-苯基-3-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（10.5毫克，收率18.65%）。 MS (ESI) M/Z: 489.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.63 (d, J= 7.8 Hz, 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.47 - 7.41 (m, 2H), 7.35 - 7.16 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.89 (t, J= 8.8 Hz, 1H), 3.42 (s, 2H), 3.12 (d, J= 9.7 Hz, 1H), 2.32 (s, 4H), 1.49 (q, J= 5.5 Hz, 4H), 1.39 (s, 2H). Example 17: ((E)-4-Phenyl-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl )methylene)pyrrolidin-2-one

The preparation method refers to Example 16, and finally the target product (E)-4-phenyl-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)pyrrolidin-2-one (10.5 mg, 18.65% yield). MS (ESI) M/Z: 489.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.47 - 7.41 (m, 2H), 7.35 - 7.16 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.89 (t, J = 8.8 Hz, 1H), 3.42 (s, 2H), 3.12 (d, J = 9.7 Hz, 1H), 2.32 (s, 4H), 1.49 (q, J = 5.5 Hz, 4H), 1.39 (s, 2H).

製備方法參考實施例17，最後得到目標產物 (E)-3-((3-((E)-4-((二甲基胺基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮（20.4毫克，收率18.0 %）。 MS (ESI) M/Z: 449.1[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.64 (d, J= 7.9 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J= 2.1 Hz, 1H), 7.46 (s, 2H), 7.35 - 7.17 (m, 8H), 4.77 (d, J= 7.7 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.39 (s, 2H), 3.12 (d, J= 9.7 Hz, 1H), 2.15 (s, 6H). Example 18: (E)-3-((3-((E)-4-((Dimethylamino)methyl)styryl)-1H-indazol-6-yl)methylene) -4-Phenylpyrrolidone-2-one

The preparation method refers to Example 17, and finally the target product (E)-3-((3-((E)-4-((dimethylamino)methyl)styryl)-1H-indazole-6 -yl)methylene)-4-phenylpyrrolidone-2-one (20.4 mg, yield 18.0%). MS (ESI) M/Z: 449.1[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.46 (s, 2H), 7.35 - 7.17 (m, 8H), 4.77 (d, J = 7.7 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.39 (s, 2H), 3.12 (d, J = 9.7 Hz, 1H), 2.15 (s, 6H).

Example 19: (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methyl)styryl)-1H -Indazol-6-yl)methylene)-5-phenylpyridine-2-one trifluoroacetate

Operation steps: Step A: (E)-3-((3-iodo-1-((tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)- 5-Phenyl-2-pyrrolidin-2-one (200.0 mg, 0.4 mmol), (2S, 6R)-2,6-dimethyl-4-(4-((E)-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzylmorphine (215.0 mg, 0.6 mmol), potassium carbonate (138.0 mg, 1.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (20.0 mg, 0.04 mmol) dissolved in 1,4-dioxane and In a mixed solvent of water (10ml, 1,4-dioxane/water=4/1). The reaction system was replaced with nitrogen to remove the air. The reaction solution was reacted at 100 degrees Celsius for 3 hours. LCMS monitoring showed that after the disappearance of the raw materials , Add water (20 ml) to the reaction system to quench. The mixture is extracted with ethyl acetate (20 ml × 3 times), the organic phases are combined, the organic phase is first washed with saturated brine (20 ml × 1 time), and then washed with Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. Concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain (E)-3-( (3-((E)-4-(((2S,6R)-2,6-dimethylmorphine)methyl)styryl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-6-yl)methylene)-5-phenylpyrrolidone-2-one (215.0 mg, yield 89.5%). MS (ESI) M/Z: 603.3 [M+H] ⁺ . Step B: At room temperature, add (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorphine)methyl) Styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-5-phenylpyrrolidone-2-one (215.0 mg, 0.4 mg mol) was dissolved in methanol (5 ml). Subsequently, methanesulfonic acid (270.0 mg, 2.9 mmol) was added. The reaction solution was stirred at 60 degrees Celsius for 2 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was added to Sodium bicarbonate aqueous solution (20 ml), extracted with dichloromethane/methanol=10/1 (20 ml × 3 times), combined the organic phase, the organic phase was first washed with saturated brine (50 ml × 1 time), and then Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue is prepared by reverse-phase liquid chromatography (containing trifluoroacetic acid in the mobile phase) to obtain (E)-3-((3-((E)-4- (((2S, 6R)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)methylene)-5-phenylpyrrolidine-2 -Kone trifluoroacetate (40 mg, 15.6% yield). MS (ESI) M /Z: 519.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.14 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.67 ( s, 1H), 7.58 - 7.52 (m, 4H), 7.48 (d, J = 2.8 Hz, 1H), 7.45 - 7.25 (m, 6H), 4.95 (dd, J = 8.2, 3.9 Hz, 1H), 4.35 (s, 2H), 3.80 (m, 3H), 3.37 (d, J = 12.3 Hz, 2H), 3.01 (dt, J = 17.9, 3.5 Hz, 1H), 2.78 (t, J = 11.7 Hz, 2H) , 1.23 (d, J = 6.2 Hz, 6H).

製備方法參考實施例19，最後得到目標產物 (E)-5-苯基-3-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（8.29，收率13%）。 MS (ESI) M/Z: 489.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.75 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.74 - 7.59 (m, 3H), 7.50 (s, 2H), 7.41 - 7.27 (m, 9H), 4.87 (dd, J= 8.4, 3.9 Hz, 1H), 3.78 - 3.66 (m, 1H), 3.43 (s, 2H), 2.86 (d, J= 17.6 Hz, 1H), 2.33 (s, 4H), 1.50 (t, J= 5.6 Hz, 4H), 1.39 (s, 2H). Example 20: (E)-5-Phenyl-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl) Methylene)pyrrolidin-2-one

The preparation method refers to Example 19, and finally the target product (E)-5-phenyl-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)pyrrolidin-2-one (8.29, 13% yield). MS (ESI) M/Z: 489.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.75 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.74 - 7.59 (m, 3H), 7.50 (s, 2H), 7.41 - 7.27 (m, 9H), 4.87 (dd, J = 8.4, 3.9 Hz, 1H), 3.78 - 3.66 (m , 1H), 3.43 (s, 2H), 2.86 (d, J = 17.6 Hz, 1H), 2.33 (s, 4H), 1.50 (t, J = 5.6 Hz, 4H), 1.39 (s, 2H).

參考實施例11的製備方法得到((E)-3-((4-氟-3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮（22.1毫克,收率20.1%）。 MS (ESI) M/Z: 549.3 [M+H]. ^{+ 1}H NMR (400 MHz, CD ₃OD): δ 7.97 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 7.6 Hz, 2H), 7.63 (d, J= 2.2 Hz, 1H), 7.52 (d, J= 12.6 Hz, 5H), 7.28 (d, J= 8.9 Hz, 1H), 7.21 (d, J= 8.7 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 4.71 (d, J= 7.8 Hz, 1H), 4.24 (s, 2H), 3.98 (dd, J= 10.0, 7.8 Hz, 1H), 3.79 (d, J= 13.0 Hz, 2H), 3.72 (s, 3H), 3.27 (d, J= 2.2 Hz, 2H), 1.21 (d, J= 6.0 Hz, 6H). Example 21: (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methylstyryl)-1H- Indazol-6-yl)methylene)-4-(4-methoxyphenyl)pyrrolidin-2-one

The preparation method of reference example 11 obtained ((E)-3-((4-fluoro-3-((E)-4-(piperidin-1-ylmethyl) styryl)-1H-indazole- 6-yl)methylene)-4-phenylpyrrolidin-2-one (22.1 mg, yield 20.1%). MS (ESI) M/Z: 549.3 [M+H]. ^{+ 1} H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 12.6 Hz, 5H), 7.28 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.71 (d, J = 7.8 Hz , 1H), 4.24 (s, 2H), 3.98 (dd, J = 10.0, 7.8 Hz, 1H), 3.79 (d, J = 13.0 Hz, 2H), 3.72 (s, 3H), 3.27 (d, J = 2.2 Hz, 2H), 1.21 (d, J = 6.0 Hz, 6H).

參考實施例19的製備方法得到(E)-3-((3-(4-(((2S,6R)- 2,6-二甲基嗎福林代)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-5-(4-甲氧基苯基) 吡咯烷-2-酮（2.1克，收率86.0%）。 MS (ESI) M/Z: 549.5 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.69 (s, 1H), 8.18 (d, J= 8.5 Hz, 1H), 7.66 (d, J= 7.5 Hz, 3H), 7.50 (d, J= 1.3 Hz, 2H), 7.43 - 7.28 (m, 4H), 7.28 - 7.20 (m, 2H), 7.00 - 6.89 (m, 2H), 4.82 (dd, J= 8.1, 3.9 Hz, 1H), 3.74 (s, 3H), 3.72 - 3.62 (m, 1H), 3.62 - 3.52 (m, 2H), 3.45 (s, 2H), 2.83 (d, J= 17.8 Hz, 1H), 2.68 (d, J= 10.6 Hz, 2H), 1.65 (t, J= 10.6 Hz, 2H), 1.02 (d, J= 6.2 Hz, 6H). Example 22: (E)-3-((3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl)-1H-indazole- 6-yl)methylene)-5-(4-methoxyphenyl)pyrrolidin-2-one

The preparation method of reference example 19 obtained (E)-3-((3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl)-1H -indazol-6-yl)methylene)-5-(4-methoxyphenyl)pyrrolidin-2-one (2.1 g, 86.0% yield). MS (ESI) M/Z: 549.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.69 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 3H), 7.50 (d, J = 1.3 Hz, 2H), 7.43 - 7.28 (m, 4H), 7.28 - 7.20 (m, 2H), 7.00 - 6.89 (m, 2H), 4.82 (dd, J = 8.1, 3.9 Hz, 1H), 3.74 (s, 3H), 3.72 - 3.62 (m, 1H), 3.62 - 3.52 (m, 2H), 3.45 (s, 2H), 2.83 (d, J = 17.8 Hz, 1H), 2.68 (d, J = 10.6 Hz, 2H), 1.65 (t, J = 10.6 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H) .

製備方法參考實施例22，最後得到目標產物 (E)-3-((3-(4-(((2S,6R)- 2,6-二甲基嗎福林代)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-5-(3-甲氧基苯基)吡咯烷-2-酮（150.0毫克，收率57.7%）。 MS (ESI) M/Z: 549.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.74 (s, 1H), 8.18 (d, J= 8.5 Hz, 1H), 7.66 (d, J= 8.1 Hz, 3H), 7.51 (d, J= 1.5 Hz, 2H), 7.41 - 7.26 (m, 5H), 6.95 - 6.82 (m, 3H), 4.85 (dd, J= 8.3, 3.9 Hz, 1H), 3.76 (s, 3H), 3.70 (ddd, J= 17.8, 8.3, 2.8 Hz, 1H), 3.57 (dqd, J= 12.6, 6.2, 1.9 Hz, 2H), 3.45 (s, 2H), 2.86 (dt, J= 18.0, 3.5 Hz, 1H), 2.68 (d, J= 9.8 Hz, 2H), 1.71 - 1.59 (m, 2H), 1.02 (d, J= 6.3 Hz, 6H). Example 23: (E)-3-((3-(4-(((2S,6R)-2,6-dimethylmorphine)methyl)styryl)-1H-indazole- 6-yl)methylene)-5-(2-methoxyphenyl)pyrrolidin-2-one

The preparation method refers to Example 22, and finally the target product (E)-3-((3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl )-1H-indazol-6-yl)methylene)-5-(3-methoxyphenyl)pyrrolidin-2-one (150.0 mg, yield 57.7%). MS (ESI) M/Z: 549.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.74 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.1 Hz, 3H), 7.51 (d, J = 1.5 Hz, 2H), 7.41 - 7.26 (m, 5H), 6.95 - 6.82 (m, 3H), 4.85 ( dd, J = 8.3, 3.9 Hz, 1H), 3.76 (s, 3H), 3.70 (ddd, J = 17.8, 8.3, 2.8 Hz, 1H), 3.57 (dqd, J = 12.6, 6.2, 1.9 Hz, 2H) , 3.45 (s, 2H), 2.86 (dt, J = 18.0, 3.5 Hz, 1H), 2.68 (d, J = 9.8 Hz, 2H), 1.71 - 1.59 (m, 2H), 1.02 (d, J = 6.3 Hz, 6H).

製備方法參考實施例19，最後得到目標產物 (E)-3-((3-(4-(((2S, 6R)- 2,6-二甲基嗎福林代)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-5-(2-甲氧基苯基)吡咯烷-2-酮（83.7毫克，收率32%）。 MS (ESI) M/Z: 549.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.20 (s, 1H), 8.61 (s, 1H), 8.19 (d, J= 8.5 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.50 (s, 2H), 7.37 - 7.24 (m, 5H), 7.18 (dd, J= 7.6, 1.7 Hz, 1H), 7.04 (dd, J= 8.3, 1.1 Hz, 1H), 6.99 - 6.92 (m, 1H), 5.07 (dd, J= 8.5, 3.2 Hz, 1H), 3.84 (s, 3H), 3.75 - 3.64 (m, 1H), 3.57 (m, 2H), 3.45 (s, 2H), 2.76 (dt, J= 17.9, 3.0 Hz, 1H), 2.68 (d, J= 10.8 Hz, 2H), 1.65 (t, J= 10.6 Hz, 2H), 1.02 (d, J= 6.2 Hz, 6H). Example 24: (E)-3-((3-(4-(((2S,6R)-2,6-dimethylmorphine)methyl)styryl)-1H-indazole- 6-yl)methylene)-5-(2-methoxyphenyl)pyrrolidin-2-one

The preparation method refers to Example 19, and finally the target product (E)-3-((3-(4-(((2S, 6R)-2,6-dimethylmorpholino)methyl)styryl )-1H-indazol-6-yl)methylene)-5-(2-methoxyphenyl)pyrrolidin-2-one (83.7 mg, yield 32%). MS (ESI) M/Z: 549.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.20 (s, 1H), 8.61 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.50 (s, 2H), 7.37 - 7.24 (m, 5H), 7.18 (dd, J = 7.6, 1.7 Hz, 1H), 7.04 (dd, J = 8.3, 1.1 Hz, 1H), 6.99 - 6.92 (m, 1H), 5.07 (dd, J = 8.5, 3.2 Hz, 1H), 3.84 (s, 3H), 3.75 - 3.64 (m, 1H), 3.57 ( m, 2H), 3.45 (s, 2H), 2.76 (dt, J = 17.9, 3.0 Hz, 1H), 2.68 (d, J = 10.8 Hz, 2H), 1.65 (t, J = 10.6 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H).

Example 25: (E)-3-((3-((E)-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl)-1H -Indazol-6-yl)methylene)-4-(3-methoxyphenyl)pyrrolidin-2-one

Reaction scheme: Refer to Example 11 for the preparation method, and finally obtain the target product (E)-3-((3-((E)-4-(((2S,6R)-2,6-dimethylmorphine )methyl)styryl)-1H-indazol-6-yl)methylene)-4-(3-methoxyphenyl)pyrrolidin-2-one (26.53 mg, yield 14%). MS (ESI) M/Z: 549.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.23 (s, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.58 (s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.46 (s, 2H), 7.35 - 7.18 (m, 4H), 6.87 - 6.74 (m, 3H), 4.74 (d, J = 7.6 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.69 (s, 3H), 3.61 - 3.52 (m, 2H), 3.44 (s, 2H), 3.12 (d, J = 9.9 Hz, 1H), 2.67 (d, J = 10.8 Hz, 2H), 1.64 (t, J = 10.7 Hz, 2H), 1.02 (d, J = 6.3 Hz , 6H).

Examples 26 & 27:

Example 26: (E)-3-((3-((E)-4-((((2R, 6S)-2,6-dimethylmorpholino)methyl)styryl)- 1H-Indazol-6-yl)methylene)-4-(2-methoxyphenyl)pyrrolidin-2-one trifluoroacetate

Example 27: (Z)-3-((3-((E)-4-((((2R, 6S)-2,6-dimethylmorpholino)methyl)styryl)- 1H-Indazol-6-yl)methylene)-4-(2-methoxyphenyl)pyrrolidin-2-one trifluoroacetate

Reaction route:

Procedure: Step A: Diethyl (4-(2-methoxyphenyl)-2-oxopyrrolidin-3-yl)phosphonate (1.2 g, 3.7 mmol) was dissolved in THF (15 mL ), add sodium bis(trimethylsilyl)amide (3.7 ml, 7.4 mmol) in ice-water bath, stir at room temperature for 0.5 hour, then add 3-iodo-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole-6-carbaldehyde (1.3 g, 3.7 mmol) in tetrahydrofuran (15 ml), stirred in an ice-water bath for 3 hours. TLC monitored most of the reaction of the starting material, and LCMS detected the product, and an aqueous ammonium chloride solution (30 ml) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (50 ml x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1) to obtain 3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-6-yl)methylene)-4-(2-methoxyphenyl)pyrrolidin-2-one (530.0 mg, yield 27.3%). MS (ESI) M/Z: 530.0, 530.3 [M+H] ⁺ . Step B: 3-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole -6-yl)methylene)-4-(2-methoxyphenyl)pyrrolidin-2-one (300.0 mg, 0.6 mmol), (2S, 6R)-2,6-dimethyl -4-(4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzylmorphine (303.7 mg, 0.8 mmol), potassium carbonate (196.0 mg, 1.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30.0 mg, 0.04 Mole) was dissolved in 1,4 dioxane (16 ml) and water (4 ml), replaced with nitrogen, and reacted at 100 degrees Celsius for three hours. TLC monitored that most of the raw materials were reacted, and LCMS monitored that after the product was released, it was sent to the reaction Water (50 ml) was added to the solution to quench. The mixture was extracted with ethyl acetate (30 ml × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 ml), and then dried over anhydrous sodium sulfate. Filtration, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 3-((3-((E)-4-((((2R ,6S)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)methylene)-4-(2-methoxyphenyl)pyrrole Alkan-2-ones (270.0 mg, 75.1% yield) MS (ESI) M/Z: 633.1 [M+H] ⁺ . Step C: 3-((3-((E)-4-((( (2R, 6S)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)methylene)-4-(2-methoxyphenyl ) pyrrolidin-2-one (270.0 mg, 0.4 mmol) was dissolved in methanol (10.0 ml), methanesulfonic acid (328.5 mg, 3.4 mmol) was added, and the temperature was raised to 60 degrees Celsius for 1.5 hours. LCMS monitoring After the disappearance of raw materials was shown, aqueous sodium bicarbonate solution (20 ml) was added to the reaction system to quench. The mixed solution was extracted with dichloromethane (30 ml × 3 times), and the organic phases were combined, and the organic phase was first washed with saturated brine (10 ml ) was washed, then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was prepared by reverse-phase liquid chromatography (containing trifluoroacetic acid in the mobile phase) to obtain (E)-3-((3-((E)-4 -((((2R, 6S)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)methylene)-4-(2-methyl oxyphenyl)pyrrolidin-2-one trifluoroacetate (10.65 mg, yield 3.7%). MS (ESI) M/Z: 549.4 [M+H] ⁺ . ¹ H NMR (4 00 MHz, CD ₃ OD): δ 7.95 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.55 - 7.44 (m , 5H), 7.24 - 7.18 (m, 2H), 7.07 - 7.02 (m, 2H), 6.78 (t, J = 7.4 Hz, 1H), 4.97 (d, J = 7.9 Hz, 1H), 4.33 (s, 2H), 4.02 - 3.97 (m, 1H), 3.95 (s, 3H), 3.82 (s, 2H), 3.35 (d, J = 12.9 Hz, 2H), 3.21 (dd, J = 10.3, 2.2 Hz, 1H ), 2.76 (t, J = 11.7 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H). (Z)-3-((3-((E)-4-(((((2R, 6S )-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)methylene)-4-(2-methoxyphenyl)pyrrolidine- 2-Ketotrifluoroacetate (19 mg, 6.7% yield). MS (ESI) M/Z: 549.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.14 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.77 ( dd, J = 7.9, 3.1 Hz, 2H), 7.58 - 7.44 (m, 5H), 7.34 - 7.25 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 6.97 (td, J = 7.4, 1.1 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 4.59 (t, J = 3.3 Hz, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.82 (m, 3H) , 3.44 (dd, J = 9.9, 4.8 Hz, 1H), 3.37 (d, J = 12.2 Hz, 2H), 2.77 (t, J = 11.8 Hz, 2H), 1.23 (d, J = 6.1 Hz, 6H) .

製備方法參考實施例11，最後得到目標產物 (E)-4-(4-甲氧基苯基)-3-((3-(4-(哌啶-1-亞甲基)苯乙烯基)-1H-吲哚-6-基)亞甲基)吡咯烷（26毫克，收率15 %）。 MS (ESI) M/Z: 519.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.19 (s, 1H), 8.05 (d, J= 8.5 Hz, 1H), 7.63 (d, J= 7.9 Hz, 2H), 7.58 (s, 1H), 7.50 (s, 1H), 7.45 (s, 2H), 7.27 (m, 3H), 7.19 (d, J= 8.7 Hz, 2H), 6.86 (d, J= 8.7 Hz, 2H), 4.69 (d, J= 7.5 Hz, 1H), 3.85 (t, J= 8.7 Hz, 1H), 3.68 (s, 3H), 3.42 (s, 2H), 3.09 (d, J= 9.7 Hz, 1H), 2.36 - 2.28 (m, 4H), 1.49 (m, 4H), 1.39 (m, 2H). Example 28: (E)-4-(4-methoxyphenyl)-3-((3-(4-(piperidin-1-methylene)styryl)-1H-indole-6 -yl)methylene)pyrrolidin-2-one

The preparation method refers to Example 11, and finally the target product (E)-4-(4-methoxyphenyl)-3-((3-(4-(piperidine-1-methylene)styryl) is obtained -1H-indol-6-yl)methylene)pyrrolidine (26 mg, yield 15%). MS (ESI) M/Z: 519.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.58 (s, 1H), 7.50 (s, 1H), 7.45 (s, 2H), 7.27 (m, 3H), 7.19 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.69 (d, J = 7.5 Hz, 1H), 3.85 (t, J = 8.7 Hz, 1H), 3.68 (s, 3H) , 3.42 (s, 2H), 3.09 (d, J = 9.7 Hz, 1H), 2.36 - 2.28 (m, 4H), 1.49 (m, 4H), 1.39 (m, 2H).

製備方法參考實施例19，最後得到目標產物 (E)-5-( 4-甲氧基苯基)-3-((3-(4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（60.7毫克，收率47%）。 MS (ESI) M/Z: 519.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.18 (s, 1H), 8.68 (s, 1H), 8.18 (d, J= 8.5 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.50 (s, 2H), 7.40 - 7.20 (m, 6H), 6.94 (d, J= 8.5 Hz, 2H), 4.82 (dd, J= 8.2, 3.9 Hz, 1H), 3.74 (s, 3H), 3.72 - 3.59 (m, 1H), 3.42 (s, 2H), 2.83 (d, J= 17.6 Hz, 1H), 2.32 (s, 4H), 1.49 (m, 4H), 1.39 (s, 2H). Example 29: (E)-5-(4-methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one

The preparation method refers to Example 19, and finally the target product (E)-5-(4-methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl) is obtained -1H-indazol-6-yl)methylene)pyrrolidin-2-one (60.7 mg, yield 47%). MS (ESI) M/Z: 519.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.18 (s, 1H), 8.68 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.50 (s, 2H), 7.40 - 7.20 (m, 6H), 6.94 (d, J = 8.5 Hz, 2H), 4.82 (dd, J = 8.2 , 3.9 Hz, 1H), 3.74 (s, 3H), 3.72 - 3.59 (m, 1H), 3.42 (s, 2H), 2.83 (d, J = 17.6 Hz, 1H), 2.32 (s, 4H), 1.49 (m, 4H), 1.39 (s, 2H).

製備方法參考實施例19，最後得到目標產物 (E)-5-( 3-甲氧基苯基)-3-((3-(4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（60.9毫克，收率35.4%）。 MS (ESI) M/Z: 519.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.18 (s, 1H), 8.74 (s, 1H), 8.18 (d, J= 8.5 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.50 (s, 2H), 7.41 - 7.27 (m, 5H), 6.95 - 6.84 (m, 3H), 4.85 (dd, J= 8.2, 3.9 Hz, 1H), 3.76 (s, 3H), 3.70 (m, 1H), 3.43 (s, 2H), 2.86 (dt, J= 17.8, 3.5 Hz, 1H), 2.33 (s, 4H), 1.50 (m, 4H), 1.39 (s, 2H). Example 30: (E)-5-(3-methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one

The preparation method refers to Example 19, and finally the target product (E)-5-(3-methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl) is obtained -1H-indazol-6-yl)methylene)pyrrolidin-2-one (60.9 mg, yield 35.4%). MS (ESI) M/Z: 519.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.18 (s, 1H), 8.74 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.71 - 7.61 (m, 3H), 7.50 (s, 2H), 7.41 - 7.27 (m, 5H), 6.95 - 6.84 (m, 3H), 4.85 (dd, J = 8.2, 3.9 Hz , 1H), 3.76 (s, 3H), 3.70 (m, 1H), 3.43 (s, 2H), 2.86 (dt, J = 17.8, 3.5 Hz, 1H), 2.33 (s, 4H), 1.50 (m, 4H), 1.39 (s, 2H).

製備方法參考實施例19，最後得到目標產物 (E)-5-( 2-甲氧基苯基)-3-((3-(4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（12.2毫克，收率4.7%）。 MS (ESI) M/Z: 519.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.60 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.64 (m, 3H), 7.49 (s, 2H), 7.33-7.26 (m, 5H), 7.18 (d, J= 7.6 Hz, 1H), 7.04 (d, J= 8.8 Hz, 1H), 6.95 (t, 1H), 5.07 (m, 1H), 3.84 (s, 3H), 3.70 (m, 1H), 2.76 (d, J= 17.6 Hz, 1H), 2.33 (br, 4H), 1.50-1.40 (m , 6H). Example 31: (E)-5-(2-Methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one

The preparation method refers to Example 19, and finally the target product (E)-5-(2-methoxyphenyl)-3-((3-(4-(piperidin-1-ylmethyl)styryl) is obtained -1H-indazol-6-yl)methylene)pyrrolidin-2-one (12.2 mg, yield 4.7%). MS (ESI) M/Z: 519.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.19 (s, 1H), 8.60 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.64 (m, 3H), 7.49 (s, 2H), 7.33-7.26 (m, 5H), 7.18 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.95 (t, 1H), 5.07 (m, 1H), 3.84 (s, 3H), 3.70 (m, 1H), 2.76 (d, J = 17.6 Hz, 1H), 2.33 (br, 4H), 1.50-1.40 (m , 6H).

製備方法參考實施例11，最後得到目標產物 (E)-4-(3-甲氧基苯基)-3-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（13.7毫克，收率7.8%）。 MS (ESI) M/Z: 518.9 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.22 (s, 1H), 8.05 (d, J= 8.5 Hz, 1H), 7.63 (d, J= 7.8 Hz, 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.46 (s, 2H), 7.32 - 7.18 (m, 4H), 6.86 - 6.80 (m, 2H), 6.77 (m, 1H), 4.74 (d, J= 7.6 Hz, 1H), 3.87 (dd, J= 9.7, 7.9 Hz, 1H), 3.69 (s, 3H), 3.42 (s, 2H), 3.12 (d, J= 9.9 Hz, 1H), 2.32 (m, 4H), 1.49 (m, 4H), 1.39 (s, 2H). Example 32: (E)-4-(3-Methoxyphenyl)-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)pyrrolidin-2-one

The preparation method refers to Example 11, and finally the target product (E)-4-(3-methoxyphenyl)-3-((3-((E)-4-(piperidin-1-ylmethyl) Styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one (13.7 mg, yield 7.8%). MS (ESI) M/Z: 518.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.22 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.58 (s, 1H), 7.52 (s, 1H), 7.46 (s, 2H), 7.32 - 7.18 (m, 4H), 6.86 - 6.80 (m, 2H), 6.77 (m, 1H), 4.74 (d, J = 7.6 Hz, 1H), 3.87 (dd, J = 9.7, 7.9 Hz, 1H), 3.69 (s, 3H), 3.42 (s , 2H), 3.12 (d, J = 9.9 Hz, 1H), 2.32 (m, 4H), 1.49 (m, 4H), 1.39 (s, 2H).

Example 33: (E)-4-(2-methoxyphenyl)-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidone-2-one trifluoroacetate

製備方法參考實施例26、27，製備得到目標產物(E)-4-(2-甲氧基苯基)-3-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷酮-2-酮三氟乙酸鹽（11.3毫克，收率6.3%）。 MS (ESI) M/Z: 519.5 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.95 (d, J= 8.6 Hz, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.51 (d, J= 6.1 Hz, 4H), 7.46 (s, 1H), 7.24 - 7.18 (m, 2H), 7.05 (m, 2H), 6.78 (t, J= 7.5 Hz, 1H), 4.97 (d, J= 7.9 Hz, 1H), 4.29 (s, 2H), 3.95 (s, 3H), 3.47 (d, J= 12.2 Hz, 2H), 3.38 - 3.33 (m, 1H), 3.21 (dd, J= 10.2, 2.3 Hz, 1H), 3.04 - 2.90 (m, 2H), 1.96 (d, J= 14.6 Hz, 2H), 1.84 (d, J= 13.7 Hz, 1H), 1.73 (q, J= 13.9, 13.4 Hz, 2H), 1.53 (t, J= 12.6 Hz, 1H). 目標產物(Z)-4-(2-甲氧基苯基)-3-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷酮-2-酮三氟乙酸鹽（24毫克，收率13.4%）。 MS (ESI) M/Z: 519.5 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.13 (s, 1H), 7.98 (d, J= 8.5 Hz, 1H), 7.73 (d, J= 8.3 Hz, 2H), 7.55 - 7.42 (m, 5H), 7.34 - 7.24 (m, 2H), 7.04 (d, J= 7.9 Hz, 1H), 6.97 (m, 1H), 6.62 (d, J= 2.5 Hz, 1H), 4.58 (m, 1H), 4.26 (s, 2H), 3.86 (s, 3H), 3.81 (dd, J= 9.9, 8.7 Hz, 1H), 3.50 - 3.40 (m, 3H), 2.94 (td, J= 12.6, 3.0 Hz, 2H), 1.93 (dt, m, 2H), 1.88 - 1.65 (m, 3H), 1.56 - 1.40 (m, 1H). Example 34: (Z)-4-(2-Methoxyphenyl)-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)pyrrolidone-2-one trifluoroacetate

The preparation method refers to Examples 26 and 27 to prepare the target product (E)-4-(2-methoxyphenyl)-3-((3-((E)-4-(piperidin-1-ylmethyl yl)styryl)-1H-indazol-6-yl)methylene)pyrrolidone-2-one trifluoroacetate (11.3 mg, yield 6.3%). MS (ESI) M/Z: 519.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 6.1 Hz, 4H), 7.46 (s, 1H), 7.24 - 7.18 (m, 2H), 7.05 (m, 2H), 6.78 (t, J = 7.5 Hz, 1H), 4.97 (d, J = 7.9 Hz, 1H), 4.29 (s, 2H), 3.95 (s, 3H), 3.47 (d, J = 12.2 Hz, 2H), 3.38 - 3.33 (m, 1H), 3.21 (dd, J = 10.2, 2.3 Hz, 1H), 3.04 - 2.90 (m, 2H), 1.96 (d, J = 14.6 Hz, 2H), 1.84 (d, J = 13.7 Hz, 1H), 1.73 (q, J = 13.9, 13.4 Hz, 2H), 1.53 (t, J = 12.6 Hz, 1H). The target product (Z)-4-(2-methoxyphenyl)- 3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene)pyrrolidone-2-one trifluoroacetate (24 mg, yield 13.4%). MS (ESI) M/Z: 519.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.13 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.73 ( d, J = 8.3 Hz, 2H), 7.55 - 7.42 (m, 5H), 7.34 - 7.24 (m, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.97 (m, 1H), 6.62 (d , J = 2.5 Hz, 1H), 4.58 (m, 1H), 4.26 (s, 2H), 3.86 (s, 3H), 3.81 (dd, J = 9.9, 8.7 Hz, 1H), 3.50 - 3.40 (m, 3H), 2.94 (td, J = 12.6, 3.0 Hz, 2H), 1.93 (dt, m, 2H), 1.88 - 1.65 (m, 3H), 1.56 - 1.40 (m, 1H).

製備方法參考實施例11，最後得到目標產物 (E)-4-苯基-3-((3-(4-(吡咯烷-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮（5.1毫克，收率6%）。 MS (ESI) M/Z: 475.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J= 2.1 Hz, 1H), 7.45 (s, 2H), 7.34 - 7.17 (m, 8H), 4.77 (d, J= 7.7 Hz, 1H), 3.89 (t, J= 8.8 Hz, 1H), 3.57 (s, 2H), 3.12 (d, J= 9.9 Hz, 1H), 2.42 (m, 4H), 1.77 - 1.63 (m, 4H). Example 35: (E)-4-Phenyl-3-((3-(4-(pyrrolidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene) pyrrolidin-2-one

The preparation method refers to Example 11, and finally the target product (E)-4-phenyl-3-((3-(4-(pyrrolidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one (5.1 mg, yield 6%). MS (ESI) M/Z: 475.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.45 (s, 2H), 7.34 - 7.17 (m, 8H), 4.77 (d, J = 7.7 Hz, 1H), 3.89 (t, J = 8.8 Hz, 1H), 3.57 (s, 2H), 3.12 (d, J = 9.9 Hz, 1H), 2.42 (m, 4H), 1.77 - 1.63 (m, 4H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-(環丁胺甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-(對甲氧基)苯基吡咯烷-2-酮三氟乙酸鹽（4毫克，收率12%）。 MS (ESI) M/Z: 461.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.95 (d, J= 8.5 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.52 (s, 1H), 7.46 (d, J= 2.9 Hz, 2H), 7.41 (d, J= 8.1 Hz, 2H), 7.32 - 7.24 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (dt, J= 7.9, 1.8 Hz, 1H), 4.14 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.90 (t, J= 7.9 Hz, 4H), 3.30 (m, 1H), 2.45 - 2.35 (m, 2H). Example 36: (E)-3-((3-((E)-4-(Cyclobutylaminomethyl)styryl)-1H-indazol-6-yl)methylene)-4-( p-methoxy)phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(cyclobutylaminomethyl)styryl)-1H-indazol-6-yl)ylidene Methyl)-4-(p-methoxy)phenylpyrrolidin-2-one trifluoroacetate (4 mg, yield 12%). MS (ESI) M/Z: 461.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95 (d, J = 8.5 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.52 (s, 1H), 7.46 (d, J = 2.9 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.32 - 7.24 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (dt, J = 7.9, 1.8 Hz, 1H), 4.14 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.90 (t, J = 7.9 Hz, 4H), 3.30 (m, 1H), 2.45 - 2.35 (m, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((4,4-二氟哌啶-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮 （39.23毫克，收率22.76%）。 MS (ESI) M/Z: 525.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.65 (d, J= 7.9 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J= 2.1 Hz, 1H), 7.46 (s, 2H), 7.36 - 7.16 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.55 (s, 2H), 3.12 (d, J= 10.1 Hz, 1H), 2.50 - 2.36 (m, 4H), 1.96 (m, 4H). Example 37: (E)-3-((3-((E)-4-((4,4-difluoropiperidin-1-yl)methyl)styryl)-1H-indazole-6 -yl)methylene)-4-phenylpyrrolidone-2-one

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((4,4-difluoropiperidin-1-yl)methyl)styryl) is obtained -1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one (39.23 mg, yield 22.76%). MS (ESI) M/Z: 525.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.46 (s, 2H), 7.36 - 7.16 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.55 (s, 2H), 3.12 (d, J = 10.1 Hz, 1H), 2.50 - 2.36 (m, 4H ), 1.96 (m, 4H).

製備方法參考實施例11，最後得到目標產物 (E)-4-(4-氟苯基)-3-(3-(4-(哌啶-1-甲基)苯乙烯基)-1H-吲唑-6-亞甲基)吡咯烷酮-2-酮三氟乙酸鹽（17.5毫克，收率12.0%）。 MS (ESI) M/Z:507.1 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.43-8.34 (m, 2H), 8.06 (d, J= 8.4Hz, 1H), 7.65 (d, J= 6.8 Hz, 2H), 7.56-7.43 (m, 5H), 7.31-7.23 (m, 4H), 6.53 (m, 1H), 4.37 (m,1H), 3.75 (m, 1H), 3.35 (m, 2H), 3.20 (m, 1H), 2.34 (m, 4H), 1.50 (m, 4H), 1.40 (m, 2H). Example 38: (E)-4-(4-fluorophenyl)-3-(3-(4-(piperidin-1-methyl)styryl)-1H-indazole-6-methylene ) pyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-4-(4-fluorophenyl)-3-(3-(4-(piperidin-1-methyl)styryl)-1H-ind Azol-6-methylene)pyrrolidinone-2-one trifluoroacetate (17.5 mg, yield 12.0%). MS (ESI) M/Z:507.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.43-8.34 (m, 2H), 8.06 (d, J = 8.4Hz, 1H), 7.65 (d, J = 6.8 Hz, 2H), 7.56-7.43 (m, 5H), 7.31-7.23 (m, 4H), 6.53 (m, 1H), 4.37 (m,1H ), 3.75 (m, 1H), 3.35 (m, 2H), 3.20 (m, 1H), 2.34 (m, 4H), 1.50 (m, 4H), 1.40 (m, 2H).

參考實施例11的製備方法得到(E)-3-((3-((E)-4-(((2S, 6R)-2,6二甲基嗎福林代)甲基)苯乙烯基)-7-氟-1H-吲唑-6-基)亞甲基)- 4-苯基吡咯烷酮-2-酮三氟乙酸鹽（11.31毫克，收率6.7%）。 MS (ESI) M/Z: 537.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.80 - 7.72 (m, 3H), 7.66 - 7.61 (m, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.50 - 7.42 (m, 2H), 7.28 - 7.04 (m, 5H), 4.74 (dt, J= 8.4, 3.0 Hz, 1H), 4.35 (s, 2H), 4.01 (dd, J= 10.0, 8.4 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.37 (d, J= 12.4 Hz, 2H), 3.29 - 3.26 (m, 1H), 2.78 (t, J= 11.6 Hz, 2H), 1.23 (d, J= 6.4 Hz, 6H). Example 39: (E)-3-(3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methyl)styryl)-7- Fluoro-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method of reference example 11 obtains (E)-3-((3-((E)-4-(((2S, 6R)-2,6 dimethylmorpholino)methyl)styryl )-7-fluoro-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate (11.31 mg, 6.7% yield). MS (ESI) M/Z: 537.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.80 - 7.72 (m, 3H), 7.66 - 7.61 (m, 1H), 7.53 (d , J = 8.0 Hz, 2H), 7.50 - 7.42 (m, 2H), 7.28 - 7.04 (m, 5H), 4.74 (dt, J = 8.4, 3.0 Hz, 1H), 4.35 (s, 2H), 4.01 ( dd, J = 10.0, 8.4 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.37 (d, J = 12.4 Hz, 2H), 3.29 - 3.26 (m, 1H), 2.78 (t, J = 11.6 Hz , 2H), 1.23 (d, J = 6.4 Hz, 6H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-(2-氧雜-6-氮雜螺[3.3]庚烷甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽（6毫克，收率10%）。 MS (ESI) M/Z: 503.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.96 (d, J= 8.6 Hz, 1H), 7.73 (d, J= 8.1 Hz, 2H), 7.65 (d, J= 2.3 Hz, 1H), 7.53 (s, 1H), 7.49 (s, 2H), 7.45 (d, J= 8.1 Hz, 2H), 7.34 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 4.84 - 4.73 (m, 4H), 4.41 - 4.29 (m, 5H), 4.01 (dd, J= 10.1, 8.0 Hz, 2H). Example 40: (E)-3-((3-((E)-4-(2-oxa-6-azaspiro[3.3]heptanemethyl)styryl)-1H-indazole- 6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(2-oxa-6-azaspiro[3.3]heptanemethyl)styryl )-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (6 mg, yield 10%). MS (ESI) M/Z: 503.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.53 (s, 1H), 7.49 (s, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.34 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 4.84 - 4.73 (m, 4H), 4.41 - 4.29 (m, 5H), 4.01 (dd, J = 10.1, 8.0 Hz, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((嗎福林甲基苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-( 3-氟苯基)吡咯烷-2-酮三氟乙酸鹽（5.0毫克，收率6.0 %）。 MS (ESI) M/Z:507.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.74 - 7.60 (m, 2H), 7.56 - 7.37 (m, 4H), 7.33 - 7.08 (m, 5H), 6.63 - 6.51 (m, 1H), 4.45 - 4.31 (m, 1H), 4.20 - 4.04 (m, 1H), 3.78 (t, J= 9.2 Hz, 1H), 3.43 (s, 2H), 2.39 - 2.22 (m, 4H), 1.56 - 1.47 (m, 4H), 0.89 - 0.81 (m, 2H). Example 41: (E)-3-((3-((E)-4-((morpholinmethylstyryl)-1H-indazol-6-yl)methylene)-4-(3- Fluorophenyl)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((morpholinmethylstyryl)-1H-indazol-6-yl)methylene )-4-(3-fluorophenyl)pyrrolidin-2-one trifluoroacetate (5.0 mg, yield 6.0 %). MS (ESI) M/Z:507.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.74 - 7.60 (m, 2H), 7.56 - 7.37 (m, 4H), 7.33 - 7.08 (m, 5H), 6.63 - 6.51 (m, 1H), 4.45 - 4.31 (m, 1H), 4.20 - 4.04 (m, 1H), 3.78 (t, J = 9.2 Hz, 1H), 3.43 (s, 2H), 2.39 - 2.22 (m, 4H), 1.56 - 1.47 (m, 4H), 0.89 - 0.81 (m, 2H).

反應路線:

Example 42: (E)-3-(3-(4-(4-Hydroxypiperidine-1-methyl)styryl)-1-H-indazole-6-methylene)-4-benzene ylpyrrolidin-2-one

Reaction route:

Operation steps: Step A: 4-(E)-2-(6-(E)-(2-oxo-4-phenylpyrrolidone-3-methylene)-1-H-indazole-3- yl)vinyl)benzaldehyde (50 mg, 0.1 mmol) and 4-hydroxypiperidine (72 mg, 0.7 mmol) in 1,2-dichloroethane (6 mL) and tetrahydrofuran (2 mL ), then added acetic acid (0.1 ml), stirred for 10 minutes, then added sodium triacetyloxyborohydride (150 mg, 0.7 mmol), and refluxed at 45 degrees Celsius overnight. LCMS monitored the complete reaction, saturated aqueous sodium bicarbonate (10 ml) and dichloromethane (10 ml) liquid separation extraction, dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative column to obtain product (E)-3-(3-(4 -(4-Hydroxypiperidin-1-methyl)styryl)-1 H-indazole-6-methylene)-4-phenylpyrrolidin-2-one (3.1 mg, yield 5.0%) . MS (ESI) M/Z: 505.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.50-7.52 (m, 5H), 7.38 - 7.25 (m, 5H), 7.20 - 7.21 (m, 1H), 4.78 (d, J = 8.0 Hz , 1H), 4.32 (d, J = 8.8 Hz, 2H), 4.00 - 4.05 (m, 2H), 3.57 - 3.45 (m, 2H), 3.07-3.09 (m, 3H), 2.13 - 2.15 (m, 2H ), 1.90-1.92 (m, 3H). C ₃₂ H ₃₂ N ₄ O ₂ .

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((4-環丙基哌𠯤-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮（4.4毫克，收率13.8%）。 MS (ESI) M/Z: 530.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 8.23 (s, 1H), 8.03 (d, J= 8.4 Hz, 1H), 7.70 - 7.55 (m, 3H), 7.47 - 7.49 (m, 3H), 7.36 - 7.09 (m, 7H), 4.77 (d, J= 7.6 Hz, 1H), 3.90 (t, J= 8.9 Hz, 1H), 3.44 (m, 4H), 3.12 (d, J= 9.6 Hz, 2H), 2.30 - 2.32 (m, 4H), 1.69 - 1.49 (m, 1H), 1.22 - 1.24 (m, 1H), 0.38 - 0.39 (m, 2H), 0.27 - 0.28 (m, 2H). Example 43: (E)-3-((3-((E)-4-((4-cyclopropylpiperol-1-yl)methyl)styryl)-1H-indazole-6- Base) methylene) -4-phenylpyrrolidone-2-one

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((4-cyclopropylpiper-1-yl)methyl)styryl)- 1H-Indazol-6-yl)methylene)-4-phenylpyrrolidon-2-one (4.4 mg, yield 13.8%). MS (ESI) M/Z: 530.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.23 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.70 - 7.55 (m, 3H), 7.47 - 7.49 (m, 3H), 7.36 - 7.09 (m, 7H), 4.77 (d, J = 7.6 Hz, 1H), 3.90 (t, J = 8.9 Hz, 1H), 3.44 (m, 4H), 3.12 (d, J = 9.6 Hz, 2H), 2.30 - 2.32 (m, 4H), 1.69 - 1.49 (m, 1H), 1.22 - 1.24 (m, 1H), 0.38 - 0.39 ( m, 2H), 0.27 - 0.28 (m, 2H).

製備方法參考實施例11，得目標產物(E)-4-苯基-3-((3-((E)-4-((4-(2,2,2-三氟乙基)哌𠯤-1-基)甲基)苯乙烯基)-1H-吲唑-6 -基)亞甲基)吡咯烷-2-酮（ 5.4毫克， 收率7%） MS (ESI) M/Z: 571.9[M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.96 (d, J= 8.8 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.63 (d, J= 2.0 Hz, 1H), 7.53-7.50 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20 - 7.19 (m, 1H), 4.76 (d, J= 8.0 Hz, 2H), 4.35(s, 2H), 4.02(t, J= 8.4 Hz, 1 H), 3.46 - 3.43(m, 2H),3.31 - 3.30(m, 6H), 2.82 - 2.76(m, 2H). Example 44: (E)-4-Phenyl-3-((3-((E)-4-((4-(2,2,2-trifluoroethyl)piperone-1-yl)methanol Base) styryl) -1H-indazol-6-yl) methylene) pyrrolidin-2-one

The preparation method refers to Example 11 to obtain the target product (E)-4-phenyl-3-((3-((E)-4-((4-(2,2,2-trifluoroethyl)piperone -1-yl)methyl)styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one (5.4 mg, yield 7%) MS (ESI) M/Z: 571.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.53-7.50 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20 - 7.19 (m, 1H), 4.76 (d, J = 8.0 Hz, 2H), 4.35(s, 2H ), 4.02(t, J = 8.4 Hz, 1H), 3.46 - 3.43(m, 2H),3.31 - 3.30(m, 6H), 2.82 - 2.76(m, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-(8-氧雜-3-氮雜雙環[3.2.1]辛烷-3-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)- 4-苯基吡咯烷酮-2-酮三氟乙酸鹽（3.4毫克，收率5.8%）。 MS (ESI) M/Z: 517.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.59 - 7.50 (m, 5H), 7.35 - 7.18 (m, 6H), 4.81 (d, J= 8.0 Hz, 1H), 4.55 (s, 2H), 4.36 (s, 2H), 4.04 (dd, J= 10.1, 8.0 Hz, 1H), 3.34 - 3.24 (m, 5H), 2.19 - 2.12 (m, 2H), 2.01 (m, 2H). Example 45: (E)-3-((3-((E)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)styryl) -1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl Methyl)styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidon-2-one trifluoroacetate (3.4 mg, 5.8% yield). MS (ESI) M/Z: 517.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.59 - 7.50 (m, 5H), 7.35 - 7.18 (m, 6H), 4.81 (d, J = 8.0 Hz, 1H), 4.55 (s, 2H ), 4.36 (s, 2H), 4.04 (dd, J = 10.1, 8.0 Hz, 1H), 3.34 - 3.24 (m, 5H), 2.19 - 2.12 (m, 2H), 2.01 (m, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-(1-嗎福林代乙基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽（8.49毫克，收率14.2%）。 MS (ESI) M/Z: 505.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 7.6 Hz, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.58 - 7.50 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (m, 1H), 4.81 (d, J= 7.6 Hz, 1H), 4.50 (q, J= 6.9 Hz, 1H), 4.13 (m, 1H), 4.04 (m, 2H), 3.81 (m, 2H), 3.70 (m, 2H), 3.33 -3.14 (m, 3H), 1.80 (d, J= 7.2 Hz, 3H). Example 46: (E)-3-((3-((E)-4-(1-morphorinoethyl)styryl)-1H-indazol-6-yl)methylene)- 4-Phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(1-morpholinoethyl)styryl)-1H-indazole-6- (yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (8.49 mg, yield 14.2%). MS (ESI) M/Z: 505.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.58 - 7.50 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (m, 1H), 4.81 (d, J = 7.6 Hz, 1H ), 4.50 (q, J = 6.9 Hz, 1H), 4.13 (m, 1H), 4.04 (m, 2H), 3.81 (m, 2H), 3.70 (m, 2H), 3.33 -3.14 (m, 3H) , 1.80 (d, J = 7.2 Hz, 3H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((1,1-二氧硫嗎福林)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮（2.27毫克，收率1.2%）。 MS (ESI) M/Z: 639.2 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.66 (d, J= 8.4 Hz, 2H), 7.58 (s, 1H), 7.58 - 7.47 (m, 3H), 7.35 - 7.19 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.89 (dd, J= 9.8, 7.8 Hz, 1H), 3.68 (s, 2H), 3.16 - 3.08 (m, 5H), 2.92 - 2.84 (m, 4H). Example 47: (E)-3-((3-((E)-4-((1,1-dioxathiomorphin)methyl)styryl)-1H-indazol-6-yl )methylene)-4-phenylpyrrolidin-2-one

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((1,1-dioxathiomorphin)methyl)styryl)-1H -indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one (2.27 mg, yield 1.2%). MS (ESI) M/Z: 639.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.58 (s, 1H), 7.58 - 7.47 (m, 3H), 7.35 - 7.19 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.89 (dd, J = 9.8, 7.8 Hz, 1H), 3.68 (s, 2H), 3.16 - 3.08 (m, 5H), 2.92 - 2.84 (m, 4H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((2S, 6R)-2,6-二甲基嗎福林-4-羰基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯吡咯烷-2-酮三氟乙酸鹽（15.22毫克，收率19.6%)。 MS (ESI) M/Z: 533.4 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.54 (m, 3H), 7.50 - 7.43 (m, 2H), 7.36 - 7.22 (m, 5H), 7.21 (m, 1H), 4.81 (d, J= 8.0 Hz, 1H), 4.52 (m, 1H), 4.03 (dd, J= 10.1, 8.0 Hz, 1H), 3.65 (s, 3H), 2.92 (br, 1H), 2.61 (br, 1H), 1.25 (s, 3H), 1.09 (s, 3H). Example 48: (E)-3-((3-((E)-4-((2S, 6R)-2,6-dimethylmorphine-4-carbonyl)styryl)-1H- Indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((2S, 6R)-2,6-dimethylmorphine-4-carbonyl) is obtained Styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (15.22 mg, 19.6% yield). MS (ESI) M/Z: 533.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.54 (m, 3H), 7.50 - 7.43 (m, 2H), 7.36 - 7.22 (m, 5H), 7.21 (m, 1H), 4.81 (d , J = 8.0 Hz, 1H), 4.52 (m, 1H), 4.03 (dd, J = 10.1, 8.0 Hz, 1H), 3.65 (s, 3H), 2.92 (br, 1H), 2.61 (br, 1H) , 1.25 (s, 3H), 1.09 (s, 3H).

製備方法參考實施例11，最後得到目標產物 (E)-4-苯基-3 -((3 -((E)-4 -((四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)甲基)苯乙烯基)-1H -吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽（3.85毫克，收率5%）。 MS (ESI) M/Z: 517.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.55-7.52 (m, 5H), 7.33 - 7.29 (m, 5H), 7.23 (m, 1H), 4.81 (d, J= 8.0 Hz, 1H), 4.39 (m, 2H), 4.04 (dd, J= 10.1, 8.0 Hz, 1H), 3.93 - 3.82 (m, 4H), 3.71-3.50 (m, 3H), 3.09 (m, 2H), 2.93 (m, 2H). Example 49: (E)-4-Phenyl-3-((3-((E)-4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl )methyl)styryl)-1H--indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-4-phenyl-3-((3-((E)-4-((tetrahydro-1H-furo[3,4-c]pyrrole -5(3H)-yl)methyl)styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (3.85 mg, yield 5%). MS (ESI) M/Z: 517.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.55-7.52 (m, 5H), 7.33 - 7.29 (m, 5H), 7.23 (m, 1H), 4.81 (d, J = 8.0 Hz, 1H ), 4.39 (m, 2H), 4.04 (dd, J = 10.1, 8.0 Hz, 1H), 3.93 - 3.82 (m, 4H), 3.71-3.50 (m, 3H), 3.09 (m, 2H), 2.93 ( m, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((3-甲氧基-3-甲基氮雜環丁烷-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮三氟乙酸鹽（5.8毫克，收率8%）。 MS (ESI) M/Z: 505.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 7.7 Hz, 2H), 7.67 (d, J= 2.2 Hz, 1H), 7.53 (d, J= 16.9 Hz, 4H), 7.39 - 7.17 (m, 6H), 4.81 (d, J= 8.1 Hz, 1H), 4.43 (d, J= 26.4 Hz, 3H), 4.26 - 3.92 (m, 6H), 3.30 (s, 2H), 1.54 (d, J= 8.3 Hz, 3H). Example 50: (E)-3-((3-((E)-4-((3-methoxy-3-methylazetidin-1-yl)methyl)styryl) -1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((3-methoxy-3-methylazetidin-1-yl) Methyl)styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidon-2-one trifluoroacetate (5.8 mg, 8% yield). MS (ESI) M/Z: 505.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 16.9 Hz, 4H), 7.39 - 7.17 (m, 6H), 4.81 (d, J = 8.1 Hz, 1H), 4.43 ( d, J = 26.4 Hz, 3H), 4.26 - 3.92 (m, 6H), 3.30 (s, 2H), 1.54 (d, J = 8.3 Hz, 3H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((3-異丙氧基氮雜環丁烷-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽（3.8毫克，收率3.7%）。 MS (ESI) M/Z: 519.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.98 (d, J= 8.6 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 2.4 Hz, 1H), 7.55 (s, 1H), 7.51 (s, 4H), 7.37 - 7.26 (m, 5H), 7.2-7.22 (m, 1H), 4.85 - 4.76 (m, 1H), 4.50 - 4.33 (m, 5H), 4.04-4.05 (m, 3H), 3.73-3.74 (m, 2H), 1.19 (d, J= 6.2 Hz, 6H). Example 51: (E)-3-((3-((E)-4-((3-isopropoxyazetidin-1-yl)methyl)styryl)-1H-ind Azol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-((3-isopropoxyazetidin-1-yl)methyl)benzene Vinyl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (3.8 mg, yield 3.7%). MS (ESI) M/Z: 519.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.98 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 2.4 Hz, 1H), 7.55 (s, 1H), 7.51 (s, 4H), 7.37 - 7.26 (m, 5H), 7.2-7.22 (m, 1H), 4.85 - 4.76 (m, 1H), 4.50 - 4.33 (m, 5H), 4.04-4.05 (m, 3H), 3.73-3.74 (m, 2H), 1.19 (d, J = 6.2 Hz, 6H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-(羥基(四氫-2H-吡喃-4-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮（6.17毫克，收率6.5%）。 MS (ESI) M/Z: 506.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.03 (d, J= 8.5 Hz, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.57 (s, 1H), 7.52 (d, J= 2.0 Hz, 1H), 7.45 (s, 2H), 7.35 - 7.12 (m, 6H), 5.21 (d, J= 4.4 Hz, 1H), 4.77 (d, J= 7.6 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.95 - 3.72 (m, 3H), 3.29 - 3.06 (m, 4H), 1.80 - 1.61 (m, 3H), 1.32 - 1.06 (m, 4H). Example 52: (E)-3-((3-((E)-4-(Hydroxy(tetrahydro-2H-pyran-4-yl)methyl)styryl)-1H-indazole-6 -yl)methylene)-4-phenylpyrrolidone-2-one

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(hydroxyl(tetrahydro-2H-pyran-4-yl)methyl)styryl) is obtained -1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one (6.17 mg, yield 6.5%). MS (ESI) M/Z: 506.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.21 (s, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.45 (s, 2H), 7.35 - 7.12 (m, 6H), 5.21 (d, J = 4.4 Hz, 1H), 4.77 (d, J = 7.6 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.95 - 3.72 (m, 3H), 3.29 - 3.06 (m , 4H), 1.80 - 1.61 (m, 3H), 1.32 - 1.06 (m, 4H).

製備方法參考實施例11，最後得到目標產物1-(4-((E)-2-(6-((E)-(2-氧代-4-苯基吡咯烷-3-亞基)甲基)-1H-吲哚唑-3-基)乙烯基)苄基)哌啶-4-甲腈三氟乙酸鹽（21.55毫克，收率29.6%）。 MS (ESI) M/Z: 514.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.79 (d, J= 8.2 Hz, 2H), 7.67 (d, J= 2.4 Hz, 1H), 7.54 (d, J= 10 Hz, 5H), 7.35 - 7.28 (m, 5H), 7.25 - 7.18 (m, 1H), 4.81 (d, J= 8.0 Hz, 1H), 4.45 (s, 1H), 4.36 (s, 1H), 4.04 (dd, J= 10.0, 8.0 Hz, 1H), 3.59-3.60 (m, 2H), 3.27-3.28 (m, 1H), 3.13 - 3.00 (m, 2H), 2.39 (d, J= 14.6 Hz, 1H), 2.28 (d, J= 14.9 Hz, 1H), 2.18 - 1.94 (m, 3H). Example 53: 1-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene)methyl)-1H-indazole -3-yl)vinyl)benzyl)piperidine-4-carbonitrile trifluoroacetate

The preparation method refers to Example 11, and finally the target product 1-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene))methanol is obtained yl)-1H-indazole-3-yl)vinyl)benzyl)piperidine-4-carbonitrile trifluoroacetate (21.55 mg, yield 29.6%). MS (ESI) M/Z: 514.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 10 Hz, 5H), 7.35 - 7.28 (m, 5H), 7.25 - 7.18 (m, 1H), 4.81 (d, J = 8.0 Hz, 1H), 4.45 (s, 1H), 4.36 (s, 1H), 4.04 (dd, J = 10.0, 8.0 Hz, 1H), 3.59-3.60 (m, 2H), 3.27-3.28 (m, 1H), 3.13 - 3.00 (m, 2H), 2.39 (d, J = 14.6 Hz, 1H), 2.28 (d, J = 14.9 Hz, 1H), 2.18 - 1.94 (m, 3H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3-((E)-4-((4-羥基-4-甲基哌啶-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮三氟乙酸鹽（1.85毫克，收率5%）。 MS (ESI) M/Z: 519.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (dd, J= 8.6, 2.4 Hz, 1H), 7.77 (dd, J= 8.0, 2.0 Hz, 2H), 7.67 (s, 1H), 7.54 (m, 5H), 7.42 - 7.27 (m, 5H), 7.22 (d, J= 2.8 Hz, 1H), 4.82 (s, 1H), 4.36 (s, 2H), 4.04 (dd, J= 10.0, 8.0 Hz, 1H), 3.36 (s, 2H), 2.05 (d, J= 6.4 Hz, 1H), 1.90 - 1.74 (m, 4H), 1.31 (d, J= 5.2 Hz, 5H). Example 54: (E)-3-((3-((E)-4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)styryl)-1H-indazole -6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally obtains the target product (E)-3-((3-((E)-4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)styrene yl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidon-2-one trifluoroacetate (1.85 mg, yield 5%). MS (ESI) M/Z: 519.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (dd, J = 8.6, 2.4 Hz, 1H), 7.77 (dd, J = 8.0 , 2.0 Hz, 2H), 7.67 (s, 1H), 7.54 (m, 5H), 7.42 - 7.27 (m, 5H), 7.22 (d, J = 2.8 Hz, 1H), 4.82 (s, 1H), 4.36 (s, 2H), 4.04 (dd, J = 10.0, 8.0 Hz, 1H), 3.36 (s, 2H), 2.05 (d, J = 6.4 Hz, 1H), 1.90 - 1.74 (m, 4H), 1.31 ( d, J = 5.2 Hz, 5H).

製備方法參考實施例11，得到產物(E)-3-(3-(4-(4-(2-氧雜-7-氮雜[3.5]壬烷-7-甲基)苯乙烯基)-1H-吲唑-6-基亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽（4.68毫克，收率9.0%）。 MS (ESI) M/Z: 531.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.96 (d, J= 8.8 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.4 Hz, 1H), 7.53 - 7.49 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20 - 7.19 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 4.29 (s, 2H), 4.02 (t, J= 8.0 Hz, 1 H), 3.47 - 3.46 (m, 2H), 3.09 - 3.05 (m, 2H), 2.40 - 2.36 (m, 2H), 1.93 - 1.89 (m, 2H). Example 55: (E)-3-(3-(4-(4-(2-Oxa-7-aza[3.5]nonane-7-methyl)styryl)-1H-indazole- 6-ylmethylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11 to obtain the product (E)-3-(3-(4-(4-(2-oxa-7-aza[3.5]nonane-7-methyl)styryl)- 1H-Indazol-6-ylmethylene)-4-phenylpyrrolidin-2-one trifluoroacetate (4.68 mg, 9.0% yield). MS (ESI) M/Z: 531.2 [M+H ] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.4 Hz, 1H ), 7.53 - 7.49 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20 - 7.19 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.56 (s, 2H), 4.41 ( s, 2H), 4.29 (s, 2H), 4.02 (t, J = 8.0 Hz, 1H), 3.47 - 3.46 (m, 2H), 3.09 - 3.05 (m, 2H), 2.40 - 2.36 (m, 2H ), 1.93 - 1.89 (m, 2H).

製備方法參考實施例11，最後得到目標產物 (E)-3-((3 -((E)-4-(2-氧雜-8-氮雜螺[4.5]癸-8-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯吡咯烷-2-酮三氟乙酸鹽（3.5毫克，收率8.7%)。 MS (ESI) M/Z: 545.0[M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 7.6 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.55 - 7.53 (m, 5H), 7.33-7.23 (m, 6H), 4.81 (d, J= 8.0 Hz, 1H), 4.36 (d, J= 10.1 Hz, 2H), 4.04 (m, 1H), 3.91 (m, 2H), 3.74 (s, 1H), 3.54-3.46 (m, 3H), 3.19-3.04 (m, 2H), 2.04 - 1.78 (m, 6H). Example 56: (E)-3-((3-((E)-4-(2-oxa-8-azaspiro[4.5]dec-8-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(2-oxa-8-azaspiro[4.5]dec-8-ylmethyl) Styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (3.5 mg, 8.7% yield). MS (ESI) M/Z: 545.0[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.55 - 7.53 (m, 5H), 7.33-7.23 (m, 6H), 4.81 (d, J = 8.0 Hz, 1H), 4.36 (d, J = 10.1 Hz, 2H), 4.04 (m, 1H), 3.91 (m, 2H), 3.74 (s, 1H), 3.54-3.46 (m, 3H), 3.19-3.04 (m, 2H), 2.04 - 1.78 ( m, 6H).

製備方法參考實施例11，最後得到目標產物1-(4 -((E)-2-(6 -((E)-(2-氧代-4-苯基吡咯烷-3-亞基)甲基)-1H-吲唑-3-基)乙烯基)苄基)哌啶 2-酮（43.7毫克，收率21.9%）。 MS (ESI) M/Z: 503.1[M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.23 (s, 1H), 8.22 (s, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.65 (d, J= 8.0 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J= 2.0 Hz, 1H), 7.46 (s, 2H), 7.37 - 7.13 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 4.50 (s, 2H), 3.89 - 3.90 (m, 1H), 3.18 (s, 2H), 3.12 - 3.13 (m, 1H), 2.31 - 2.32 (m, 2H), 1.71 - 1.72 (m, 4H). Example 57: 1-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene)methyl)-1H-indazole -3-yl)vinyl)benzyl)piperidin-2-one

The preparation method refers to Example 11, and finally the target product 1-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene))methanol is obtained yl)-1H-indazol-3-yl)vinyl)benzyl)piperidin 2-one (43.7 mg, yield 21.9%). MS (ESI) M/Z: 503.1[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.23 (s, 1H), 8.22 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.46 (s, 2H), 7.37 - 7.13 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 4.50 (s, 2H), 3.89 - 3.90 (m, 1H), 3.18 (s, 2H), 3.12 - 3.13 (m, 1H), 2.31 - 2.32 (m, 2H), 1.71 - 1.72 (m, 4H).

製備方法參考實施例11，最後得到目標產物 (E)-3 -((3 -((E)-4-(7-氧雜-2-氮雜螺[3.5]壬-2-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯吡咯烷-2-酮三氟乙酸鹽（5.6毫克，收率5.9%）。 MS (ESI) M/Z: 531.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 2.0 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.35 - 7.18 (m, 6H), 4.81 (d, J= 8.0 Hz, 1H), 4.43 (s, 2H), 4.11 - 3.98 (m, 5H), 3.69 - 3.59 (m, 4H), 1.90 (d, J= 6.0Hz, 4H). Example 58: (E)-3-((3-((E)-4-(7-oxa-2-azaspiro[3.5]non-2-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(7-oxa-2-azaspiro[3.5]non-2-ylmethyl) Styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (5.6 mg, yield 5.9%). MS (ESI) M/Z: 531.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.35 - 7.18 (m, 6H), 4.81 (d, J = 8.0 Hz, 1H), 4.43 (s, 2H ), 4.11 - 3.98 (m, 5H), 3.69 - 3.59 (m, 4H), 1.90 (d, J = 6.0Hz, 4H).

製備方法參考實施例11，得到(E)-3-((4-甲氧基-3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮三氟乙酸鹽(15.47毫克，收率13.1%）。 MS (ESI) M/Z: 519.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.68 (d, J= 3.6 Hz, 1H), 7.65 (d, J= 4.8 Hz, 2H), 7.63 (d, J= 2.1 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J= 8.3 Hz, 2H), 7.33 (d, J= 3.7 Hz, 4H), 7.28 - 7.22 (m, 1H), 7.15 (s, 1H), 6.51 (s, 1H), 4.80 (d, J= 8.0 Hz, 1H), 4.29 (s, 2H), 4.02 (dd, J= 10.1, 8.0 Hz, 2H), 3.71 (s, 3H), 3.50 - 3.43 (m, 2H), 3.03 - 2.93 (m, 3H), 2.03 - 1.93 (m, 2H), 1.88 - 1.80 (m, 1H), 1.79 - 1.66 (m, 2H), 1.58 - 1.46 (m, 1H). Example 59: (E)-3-((4-Methoxy-3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl )methylene)-4-phenylpyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11 to obtain (E)-3-((4-methoxy-3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazole -6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (15.47 mg, yield 13.1%). MS (ESI) M/Z: 519.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.68 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 4.8 Hz, 2H), 7.63 (d, J = 2.1 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 3.7 Hz, 4H), 7.28 - 7.22 ( m, 1H), 7.15 (s, 1H), 6.51 (s, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.29 (s, 2H), 4.02 (dd, J = 10.1, 8.0 Hz, 2H ), 3.71 (s, 3H), 3.50 - 3.43 (m, 2H), 3.03 - 2.93 (m, 3H), 2.03 - 1.93 (m, 2H), 1.88 - 1.80 (m, 1H), 1.79 - 1.66 (m , 2H), 1.58 - 1.46 (m, 1H).

反應路線:

Example 60: (E)-4-Phenyl-3-((3-((E)-4-(3-(piperidin-1-yl)oxetan-3-yl)styryl) -1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

Reaction route:

Operation steps: Step A: Dissolve oxetan-3-one (5.0 g, 0.07 mol) in dichloromethane (100 ml) at room temperature under nitrogen protection, and then add tert-butylsulfin Amide (10.0 g, 0.08 mol), followed by tetraisopropyl titanate (39 g, 0.14 mol), and stirred overnight at 45°C. After cooling to room temperature, aqueous sodium bicarbonate solution (200 ml) was added to the system to quench it. Stir for 30 minutes, filter through diatomaceous earth, wash diatomaceous earth with dichloromethane (50 ml), separate the layers of the filtrate, wash the organic phase with saturated brine (50 ml), then dry with anhydrous sodium sulfate, filter, and finally Concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 2-methyl-N-(oxetane-3-alkylene)propane-2-ethylene Sulfonamide (7.6 g, 62.5% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.83-5.64 (m, 2H), 5.56 - 5.31 (m, 2H), 1.27 (s, 9H). Add bromobenzene (13.2 g, 0.056 mol) to anhydrous tetrahydrofuran (120 ml), cool down to minus 78 degrees Celsius, add n-butyllithium (2.5M, 23 ml, 0.057 moles), and stir for 1 hour at minus 78 degrees Celsius , then slowly add 2-methyl-N-(oxetane-3-alkylene) propane-2-sulfinamide (6.6 g, 0.038 mole) to the mixed solution and stir at minus 78 degrees Celsius for 30 minutes, warmed to room temperature, and the reaction was stirred at room temperature for 1 hour. After spot plate monitoring showed that the raw material disappeared, an aqueous solution of ammonium chloride (200 ml) was added to the system to quench it. The mixture was extracted with ethyl acetate (300 ml x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain N-(3-(4-bromophenyl)oxetan-3-yl)-2- Methylpropane-2-sulfinamide (9.5 g, 76.0% yield). MS (ESI) M/Z: 333.9 [M+H] ⁺ . Step C: Add N-(3-(4-bromophenyl)oxetan-3-yl)-2-methylpropane-2- Sulfinamide (1.1 g, 3.4 mmol) was dissolved in ethyl acetate (10 ml), cooled to 0°C, and dioxane hydrochloride solution (5M) (2 ml, 10.0 mmol) was added, The reaction was then stirred at 0 °C for 2 hours. Spot the plate to monitor the incomplete reaction, warm up to room temperature, and stir at room temperature for 30 minutes. After spot plate monitoring showed that the raw materials disappeared, petroleum ether (20 ml) was added to the reaction solution, stirred at room temperature for 30 minutes, and filtered to obtain 3-(4-bromophenyl)oxetane-3-amine salt acid salt (830.0 mg, yield 91.7%). Step D: 3-(4-Bromophenyl)oxetan-3-amine hydrochloride (830.0 mg, 3.4 mmol) was dissolved in anhydrous acetonitrile (40 mL) at room temperature. Add 1,5-diiodopentane (1.3 g, 4.1 mmol), potassium carbonate (1.9 g, 13.7 mmol), followed by tetrabutylammonium bromide (110.0 mg, 0.34 mmol) to the reaction solution Stir at 60°C for 64 hours. After LCMS monitoring showed that the raw material disappeared, ethyl acetate (40 ml) was added, the mixture was filtered, the filtrate was concentrated, then water (50 ml) was added, the mixture was extracted with ethyl acetate (50 ml × 2 times), and the organic phases were combined. The organic phase was washed with brine (40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain 1-(3-(4-bromophenyl)oxetan-3-yl)piperidine ( 600 mg, yield 64.7%). MS (ESI) M/Z: 296.1 [M+H] ⁺ . Step E: 1-(3-(4-bromophenyl)oxetan-3-yl)piperidine (600.0 mg, 2.0 mmol) dissolved in toluene (12 ml). Subsequently, after adding 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (405 mg, 2.6 mmol) and N,N-di Isopropylethylamine (523 mg, 4.0 mmol). Then tri-tert-butylphosphine tetrafluoroborate (1.8 g, 5.1 mmol) and Pd ₂ (dba) ₃ (58.0 mg, 0.1 mmol) were added, followed by nitrogen replacement and stirring at 90°C for 3 hours. After LCMS monitoring showed that the raw material disappeared, ammonium chloride solution (50 milliliters) was added, and the mixed solution was extracted with ethyl acetate (100 milliliters × 2 times), and the combined organic phases were washed with saturated brine (50 milliliters) earlier, and then Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain 1-(3-(4-((E)-2-(tetramethyl-1,3, 2-dioxaborolan-2-yl)vinyl)phenyl)oxetan-3-yl)piperidine (560.0 mg, yield 74.8%). MS (ESI) M/Z: 370.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.50 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 18.4 Hz, 1H ), 7.04 (d, J = 8.0 Hz, 2H), 6.19 (d, J = 18.4 Hz, 1H), 4.90 (s, 4H), 2.18 (br, 4H), 1.62 (br, 4H), 1.34 (s , 12H), 1.27 (m, 2H). Step F: (3E)-3-((3-iodo-1-(tetrahydropyran-2-yl)-1H-ind Azol-6-yl)methylene)-4-phenylpyrrolidin-2-one (200.0 mg, 0.4 mmol) and 1-(3-(4-((E)-2-(tetramethyl -1,3,2-dioxaborolan-2-yl)vinyl)phenyl)oxetan-3-yl)piperidine (210.0 mg, 0.57 mmol) dissolved in 1,4 - Dioxane (4 ml). Subsequently, potassium carbonate (138.0 mg, 1.0 mmol), water (1 mL), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (20.0 mg, 0.027 mmol) were added ear), followed by nitrogen replacement. Stir at 100 °C for 2 hours. After LCMS monitoring showed that the raw material disappeared, ammonium chloride solution (30 milliliters) was added, and the mixed solution was extracted with ethyl acetate (50 milliliters × 2 times), and the organic phases were combined, and the organic phase was washed with saturated brine (40 milliliters) earlier, and then Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain (3E)-3-((1-(oxa-2-yl)-3-((E) -2-(4-(3-(Piperidin-1-yl)oxetan-3-yl)phenyl)vinyl))-1H-indazol-6-yl)methylene)-4- Phenylpyrrolidin-2-one (140 mg, 57.0% yield). MS (ESI) M/Z: 614.9 [M+H] ⁺ . Step G: (3E)-3-((1-(oxa-2-yl)-3-((E) -2-(4-(3-(piperidin-1-yl)oxetan-3-yl)phenyl)vinyl))-1H-indazol-6-yl)methylene}-4- Phenylpyrrolidin-2-one (140.0 mg, 0.22 mmol) was dissolved in methanol (4 ml), subsequently, methanesulfonic acid (250.0 mg, 2.6 mmol) was added, and the reaction solution was stirred at 60 degrees Celsius for 2 Hour. After spot plate monitoring showed that the raw materials disappeared, aqueous sodium bicarbonate solution (30 ml) was added, the mixture was extracted with dichloromethane (40 ml × 2 times), the organic phases were combined, and the organic phase was first washed with saturated brine (30 ml). It was then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was prepared and purified (trifluoroacetic acid was contained in the purification reagent) to obtain (E)-4-phenyl-3-((3-((E)-4-(3-(piperidin-1-yl)oxa Cyclobut-3-yl)styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (54.9 mg, 37.4% yield). MS (ESI) M/Z: 531.1[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.90 (dd, J = 8.6, 2.7 Hz, 1H), 7.79 - 7.69 (m, 2H ), 7.58 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 2.5 Hz, 3H), 7.40 (d, J = 8.2 Hz, 2H), 7.28 - 7.16 (m, 5H), 7.16 - 7.07 (m, 1H), 5.17 - 5.06 (m, 4H), 4.73 (m, 1H), 3.94 (dd, J = 10.1, 8.1 Hz, 1H), 3.55 (m, 2H), 2.46 (m, 2H), 1.84 (m, 5H), 1.23 (m, 1H).

反應路線:

Example 61: (E)-4-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene)- 8-Oxa-2-azaspiro[4.5]decan-3-one trifluoroacetate

Reaction route:

Procedure: Step A: Dissolve 8-oxa-2-azaspiro[4.5]dec-3-one (500 mg, 3.2 mmol) in THF (7.5 mL) and add 4-dimethylaminopyridine (196.8 mg, 1.6 mmol) and BOC-anhydride (1.05 g, 4.8 mmol), stirred overnight at room temperature. After TLC monitoring showed that the raw materials disappeared, water (20 ml) was added to the reaction solution to quench, extracted with ethyl acetate (50 ml × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 ml × 2 times) ), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 3-oxa-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid Tertiary butyl ester (750 mg, yield 91.2%). Step B: tert-butyl 3-oxa-8-oxa-2-azaspiro[4.5]decane-2-carboxylate (200 mg, 0.78 mmol) was dissolved in THF (3 mL),- LiHMDS (1 mol/L, 0.78 mL, 0.78 mmol) was added dropwise at 78 °C. Stir at -78°C for 30 minutes, add 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (232.6 mg, 0.65 mmol) in tetrahydrofuran (3 mL ) solution was stirred at room temperature for 2 hours. After TLC monitoring showed that most of the raw materials disappeared, and LC-MS monitoring showed that it was the product, ammonium chloride solution (20 ml) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (30 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (E)-4 ((3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-6-yl)methylene)-8-oxa-2-azaspiro[4.5]decan-3-one (100 mg, yield 31.3%). MS (ESI) M/Z: 493.8 [M+H] ⁺ . Step C: Add (E)-4-((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-6-yl)methylene)-8-oxa-2-azaspiro[4.5]decan-3-one (100 mg, 0.20 mmol), (E)-1-(4-( 2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl)piperidine (99.6 mg, 0.30 mmol ), potassium carbonate (70 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14.8 mg, 0.02 mmol) dissolved in 1,4 In dioxane (4 ml) and water (1 ml), replace with nitrogen, and react at 100 degrees Celsius for three hours. TLC monitors that most of the raw materials have reacted, and LCMS monitors that the product is detected, and water (15 ml) is added to the reaction solution. Quenched. The mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, the organic phase was first washed with saturated brine (15 ml × 3 times), then dried with anhydrous sodium sulfate, filtered, and finally reduced pressure Concentration. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain (E)-4-((3-((E)-4-(piperidine-1- Methyl) styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-8-oxa-2-azaspiro[ 4.5] Decane-3-one (80 mg, yield 69.7%). MS (ESI) M/Z: 567.1 [M+H] ⁺ . Step D: Add (E)-4-((3-(( E)-4-(piperidin-1-ylmethyl)styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)- 8-Oxa-2-azaspiro[4.5]decane-3-one (80 mg, 0.14 mmol) was dissolved in methanol (4 mL) and methanesulfonic acid (135.8 mg, 1.4 mmol ), heated up to 60 degrees Celsius and reacted for 1.5 hours. TLC monitoring raw material reaction, LCMS monitoring shows that after the raw material disappeared, into the reaction system into sodium bicarbonate aqueous solution (20 milliliters) to quench, the mixed solution with dichloromethane (30 milliliters × 3 times) extraction, combined organic phase, the organic phase was washed with saturated brine (10 ml), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was prepared and purified (containing trifluoroacetic acid in the purification reagent) to obtain (E )-4-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene)-8-oxa-2 -Azaspiro[4.5]decan-3-one trifluoroacetate (4.77 mg, 5% yield). MS (ESI) M/Z: 483.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8. 20 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.73 - 7.45 (m, 6H), 7.32 (d, J = 8.4 Hz, 1H), 4.34 (s, 2H ), 3.82 (dd, J = 12.0, 4.9 Hz, 2H), 3.54-3.49 (m, 4H), 3.01 (t, J = 12.5 Hz, 2H), 2.22 (m, 2H), 2.05 - 1.67 (m, 7H), 1.57 (m, 3H).

製備方法參考實施例11，得(E)-4-苯基-3-((3-((E)-2-(6-(哌啶-1-基甲基)吡啶-3-基)乙烯基)-1H-吲唑-6-基)亞甲基) 吡咯烷-2-酮三氟乙酸鹽（31.5毫克，收率21.4%）。 MS (ESI) M/Z: 490.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.91 (d, J= 2.2 Hz, 1H), 8.20 (dd, J= 8.2, 2.2 Hz, 1H), 8.01 (d, J= 8.5 Hz, 1H), 7.79 - 7.44 (m, 5H), 7.44 - 7.23 (m, 5H), 7.21 (dq, J= 5.9, 2.8 Hz, 1H), 4.81 (d, J= 8.0 Hz, 1H), 4.46 (s, 2H), 4.04 (dd, J= 10.1, 8.0 Hz, 2H), 3.28-3.20 (m, 4H), 2.02 - 1.50 (m, 6H). Example 62: (E)-4-Phenyl-3-((3-((E)-2-(6-(piperidin-1-ylmethyl)pyridin-3-yl)vinyl)-1H -Indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11 to obtain (E)-4-phenyl-3-((3-((E)-2-(6-(piperidin-1-ylmethyl)pyridin-3-yl)ethylene (yl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (31.5 mg, yield 21.4%). MS (ESI) M/Z: 490.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.2, 2.2 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.79 - 7.44 (m, 5H), 7.44 - 7.23 (m, 5H), 7.21 (dq, J = 5.9, 2.8 Hz, 1H), 4.81 (d, J = 8.0 Hz, 1H), 4.46 (s, 2H), 4.04 (dd, J = 10.1, 8.0 Hz, 2H), 3.28-3.20 (m, 4H), 2.02 - 1.50 (m, 6H).

參考實施例11的製備方法得到(E)-3-((3-((E)-2-甲氧基-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽(1.7毫克，收率2%）。 MS (ESI) M/Z: 519.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.79 (d, J= 8.5 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.55 (d, J= 2.2 Hz, 1H), 7.48 - 7.32 (m, 2H), 7.29 - 7.06 (m, 7H), 7.01 (d, J= 7.8 Hz, 1H), 5.24 (t, J= 4.9 Hz, 1H), 4.20 (s, 2H), 4.00 - 3.85 (m, 4H), 3.39 (m, 2H), 2.89 (t, J= 12.3 Hz, 2H), 2.00 - 1.31 (m, 7H). Example 63: (E)-3-((3-((E)-2-methoxy-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl )methylene)-4-phenylpyrrolidin-2-one trifluoroacetate

The preparation method of reference example 11 obtains (E)-3-((3-((E)-2-methoxy-4-(piperidin-1-ylmethyl) styryl)-1H-indazole -6-yl)methylene)-4-phenylpyrrolidin-2-one trifluoroacetate (1.7 mg, yield 2%). MS (ESI) M/Z: 519.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.79 (d, J = 8.5 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.55 (d, J = 2.2 Hz, 1H), 7.48 - 7.32 (m, 2H), 7.29 - 7.06 (m, 7H), 7.01 (d, J = 7.8 Hz, 1H), 5.24 (t, J = 4.9 Hz , 1H), 4.20 (s, 2H), 4.00 - 3.85 (m, 4H), 3.39 (m, 2H), 2.89 (t, J = 12.3 Hz, 2H), 2.00 - 1.31 (m, 7H).

反應路線:

Example 64: (E)-3-(3-(4-(piperidin-1-methyl)styryl)-1-H-ind-6-methylene)pyrrolidinone-2-one trifluoroacetic acid Salt

Reaction route:

Procedure: Step A: Compound 1-acetylpyrrolidin-2-one (200 mg, 1.5 mmol) was dissolved in dry THF (5 mL). Cool in an ice-salt bath to less than 0°C, add sodium hydride (60%, 0.2 g, 4.2 mmol) with stirring, and react at this temperature for 20 minutes. Add (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazole-6-carbaldehyde (0.5 mg, 1.4 mmol) and react at room temperature overnight. LCMS monitoring showed that the starting material After disappearing, add saturated aqueous ammonium chloride solution to quench the reaction, and wash the aqueous phase twice with dichloromethane. Combine the organic phases, dry, and concentrate under reduced pressure. The resulting residue is purified with a preparative column (methanol/dichloromethane 1:10 ), to obtain (E)-3-(3-iodo-1-tetrahydro-2H-pyran-2-yl)-1-H-indazol-6-ylmethylene)pyrrolidin-2-one ( 230 mg, yield 38.7%). MS (ESI) M/Z: 423.6 [M+H] ⁺ . Step B: Add (E)-3-(3-iodo-1-tetrahydro-2H-pyran-2-yl)-1-H- Indazol-6-ylmethylene)pyrrolidin-2-one (230 mg, 0.5 mmol) and (E)-1-(4-(2-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)vinyl)benzyl)piperidine (267 mg, 0.8 mmol) dissolved in 1,4-dioxane (8 mL), Then potassium carbonate (186 mg, 1.4 mmol), water (2 ml), Pd(dppf)Cl ₂ (40 mg, 0.05 mmol) were added thereto, and the reaction system was heated to 80°C and stirred for 12 hours. After LCMS monitoring showed that the raw material disappeared, it was extracted with ethyl acetate (20 ml), the organic phase was washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The crude product was purified using a preparative column (methanol/ Dichloromethane 1:10) to obtain product (E)-3-(3-(4-(piperidine-1-methyl)styryl)-1-(tetrahydro-2Hpyran-2-yl)- 1 H-indazol-6-yl)methylene)pyrrolidone-2-one (90 mg, yield 33.3%). MS (ESI) M/Z: 497.0 [M+H] ⁺ . Step C: Add (E)-3-(3-(4-(piperidin-1-methyl)styryl)-1-(tetra Hydrogen-2H-pyran-2-yl)-1-H-indazol-6-yl)methylene)pyrrolidon-2-one (90 mg, 0.2 mmol) was dissolved in methanol (6 mL), Then methanesulfonic acid (174 mg, 1.8 mmol) was added thereto, and the reaction system was heated to 60°C and stirred for 1 hour. After LCMS monitoring showed that the raw materials disappeared, sodium bicarbonate solution was added to neutralize the pH to make it alkaline, then extracted with dichloromethane (10 ml), the organic phase was first washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate , concentrated under reduced pressure. The crude product was pulped with dichloromethane, filtered with suction, and the filter cake was dried. Water (2 mL), acetonitrile (2 mL) and trifluoroacetic acid (1 drop) were added to lyophilize to give (E)-3-(3-(4-(piperidin-1-methyl)styryl)- 1-H-ind-6-methylene)pyrrolidon-2-one trifluoroacetate (18.1 mg, yield 19.1%). MS (ESI) M/Z: 413.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.17 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.61 - 7.56 (m, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 8.7, 1.4 Hz, 1H), 7.39 (t, J = 2.9 Hz, 1H), 4.31 (s, 2H), 3.58 (dd, J = 7.0, 5.8 Hz, 2H), 3.53 - 3.44 (m, 2H), 3.29 - 3.24 (m, 2H), 3.05 - 2.92 ( m, 2H), 1.97 (d, J = 14.9 Hz, 2H), 1.85 (d, J = 13.2 Hz, 1H), 1.74 (q, J = 13.6, 13.1 Hz, 2H), 1.52 (q, J = 12.7 Hz, 1H).

製備方法參考實施例64，得目標產物(E)-4-((3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-2-氮雜-螺[4.5]癸-3-酮三氟乙酸鹽（14.71毫克，收率29.2%）。 MS (ESI) M/Z: 441.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.17 (d, J= 8.4 Hz, 1H), 7.82 (dd, J= 8.1, 1.7 Hz, 2H), 7.63 - 7.51 (m, 5H), 7.29 (d, J= 8.3 Hz, 1H), 4.34 (s, 2H), 3.58 - 3.46 (m, 2H), 3.20 (s, 2H), 3.08 - 2.94 (m, 2H), 2.06 - 1.93 (m, 2H), 1.91 - 1.84 (m, 1H), 1.82 - 1.70 (m, 2H), 1.61 - 1.48 (m, 1H), 1.33 (s, 6H). Example 65: (E)-4,4-Dimethyl-3-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazole-6 -yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 64 to obtain the target product (E)-4-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl )methylene)-2-aza-spiro[4.5]dec-3-one trifluoroacetate (14.71 mg, 29.2% yield). MS (ESI) M/Z: 441.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.17 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 8.1, 1.7 Hz, 2H), 7.63 - 7.51 (m, 5H), 7.29 (d, J = 8.3 Hz, 1H), 4.34 (s, 2H), 3.58 - 3.46 (m, 2H), 3.20 (s, 2H), 3.08 - 2.94 (m, 2H), 2.06 - 1.93 (m, 2H), 1.91 - 1.84 (m, 1H), 1.82 - 1.70 (m, 2H), 1.61 - 1.48 (m, 1H), 1.33 (s, 6H) .

製備方法參考實施例16，得到(S或R, E)-3-((4-甲氧基-3-((E)-4-(哌啶-1-基甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮，採用HPLC分離，實施例66化合物，出峰時間4.1min和實施例67化合物，出峰時間5.6min。 HPLC條件： 色譜柱：手性柱 S-AD  0.46cmI.D. ×15cm L，5um 流動相：甲醇//乙腈/二乙醇胺=50/50/0.05(v/v/v) 流速：0.8ml/min. Example 66 & 67: (S or R, E)-3-((4-methoxy-3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H- Indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one

The preparation method refers to Example 16 to obtain (S or R, E)-3-((4-methoxy-3-((E)-4-(piperidin-1-ylmethyl)styryl)- 1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one, separated by HPLC, the compound of Example 66, the elution time was 4.1min and the compound of Example 67, the elution time was 5.6min. HPLC conditions: Chromatographic column: chiral column S-AD 0.46cmI.D. ×15cm L, 5um mobile phase: methanol//acetonitrile/diethanolamine=50/50/0.05(v/v/v) flow rate: 0.8ml/ min.

Example 66: MS (ESI) M/Z: 519.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.22 (s, 1H), 7.55 - 7.40 (m, 5H), 7.37 - 7.25 (m, 6H), 7.27 - 7.17 (m, 2H), 6.50 (s, 1H), 4.80 (dt, J = 8.0, 2.2 Hz, 1H), 3.89 (dd, J = 9.7, 7.8 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 2H), 3.13 - 3.06 (m, 1H), 2.37 - 2.31 (m, 4H), 1.50 (m, 4H), 1.39 (m, 2H). C ₃₃ H ₃₄ N ₄ O ₂ .

Example 67: MS (ESI) M/Z: 519.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.22 (s, 1H), 7.55 - 7.40 (m, 5H), 7.37 - 7.25 (m, 6H), 7.27 - 7.17 (m, 2H), 6.50 (s, 1H), 4.80 (dt, J = 8.0, 2.2 Hz, 1H), 3.89 (dd, J = 9.7, 7.8 Hz, 1H), 3.69 (s, 3H), 3.35 (s, 2H), 3.13 - 3.06 (m, 1H), 2.37 - 2.31 (m, 4H), 1.50 (m, 4H), 1.39 (m, 2H). C ₃₃ H ₃₄ N ₄ O ₂ .

Example 68: (E)-4-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1H-indazol-6-yl)methylene)- 2,8-Diazaspiro[4.5]decan-3-one trifluoroacetate

Reaction route:

Procedure: Step A: Dissolve tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (500 mg, 1.96 mmol) in THF (10 mL) 4-Dimethylaminopyridine (120 mg, 0.99 mmol) and BOC-anhydride (643 mg, 2.95 mmol) were added, and stirred at room temperature overnight. After TLC monitoring showed that the raw materials disappeared, water (20 ml) was added to the reaction solution to quench, extracted with ethyl acetate (50 ml × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 ml × 2 times) ), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 3-oxo-2,8-diazaspiro[4.5]decane-2,8-di Di-tert-butyl carboxylate (0.69 g, white solid, 99% yield). Step B: Di-tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-2,8-dicarboxylate (299 mg, mmol) in THF (4 mL) LiHMDS (1 mol/L, 0.84 ml, 0.84 mmol) was added dropwise at -78°C. Stir at -78°C for 30 minutes, add 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (250 mg, 0.70 mmol) in tetrahydrofuran (1 mL ) solution was stirred at room temperature for 2 hours. After TLC monitoring showed that most of the raw materials disappeared, and LC-MS monitoring showed that it was the product, ammonium chloride solution (20 ml) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (30 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain tert-butyl (E)-4-((3-iodo-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-6-yl)methylene)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (160 mg, yellow solid, Yield 38.5%). MS (ESI) M/Z: 592.8 [M+H] ⁺ . Step C: Add tert-butyl (E)-4-((3-iodo-1-(tetrahydro-2H-pyran-2-yl )-1H-indazol-6-yl)methylene)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (160 mg, 0.27 mmol), (E)-1-(4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl) Piperidine (133 mg, 0.41 mmol), sodium carbonate (72 mg, 0.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg) Dissolve in 1,4-dioxane (4 ml) and water (1 ml), replace with nitrogen, and react at 100 degrees Celsius for three hours. TLC monitors that most of the raw materials have reacted, and LCMS monitors that the product is detected. Add to the reaction solution Quenched with water (15 ml). The mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (15 ml × 3 times), and then dried over anhydrous sodium sulfate. Filtration, and finally concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain tert-butyl (E)-3-oxo-4-((3 -((E)-4-(piperidin-1-ylmethyl)styryl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene base)-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, pale yellow solid, yield 83.7%). MS (ESI) M/Z:666.2 [M+H] ⁺ . Step D: (E)-3-oxo-4-((3-((E)-4-(piperidin-1-ylmethyl)styryl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazol-6-yl)methylene)-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.23 mmol ) was dissolved in methanol (5 milliliters), methanesulfonic acid (325 mg, 3.38 mmol) was added, and the temperature was raised to 60 degrees Celsius for 1.5 hours. TLC monitoring of the reaction of raw materials, after LCMS monitoring showed that the raw materials disappeared, added to the reaction system Quenched with aqueous sodium bicarbonate (20 ml), the mixture was extracted with dichloromethane (30 ml x 3 times), the organic phases were combined, the organic phase was washed with saturated brine (10 ml), and then dried over anhydrous sodium sulfate , filtered, and finally concentrated under reduced pressure. The crude product was prepared and purified (trifluoroacetic acid was contained in the purification reagent) to obtain (E)-4-((3-((E)-4-(piperidin-1-ylmethyl)styrene Base)-1H-indazol-6-yl)methylene)-2,8-diazaspiro[4.5]decane-3-one trifluoroacetate (21.75 mg, yield 16.2%). MS ( ESI) M/Z: 482.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.10 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (s, 1H), 7.50 (s, 2H) , 7.48 - 7.43 (m, 3H), 7.13 (d, J = 8.4 Hz, 1H), 4.22 (s, 2H), 3.39 (m, 4H), 3.15 (d, J = 13.1 Hz, 2H), 3.01 - 2.84 (m, 4H), 2.04 (t, J = 14.1 Hz, 2H), 1.89-1.44 (m, 8H).

製備方法參考實例11，最後得到目標產物 (E)-4-苯基-3-((3-((E)-4-((四氫-2H-吡喃-4-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷酮-2-酮三氟乙酸鹽（13.5毫克，收率7.5%）。 MS (ESI) M/Z: 490.3 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆): δ 13.20 (s, 1H), 8.22 (s, 1H), 8.03 (d, J= 8.5 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.51 (d, J= 2.1 Hz, 1H), 7.43 (s, 2H), 7.34 - 7.13 (m, 8H), 4.77 (d, J= 7.6 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.84 - 3.76 (m, 2H), 3.28 - 3.17 (m, 2H), 3.12 (d, J= 9.8 Hz, 1H), 1.78 - 1.67 (m, 1H), 1.53 - 1.43 (m, 2H), 1.28 - 1.13 (m, 3H). Example 69: (E)-4-Phenyl-3-((3-((E)-4-((tetrahydro-2H-pyran-4-yl)methyl)styryl)-1H- Indazol-6-yl)methylene)pyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-4-phenyl-3-((3-((E)-4-((tetrahydro-2H-pyran-4-yl)methyl)benzene Vinyl)-1H-indazol-6-yl)methylene)pyrrolidon-2-one trifluoroacetate (13.5 mg, yield 7.5%). MS (ESI) M/Z: 490.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.20 (s, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.51 (d, J = 2.1 Hz, 1H), 7.43 (s, 2H), 7.34 - 7.13 (m, 8H), 4.77 (d, J = 7.6 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.84 - 3.76 (m, 2H), 3.28 - 3.17 (m, 2H), 3.12 (d, J = 9.8 Hz, 1H), 1.78 - 1.67 (m, 1H), 1.53 - 1.43 (m, 2H), 1.28 - 1.13 (m, 3H).

反應路線:

Example 70: (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)isoindole-1 -Ketotrifluoroacetate

Reaction route:

Procedure: Step A: Dissolve (2,4-dimethoxyphenyl)methanamine (1.0 g, 6.0 mmol) and triethylamine (909 mg, 9.0 mmol) in dichloromethane (20 ml). 2-Bromobenzoyl chloride (1.3 g, 6.0 mmol) was added dropwise thereto under an ice-water bath, and the mixture was reacted at room temperature for 1 hour. After TLC monitoring showed that the starting material disappeared, 1M dilute hydrochloric acid (20 ml) was added to the reaction solution. The mixture was extracted with DCM (30 ml × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml × 1 time), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-bromo -N-(2,4-dimethoxybenzyl)benzamide (1.6 g, yield 76.6%). Step B: Add (E)-1-(4-methoxybenzyl)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (184.7 mg, 0.5 mg mol), (1-diazo-2-oxopropyl) dimethyl phosphonate (134.5 mg, 0.7 mmol) and potassium carbonate (149.6 mg, 1.1 mmol) were added to methanol (2 ml), Stir at room temperature for 3 hours. After LCMS monitoring showed that the starting material disappeared, water (4 mL) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (10 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL x 1 time), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 3/1) to obtain (E)-6-ethynyl-1-(4-methoxybenzyl)-3-(2 -(pyridin-4-yl)vinyl)-1H-indazole (138.3 mg, yield 75.8%). MS (ESI) M/Z: 376.2 [M+H] ⁺ . Step C: Add (E)-6-ethynyl-1-(4-methoxybenzyl)-3-(2-(pyridine-4 -yl)vinyl)-1H-indazole (182.5 mg, 0.50 mmol), 2-bromo-N-(2,4-dimethoxybenzyl)benzamide (525.3 mg, 1.5 mmol ear), triethylamine (506.0 mg, 5.0 mmol), cuprous iodide (11.4 mg, 0.06 mmol) and bis(triphenylphosphine)palladium dichloride (42.1 mg, 0.06 mmol) Add acetonitrile (2 ml), replace with nitrogen three times, and stir overnight at room temperature. After LCMS monitoring showed disappearance of starting material, water (4 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL x 1 time), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1/1) to obtain (E)-N-(2,4-dimethoxybenzyl)-2-((1- (4-Methoxybenzyl)-3-(2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)ethynylbenzamide (105.7 mg, yield 33.3%) .MS (ESI) M/Z: 635.5 [M+H] ⁺ .Step D: Add (E)-N-(2,4-dimethoxybenzyl)-2-((1-(4-methoxybenzyl) Oxybenzyl)-3-(2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)ethynylbenzamide (253.9 mg, 0.4 mmol) dissolved in N, N-dimethylformamide (5 milliliters). Then add sodium tert-butoxide (38.4 milligrams, 0.4 millimolar) reaction system to react at room temperature for 1 hour. After LCMS monitoring shows that the raw material disappears, add to the reaction solution Add water (40 ml) to quench. The mixture is extracted with ethyl acetate (30 ml × 3 times), the organic phases are combined, the organic phase is first washed with saturated brine (30 ml × 1 time), and then washed with anhydrous sodium sulfate Dry, filter, and finally concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: ethyl acetate) to obtain (E)-2-(2,4-dimethoxybenzyl)-3-( (1-(4-methoxybenzyl)-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)isoindole- 1-Keto (214.8 mg, 84.6% yield). MS (ESI) M/Z: 635.3 [M+H] ⁺ . Step E: At room temperature, (E)-2-(2,4-di Methoxybenzyl)-3-((1-(4-methoxybenzyl)-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazole-6- Base) methylene) isoindol-1-one (190.4 mg, 0.3 mmol) was dissolved in trifluoroacetic acid (5 milliliters). The reaction solution was reacted overnight at 60 degrees Celsius. After LCMS monitoring showed that the starting material disappeared, the The reaction system was quenched by adding aqueous sodium bicarbonate solution (40 ml). The mixed solution was extracted with dichloromethane/methanol=10/1 (30 ml × 3 times), and the organic phase was combined. The organic phase was first washed with saturated brine (20 ml × 1 time), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was prepared and purified (purification reagents contained trifluoroacetic acid) to obtain (E)-3-((3-((E)- 2-(Pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)isoindol-1-one trifluoroacetate (24.0 mg, 22.0% yield). MS (ESI ) M/Z: 365.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- d ₆ ): δ 13.63 (s, 1H), 10.96 (s, 1H), 8.75 (d, J = 5.8 Hz, 2H), 8.29 (d, J = 8.6 Hz, 1H), 8.19 - 8.06 (m, 4H), 7.84 (s, 1H), 7.81 - 7.77 (m, 1H), 7.77 - 7.72 (m , 1H), 7.67 (d, J = 16.7 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.55 - 7.49 (m, 1H), 6.97 (s, 1H).

製備方法參考實例11，最後得到目標產物1-(4-(E)-2-(6-(E)-(2-氧代-4-苯基吡咯烷酮-3-亞甲基)-2-基)-1-H-吲唑-3-基乙烯基)苄基)3-氰基哌啶三氟乙酸鹽（4.1毫克，收率4%）。 MS (ESI) M/Z: 514.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.97 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.53-7.51 (m, 5H), 7.30-7.26 (m, 5H), 7.20-7.18 (m,1H), 4.76 (d, J= 8.0Hz, 1H), 4.37(s, 2H), 4.04-3.99 (m, 1H), 3.50(m, 2H), 3.31-3.30 (m, 2H), 2.15- 189 (m,4H). Example 71: 1-(4-(E)-2-(6-(E)-(2-oxo-4-phenylpyrrolidinone-3-methylene)-2-yl)-1-H- Indazol-3-ylvinyl)benzyl)3-cyanopiperidine trifluoroacetate

The preparation method refers to Example 11, and finally the target product 1-(4-(E)-2-(6-(E)-(2-oxo-4-phenylpyrrolidone-3-methylene)-2-yl )-1-H-indazol-3-ylvinyl)benzyl)3-cyanopiperidine trifluoroacetate (4.1 mg, yield 4%). MS (ESI) M/Z: 514.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 5H), 7.30-7.26 (m, 5H), 7.20-7.18 (m, 1H), 4.76 (d, J = 8.0Hz , 1H), 4.37(s, 2H), 4.04-3.99 (m, 1H), 3.50(m, 2H), 3.31-3.30 (m, 2H), 2.15- 189 (m,4H).

製備方法參考實例11，最後得到目標產物(E)-3-((3-((E)-4-(嗎福林代甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮 (60毫克，收率59.1%）。 MS (ESI) M/Z: 591.4 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.65-7.45 (m, 6H), 7.32-7.19 (m, 8H), 4.77 (d, J= 6.8 Hz, 1H), 3.89 (t, 1H), 3.58 (m, 4H), 3.46 (m, 2H), 3.12 (d, J= 9.6 Hz, 1H), 2.36 (m, 4H). Example 72: (E)-3-((3-((E)-4-(morpholinomethyl)styryl)-1H-indazol-6-yl)methylene)-4- Phenylpyrrolidin-2-one

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(morpholinomethyl)styryl)-1H-indazol-6-yl)ylidene Methyl)-4-phenylpyrrolidin-2-one (60 mg, yield 59.1%). MS (ESI) M/Z: 591.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.65-7.45 (m, 6H), 7.32-7.19 (m, 8H), 4.77 (d, J = 6.8 Hz, 1H), 3.89 (t, 1H), 3.58 (m, 4H), 3.46 (m, 2H), 3.12 (d, J = 9.6 Hz, 1H), 2.36 (m, 4H).

製備方法參考實例11，最後得到目標產物 (E)-4-苯基-3-((3-((E)-4-(1-(哌啶-1-基)環丙基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽（16.6毫克，收率31.6%）。 MS (ESI) M/Z: 515.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (dd, J= 8.8, 3.9 Hz, 1H), 7.77 (dd, J= 8.3, 2.5 Hz, 2H), 7.70 -7.60 (m, 3H), 7.58 -7.50 (m, 3H), 7.37 -7.26 (m, 5H), 7.22 (tt, J= 5.5, 3.0 Hz, 1H), 4.84 -4.77 (m, 1H), 4.04 (ddd, J= 9.4, 8.0, 1.2 Hz, 1H), 3.77 (d, J= 12.0 Hz, 2H), 2.90 (t, J= 12.7 Hz, 2H), 1.96 (d, J= 14.3 Hz, 2H), 1.78 (m, 4H), 1.55 (s, 2H), 1.36 (m, 3H). Example 73: (E)-4-Phenyl-3-((3-((E)-4-(1-(piperidin-1-yl)cyclopropyl)styryl)-1H-indazole -6-yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-4-phenyl-3-((3-((E)-4-(1-(piperidin-1-yl)cyclopropyl)styryl) is obtained )-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (16.6 mg, yield 31.6%). MS (ESI) M/Z: 515.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (dd, J = 8.8, 3.9 Hz, 1H), 7.77 (dd, J = 8.3 , 2.5 Hz, 2H), 7.70 -7.60 (m, 3H), 7.58 -7.50 (m, 3H), 7.37 -7.26 (m, 5H), 7.22 (tt, J = 5.5, 3.0 Hz, 1H), 4.84 - 4.77 (m, 1H), 4.04 (ddd, J = 9.4, 8.0, 1.2 Hz, 1H), 3.77 (d, J = 12.0 Hz, 2H), 2.90 (t, J = 12.7 Hz, 2H), 1.96 (d , J = 14.3 Hz, 2H), 1.78 (m, 4H), 1.55 (s, 2H), 1.36 (m, 3H).

製備方法參考實例11，最後得到目標產物4-(4-((E)-2-(6-((E)-(2-氧代-4-苯基吡咯烷-3-亞基)甲基)-1H-吲唑-3-基)乙烯基)苄基)哌𠯤-2-酮三氟乙酸鹽（13.3毫克，收率18%）。 MS (ESI) M/Z: 504.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.96 (d, J= 8.6 Hz, 1H), 7.76 (d, J= 8.2 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.56 -7.47 (m, 5H), 7.32 - 7.23 (m, 5H), 7.19 (tt, J= 5.8, 3.1 Hz, 1H), 5.01 - 4.83 (m, 2H), 4.81 - 4.74 (m, 1H), 4.41 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.80 (s, 2H), 3.58 -3.50 (m, 4H), 3.45 -3.29 (m, 2H). Example 74: 4-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene)methyl)-1H-indazole -3-yl)vinyl)benzyl)piperone-2-one trifluoroacetate

Refer to Example 11 for the preparation method, and finally obtain the target product 4-(4-((E)-2-(6-((E)-(2-oxo-4-phenylpyrrolidin-3-ylidene)methyl) )-1H-indazol-3-yl)vinyl)benzyl)piperone-2-one trifluoroacetate (13.3 mg, yield 18%). MS (ESI) M/Z: 504.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.56 -7.47 (m, 5H), 7.32 - 7.23 (m, 5H), 7.19 (tt, J = 5.8, 3.1 Hz, 1H), 5.01 - 4.83 (m, 2H), 4.81 - 4.74 (m, 1H), 4.41 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.80 (s, 2H), 3.58 -3.50 (m, 4H ), 3.45 -3.29 (m, 2H).

製備方法參考實例11，最後得到目標產物 (E)-3-((3-((E)-4-(((R)-2-(甲氧基甲基)吡咯烷-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮 (8.3毫克，收率11.3%)。 MS (ESI) M/Z: 519.0 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.00 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.2 Hz, 2H), 7.68 (d, J= 2.2 Hz, 1H), 7.59 - 7.50 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (tt, J= 5.7, 2.9 Hz, 1H), 4.86 - 4.78 (m, 1H), 4.62 (d, J= 13.0 Hz, 1H), 4.31 (d, J= 13.0 Hz, 1H), 4.05 (dd, J= 10.1, 8.0 Hz, 1H), 3.87 (m, 1H), 3.60 (d, J= 5.1 Hz, 2H), 3.50 - 3.41 (m, 1H), 3.45 (s, 3H), 2.31 (m, 1H), 2.23 - 2.10 (m, 1H), 2.07 - 1.86 (m, 2H). Example 75: (E)-3-((3-((E)-4-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)styryl) -1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one

Refer to Example 11 for the preparation method, and finally obtain the target product (E)-3-((3-((E)-4-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methanol yl)styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one (8.3 mg, yield 11.3%). MS (ESI) M/Z: 519.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.00 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.59 - 7.50 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (tt, J = 5.7, 2.9 Hz, 1H), 4.86 - 4.78 (m, 1H), 4.62 (d, J = 13.0 Hz, 1H), 4.31 (d, J = 13.0 Hz, 1H), 4.05 (dd, J = 10.1, 8.0 Hz, 1H), 3.87 (m, 1H) , 3.60 (d, J = 5.1 Hz, 2H), 3.50 - 3.41 (m, 1H), 3.45 (s, 3H), 2.31 (m, 1H), 2.23 - 2.10 (m, 1H), 2.07 - 1.86 (m , 2H).

製備方法參考實例11，最後得到目標產物 (E)-3-((3-((E)-4-(((R)-2-((二甲基胺基)甲基)吡咯烷-1-基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷酮-2-酮三氟乙酸鹽（5.4毫克，收率6.4%）。 MS (ESI) M/Z: 531.9 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.99 (d, J= 8.5 Hz, 1H), 7.76 (d, J= 7.9 Hz, 2H), 7.67 (d, J= 2.2 Hz, 1H), 7.60 - 7.49 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (m, 1H), 4.85 - 4.77 (m, 1H), 4.52 (d, J= 12.8 Hz, 1H), 4.21 (d, J= 12.8 Hz, 1H), 4.04 (dd, J= 10.1, 8.0 Hz, 1H), 3.88 (m, 1H), 3.41 (m, 2H), 3.25 (m, 3H), 2.82 (s, 6H), 2.49 (dd, J= 13.6, 7.0 Hz, 1H), 2.20 (m, 1H), 2.06 (m, 1H), 1.98 - 1.89 (m, 1H). C ₃₄H ₃₇N ₅O. Example 76: (E)-3-((3-((E)-4-(((R)-2-((dimethylamino)methyl)pyrrolidin-1-yl)methyl) Styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidone-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-((3-((E)-4-(((R)-2-((dimethylamino)methyl)pyrrolidine-1 -yl)methyl)styryl)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidon-2-one trifluoroacetate (5.4 mg, yield 6.4%). MS (ESI) M/Z: 531.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.99 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.60 - 7.49 (m, 5H), 7.37 - 7.26 (m, 5H), 7.22 (m, 1H), 4.85 - 4.77 (m, 1H), 4.52 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.8 Hz, 1H), 4.04 (dd, J = 10.1, 8.0 Hz, 1H), 3.88 (m, 1H), 3.41 (m, 2H) , 3.25 (m, 3H), 2.82 (s, 6H), 2.49 (dd, J = 13.6, 7.0 Hz, 1H), 2.20 (m, 1H), 2.06 (m, 1H), 1.98 - 1.89 (m, 1H ). C ₃₄ H ₃₇ N ₅ O.

製備方法參考實例11，最後得到目標產物1-(4-((E)-2-(6-(E)-(2-氧代-4-苯基吡咯烷 -3-亞甲基)-1 H-吲唑-3-基)乙烯基)苄基) L-脯胺酸三氟乙酸鹽(4.59毫克，收率8.0%)。 MS (ESI) M/Z: 518.9 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.92 (d, J= 7.2 Hz, 1H), 7.69 (d, J= 7.6 Hz, 2H), 7.63 (s, 1H), 7.55-7.45 (m, 3H), 7.29 (d, J= 4.4 Hz, 2H), 7.26-7.20 (m, 6H), 4.76 (d, J= 7.6 Hz, 1H), 4.53-4.50 (m, 1H), 4.28 (d, J= 8.8 Hz, 1H), 4.11 (m, 1H), 4.03-3.98 (m, 1H), 3.98 (m,1H), 3.56 (m, 1H), 2.53 (m, 1H), 2.15 (m, 2H), 1.99 (m, 1H). Example 77: 1-(4-((E)-2-(6-(E)-(2-oxo-4-phenylpyrrolidine-3-methylene)-1 H-indazole-3 -yl)vinyl)benzyl)L-proline trifluoroacetate

The preparation method refers to Example 11, and finally the target product 1-(4-((E)-2-(6-(E)-(2-oxo-4-phenylpyrrolidine-3-methylene)-1 H-indazol-3-yl)vinyl)benzyl)L-proline trifluoroacetate (4.59 mg, yield 8.0%). MS (ESI) M/Z: 518.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.92 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.63 (s, 1H), 7.55-7.45 (m, 3H), 7.29 (d, J = 4.4 Hz, 2H), 7.26-7.20 (m, 6H), 4.76 (d, J = 7.6 Hz, 1H ), 4.53-4.50 (m, 1H), 4.28 (d, J = 8.8 Hz, 1H), 4.11 (m, 1H), 4.03-3.98 (m, 1H), 3.98 (m,1H), 3.56 (m, 1H), 2.53 (m, 1H), 2.15 (m, 2H), 1.99 (m, 1H).

製備方法參考實例11，最後得到目標產物 (E)-3-(3-(4-(3-甲氧基吡咯烷 -1-基)苯乙烯基)-1 H-吲唑-6-基亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽(8.76毫克，收率16.6%)。 MS (ESI) M/Z: 505.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.97 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.65 (d, J= 2.0 Hz, 1H), 7.53-7.49 (m, 5H), 7.30-7.26 (m, 5H), 7.20-7.19 (m, 1H), 4.79-4.77 (m, 1H), 4.44-4.34 (m, 2H), 4.19 (m, 1H), 4.04-3.99 (m, 1H), 3.61-3.32 (m, 2H), 3.39 (s, 3H), 3.30 (m, 1H), 2.40-2.37 (m, 2H), 2.17 (m, 2H). Example 78: (E)-3-(3-(4-(3-methoxypyrrolidin-1-yl)styryl)-1-H-indazol-6-ylmethylene)-4 -Phenylpyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-3-(3-(4-(3-methoxypyrrolidin-1-yl) styryl)-1 H-indazol-6-ylidene Methyl)-4-phenylpyrrolidin-2-one trifluoroacetate (8.76 mg, yield 16.6%). MS (ESI) M/Z: 505.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.53-7.49 (m, 5H), 7.30-7.26 (m, 5H), 7.20-7.19 (m, 1H), 4.79-4.77 (m, 1H) , 4.44-4.34 (m, 2H), 4.19 (m, 1H), 4.04-3.99 (m, 1H), 3.61-3.32 (m, 2H), 3.39 (s, 3H), 3.30 (m, 1H), 2.40 -2.37 (m, 2H), 2.17 (m, 2H).

製備方法參考實例11，最後得到目標產物 (E)-3-(3-(4-((3-((3-(二甲胺基)吡咯烷-1-基)甲基)苯乙烯基)-1H-吲唑-6-基亞甲基)-4-苯基吡咯烷-2-酮三氟乙酸鹽 （9.0毫克，收率15.4%）。 MS (ESI) M/Z: 518.2 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.96 (d, J= 8.8 Hz, 1H), 7.71 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 2.0 Hz, 1H), 7.52 - 7.47 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20-7.19 (m, 1H), 4.78 (d, J= 8.4 Hz, 1H), 4.24 (s, 2H), 4.04 - 4.01 (m, 2H), 3.99 - 3.97 (m, 4H), 3.30 - 3.31 (m, 1H), 2.89 - 2.92 (s, 6H), 2.55 - 2.57 (m, 1H), 2.30 - 2.32 (m, 1H). Example 79: (E)-3-(3-(4-((3-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)styryl)-1H-indazole- 6-ylmethylene)-4-phenylpyrrolidin-2-one trifluoroacetate

Refer to Example 11 for the preparation method, and finally obtain the target product (E)-3-(3-(4-((3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)styryl) -1H-Indazol-6-ylmethylene)-4-phenylpyrrolidin-2-one trifluoroacetate (9.0 mg, yield 15.4%). MS (ESI) M/Z: 518.2 [M+ H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.52 - 7.47 (m, 5H), 7.30 - 7.26 (m, 5H), 7.20-7.19 (m, 1H), 4.78 (d, J = 8.4 Hz, 1H), 4.24 (s, 2H), 4.04 - 4.01 (m, 2H), 3.99 - 3.97 (m, 4H), 3.30 - 3.31 (m, 1H), 2.89 - 2.92 (s, 6H), 2.55 - 2.57 (m, 1H), 2.30 - 2.32 (m, 1H).

製備方法參考實例11，最後得到目標產物 (E)-4-苯基-3-((3-((E)-4-((((R)-四氫呋喃-3-基)胺基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽 （2.03毫克，收率4.8%）。 MS (ESI) M/Z: 491.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.98 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 2.2 Hz, 1H), 7.57 - 7.48 (m, 5H), 7.36 - 7.25 (m, 5H), 7.22 (m, 1H), 4.81 (d, J= 7.9 Hz, 1H), 4.27 (d, J= 2.2 Hz, 2H), 4.19 - 3.99 (m, 3H), 3.98 (q, J= 5.0 Hz, 1H), 3.87 - 3.88 (m, 1H), 3.77 (q, J= 8.1 Hz, 1H), 2.43 -2.46 (m, 2H), 2.10 -2.12 (m, 2H). Example 80: (E)-4-Phenyl-3-((3-((E)-4-((((R)-tetrahydrofuran-3-yl)amino)methyl)styryl)- 1H-Indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

Refer to Example 11 for the preparation method, and finally obtain the target product (E)-4-phenyl-3-((3-((E)-4-((((R)-tetrahydrofuran-3-yl)amino)methyl )styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (2.03 mg, yield 4.8%). MS (ESI) M/Z: 491.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.98 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 2.2 Hz, 1H), 7.57 - 7.48 (m, 5H), 7.36 - 7.25 (m, 5H), 7.22 (m, 1H), 4.81 (d, J = 7.9 Hz, 1H ), 4.27 (d, J = 2.2 Hz, 2H), 4.19 - 3.99 (m, 3H), 3.98 (q, J = 5.0 Hz, 1H), 3.87 - 3.88 (m, 1H), 3.77 (q, J = 8.1 Hz, 1H), 2.43 -2.46 (m, 2H), 2.10 -2.12 (m, 2H).

製備方法參考實例11，最後得到目標產物 (E)-4-苯基-3-((3-((E)-4-((((S)-四氫呋喃-3-基)胺基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽(12.06毫克，收率22.9%)。 MS (ESI) M/Z: 490.9 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 7.87 (d, J= 8.5 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.55 (d, J= 2.2 Hz, 1H), 7.46 - 7.37 (m, 5H), 7.25 - 7.14 (m, 5H), 7.09 (tt, J= 5.8, 3.0 Hz, 1H), 4.69 (dt, J= 8.1, 2.3 Hz, 1H), 4.15 (d, J= 2.1 Hz, 2H), 4.02 - 3.82 (m, 4H), 3.75 (dd, J= 10.6, 5.8 Hz, 1H), 3.65 (q, J= 8.1 Hz, 1H), 2.33 (m, 2H), 2.13 - 1.90 (m, 2H). Example 81: (E)-4-Phenyl-3-((3-((E)-4-((((S)-tetrahydrofuran-3-yl)amino)methyl)styryl)- 1H-Indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

Refer to Example 11 for the preparation method, and finally obtain the target product (E)-4-phenyl-3-((3-((E)-4-((((S)-tetrahydrofuran-3-yl)amino)methyl ) styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (12.06 mg, 22.9% yield). MS (ESI) M/Z: 490.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 7.87 (d, J = 8.5 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.55 (d, J = 2.2 Hz, 1H), 7.46 - 7.37 (m, 5H), 7.25 - 7.14 (m, 5H), 7.09 (tt, J = 5.8, 3.0 Hz, 1H), 4.69 (dt, J = 8.1, 2.3 Hz, 1H), 4.15 (d, J = 2.1 Hz, 2H), 4.02 - 3.82 (m, 4H), 3.75 (dd, J = 10.6, 5.8 Hz, 1H), 3.65 (q, J = 8.1 Hz, 1H), 2.33 (m, 2H), 2.13 - 1.90 (m, 2H).

製備方法參考實例11，最後得到目標產物(E)-4-苯基-3 - ((3 - ((E)-4 - ((((四氫-2H-吡喃-4-基)甲基)胺基)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)吡咯烷-2-酮三氟乙酸鹽(8.58毫克，收率13.6%)。 MS (ESI) M/Z: 519.1 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ 7.99 (d, J= 8.5 Hz, 1H), 7.76 (d, J= 8.2 Hz, 2H), 7.67 (d, J= 2.2 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.37 - 7.18 (m, 5H), 4.81 (d, J= 8.1 Hz, 1H), 4.26 (s, 2H), 4.01 (ddd, J= 19.3, 10.8, 6.3 Hz, 3H), 3.45 (td, J= 11.8, 2.0 Hz, 2H), 3.00 (d, J= 7.1 Hz, 2H), 2.08 - 1.97 (m, 1H), 1.72 (m, 2H), 1.39 (m, 2H). C ₃₃H ₃₄N ₄O ₂. Example 82: (E)-4-Phenyl-3-((3-((E)-4-(((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl )Styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate

The preparation method refers to Example 11, and finally the target product (E)-4-phenyl-3-((3-((E)-4-((((tetrahydro-2H-pyran-4-yl)methyl) )amino)methyl)styryl)-1H-indazol-6-yl)methylene)pyrrolidin-2-one trifluoroacetate (8.58 mg, 13.6% yield). MS (ESI) M/Z: 519.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H ), 7.67 (d, J = 2.2 Hz, 1H), 7.58 - 7.49 (m, 5H), 7.37 - 7.18 (m, 5H), 4.81 (d, J = 8.1 Hz, 1H), 4.26 (s, 2H) , 4.01 (ddd, J = 19.3, 10.8, 6.3 Hz, 3H), 3.45 (td, J = 11.8, 2.0 Hz, 2H), 3.00 (d, J = 7.1 Hz, 2H), 2.08 - 1.97 (m, 1H ), 1.72 (m, 2H), 1.39 (m, 2H). C ₃₃ H ₃₄ N ₄ O ₂ .

製備方法參考實例11，最後得到目標產物(E)-3-((3-((E)-4-(((2S, 6R)-2,6-二甲基嗎福林代)甲基)苯乙烯基)-1H-吲唑-6-基)亞甲基)-4-(2-氟苯基)吡咯烷-2-酮（8.9毫克，收率10.3%）。 MS (ESI) M/Z: 537.1 [M+H] ⁺. ¹H NMR (400 MHz, DMSO- d ₆): δ 13.22 (s, 1H), 8.28 (s, 1H), 8.04 (d, J= 8.5 Hz, 1H), 7.64 (d, J= 7.9 Hz, 2H), 7.58 - 7.50 (m, 2H), 7.45 (s, 2H), 7.31-7.04 (m, 7H), 4.96 (dt, J= 8.4, 2.4 Hz, 1H), 3.94 (dd, J= 9.8, 8.1 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.44 (s, 2H), 3.12 (d, J= 9.5 Hz, 1H), 2.71 - 2.63 (m, 3H), 1.64 (t, J= 10.6 Hz, 2H), 1.02 (d, J= 6.2 Hz, 6H). Example 83: (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methyl)styryl)-1H -Indazol-6-yl)methylene)-4-(2-fluorophenyl)pyrrolidin-2-one

Refer to Example 11 for the preparation method, and finally obtain the target product (E)-3-((3-((E)-4-(((2S, 6R)-2,6-dimethylmorpholino)methyl) Styryl)-1H-indazol-6-yl)methylene)-4-(2-fluorophenyl)pyrrolidin-2-one (8.9 mg, 10.3% yield). MS (ESI) M/Z: 537.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 13.22 (s, 1H), 8.28 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.58 - 7.50 (m, 2H), 7.45 (s, 2H), 7.31-7.04 (m, 7H), 4.96 (dt, J = 8.4 , 2.4 Hz, 1H), 3.94 (dd, J = 9.8, 8.1 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.44 (s, 2H), 3.12 (d, J = 9.5 Hz, 1H), 2.71 - 2.63 (m, 3H), 1.64 (t, J = 10.6 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H).

反應路線:

Example 84: (E)-3-((3-((E)-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)styryl)-4 -Methoxy-1H-indazol-6-yl)methylene)-5-methoxyindol-2-one trifluoroacetate

Reaction route:

Procedure: Step A: Add 3-iodo-4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (400.0 mg, 1.0 mmol) and 5-methoxyindolin-2-one (186.0 mg, 1.1 mmol) were dissolved in ethanol (20 ml). Subsequently, piperidine (17.6 mg, 0.2 mmol) was added thereto, and the reaction solution was refluxed and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (30 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. (E)-3-((3-iodo-4-methoxy-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (280.0 mg, Yield 50.9%). MS (ESI) M/Z: 532.0 [M+H] ⁺ . Step B: (E)-3-((3-iodo-4-methoxy-1H-indazole-6 -yl)methylene)-5-methoxyindolin-2-one (200.0 mg, 0.4 mmol) and (2R,6S)-2,6-dimethyl-4-(4- ((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzylmorphine (201.7 mg, 0.6 mmol) in 1,4-dioxane (8 mL). Subsequently, potassium carbonate (130.0 mg, 0.9 mmol), water (2 mL), Pd(dppf)Cl ₂ (27.0 mg , 0.04 mmol), then nitrogen replacement. Stirred at 100 degrees Celsius for 3 hours. After point plate monitoring showed that the raw material disappeared, ammonium chloride solution (20 ml) was added, and the mixture was washed with ethyl acetate (50 ml × 2 times). Extraction, combined organic phase, the organic phase was first washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane /methanol=100/1) to get (E)-3-((3-((E)-4-((2,6-dimethylmorpholino)methyl)styryl)-4-methanol Oxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (100.0 mg, Yield 41.8%). MS (ESI) M/Z: 532.0 [M+H] ⁺ . Step C: At room temperature, (E)-3-((3-((E)-4-(( 2,6-Dimethylmorpholino)methyl)styryl)-4-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl )methylene)-5-methoxyindolin-2-one (100.0 mg, 0.15 mmol) was dissolved in methanol (4 ml), and subsequently, methanesulfonic acid (200.0 mg, 2.1 mmol ear), the reaction solution was stirred at 60 degrees Celsius for 2 hours. After the spot plate monitoring showed that the raw materials disappeared, an aqueous solution of sodium bicarbonate was added, and the mixture was extracted with dichloromethane (30 ml × 3 times), and the organic phases were combined. Saturated brine (20 ml) was washed, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was prepared with a reverse-phase preparative column (containing trifluoroacetic acid in the mobile phase) to obtain (E)-3-(( 3-((E)-4-((2,6-Dimethylmorpholino)methyl)styryl)-4-methoxy-1H-indazol-6-yl)methylene) -5-Methoxyindoline-2-one trifluoroacetate (19.13 mg, yield 18.1%). MS (ESI) M/Z: 551.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD ): δ 7.85 (d, J = 4.8 Hz, 1H), 7.83 - 7.73 (m, 3H), 7.65 (d, J = 16.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 ( s, 1H), 7.35 (s, 1H), 6.91 (s, 1H), 6.88 (s, 2H), 4.39 (s, 2H), 4.11 (s, 3H), 3.90 - 3.78 (m, 2H), 3.66 (s, 3H), 3.40 (d, J = 12.2 Hz, 2H), 2.81 (t, J = 11.7 Hz, 2H), 1.26 (d, J = 6.4 Hz, 6H).

反應路線:

Example 85: (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indoline- 2-keto

Reaction route:

Procedure: Step A: Tetrahydro-2H-indol-2-one (94.6 mg, 0.7 mmol) and (E)-3-(2-(pyridin-4-yl)ethenyl)-1H- Indazole-6-carbaldehyde (174.5 mg, 0.7 mmol) was dissolved in ethanol (4 ml). Subsequently, piperidine (34 mg, 0.4 mmol) was added thereto, and the reaction solution was stirred at 70°C for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered. Obtaining (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (100.0 mg, yield 39.2%). MS (ESI) M/Z: 365.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- d ₆ ): δ 13.58 (s, 1H), 10.66 (s, 1H), 8.66 – 8.53 (m, 2H ), 8.39 (d, J = 8.5 Hz, 1H), 7.96 - 7.79 (m, 3H), 7.76 - 7.70 (m, 2H), 7.64 - 7.54 (m, 3H), 7.25 (t, J = 7.6 Hz, 1H), 6.99 - 6.79 (m, 2H).

反應路線:

Example 86: (3E)-3-((3-(2-(Pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-onetri Fluoroacetate

Reaction route:

Procedure: Step A: Dissolve indolin-2-one (0.2 g, 1.5 mmol) and 3-iodo-1H-indole-6-carbaldehyde (0.4 g, 1.5 mmol) in ethanol ( 10 ml). The reaction system was heated to 70°C and stirred for 4 hours. After LCMS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (40 ml x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. (E)-1-((3-iodo-1H-indol-6-yl)methylene)-1H-inden-2(3H)-one (0.33 g, yield 56.9%) was obtained. MS (ESI) M/Z: 386.7 [M+H] ⁺ . Step B: (E)-1-((3-iodo-1H-indol-6-yl)methylene (1)-1H-inden-2(3H)-one (0.5 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (10 mL). Subsequently, 4-vinylpyridine (210 mg, 2.0 mmol), diisopropylethylamine (350 mg, 2.7 mmol), palladium acetate (15.0 mg, 0.06 mmol), P (o-tol)3 (40.0 mg, 0.12 mmol). The reaction solution was stirred at 135° C. for 5 hours. After LCMS monitoring showed that the starting material disappeared, water (40 mL) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (40 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL x 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was prepared with a reverse-phase preparative column (the mobile phase contained trifluoroacetic acid) to prepare two product peaks, and the preparation solution was directly lyophilized to obtain (3E)-3-((3-(2-(pyridin-4-yl) Vinyl)-1H-indol-6-yl)methylene)indolin-2-one trifluoroacetate (5.1 mg, yield 0.8%). MS (ESI) M/Z: 364.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.96 (s, 0.4H), 8.53 (m, 2H), 8.22-8.17 (m, 1.6H), 8.13-8.06 (m, 2H), 7.99 (s, 1H), 7.89 - 7.81 (m, 2H), 7.65 (t, 1H), 7.37-7.20 (m, 2H), 7.04 (t, 0.4 H), 6.94 - 6.87 (m, 1.6H).

反應路線:

Example 87: (Z)-3-(Hydroxy(3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indoline -2-Ketotrifluoroacetate

Reaction route:

Procedure: Step A: Mix 1-acetoindol-2-one (87.6 mg, 0.5 mmol) with (E)-3-(2-(pyridin-4-yl)ethenyl)-1-( (2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carboxylic acid (196.8 mg, 0.5 mmol) dissolved in N,N-dimethylformamide ( 4 ml). Then TBTU (160.0 mg, 0.5 mmol), HOBT (70.0 mg, 0.5 mmol), and DIPEA (296.7 mg, 2.3 mmol) were added and the reaction system was stirred at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench it. Then adjust the pH of the reaction solution to 6-7, extract the mixture with ethyl acetate (40 ml), combine the organic phases, wash the organic phase with saturated brine (10 ml), then dry with anhydrous sodium sulfate, filter, and finally Concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (E)-1-acetyl-3-(3-(2-(pyridin-4-yl )vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonyl)indole-2-one (167.5 mg, yield 60.6% ). MS (ESI) M/Z: 553.4 [M+H] ⁺ . Step B: (E)-1-acetyl-3-(3-(2-(pyridine-4- Base) vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonyl)indole-2-one (221.1 mg, 0.4 mg Mole) was dissolved in trifluoroacetic acid (10 ml). The reaction solution was stirred at 60° C. for 16 hours. After LCMS monitoring showed disappearance of starting material, it was concentrated under reduced pressure. Obtain (E)-1-acetyl-3-(3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonyl)indolin-2-one crude product (157 mg) were used directly in the next step. MS (ESI) M/Z: 423.4 [M+H] ⁺ . Step C: In the previous step (E)-1-acetyl-3-(3-(2-(pyridine- Crude 4-yl)vinyl)-1H-indazole-6-carbonyl)indolin-2-one (157 mg) was dissolved in tetrahydrofuran (4 ml). Then 1% aqueous sodium hydroxide solution (42 mg, 1.1 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (20 ml), and the combined organic phases were washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was prepared with a reverse-phase preparative column (the mobile phase contained trifluoroacetic acid) to prepare two product peaks, and the preparation solution was directly lyophilized to obtain (Z)-3-(hydroxyl(3-((E)-2-(pyridine -4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one trifluoroacetate (5.9 mg, 3.9% yield for two steps). MS (ESI) M/Z: 381.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.73 (d, J = 5.4 Hz, 2H), 8.41 (d, J = 7.8 Hz, 1H), 8.25 (d, J = 17.6 Hz, 3H), 8.06 (s, 1H), 7.75 (dd, J = 33.2, 12.2 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 7.01 ( d, J = 7.8 Hz, 1H), 6.83 (s, 1H).

製備方法參考實施例84，得到目標產物(E)-3-((5-氟-3-((E)-2-(吡啶-4-基)乙烯基)-1H-吲唑-6-基)亞甲基)吲哚-2-酮（4.7毫克，產率4.1％）。 MS (ESI) M/Z:383.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.77 - 8.72 (m, 2H), 8.35 - 8.30 (m, 2H), 8.23 (d, J= 16.5 Hz, 1H), 8.13 (d, J= 10.1 Hz, 1H), 8.03 (d, J= 5.8 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J= 16.6 Hz, 1H), 7.46 (d, J= 7.7 Hz, 1H), 7.26 (td, J= 7.7, 1.2 Hz, 1H), 6.94 (d, J= 7.8 Hz, 1H), 6.85 - 6.87 (m, 1H). Example 88: (E)-3-((5-fluoro-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)ind Indol-2-one

The preparation method refers to Example 84 to obtain the target product (E)-3-((5-fluoro-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl )methylene)indol-2-one (4.7 mg, 4.1% yield). MS (ESI) M/Z: 383.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.77 - 8.72 (m, 2H), 8.35 - 8.30 (m, 2H), 8.23 (d , J = 16.5 Hz, 1H), 8.13 (d, J = 10.1 Hz, 1H), 8.03 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 16.6 Hz, 1H ), 7.46 (d, J = 7.7 Hz, 1H), 7.26 (td, J = 7.7, 1.2 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.85 - 6.87 (m, 1H).

反應路線:

Example 89: (E)-3-((3-(2-(Pyridin-4-yl)ethyl)-1H-indazol-6-yl)methylene)indol-2-one trifluoroacetic acid Salt

Reaction route:

Operation steps: Step A: Add (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -Indazole-6-carbaldehyde (986.8 mg, 2.6 mmol) was dissolved in methanol (20 mL) and PD/C (20 mg) was added. The reaction system was stirred at room temperature under hydrogen atmosphere for 6 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is 3-(2-(pyridin-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde The crude product (1.0 g) was used directly in the next step. MS (ESI) M/Z: 382.6 [M+H] ⁺ . Step B: 3-(2-(pyridin-4-yl)ethyl)-1-((2-(trimethyl Crude ((1.0 g) of (silylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde was dissolved in dichloromethane (60 ml). Subsequently, boron trifluoride ether solution (33 ml, 26.25 mmol) was added to the above solution under an ice-water bath. The reaction solution was stirred at room temperature for 4 hours. After concentration under reduced pressure, ethanol (70 ml) was added to the obtained residue, and the reaction solution was stirred at 60° C. overnight with 2 mol/L hydrochloric acid aqueous solution (36 ml). After LCMS monitoring showed that the starting material disappeared, aqueous sodium bicarbonate solution (50 ml) was added to the reaction system to quench it. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 3-(2-(pyridin-4-yl)ethyl)-1H-indazole-6-carbaldehyde (400 mg, two steps rate of 61.3%). MS (ESI) M/Z: 252.1 [M+H] ⁺ . Step C: 3-(2-(pyridin-4-yl)ethyl)-1H-indazole-6-carbaldehyde (301.5 mg, 1.2 mM mol) and indolin-2-one (159.8 mg, 1.2 mmol) were dissolved in methanol (8 ml). To this was added piperidine (6 drops). React at 60°C for 1 hour. After LCMS monitoring shows that the raw material disappears, add sodium bicarbonate aqueous solution (30 ml) to the reaction solution, extract with dichloromethane/methanol=10/1 (20 ml×3 times), combine the organic phases, and use the organic phases first Wash with saturated brine (50 mL x 1 time), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was preparatively purified (trifluoroacetic acid was included in the purification reagent) to give (E)-3-((3-(2-(pyridin-4-yl)ethyl)-1H-indazol-6-yl)ylidene Methyl)indol-2-one trifluoroacetate (93.9 mg, yield: 21.4%). MS (ESI) M/Z: 367.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.65 (m, 2H), 7.85 - 7.81 (m, 4H), 7.81 (s, 1H ), 7.61 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.87 - 6.83 (m, 1H), 3.50 (m, 4H).

反應路線: 製備方法參考實施例84，得到目標產物((E)-3-((4-甲氧基-3-((E)-2-(吡啶-4-基)乙烯基)-1H-吲唑-6-基)亞甲基)吲哚-2-酮三氟乙酸鹽（14.3毫克，收率18.1%）。 MS (ESI) M/Z: 395.3 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD): δ 8.72 - 8.65 (m, 2H), 8.30 (d, J= 16.3 Hz, 1H), 8.13 (d, J= 6.4 Hz, 2H), 7.84 (s, 1H), 7.80 (d, J= 16.3 Hz, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.51 (t, J= 1.0 Hz, 1H), 7.28 - 7.21 (m, 1H), 6.97 (s, 1H), 6.96 - 6.85 (m, 2H), 4.11 (s, 3H). Example 90: ((E)-3-((4-Methoxy-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene base) indol-2-one trifluoroacetate

Reaction scheme: The preparation method refers to Example 84 to obtain the target product ((E)-3-((4-methoxy-3-((E)-2-(pyridin-4-yl)vinyl)-1H- Indazol-6-yl)methylene)indol-2-one trifluoroacetate (14.3 mg, 18.1% yield). MS (ESI) M/Z: 395.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ 8.72 - 8.65 (m, 2H), 8.30 (d, J = 16.3 Hz, 1H), 8.13 (d, J = 6.4 Hz, 2H), 7.84 (s, 1H), 7.80 (d, J = 16.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 1.0 Hz, 1H), 7.28 - 7.21 (m, 1H), 6.97 (s, 1H ), 6.96 - 6.85 (m, 2H), 4.11 (s, 3H).

反應路線

步驟A：將對溴溴苄（36克，144毫莫耳），順-2,6-二甲基哌啶（19.6克，173毫莫耳）和碳酸鉀（49.7克， 360毫莫耳）加入乙腈（1520毫升）中，反應液在90攝氏度下攪拌3小時。 TLC顯示原料消失後，冷卻至室溫，反應液用乙酸乙酯（500毫升）稀釋，過濾，濾液濃縮乾。粗品再溶於甲基第三丁基醚（500毫升中），過濾掉少量不溶物，濾液在濃縮乾得順-1-(4-溴苄基)-2,6-二甲基哌啶（40克，收率98%）直接用於下一步。 步驟B：將順-1-(4-溴苄基)-2,6-二甲基哌啶（40克，142毫莫耳）溶於甲苯（800毫升）。向其中加入2-乙烯基-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷（24克，156毫莫耳）和N,N-二異丙基乙胺（36.6克，284毫莫耳）。隨後加入四氟硼酸三第三丁基膦（4.12克，14.2毫莫耳）和三(二亞苄基丙酮)二鈀（6.4克，7.1毫莫耳)，然後氮氣置換，在90攝氏度下攪拌3小時。 LCMS監測顯示原料消失後，加入氯化銨溶液(500毫升)，混合液用乙酸乙酯（300毫升×2次）萃取，合併有機相，有機相先用飽和食鹽水（100毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 10/ 1）得到順-2,6-二甲基-1-(4- ((E)-2-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)乙烯基)苄基)哌啶（32克，收率64%）。 MS (ESI) M/Z: 356.0 [M+H] ⁺. 步驟C：在室溫下，將1H-吲唑-6-甲醛（50克，342毫莫耳）溶於N,N-二甲基甲醯胺（350毫升），加入碳酸鉀（94.4克，684毫莫耳）中，隨後，將碘（147.7克，581.4毫莫耳）溶於N,N-二甲基甲醯胺（350毫升）滴加加入反應液中，室溫攪拌兩個小時。 TLC檢測原料反應完，向反應體系中加入硫代硫酸鈉（80 克）/碳酸鉀（5克）/水（750毫升） 的混合溶液，攪拌一小時，再加入一升的冰水，有固體析出，過濾晾乾，得到3-碘-1H-吲唑-6-甲醛（88克，收率95%）。 步驟D：將3-碘-1H-吲唑-6-甲醛（88克，323毫莫耳）溶於二氯甲烷（1760毫升）中。隨後，向其中加入對甲苯磺酸一水合物（12.3克，64.6毫莫耳）,3.4-二氫-2H吡喃（54.3克，646毫莫耳），無水硫酸鎂（66.1克，549毫莫耳）。反應液在40攝氏度下攪拌兩小時。 TLC檢測原料反應完，LCMS監測顯示是產物後，將反應液過濾，向反應液中加入碳酸氫鈉水溶液（1升）淬滅，混合液用二氯甲烷（500毫升×3次）萃取，合併有機相，有機相先用飽和食鹽水（500毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 8/ 1）得到3-碘-1-(四氫-2H-吡喃-2-基)-1H-吲唑-6-甲醛（72克，收率63%）。 MS (ESI) M/Z: 357.1 [M+H] ⁺. 步驟E：將肉桂醛（180克，1.36莫耳），苯甲酸（33.2克，0.27莫耳）和硝基甲烷（249克，4.08莫耳）和(S)-2-(二苯基((三甲基甲矽烷基)氧基)甲基)吡咯烷（44.3克，0.136莫耳）加入甲醇（1.8升）中，室溫攪拌過夜。第二天，冰水浴冷卻，分批向反應液裡加入NBS（363克，2.04莫耳）。反應液在冰水浴下攪拌6小時，再室溫攪拌過夜。 TLC原料消失，加入飽和碳酸氫鈉水溶液（2升）和乙酸乙酯（1.5升）攪拌分液。有機相飽和食鹽水洗，乾燥，濃縮。粗品柱層析提純（洗脫劑：石油醚/乙酸乙酯= 5/1- 2/1）得(S)-3-苯基-4-硝基丁酸甲酯（140克，收率46%）。 ¹H NMR (400 MHz, CDCl ₃) δ: 7.33 - 7.21 (m, 5H), 4.74 - 4.71 (m, 2H), 4.10 - 4.09 (m, 1H), 3.59 (s, 3H), 2.75 (dd, J= 7.6, 2.4 Hz, 2H). 步驟F：室溫下將(S)-3-苯基-4-硝基丁酸甲酯（140克，0.627莫耳）溶於乙酸乙酯（840毫升）和乙醇（840毫升），加入飽和氯化銨水溶液（700毫升），再分批加入鋅粉（328克，5莫耳）。然後在90攝氏度下回流過夜。 TLC監測,顯示原料消失後，冷卻，向反應體系中入水（1升）和乙酸乙酯（1升），過濾。濾液分液，有機相先用飽和食鹽水（500毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得粗品柱層析提純（洗脫劑：二氯甲烷/甲醇= 15/1）得(S)-4-苯基吡咯烷-2-酮（41克，收率40%）。 MS (ESI) M/Z: 162.0 [M+H] ⁺. 步驟G：將化合物(S)-4-苯基吡咯烷-2-酮（41克，254毫莫耳）溶於乙酸酐（400毫升）中，在145攝氏度下回流反應2小時。 TLC監測原料反應完，濃縮去乙酸酐，再加入碳酸氫鈉水溶液（300毫升），混合液用乙酸乙酯（200毫升×2次）萃取，合併有機相，有機相先用飽和食鹽水（200毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得粗品柱層析提純（洗脫劑：石油醚/乙酸乙酯=5:1）得(S)-1-乙醯基-4-苯基吡咯烷-2-酮（33克，收率64%）。 步驟H：將氫化鈉（60%，13.2克，0.33莫耳）分散於四氫呋喃（180毫升）中，冷卻至0攝氏度再滴加(S)-1-乙醯基-4-苯基吡咯烷-2-酮（27克，0.133莫耳）和3-碘-1-(四氫-2H-吡喃-2-基)-1H-吲唑-6-甲醛（39.3克，0.11莫耳）的四氫呋喃（180毫升）溶液，在此溫度下在攪拌1小時。 LCMS監測原料反應完，向反應液中加入氯化銨水溶液（200毫升）。混合液用乙酸乙酯（200毫升×3次）萃取，合併有機相，有機相先用飽和食鹽水（200毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得粗品柱層析提純（洗脫劑：石油醚/乙酸乙酯=1/2）得(4R,E)-3-((3-碘-1-(四氫-2H-吡喃)-1H-吲唑-6-基)亞甲基)-4-苯基-2-吡咯烷酮（20.7克，收率37%）。 MS (ESI) M/Z: 202.9 [M+H] ⁺. 步驟I：將化合物(R,E)-3-((3-碘-1-(四氫-2H-吡喃)-1H-吲唑-6-基)亞甲基)-4-苯基-2-吡咯烷酮（20.7克，41.45毫莫耳）和順-2,6-二甲基-1-(4- ((E)-2-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)乙烯基)苄基)哌啶（29.5克，82.9毫莫耳）溶於1,4-二氧六環（400毫升）。隨後，加入碳酸鉀（14.3克，103.6毫莫耳），水（100毫升）和[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(1.5克，2.07毫莫耳)，然後氮氣置換三次。反應液加熱至100攝氏度，攪拌2小時。 LCMS監測顯示原料消失後，加入水(500毫升)，混合液用乙酸乙酯（500毫升×2次）萃取，合併有機相，有機相先用飽和食鹽水（50毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/ 1）得到(R,E)-3-((3-((E)-4-(((順)-2,6-二甲基哌啶-1-基)甲基)苯乙烯基)-1-(四氫-2H-吡喃基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮（17克，收率68%）。 MS (ESI) M/Z: 601.5 [M+H] ⁺. 步驟J：在室溫下，將化合物(R,E)-3-((3-((E)-4-(((順)-2,6-二甲基哌啶-1-基)甲基)苯乙烯基)-1-(四氫-2H-吡喃基)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2-酮（17克，28.3毫莫耳）溶於甲醇（340毫升），隨後，加入甲基磺酸（21.7克，226毫莫耳），反應液在60攝氏度下攪拌2小時。 點板監測顯示原料消失後，加入碳酸氫鈉水溶液（500毫升），混合液用二氯甲烷（50毫升×2次）萃取，合併有機相，有機相先用飽和食鹽水（200毫升）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/ 1）得到產品粗品。所得粗品加入乙醇（100毫升）中攪拌2小時。過濾的純產品。所得產品分散於乙腈（50毫升）和純水（50毫升）中，加入三氟乙酸（1毫升）溶清，得(R,E)-3-((3-((E)-4-(((順)-2,6-二甲基哌啶-1-基)甲基)苯乙烯)-1H-吲唑-6-基)亞甲基)-4-苯基吡咯烷-2酮三氟乙酸鹽（6.2克，收率35%）。 MS (ESI) M/Z: 517.4 [M+H] ⁺. ¹H NMR (400 MHz, CD ₃OD) δ 7.93 (dd, J= 8.5, 6.0 Hz, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.58 (d, J= 8.2 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.32 - 7.23 (m, 5H), 7.21 - 7.14 (m, 1H), 4.77 (dt, J= 8.1, 2.0 Hz, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.56 (q, J= 7.0 Hz, 1H), 3.30 - 3.16 (m, 2H), 2.06 - 1.96 (m, 1H), 1.93 - 1.69 (m, 3H), 1.69 - 1.53 (m, 5H), 1.42 (d, J= 6.7 Hz, 3H). ¹⁹F NMR: -77. Example 91: (R,E)-3-((3-((E)-4-(((cis)-2,6-dimethylpiperidin-1-yl)methyl)styryl) -1H-Indazol-6-yl)methylene)-4-phenylpyrrol-2-one trifluoroacetate

reaction route

Step A: Combine p-bromobenzyl bromide (36 g, 144 mmol), cis-2,6-dimethylpiperidine (19.6 g, 173 mmol) and potassium carbonate (49.7 g, 360 mmol) Acetonitrile (1520 ml) was added, and the reaction solution was stirred at 90°C for 3 hours. After TLC showed that the starting material disappeared, it was cooled to room temperature, the reaction solution was diluted with ethyl acetate (500 ml), filtered, and the filtrate was concentrated to dryness. The crude product was redissolved in methyl tertiary butyl ether (500 ml), filtered off a small amount of insoluble matter, and the filtrate was concentrated to dryness to obtain cis-1-(4-bromobenzyl)-2,6-dimethylpiperidine ( 40 g, yield 98%) was used directly in the next step. Step B: Dissolve cis-1-(4-bromobenzyl)-2,6-dimethylpiperidine (40 g, 142 mmol) in toluene (800 mL). To this was added 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 g, 156 mmol) and N,N-diiso Propylethylamine (36.6 g, 284 mmol). Then add tri-tertiary butylphosphine tetrafluoroborate (4.12 g, 14.2 mmol) and tris(dibenzylideneacetone) dipalladium (6.4 g, 7.1 mmol), then replace with nitrogen, and stir at 90 degrees Celsius 3 hours. After LCMS monitoring showed that the raw material disappeared, ammonium chloride solution (500 milliliters) was added, and the mixed solution was extracted with ethyl acetate (300 milliliters × 2 times), and the combined organic phases were washed with saturated brine (100 milliliters) earlier, and then Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain cis-2,6-dimethyl-1-(4-((E)-2-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl)piperidine (32 g, yield 64%). MS (ESI) M/Z: 356.0 [M+H] ⁺ . Step C: Dissolve 1H-indazole-6-carbaldehyde (50 g, 342 mmol) in N,N-dimethylformaldehyde at room temperature Dimethylformamide (350 ml) was added to potassium carbonate (94.4 g, 684 mmol), and then iodine (147.7 g, 581.4 mmol) was dissolved in N,N-dimethylformamide (350 mL) was added dropwise to the reaction solution, and stirred at room temperature for two hours. TLC detects that the reaction of the raw materials is complete, and a mixed solution of sodium thiosulfate (80 g)/potassium carbonate (5 g)/water (750 ml) is added to the reaction system, stirred for one hour, and then one liter of ice water is added, and a solid Precipitated, filtered and dried to obtain 3-iodo-1H-indazole-6-carbaldehyde (88 g, yield 95%). Step D: 3-Iodo-1H-indazole-6-carbaldehyde (88 g, 323 mmol) was dissolved in dichloromethane (1760 ml). Subsequently, p-toluenesulfonic acid monohydrate (12.3 g, 64.6 mmol), 3.4-dihydro-2H pyran (54.3 g, 646 mmol), anhydrous magnesium sulfate (66.1 g, 549 mmol) were added thereto Ear). The reaction solution was stirred at 40°C for two hours. After the reaction of the raw materials was detected by TLC, and LCMS monitoring showed that it was the product, the reaction solution was filtered, and aqueous sodium bicarbonate (1 liter) was added to the reaction solution to quench it, and the mixture was extracted with dichloromethane (500 ml × 3 times), and combined The organic phase was washed with saturated brine (500 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1) to obtain 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole -6-Carboxaldehyde (72 g, 63% yield). MS (ESI) M/Z: 357.1 [M+H] ⁺ . Step E: Cinnamaldehyde (180 g, 1.36 mol), benzoic acid (33.2 g, 0.27 mol) and nitromethane (249 g, 4.08 mol) and (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (44.3 g, 0.136 mol) were added to methanol (1.8 liters) and stirred at room temperature overnight. The next day, cooling in an ice-water bath, NBS (363 g, 2.04 mol) was added batchwise to the reaction solution. The reaction solution was stirred for 6 hours in an ice-water bath, and then stirred overnight at room temperature. The starting material disappeared on TLC, and saturated aqueous sodium bicarbonate (2 L) and ethyl acetate (1.5 L) were added and the mixture was stirred and separated. The organic phase was washed with saturated brine, dried and concentrated. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 5/1- 2/1) to obtain (S)-3-phenyl-4-nitrobutyric acid methyl ester (140 g, yield 46 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.33 - 7.21 (m, 5H), 4.74 - 4.71 (m, 2H), 4.10 - 4.09 (m, 1H), 3.59 (s, 3H), 2.75 (dd, J = 7.6, 2.4 Hz, 2H). Step F: Dissolve (S)-methyl 3-phenyl-4-nitrobutyrate (140 g, 0.627 mol) in ethyl acetate (840 mL) at room temperature ) and ethanol (840 ml), add saturated aqueous ammonium chloride solution (700 ml), and then add zinc powder (328 g, 5 moles) in batches. Then reflux overnight at 90°C. After TLC monitoring showed that the starting material disappeared, it was cooled, water (1 L) and ethyl acetate (1 L) were added to the reaction system, and filtered. The filtrate was separated, and the organic phase was washed with saturated brine (500 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol = 15/1) to obtain (S)-4-phenylpyrrolidin-2-one (41 g, yield 40%). MS (ESI) M/Z: 162.0 [M+H] ⁺ . Step G: Compound (S)-4-phenylpyrrolidin-2-one (41 g, 254 mmol) was dissolved in acetic anhydride (400 mL), reflux at 145°C for 2 hours. The reaction of the raw materials was monitored by TLC, concentrated to remove acetic anhydride, then added aqueous sodium bicarbonate (300 ml), the mixture was extracted with ethyl acetate (200 ml × 2 times), the organic phase was combined, and the organic phase was first washed with saturated brine (200 ml) mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain (S)-1-acetyl-4-phenylpyrrolidin-2-one (33 g, yield 64 %). Step H: Sodium hydride (60%, 13.2 g, 0.33 mol) was dispersed in tetrahydrofuran (180 ml), cooled to 0 degrees Celsius, and (S)-1-acetyl-4-phenylpyrrolidine- 2-Keto (27 g, 0.133 mol) and 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (39.3 g, 0.11 mol) in tetrahydrofuran (180 ml) and the solution was stirred at this temperature for 1 hour. LCMS monitored the completion of the reaction of the raw materials, and an aqueous ammonium chloride solution (200 ml) was added to the reaction solution. The mixture was extracted with ethyl acetate (200 ml x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (200 ml), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/2) to obtain (4R,E)-3-((3-iodo-1-(tetrahydro-2H-pyran)-1H -indazol-6-yl)methylene)-4-phenyl-2-pyrrolidone (20.7 g, 37% yield). MS (ESI) M/Z: 202.9 [M+H] ⁺ . Step I: Compound (R,E)-3-((3-iodo-1-(tetrahydro-2H-pyran)-1H-ind Azol-6-yl)methylene)-4-phenyl-2-pyrrolidone (20.7 g, 41.45 mmol) and cis-2,6-dimethyl-1-(4-((E)-2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzyl)piperidine (29.5 g, 82.9 mmol) dissolved in 1,4-dioxane (400 ml). Subsequently, potassium carbonate (14.3 g, 103.6 mmol), water (100 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.5 g, 2.07 mmol ear), followed by nitrogen replacement three times. The reaction solution was heated to 100°C and stirred for 2 hours. After LCMS monitoring showed that the raw material disappeared, water (500 ml) was added, the mixture was extracted with ethyl acetate (500 ml × 2 times), the organic phases were combined, and the organic phase was first washed with saturated brine (50 ml), and then washed with anhydrous sulfuric acid Dry over sodium, filter and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain (R,E)-3-((3-((E)-4-(((cis)- 2,6-Dimethylpiperidin-1-yl)methyl)styryl)-1-(tetrahydro-2H-pyranyl)-1H-indazol-6-yl)methylene)-4 -Phenylpyrrolidin-2-one (17 g, 68% yield). MS (ESI) M/Z: 601.5 [M+H] ⁺ . Step J: Compound (R,E)-3-((3-((E)-4-(((cis) -2,6-Dimethylpiperidin-1-yl)methyl)styryl)-1-(tetrahydro-2H-pyranyl)-1H-indazol-6-yl)methylene)- 4-Phenylpyrrolidin-2-one (17 g, 28.3 mmol) was dissolved in methanol (340 ml), subsequently, methanesulfonic acid (21.7 g, 226 mmol) was added, and the reaction solution was heated at 60 degrees Celsius Stir for 2 hours. After spot plate monitoring showed that the raw materials disappeared, aqueous sodium bicarbonate solution (500 ml) was added, the mixture was extracted with dichloromethane (50 ml × 2 times), the organic phases were combined, and the organic phase was first washed with saturated brine (200 ml). It was then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain a crude product. The resulting crude product was added to ethanol (100 ml) and stirred for 2 hours. Filtered pure product. The obtained product was dispersed in acetonitrile (50 ml) and pure water (50 ml), and trifluoroacetic acid (1 ml) was added to dissolve it to obtain (R,E)-3-((3-((E)-4-( ((cis)-2,6-dimethylpiperidin-1-yl)methyl)styrene)-1H-indazol-6-yl)methylene)-4-phenylpyrrolidin-2-onetri Fluoroacetate (6.2 g, 35% yield). MS (ESI) M/Z: 517.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (dd, J = 8.5, 6.0 Hz, 1H), 7.73 (d, J = 8.3 Hz , 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.32 - 7.23 ( m, 5H), 7.21 - 7.14 (m, 1H), 4.77 (dt, J = 8.1, 2.0 Hz, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.56 (q, J = 7.0 Hz, 1H), 3.30 - 3.16 (m, 2H), 2.06 - 1.96 (m, 1H), 1.93 - 1.69 (m, 3H), 1.69 - 1.53 (m , 5H), 1.42 (d, J = 6.7 Hz, 3H). ¹⁹ F NMR: -77.

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.64 (d, J= 2.0 Hz, 1H), 7.52 - 7.48 (m, 5H), 7.30 - 7.23 (m, 5H), 7.19 - 7.14 (m, 1H), 4.77 (dt, J= 8.0, 2.4 Hz, 1H), 4.30 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.44 (d, J= 12.4 Hz, 2H), 3.33 - 3.17 (m, 2H), 3.07 (t, J= 12.4 Hz, 1H), 2.38 (d, J= 14.4Hz, 1H), 2.15 - 2.02 (m, 1H), 1.98 - 1.95 (m, 1H), 1.66 (t, J= 13.2 Hz, 1H), 1.25 (s, 3H) 546.3 [M+H] ⁺.    93

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.57 - 7.50 (m, 5H), 7.31 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.43 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.61 (d, J= 13.3 Hz, 2H), 3.29 - 3.22 (m, 3H), 2.33 - 2.23 (m, 2H), 1.87 - 1.71 (m, 2H), 1.47 (s, 3H). 528.0 [M+H] ⁺.    94

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.63 (s, 1H), 7.57 - 7.39 (m, 5H), 7.35 - 7.23 (m, 5H), 7.23 - 7.15 (m, 1H), 4.77 (d, J= 7.8 Hz, 1H), 4.24 (s, 2H), 4.07 - 3.97 (m, 1H), 3.23 - 3.11 (m, 1H), 2.94 - 2.80 (m, 1H), 2.38 - 2.24 (m, 3H), 2.21 - 2.11 (m, 2H), 1.61 - 1.43 (m, 4H). 547.2 [M+H] ⁺.    95

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.71 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.53 - 7.47 (m, 5H), 7.32 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.82 - 4.75 (m, 1H), 4.22 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.29 - 3.28 (m, 1H), 3.24 - 3.15 (m, 1H), 2.74 - 2.66 (m, 1H), 2.31 - 2.23 (m, 2H), 2.14 - 2.04 (m, 2H), 1.71 - 1.63 (m, 4H). 547.1 [M+H] ⁺.    96

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 7.5 Hz, 2H), 7.56 (d, J= 10.8 Hz, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.45 (s, 2H), 4.15 (br, 1H), 3.79 (br, 2H), 3.62 (br, 1H), 3.43 (br, 1H), 2.95 (s, 6H), 2.61 (br, 1H), 2.36 (br, 1H), 1.84 - 1.77 (m, 2H), 1.65 - 1.57 (m, 5H), 1.42 - 1.22 (m, 4H), 1.04 - 1.10 (m, 1H). 510.3 [M+H] ⁺. 97

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 7.4 Hz, 2H), 7.62 - 7.51 (m, 6H), 7.25 (d, J= 8.4 Hz, 1H), 4.49 (s, 2H), 4.25 - 4.12 (m, 1H), 3.95 - 3.78 (m, 2H), 3.71 - 3.59 (m, 1H), 3.54 - 3.44 (m, 1H), 3.31 (s, 2H), 2.97 (s, 6H), 2.70 - 2.58 (m, 1H), 2.48 - 2.33 (m, 1H), 1.86 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H), 1.39 - 1.27 (m, 2H), 1.11 - 0.99 (m, 1H). 510.3 [M+H] ⁺.    98

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.61 - 7.50 (m, 6H), 7.26 (d, J= 8.5 Hz, 1H), 4.49 - 4.35 (m, 2H), 4.23 - 4.14 (m, 1H), 3.70 - 3.51 (m, 2H), 3.38 (s, 2H), 3.31 (s, 3H), 3.30 - 3.23 (m, 2H), 2.45 - 2.30 (m, 1H), 2.21 - 2.03 (m, 1H), 1.87 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H), 1.42 - 1.27 (m, 2H), 1.13 - 1.01 (m, 1H). 497.3 [M+H] ⁺.    99

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 7.9 Hz, 2H), 7.64 - 7.50 (m, 6H), 7.26 (d, J= 8.6 Hz, 1H), 4.52 - 4.32 (m, 2H), 4.25 - 4.13 (m, 1H), 3.71 - 3.50 (m, 2H), 3.39 (s, 2H), 3.32 (s, 3H), 3.30 - 3.22 (m, 2H), 2.49 - 2.30 (m, 1H), 2.21 - 2.03 (m, 1H), 1.88 - 1.72 (m, 2H), 1.70 - 1.55 (m, 5H), 1.40 - 1.27 (m, 2H), 1.16 - 0.95 (m, 1H). 497.3 [M+H] ⁺.    100

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.79 (d, J= 7.5 Hz, 2H), 7.67 - 7.46 (m, 6H), 7.27 (d, J= 8.4 Hz, 1H), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.51 - 3.40 (m, 2H), 3.17 (s, 2H), 3.08 - 2.94 (m, 2H), 2.49 - 2.16 (m, 2H), 2.00 - 1.83 (m, 2H), 1.30 (s, 6H). 483.1 [M+H] ⁺.    101

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 7.8 Hz, 2H), 7.58 - 7.47 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.38 (s, 2H), 4.07 (s, 4H), 3.61 (s, 2H), 3.54 (s, 2H), 3.16 (s, 2H), 1.30 (s, 6H). 455.2 [M+H] ⁺.    102

¹H NMR (400 MHz, CD ₃OD) δ 7.94 (d, J= 8.5 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.63 (d, J= 2.2 Hz, 1H), 7.54 - 7.49 (m, 3H), 7.45 (s, 2H), 7.34 - 7.22 (m, 5H), 7.19 (m, 1H), 4.78 (dt, J= 8.1, 2.3 Hz, 1H), 4.42 (s, 2H), 4.08 - 3.96 (m, 5H), 3.61 (dt, J= 20.3, 5.3 Hz, 4H), 3.30-3.27 (m, 1H), 1.89 (dt, J= 16.1, 5.4 Hz, 4H). 531.2 [M+H] ⁺. 103

(400 MHz, CD ₃OD) δ 8.14 (dd, J= 8.4, 1.8 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.59 - 7.51 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.52 - 3.44 (m, 2H), 3.08 - 2.95 (m, 2H), 2.38 (m, 2H), 1.92 (m, 2H), 1.80 (m, 6.9 Hz, 3H), 1.61 (m, 6H), 1.34 (m, 3H), 1.07 (m, 1H). 523.1 [M+H] ⁺. 104

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.3 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.61 - 7.52 (m, 6H), 7.27 (d, J= 8.2 Hz, 1H), 4.41 (s, 2H), 3.95 - 3.75 (m, 4H), 3.30 (s, 2H), 3.13 - 3.00 (m, 2H), 2.99 - 2.84 (m, 2H), 1.86 - 1.75 (m, 2H), 1.71 - 1.53 (m, 6H), 1.44 - 1.22 (m, 3H), 1.12 - 1.02 (m, 1H). 509.3 [M+H] ⁺.    105

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.63 - 7.47 (m, 6H), 7.26 (d, J= 8.5Hz, 1H), 4.27 (s, 2H), 4.10 - 4.02 (m, 2H), 3.51 - 3.42 (m, 3H), 3.32 (s, 2H), 2.17 - 2.06 (m, 2H), 1.85 - 1.57 (m, 9H), 1.40 - 1.28 (m, 2H), 1.14 - 0.99 (m, 1H). 497.2 [M+H] ⁺.    106

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.4 Hz, 1H), 7.89 - 7.76 (m, 2H), 7.67 - 7.33 (m, 6H), 7.27 (d, J= 8.3 Hz, 1H), 4.46 (s, 2H), 3.85 (s, 2H), 3.70 - 3.49 (m, 4H), 3.30 (s, 2H), 1.87 - 1.76 (m, 2H), 1.73 - 1.46 (m, 5H), 1.36 - 1.28 (m, 2H), 1.12 - 1.03 (m, 1H). 496.1 [M+H] ⁺. 107

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.64 - 7.43 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.50 - 4.35 (m, 2H), 4.08 (s, 3H), 3.31 - 3.25 (m, 6H), 1.88 - 1.73 (m, 2H), 1.70 - 1.45 (m, 8H), 1.41 - 1.25 (m, 2H), 1.13 - 0.98 (m, 1H) 497.1 [M+H] ⁺ 108

(400 MHz, CD ₃OD) δ 8.18 - 8.10 (m, 1H), 7.84 - 7.74 (m, 2H), 7.72 - 7.46 (m, 6H), 7.30 - 7.22 (m, 1H), 4.73 - 4.58 (m, 1H), 4.38 - 4.26 (m, 1H), 4.15 - 3.98 (m, 1H), 3.77 - 3.43 (m, 3H), 3.40 - 3.31 (m, 2H), 2.94 (s, 6H), 2.62 - 2.51 (m, 1H), 2.29 - 1.99 (m, 3H), 1.87 - 1.70 (m, 2H), 1.67 - 1.46 (m, 5H), 1.41 - 1.25 (m, 2H), 1.13 - 0.99 (m, 1H) 524.2 [M+H] ⁺ 109

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.67 - 7.47 (m, 6H), 7.26 (d, J= 8.5 Hz, 1H), 4.42 (s, 2H), 4.09 - 3.97 (m, 4H), 3.68 - 3.55 (m, 4H), 3.32 (s, 2H), 1.93 - 1.75 (m, 6H), 1.68 - 1.55 (m, 5H), 1.39 - 1.27 (m, 2H), 1.11 - 1.01 (m, 1H) 523.2 [M+H] ⁺ 110

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.76 (dd, J= 8.3, 2.0 Hz, 2H), 7.58 - 7.53 (m, 4H), 7.49 (m, 2H), 7.26 (dd, J= 8.5, 1.2 Hz, 1H), 4.80 (m, 3H), 4.47 - 4.24 (m, 5H), 4.07 (s, 1H), 3.57 (m, 1H), 1.81 (m, 2H), 1.61 (m, 5H), 1.34 (m, 2H), 1.07 (m, 1H). 495.1 [M+H] ⁺. 111

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.4 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.67 - 7.47 (m, 6H), 7.26 (d, J= 8.5 Hz, 1H), 4.38 (s, 2H), 3.40 - 3.31 (m, 6H), 2.01 - 1.71 (m, 6H), 1.70 - 1.51 (m, 5H), 1.42 - 1.32 (m, 2H), 1.28 (s, 3H), 1.14 - 0.98 (m, 1H). 511.2 [M+H] ⁺ 112

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.65 - 7.49 (m, 6H), 7.26 (d, J= 8.8 Hz, 1H), 4.29 (s, 2H), 3.68 - 3.55 (m, 4H), 3.45 - 3.36 (m, 4H), 3.31 (s, 2H), 1.85 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H), 1.39 - 1.28 (m, 2H), 1.12 - 1.03 (m, 1H) 531.1 [M+H] ⁺. 113

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 8.3 Hz, 2H), 7.66 - 7.50 (m, 6H), 7.26 (d, J= 9.0 Hz, 1H), 4.26 (s, 2H), 4.10 - 4.02 (m, 2H), 4.00 - 3.95 (m, 1H), 3.88 - 3.83 (m, 1H), 3.78 - 3.72 (m, 1H), 3.32 (s, 2H), 2.48 - 2.40 (m, 1H), 2.14 - 2.07 (m, 1H), 1.85 - 1.77 (m, 2H), 1.68 - 1.55 (m, 5H), 1.39 - 1.29 (m, 2H), 1.10 - 1.03 (m, 1H). 483.2 [M+H] ⁺. 114

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.5 Hz, 1H), 7.79 (d, J= 8.3 Hz, 2H), 7.65 - 7.51 (m, 6H), 7.27 (d, J= 7.2 Hz, 1H), 4.61 (d, J= 12.9 Hz, 1H), 4.29 (d, J= 13.0 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.58 (d, J= 5.1 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.43 (s, 3H), 3.32 - 3.31 (m, 3H), 2.32 - 2.24 (m, 1H), 2.17 - 2.09 (m, 1H), 2.01 - 1.88 (m, 2H), 1.85 - 1.76 (m, 2H), 1.70 - 1.56 (m, 5H), 1.40 - 1.30 (m, 2H), 1.12 - 1.03 (m, 1H). 511.4 [M+H] ⁺ 115

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.3 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (d, J= 7.3 Hz, 1H), 4.61 (d, J= 13.0 Hz, 1H), 4.29 (d, J= 13.0 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.58 (d, J= 5.1 Hz, 2H), 3.50 - 3.43 (m, 1H), 3.42 (s, 3H), 3.31 - 3.30 (m, 3H), 2.36 - 2.23 (m, 1H), 2.19 - 2.08 (m, 1H), 2.03 - 1.87 (m, 2H), 1.86 - 1.76 (m, 2H), 1.69 - 1.54 (m, 5H), 1.39 - 1.28 (m, 2H), 1.12 - 1.01 (m, 1H). 511.3 [M+H] ⁺   116

(400 MHz, CD ₃OD) δ 8.16 (d, J= 8.5 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.70 - 7.53 (m, 6H), 7.28 (d, J= 8.6 Hz, 1H), 4.38 (s, 2H), 3.92 - 3.80 (m, 2H), 3.43 - 3.36 (m, 2H), 3.32 (s, 2H), 2.88 - 2.73 (m, 2H), 1.89 - 1.77 (m, 2H), 1.71 - 1.57 (m, 5H), 1.42 - 1.31 (m, 2H), 1.30 - 1.20 (m, 6H), 1.13 - 1.05 (m, 1H). 511.3 [M+H] ⁺ 117

(400 MHz, CD ₃OD) δ 8.17 (d, J= 8.4 Hz, 1H), 7.83 (d, J= 8.1 Hz, 2H), 7.65 - 7.54 (m, 6H), 7.29 (d, J= 7.3 Hz, 1H), 4.41 (s, 2H), 4.13 - 3.98 (m, 2H), 3.86 - 3.71 (m, 2H), 3.51 - 3.34 (m, 4H), 3.30 - 3.17 (m, 2H), 1.88 - 1.79 (m, 2H), 1.71 - 1.59 (m, 5H), 1.43 - 1.32 (m, 2H), 1.14 - 1.06 (m, 1H) 531.1 [M+H] ⁺ 118

(400 MHz, DMSO- d ₆) δ 13.21 (s, 1H), 8.26 - 8.13 (m, 2H), 7.69 (d, J= 8.0 Hz, 2H), 7.60 - 7.50 (m, 3H), 7.36 (s, 1H), 7.31 - 7.21 (m, 3H), 4.52 (s, 2H), 3.24 - 3.13 (m, 4H), 2.38 - 2.29 (m, 2H), 1.81 - 1.68 (m, 6H), 1.62 - 1.47 (m, 5H), 1.34 - 1.25 (m, 2H), 1.09 - 1.00 (m, 1H). 495.3 [M+H] ⁺ 119

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.66 (d, J= 7.8 Hz, 2H), 7.58 - 7.49 (m, 4H), 7.34 (d, J= 7.9 Hz, 2H), 7.25 (d, J= 8.4 Hz, 1H), 4.66 (s, 2H), 4.22 (s, 2H), 3.88 (t, J= 5.1 Hz, 2H), 3.37 - 3.35 (m, 4H), 1.85 - 1.81 (m, 2H), 1.65 - 1.62 (m, 5H), 1.37 - 1.27 (m, 2H), 1.11-1.05 (m, 1H). 497.1 [M+H] ⁺ 120

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.2 Hz, 2H), 7.66 - 7.50 (m, 6H), 7.26 (d, J= 7.3 Hz, 1H), 4.27 (s, 2H), 4.11 - 4.01 (m, 2H), 4.01 - 3.94 (m, 1H), 3.89 - 3.82 (m, 1H), 3.79 - 3.71 (m, 1H), 3.32 (s, 2H), 2.50 - 2.38 (m, 1H), 2.14 - 2.06 (m, 1H), 1.87 - 1.76 (m, 2H), 1.69 - 1.54 (m, 5H), 1.40 - 1.29 (m, 2H), 1.12 - 1.02 (m, 1H) 483.2 [M+H] ⁺ 121

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 7.9 Hz, 2H), 7.64 - 7.45 (m, 6H), 7.26 (d, J= 8.5 Hz, 1H), 4.37 (s, 2H), 4.26 - 4.18 (m, 2H), 4.15 - 4.07 (m, 2H), 3.32 (s, 2H), 2.61 - 2.54 (m, 1H), 2.50 - 2.44 (m, 1H), 1.84 - 1.76 (m, 2H), 1.70 - 1.53 (m, 5H), 1.39 - 1.30 (m, 2H), 1.10 - 1.03 (m, 1H). 453.0 [M+H] ⁺ 122

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.66 - 7.49 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.40 (s, 2H), 3.59 - 3.45 (m, 2H), 3.30 - 3.17 (m, 4H), 2.25 - 2.02 (m, 4H), 1.86 - 1.75 (m, 2H), 1.70 - 1.54 (m, 5H), 1.39 - 1.29 (m, 2H), 1.10 - 1.01 (m, 1H) 467.3 [M+H] ⁺ 123

(400 MHz, CD ₃OD) δ 8.15 (d, J= 8.5 Hz, 1H), 7.80 (d, J= 8.2 Hz, 2H), 7.68 - 7.49 (m, 6H), 7.27 (d, J= 7.4 Hz, 1H), 4.34 (s, 2H), 3.32 (s, 2H), 2.89 (s, 6H), 1.85 - 1.76 (m, 2H), 1.69 - 1.53 (m, 5H), 1.38 - 1.28 (m, 2H), 1.11 - 1.03 (m, 1H). 441.2 [M+H] ⁺ 124

(400 MHz, CD ₃OD) δ 7.83 - 7.69 (m, 3H), 7.67 - 7.48 (m, 4H), 7.14 (s, 1H), 6.61 (s, 1H), 4.33 (s, 2H), 4.08 (s, 3H), 3.56 - 3.45 (m, 2H), 3.34 (s, 2H), 3.07 - 2.94 (m, 2H), 2.03 - 1.52 (m, 13H), 1.42 - 1.31 (m, 2H), 1.16 - 1.05 (m, 1H). 511.1 [M+H] ⁺ 125

(400 MHz, CD ₃OD) δ 7.84 - 7.70 (m, 3H), 7.67 - 7.50 (m, 4H), 7.14 (s, 1H), 6.61 (s, 1H), 4.38 (s, 2H), 4.08 (s, 3H), 3.90 - 3.80 (m, 2H), 3.43 - 3.36 (m, 2H), 3.32 (s, 2H), 2.86 - 2.74 (m, 2H), 1.94 - 1.84 (m, 2H), 1.74 - 1.55 (m, 5H), 1.43 - 1.32 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.15 - 1.06 (m, 1H). 541.1 [M+H] ⁺ 126

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.79 (d, J= 7.2 Hz, 2H), 7.55 (m, 6H), 7.27 (d, J= 8.4 Hz, 1H), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.46 (d, J= 12.8 Hz, 2H), 3.17 (s, 2H), 3.01 (m, 2H), 2.39 (d, J= 13.6 Hz, 2H), 1.97- 1.85 (m, 2H), 1.30 (s, 6H). 483.1 [M+H] ⁺ 127

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (dd, J= 8.0, 1.9 Hz, 2H), 7.60 - 7.50 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.38 (m, 2H), 3.93-3.77 (m, 3H), 3.73 - 3.21 (m, 4H), 3.17 (s, 2H), 3.08-2.95 (m, 3H), 1.30 (s, 6H). 553.1 [M+H] ⁺ 128

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.2 Hz, 2H), 7.66 - 7.48 (m, 6H), 7.26 (d, J= 9.9 Hz, 1H), 4.27 (s, 2H), 4.06 (dd, J= 11.8, 4.6 Hz, 2H), 3.54 - 3.42 (m, 3H), 3.17 (s, 2H), 2.16 - 2.07 (m, 2H), 1.78 - 1.65 (m, 2H), 1.30 (s, 6H). 457.3 [M+H] ⁺ 129

(400 MHz, CD ₃OD) δ 8.04 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 7.7 Hz, 2H), 7.55 - 7.38 (m, 6H), 7.16 (d, J= 9.7 Hz, 1H), 4.33 (s, 2H), 3.72 (s, 2H), 3.54 - 3.38 (m, 4H), 3.07 (s, 2H), 1.20 (s, 6H). 456 [M+H] ⁺   130

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.3 Hz, 1H), 7.76 (d, J= 7.9 Hz, 2H), 7.63 - 7.49 (m, 6H), 7.26 (d, J= 9.9 Hz, 1H), 4.44 (d, J= 17.7 Hz, 2H), 4.17 - 4.03 (m, 4H), 3.29 (d, J= 3.6 Hz, 3H), 3.17 (s, 2H), 1.54 (d, J= 15.4 Hz, 3H), 1.30 (s, 6H). 457.1 [M+H] ⁺   131

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 8.1 Hz, 2H), 7.67 - 7.50 (m, 6H), 7.26 (d, J= 9.9 Hz, 1H), 4.56 (d, J= 12.8 Hz, 1H), 4.24 (d, J= 12.8 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.51 - 3.39 (m, 2H), 3.30 - 3.21 (m, 2H), 3.17 (s, 2H), 2.84 (s, 6H), 2.54 - 2.44 (m, 1H), 2.25 - 2.13 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.90 (m, 1H), 1.30 (s, 6H). 484.2 [M+H] ⁺   132

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.3 Hz, 2H), 7.62 - 7.49 (m, 6H), 7.26 (d, J= 10.0 Hz, 1H), 4.41 (s, 2H), 4.02 (s, 4H), 3.62 (t, J = 5.2 Hz, 4H), 3.17 (s, 2H), 1.88 (t, J = 5.3 Hz, 4H), 1.30 (s, 6H). 483.3 [M+H] ⁺   133

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.67 - 7.50 (m, 6H), 7.26 (d, J= 8.6 Hz, 1H), 4.35 (s, 2H), 3.39 - 3.31 (m, 4H), 3.17 (s, 2H), 1.89 - 1.72 (m, 4H), 1.30 (s, 6H), 1.28 (s, 3H). 471.3 [M+H] ⁺   134

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.3 Hz, 2H), 7.62 - 7.45 (m, 6H), 7.26 (d, J= 10.0 Hz, 1H), 4.24 (s, 2H), 3.60 - 3.51 (m, 4H), 3.43 - 3.36 (m, 4H), 3.16 (s, 2H), 1.30 (s, 6H). 491.1 [M+H] ⁺   135

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.2 Hz, 2H), 7.63 - 7.50 (m, 6H), 7.26 (d, J= 10.0 Hz, 1H), 4.26 (s, 2H), 4.10 - 4.02 (m, 2H), 3.99 - 3.94 (m, 1H), 3.88 - 3.82 (m, 1H), 3.78 - 3.72 (m, 1H), 3.17 (s, 2H), 2.47 - 2.40 (m, 1H), 2.13 - 2.07 (m, 1H), 1.30 (s, 6H). 443.2 [M+H] ⁺ 136

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 8.1 Hz, 2H), 7.67 - 7.50 (m, 6H), 7.27 (d, J= 9.9 Hz, 1H), 4.60 (d, J= 12.9 Hz, 1H), 4.29 (d, J= 13.0 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.58 (d, J= 5.0 Hz, 2H), 3.42 (s, 3H), 3.35 - 3.31 (m, 2H), 3.17 (s, 2H), 2.34 - 2.25 (m, 1H), 2.17 - 2.09 (m, 1H), 2.02 - 1.87 (m, 2H), 1.30 (s, 6H). 471.3 [M+H] ⁺ 137

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 7.9 Hz, 2H), 7.69 - 7.49 (m, 6H), 7.26 (d, J= 9.8 Hz, 1H), 4.61 - 4.48 (m, 1H), 4.30 - 4.14 (m, 1H), 3.83 - 3.68 (m, 1H), 3.57 (d, J= 5.1 Hz, 2H), 3.42 (s, 3H), 3.40 - 3.31 (m, 2H), 3.17 (s, 2H), 2.32 - 2.19 (m, 1H), 2.16 - 2.03 (m, 1H), 2.00 - 1.84 (m, 2H), 1.30 (s, 6H). 472.2 [M+H] ⁺ 138

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 8.1 Hz, 2H), 7.61 - 7.52 (m, 6H), 7.27 (d, J= 7.6 Hz, 1H), 4.36 (s, 2H), 3.91 - 3.78 (m, 2H), 3.38 (d, J= 12.2 Hz, 2H), 3.17 (s, 2H), 2.78 (t, J= 11.7 Hz, 2H), 1.30 (s, 6H), 1.24 (s, 3H), 1.23 (s, 3H). 471.2 [M+H] ⁺   139

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 7.9 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.27 (d, J= 7.3 Hz, 1H), 4.39 (s, 2H), 4.13 - 4.01 (m, 2H), 3.72 (t, J= 12.6 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.28 - 3.20 (m, 2H), 3.17 (s, 2H), 1.30 (s, 6H). 443.0 [M+H] ⁺ 140

(400 MHz, DMSO- d ₆) δ 13.18 (s, 1H), 8.20 (d, J= 8.4 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J= 8.2 Hz, 2H), 7.56 - 7.49 (m, 3H), 7.35 (s, 1H), 7.30 - 7.18 (m, 3H), 4.52 (s, 2H), 3.24 - 3.16 (m, 2H), 3.04 (s, 2H), 2.37 - 2.28 (m, 2H), 1.76 - 1.68 (m, 4H), 1.24 (s, 6H). 455.2 [M+H] ⁺ 141

 (400 MHz, CD ₃OD) δ 8.10 (d, J= 8.4 Hz, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.59 -7.40 (m, 5H), 7.31 (d, J= 8.0 Hz, 2H), 7.23 (d, J= 8.4 Hz，1H), 4.63 (s, 2H), 4.20 (s, 2H), 3.85 (t, J= 5.2 Hz, 2H), 3.33 (t, J= 5.2 Hz, 2H), 3.14 (s, 2H), 1.28 (s, 6H). 457.1 [M+H] ⁺ 142

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.3 Hz, 1H), 7.77 (d, J= 8.0 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (d, J= 8.4 Hz, 1H), 4.26 (s, 2H), 4.11 - 4.01 (m, 2H), 4.01 - 3.92 (m, 1H), 3.90 - 3.83 (m, 1H), 3.75 (q, J= 8.1 Hz, 1H), 3.17 (s, 2H), 2.48 - 2.38 (m, 1H), 2.16 - 2.06 (m, 1H), 1.30 (s, 6H). 443.3 [M+H] ⁺ 143

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.57 - 7.54 (m, 6H), 7.27 (d, J= 8.4Hz, 1H), 4.41 (s, 2H), 4.14 - 4.11 (m, 1H), 3.75-3.73(m, 2H), 3.65 - 3.52 (m, 1H), 3.31-3.30 (m, 1H), 3.17 (s, 2H), 2.94 (s, 6H), 2.59 (m, 1H), 2.34 (m, 1H), 1.30 (s, 6H). 470.2 [M+H] ⁺ 144

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.60 - 7.51 (m, 6H), 7.27 (d, J= 8.4 Hz,1H), 4.42 (s, 2H), 4.13 (t, J= 8.4 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.59 (m, 1H), 3.41 (m, 2H), 3.17 (s, 2H), 2.95 (s, 6H), 2.61 (m, 1H), 2.36 (q,7.2, 6.8 Hz, 1H), 1.30 (s, 6H). 470.3 [M+H] ⁺   145

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.64 - 7.51 (m, 6H), 7.26 (d, J= 8.0 Hz, 1H), 4.43 - 4.39 (m, 2H), 4.19 (s, 1H), 3.63 (m, 1H), 3.55 (d, J= 11.6 Hz, 1H), 3.39 (s, 3H), 3.26 - 3.20 (m, 1H), 3.17 (s, 2H), 2.37 (m, 1H), 2.17-2.14 (m, 1H), 1.30 (s, 6H). 457.3 [M+H] ⁺ 146

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.58 - 7.54 (m, 6H), 7.27 (d, J= 8.4 Hz, 1H), 4.42 (dd, J= 20.0, 8.0 Hz, 2H), 4.19 (s, 1H), 3.68 - 3.58 (m, 1H), 3.55 (d, J= 12.4 Hz, 1H), 3.17 (s, 2H), 2.38 (m, 1H), 2.20 -2.11 (m, 1H), 1.30 (s, 6H). 457.1 [M+H] ⁺ 147

(400 MHz, CD ₃OD) δ 8.13 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 8.2 Hz, 2H), 7.58 - 7.52 (m, 4H), 7.48 (d, J= 8.3 Hz, 2H), 7.26 (d, J= 7.2 Hz, 1H), 4.37 (s, 2H), 4.26 - 4.17 (m, 2H), 4.15 - 4.06 (m, 2H), 3.17 (s, 2H), 2.64 - 2.53 (m, 1H), 2.52 - 2.41 (m, 1H), 1.30 (s, 6H). 412.9 [M+H] ⁺ 148

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.5, 2H), 7.60 - 7.50 (m, 6H), 7.26 (dd, J= 8.5, 1.5 Hz, 1H), 4.39 (s, 2H), 3.55 - 3.48 (m, 2H), 3.25-3.18 (m, 2H), 3.16 (s, 2H), 2.20 (s, 2H), 2.06 - 1.97 (m, 2H), 1.30 (s, 6H). 427.0 [M+H] ⁺ 149

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H), 7.59 (s, 2H), 7.56 - 7.50 (m, 4H), 7.27 (d, J= 9.4 Hz, 1H), 4.33 (s, 2H), 3.17 (s, 2H), 2.89 (s, 6H), 1.30 (s, 6H). 401.1 [M+H] ⁺ 150

(400 MHz, CD ₃OD) δ 8.19 (d, J= 8.3 Hz, 1H), 7.80 (d, J= 8.1 Hz, 2H), 7.72 (d, J= 1.3 Hz, 1H), 7.59 (d, J= 8.7 Hz, 3H), 7.53 (d, J= 8.1 Hz, 2H), 7.40 (d, J= 8.2 Hz, 1H), 4.31 (s, 2H), 3.59 (s, 2H), 3.54 - 3.45 (m, 2H), 2.99 (m, 2H), 2.64 (m, 2H), 2.12 - 1.93 (m, 5H), 1.90 - 1.47 (m, 5H). 453.3 [M+H] ⁺ 151

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.5 Hz, 1H), 7.79 (d, J= 8.1 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (dd, J= 8.7, 1.4 Hz, 1H), 4.31 (s, 2H), 3.48 (d, J= 12.2 Hz, 2H), 3.22 (s, 2H), 3.05 - 2.93 (m, 2H), 2.13 - 2.09 (m, 2H), 1.98 - 1.95 (m, 2H), 1.86 - 171 (m, 9H), 1.53 - 1.50 (m, 1H). 467.3 [M+H] ⁺ 152

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.4 Hz, 1H), 7.79 (d, J= 8.3 Hz, 2H), 7.59 (d, J= 3.1 Hz, 2H), 7.53 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 1.9 Hz, 1H), 7.20 (dd, J= 8.4, 6.1 Hz, 1H), 4.31 (s, 2H), 3.48 (d, J= 12.2 Hz, 2H), 3.32 (s, 2H), 3.04 - 2.93 (m, 2H), 1.97 (d, J= 14.5 Hz, 2H), 1.87 - 1.52 (m, 11H), 1.31 (d, J= 16.1 Hz, 2H), 1.01 - 0.88 (m, 1H). 499.2 [M+H ⁺]. 153

(400 MHz, CD ₃OD) δ 8.07 (d, J= 8.4 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.62 - 7.52 (m, 3H), 7.25 (d, J= 8.4 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J= 7.6 Hz, 1H), 4.31 (s, 2H), 4.02 (s, 3H), 3.52 - 3.47 (m, 2H), 3.33 (s, 2H), 3.00 (t, J= 12.4 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.90 - 1.68 (m, 6H), 1.67 - 1.59 (m, 5H), 1.35 - 1.29 (m, 2H), 1.13 - 1.01 (m, 1H). 511.3 [M+H ⁺].    154

(400 MHz, CD ₃OD) δ 7.77 - 7.67 (m, 3H), 7.62 - 7.55 (m, 1H), 7.54 - 7.48 (m, 3H), 7.11 (s, 1H), 6.58 (s, 1H), 4.42 (s, 2H), 4.06 (s, 3H), 4.05 - 3.96 (m, 4H), 3.65 - 3.56 (m, 4H), 3.33 (s, 2H), 1.93 - 1.82 (m, 6H), 1.68 - 1.58 (m, 5H), 1.39 - 1.29 (m, 2H), 1.14 - 1.02 (m, 1H). 553.2 [M+H ⁺]. 155

(400 MHz, CD ₃OD) δ 7.77 - 7.67 (m, 3H), 7.58 (d, J= 16.5 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.10 (s, 1H), 6.58 (s, 1H), 4.42 (s, 2H), 4.05 (s, 3H), 4.05 - 3.97 (m, 4H), 3.71 - 3.53 (m, 4H), 3.17 (s, 2H), 1.95 - 1.80 (m, 4H), 1.32 (s, 6H). 513.0 [M+H ⁺].    156

(400 MHz, CD ₃OD) δ 8.19 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 8.2 Hz, 2H), 7.71 (s, 1H), 7.57 (s, 2H), 7.56 - 7.50 (m, 3H), 7.27 - 7.20 (m, 1H), 4.43 (s, 2H), 4.03 (d, J= 6.3 Hz, 4H), 3.69 - 3.54 (m, 4H), 3.47 (s, 2H), 3.28 - 3.22 (m, 2H), 3.05 (t, J= 13.2 Hz, 2H), 2.16 (td, J= 14.1, 4.3 Hz, 2H), 1.95 - 1.85 (m, 6H). 524.1 [M+H ⁺].    157

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.79 (d, J= 8.0 Hz, 2H), 7.71 (s, 1H), 7.64 (q, J= 1.0 Hz, 1H), 7.58 (s, 2H), 7.53 (d, J= 8.0 Hz, 2H), 7.30 - 7.24 (m, 1H), 4.31 (s, 2H), 3.58 (d, J= 2.1 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.41 - 3.39 (m, 2H), 3.37 - 3.35 (m, 2H), 3.19 (s, 3H), 3.02 - 2.96 (m, 2H), 1.98 - 1.93 (m, 2H), 1.86 - 1.69 (m, 3H), 1.57 - 1.50 (m, 1H). 487.2 [M+H ⁺]. 158

(400 MHz, CD ₃OD) δ 8.34 (d, J= 9.5 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J= 8.6 Hz, 1H), 7.64 (d, J= 2.2 Hz, 1H), 7.53 (s, 1H), 7.49-7.34 (m, 3H), 7.34 - 7.23 (m, 5H), 7.28 - 7.14 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.37 (s, 2H), 4.01 (dd, J= 10.1, 7.9 Hz, 1H), 3.30-3.27 (m, 1H), 2.09-1.77 (m, 5H), 1.66 (s, 1H), 1.32 (s, 6H). 504.1 [M+H ⁺] 159

(400 MHz, CD ₃OD) δ 8.12 - 8.04 (m, 2H), 8.01 (d, J= 8.6 Hz, 1H), 7.80 (d, J= 8.1 Hz, 1H), 7.67 - 7.53 (m, 4H), 7.36 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J= 7.9 Hz, 1H), 4.49 (s, 2H), 4.07 - 3.96 (m, 1H), 3.53 (d, J= 12.4 Hz, 2H), 3.13 (t, J= 12.3 Hz, 2H), 1.99 - 1.95 (m, 2H), 1.91 - 1.68 (m, 4H), 1.58 - 1.55 (m, 1H). 557.2 [M+H ⁺]. 160

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.6 Hz, 1H), 7.86 (d, J= 1.8 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.67 - 7.58 (m, 2H), 7.57 - 7.42 (m, 3H), 7.35 - 7.25 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.47 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.54 (d, J= 12.4 Hz, 2H), 3.13 (t, J= 12.2 Hz, 2H), 1.90 - 1.48 (d, J= 14.5 Hz, 2H), 1.90 - 1.48 (m, 5H). 523.0 [M+H ⁺].    161

(400 MHz, CD ₃OD) δ 7.98 - 7.91 (m, 1H), 7.89 (d, J= 2.2 Hz, 1H), 7.77 (dd, J= 8.4, 2.3 Hz, 1H), 7.65 (d, J= 2.4 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.54 (d, J= 4.5 Hz, 1H), 7.50 (d, J= 5.3 Hz, 2H), 7.31 - 7.24 (m, 5H), 7.23 - 7.15 (m, 1H), 4.82 - 4.74 (m, 1H), 4.50 (s, 2H), 4.06 - 3.96 (m, 1H), 3.61 - 3.51 (m, 2H), 3.33 (m, 1H), 3.22 - 3.09 (m, 2H), 2.05 - 1.92 (m, 2H), 1.87 - 1.73 (m, 3H), 1.63 - 1.50 (m, 1H). 523.1 [M+H ⁺].    162

(400 MHz, CD ₃OD) δ 9.12 (s, 2H), 8.00 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 16.8 Hz, 1H), 7.65 (d, J= 2.3 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J= 16.8 Hz, 1H), 7.32 - 7.27 (m, 5H), 7.21 - 7.16 (m, 1H), 4.81 - 4.75 (m, 1H), 4.58 (s, 2H), 4.01 (dd, J= 10.1, 7.9 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.29 - 3.28 (m, 1H), 3.18 - 3.11 (m, 2H), 2.04 - 1.87 (m, 5H), 1.65 - 1.53 (m, 1H). 491.3 [M+H ⁺].    163

(400 MHz, CD ₃OD) δ 7.90 (d, J= 8.6 Hz, 1H), 7.74 (d, J= 2.4 Hz, 1H), 7.67 (d, J= 2.2 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J= 1.1 Hz, 2H), 7.34 - 7.19 (m, 6H), 6.71 (d, J= 2.4 Hz, 1H), 5.52 (s, 1H), 4.81 (d, J= 8.1 Hz, 1H), 4.62 (t, J= 6.0 Hz, 2H), 4.04 (dd, J= 10.1, 8.0 Hz, 1H), 3.71 - 3.60 (m, 4H), 3.06 (t, J= 12.1 Hz, 2H), 2.01 (m, 2H), 1.90 - 1.78 (m, 3H), 1.57 (m, 1H). 493.1 [M+H ⁺]. 164

(400 MHz, CD ₃OD) δ 7.86 (d, J= 8.6 Hz, 1H), 7.78 (d, J= 4.4 Hz, 1H), 7.75 (d, J= 4.7 Hz, 1H), 7.65 (d, J= 2.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.32 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 7.13 (s, 1H), 7.09 (d, J= 7.9 Hz, 1H), 4.81 - 4.75 (m, 1H), 4.27 (s, 2H), 4.21 (q, J= 6.9 Hz, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.53 - 3.43 (m, 2H), 3.29 - 3.28 (m, 1H), 3.04 - 2.92 (m, 2H), 2.00 - 1.92 (m, 2H), 1.89 - 1.81 (m, 1H), 1.79 - 1.68 (m, 2H), 1.59 - 1.49 (m, 4H). 533.1 [M+H ⁺]. 165

(400 MHz, CD ₃OD) δ 7.85 (d, J= 8.6 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.65 (d, J= 2.3 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.34 - 7.23 (m, 5H), 7.23 - 7.15 (m, 2H), 7.08 (dd, J= 8.0, 1.6 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.28 (s, 2H), 4.01 (m, 1H), 3.53 - 3.44 (m, 2H), 3.05 - 2.92 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H), 1.74 (m, 2H), 1.52 (m, 1H), 1.45 (dd, J= 6.1, 1.5 Hz, 6H). 547.4 [M+H ⁺]. 166

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 7.7 Hz, 2H), 7.54 (dd, J= 17.5, 7.7 Hz, 6H), 7.26 (d, J= 8.5 Hz, 1H), 4.43 (d, J= 14.8 Hz, 2H), 4.20 - 4.04 (m, 4H), 3.84 (s, 2H), 3.75 - 3.65 (m, 2H), 1.85 - 1.77 (m, 2H), 1.65 - 1.58 (m, 5H), 1.39 - 1.29 (m, 2H), 1.14 - 0.99 (m, 1H). 531.1 [M+H ⁺]. 167

(400 MHz, CD ₃OD) δ 7.95 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 7.8 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.50 (d, J= 13.1 Hz, 5H), 7.34 - 7.25 (m, 5H), 7.19 (dd, J= 5.7, 3.0 Hz, 1H), 4.78 (d, J= 7.8 Hz, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 4.29 (s, 2H), 4.07 - 3.96 (m, 1H), 3.45 (d, J= 13.0 Hz, 2H), 3.00 (t, J= 13.1 Hz, 2H), 2.37 (d, J= 14.5 Hz, 2H), 2.02 (d, J= 7.1 Hz, 1H), 1.92 (t, J= 12.9 Hz, 2H). 531.3 [M+H ⁺]. 168

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.6 Hz, 1H), 7.74 (d, J= 7.9 Hz, 2H), 7.65 (s, 1H), 7.58 - 7.46 (m, 5H), 7.34 - 7.24 (m, 5H), 7.24 - 7.15 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.43 - 4.30 (m, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.93 - 3.63 (m, 4H), 3.61 - 3.45 (m, 2H), 3.41 - 3.34 (m, 1H), 3.27 - 3.19 (m, 1H), 3.15 - 2.84 (m, 3H). 517.2 [M+H] ⁺.    169

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.1 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.57 - 7.48 (m, 5H), 7.34 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.81 - 4.75 (m, 1H), 4.44 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.83 (s, 2H), 3.56 (s, 4H), 3.29 - 3.28 (m, 1H). 504.1 [M+H ⁺].    170

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.6 Hz, 1H), 7.72 (d, J= 7.9 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.54 - 7.45 (m, 5H), 7.32 - 7.27 (m, 5H), 7.22 - 7.16 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.41 (d, J= 27.1 Hz, 2H), 4.14 (d, J= 11.2 Hz, 1H), 4.06 (s, 3H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.29 - 3.26 (m, 4H), 1.52 (d, J= 9.9 Hz, 3H). 505.2 [M+H ⁺].    171

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.5 Hz, 1H), 7.71 (d, J= 7.7 Hz, 2H), 7.63 (d, J= 2.2 Hz, 1H), 7.51 (s, 1H), 7.46 - 7.44 (m, 4H), 7.32 - 7.26 (m, 5H), 7.21 - 7.17 (m, 1H), 4.86 - 4.68 (m, 6H), 4.35 - 4.33 (m, 6H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H). 503.0 [M+H ⁺]. 172

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.55 - 7.47 (m, 5H), 7.32 - 7.26 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.73 (m, 1H), 4.33 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.37 - 3.32 (m, 4H), 3.29 - 3.27 (m, 1H), 1.85 - 1.74 (m, 4H), 1.28 (s, 3H). 519.3 [M+H ⁺].    173

(400 MHz, CD ₃OD) δ 7.95 (d, J= 8.5 Hz, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.44 (m, 4H), 7.33 - 7.25 (m, 5H), 7.19 (m, 1H), 4.78 (m, 1H), 4.17 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.48 (m, 4H), 3.35 (m, 4H). 539.1 [M+H ⁺]. 174

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.73 (d, J= 7.9 Hz, 2H), 7.65 (d, J= 2.3 Hz, 1H), 7.56 - 7.46 (m, 5H), 7.34 - 7.25 (m, 5H), 7.23 - 7.15 (m, 1H), 4.81 - 4.75 (m, 1H), 4.25 (s, 2H), 4.10 - 3.93 (m, 4H), 3.88 - 3.82 (m, 1H), 3.79 - 3.70 (m, 1H), 3.29 - 3.27 (m, 1H), 2.48 - 2.36 (m, 1H), 2.15 - 2.03 (m, 1H). 491.3 [M+H ⁺].    175

(400 MHz, DMSO- d ₆) δ 13.24 (s, 1H), 8.23 (s, 1H), 8.05 (d, J= 8.5 Hz, 1H), 7.68 (d, J= 7.9 Hz, 2H), 7.57 (s, 1H), 7.51 (d, J= 2.1 Hz, 1H), 7.46 (d, J= 1.4 Hz, 2H), 7.35-7.14 (m, 8H), 4.76 (d, J= 7.6 Hz, 1H), 4.56 (s, 2H), 4.13 (s, 2H), 3.89 (dd, J= 9.8, 7.8 Hz, 1H), 3.82 (dd, J= 6.0, 4.4 Hz, 2H), 3.27 (t, J= 5.2 Hz, 2H), 3.16 - 3.08 (m, 1H). 505.0 [M+H ⁺]. 176

(400 MHz, CD ₃OD) δ 7.98 -7.94 (m, 1H), 7.78 - 7.70 (m, 2H), 7.64 (t, J= 2.5 Hz, 1H), 7.54 - 7.49 (m, 5H), 7.34 - 7.23 (m, 5H), 7.22 - 7.15 (m, 1H), 4.82 - 4.74 (m, 1H), 4.35 (s, 2H), 4.01 (dd, J= 10.2, 7.8 Hz, 1H), 3.65 - 3.54 (m, 2H), 3.37 (d, J= 12.1 Hz, 2H), 3.28 (m, 1H), 2.81 (t, J= 11.7 Hz, 2H), 1.56 (p, J= 7.3 Hz, 4H), 0.99 (t, J= 7.4 Hz, 6H). 547.2 [M+H ⁺]. 177

(400 MHz, CD ₃O) δ 7.95 (d, J= 8.5 Hz, 1H), 7.72 (d, J= 7.7 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.55 - 7.46 (m, 5H), 7.33 - 7.24 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (dt, J= 8.1, 2.3 Hz, 1H), 4.34 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.44 (d, J= 12.5 Hz, 2H), 3.30 - 3.28 (m, 1H), 3.25 - 2.98 (m, 2H), 2.38 (d, J= 14.7 Hz, 2H), 1.65 (td, J= 14.5, 14.0, 3.8 Hz, 2H), 1.25 (s, 3H). 546.2 [M+H ⁺].    178

(400 MHz, CD ₃OD) δ 8.17 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.71 (s, 1H), 7.58 - 7.48 (m, 5H), 7.23 (d, J= 8.4 Hz, 1H), 4.42 (s, 2H), 4.03 (s, 4H), 3.66 - 3.57 (m, 4H), 3.46 (s, 2H), 3.37 (d, J= 13.3 Hz, 2H), 3.14 - 2.99 (m, 2H), 2.76 (s, 3H), 2.33 - 2.14 (m, 2H), 1.98 - 1.88 (m, 4H), 1.38 - 1.24 (m, 2H). 538.4 [M+H ⁺].    179

(400 MHz, CD ₃OD) δ 8.12 (d, J= 8.4 Hz, 1H), 7.76 (d, J= 7.8 Hz, 2H), 7.62 (s, 1H), 7.59 - 7.46 (m, 5H), 7.21 (d, J= 8.4 Hz, 1H), 4.42 (s, 2H), 4.42 - 4.33 (m, 1H), 4.08 - 3.97 (m, 4H), 3.83 - 3.72 (m, 1H), 3.67 - 3.53 (m, 4H), 3.51 - 3.41 (m, 2H), 3.22 - 3.10 (m, 1H), 2.73 - 2.60 (m, 1H), 2.03 - 1.97 (m, 2H), 1.96 (s, 3H), 1.92 - 1.84 (m, 4H), 1.74 - 1.64 (m, 2H). 566.3 [M+H ⁺].    180

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.76 (d, J= 8.1 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.56 - 7.52 (m, 3H), 7.51 (s, 2H), 7.32 - 7.26 (m, 5H), 7.22 - 7.16 (m, 1H), 4.78 (d, J= 8.1 Hz, 1H), 4.42 (s, 2H), 4.01 (dd, J= 10.0, 8.0 Hz, 1H), 3.68 - 3.54 (m, 2H), 3.29 - 3.20 (m, 3H), 2.33 - 2.22 (m, 2H), 1.80 (t, J= 14.2 Hz, 2H), 1.47 (s, 3H). 528.2 [M+H ⁺]. 181

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.56-7.47 (m, 5H), 7.34 - 7.24 (m, 5H), 7.28 - 7.15 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.32 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.40-3.07 (m, 8H), 2.06 (d, J= 14.8 Hz, 2H), 1.76 - 1.63 (m, 2H), 1.22 (s, 3H). 533.3 [M+H ⁺]. 182

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 7.9 Hz, 2H), 7.65 (d, J= 2.3 Hz, 1H), 7.51 (d, J= 11.6 Hz, 5H), 7.37 - 7.24 (m, 5H), 7.28 - 7.15 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.56 (dt, J= 15.6, 7.6 Hz, 2H), 4.36 - 4.29 (m, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.51 - 3.36 (m, 3H), 3.21 - 3.03 (m, 2H), 2.54 - 2.46 (m, 2H), 2.43 - 2.32 (m, 2H), 1.96 - 1.83 (m, 2H). 531.2 [M+H ⁺]. 183

(400 MHz, CD ₃OD) δ 8.19 (d, J= 8.4 Hz, 1H), 7.80 (d, J= 7.9 Hz, 2H), 7.66 (s, 1H), 7.61 - 7.51 (m, 5H), 7.30 (d, J= 8.4 Hz, 1H), 4.45 (s, 2H), 4.11 - 4.00 (m, 4H), 3.68 - 3.59 (m, 6H), 3.43 (s, 2H), 2.87 - 2.79 (m, 2H), 2.77 (s, 3H), 2.25 - 2.13 (m, 2H), 1.95 - 1.89 (m, 4H), 1.81 - 1.74 (m, 2H). 601.9 [M+H ⁺].    184

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.55 - 7.49 (m, 5H), 7.30 - 7.26 (m, 5H), 7.21 - 7.18 (m, 1H), 4.78 (d, J= 7.9 Hz, 1H), 4.59 (d, J= 13.0 Hz, 1H), 4.28 (d, J= 13.0 Hz, 1H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.57 (d, J= 5.0 Hz, 2H), 3.49 - 3.38 (m, 5H), 2.31 - 2.24 (m, 1H), 2.18 - 2.07 (m, 1H), 2.02 - 1.85 (m, 2H). 519.2 [M+H ⁺]. 185

(400 MHz, CD ₃OD) δ 7.95 (d, J= 8.5 Hz, 1H), 7.72 (d, J= 7.9 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.55 - 7.50 (m, 3H), 7.48 (s, 2H), 7.34 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.74 (m, 1H), 4.23 (s, 2H), 4.06 - 3.90 (m, 3H), 3.49 - 3.37 (m, 2H), 3.29 - 3.28 (m, 1H), 2.97 (d, J= 7.1 Hz, 2H), 2.08 - 1.94 (m, 1H), 1.75 - 1.66 (m, 2H), 1.44 - 1.32 (m, 2H). 519.2 [M+H ⁺].    186

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.52 (m, 5H), 7.32 - 7.26 (m, 5H), 7.20 (m, 1H), 4.78 (m, 1H), 4.34 (s, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.66 - 3.46 (m, 2H), 3.04 (m, 2H), 2.53 (m, 1H), 2.13 - 1.85 (m, 4H). 532.4 [M+H ⁺]. 187

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 7.8 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.56 - 7.48 (m, 5H), 7.32 - 7.26 (m, 5H), 7.20 - 7.18 (m, 1H), 4.78 (d, J= 8.0 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.18 (br, 1H), 4.18 (dd, J= 10.1, 8.0 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.38 (s, 3H), 2.43 - 2.36 (m, 1H), 2.17 - 2.15 (m, 1H). 505.2 [M+H ⁺]. 188

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.5 Hz, 1H), 7.73 (d, J= 7.8 Hz, 2H), 7.64 (d, J= 2.2 Hz, 1H), 7.55 - 7.48 (m, 5H), 7.32 - 7.26 (m, 5H), 7.21 - 7.18 (m, 1H), 4.78 (d, J= 7.8 Hz, 1H), 4.44 - 4.34 (m, 2H), 4.18 (br, 1H), 4.01 (dd, J= 10.0, 8.0 Hz, 1H), 3.67 - 3.51 (m, 2H), 3.38 (s, 3H), 2.44 - 2.32 (m, 1H), 2.21 - 2.00 (m, 1H). 505.1 [M+H ⁺]. 189

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.5 Hz, 1H), 7.72 (d, J= 7.9 Hz, 2H), 7.64 (d, J= 2.3 Hz, 1H), 7.57 - 7.44 (m, 5H), 7.37 - 7.23 (m, 5H), 7.19 (m, 1H), 4.77 (m, 1H), 4.56 - 4.25 (m, 2H), 4.01 (m, 1H), 3.81 - 3.39 (m, 2H), 3.29 - 3.08 (m, 2H), 2.31 - 1.91 (m, 2H), 1.44 (s, 3H). 505.4 [M+H ⁺]. 190

(400 MHz, CD ₃OD) δ 7.98 (d, J= 8.5 Hz, 1H), 7.81 (d, J= 8.2 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.54 (s, 3H), 7.48 (m, 2H), 7.32 - 7.27 (m, 5H), 7.19 (m, 1H), 5.23 - 5.16 (m, 4H), 5.14 - 5.07 (m, 1H), 4.79 (m, 1H), 4.02 (m, 1H), 3.64 (m, 2H), 2.54 (m, 2H), 1.97 - 1.78 (m, 6H). 531.2 [M+H ⁺]. 191

(400 MHz, CD ₃OD) δ 7.69 - 7.61 (m, 4H), 7.56 - 7.47 (m, 3H), 7.33 (m, 4H), 7.28 - 7.20 (m, 1H), 7.14 (s, 1H), 6.50 (s, 1H), 4.84 - 4.76 (m, 1H), 4.29 (s, 2H), 4.01 (m, 1H), 3.70 (s, 3H), 3.50 - 3.44 (m, 2H), 3.03 - 2.92 (m, 2H), 1.95 (m, 2H), 1.84 (m, 1H), 1.73 (m, 2H), 1.51 (m, 1H). 519.4 [M+H ⁺]. 192

(400 MHz, CD ₃OD) δ 7.65 (m, 4H), 7.55 - 7.46 (m, 3H), 7.34 - 7.31 (m, 4H), 7.24 (m, 1H), 7.15 (s, 1H), 6.50 (s, 1H), 4.79 (m, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 4.28 (s, 2H), 4.02 (m, 1H), 3.70 (s, 3H), 3.51 - 3.42 (m, 2H), 2.99 (m, 2H), 2.38 (m, 2H), 1.89 (m, 2H). 561.4 [M+H ⁺]. 193

(400 MHz, CD ₃OD) δ 7.65 - 7.54 (m, 4H), 7.51 - 7.44 (m, 3H), 7.36 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 7.10 (s, 1H), 6.43 (s, 1H), 4.80 - 4.70 (m, 1H), 4.40 (s, 2H), 4.09 - 3.95 (m, 5H), 3.71 - 3.55 (m, 7H), 3.27 (m, 1H), 1.88 (m, 4H). 561.3 [M+H ⁺]. 194

(400 MHz, CD ₃OD) δ 7.99 - 7.91 (m, 1H), 7.74 (d, J= 8.3 Hz, 2H), 7.64 (d, J= 2.3 Hz, 1H), 7.54 - 7.43 (m, 5H), 7.25 - 7.18 (m, 2H), 7.09 - 7.03 (m, 2H), 6.78 (m, 1H), 5.02 - 4.94 (m, 1H), 4.29 (s, 2H), 4.02 - 3.97 (m, 1H), 3.95 (s, 3H), 3.47 (m, 2H), 3.21 (dd, J= 10.2, 2.2 Hz, 1H), 2.97 (m, 2H), 2.01 - 1.43 (m, 6H). 519.5 [M+H ⁺].    195

(400 MHz, DMSO- d ₆) δ 13.26 (s, 1H), 8.24 (d, J= 8.4 Hz, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.67 (d, J= 7.8 Hz, 2H), 7.53 (s, 2H), 7.40 (s, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 7.8 Hz, 2H), 4.27 (s, 4H), 3.46 (s, 2H), 3.42 (s, 2H), 2.62 - 2.53 (m, 2H), 2.21 (m, 4H), 2.08 - 1.93 (m, 3H), 1.92 - 1.69 (m, 5H). 495.3 [M+H ⁺]. 196

(400 MHz, CD ₃OD) δ 8.18 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 8.2 Hz, 2H), 7.71 (d, J= 1.2 Hz, 1H), 7.61 - 7.56 (m, 3H), 7.53 (d, J= 8.1 Hz, 2H), 7.39 (dd, J= 8.5, 1.4 Hz, 1H), 4.43 (s, 2H), 4.03 (m, 4H), 3.61 (m, 6H), 2.73 - 2.59 (m, 2H), 2.12 - 2.00 (m, 3H), 1.89 (m, 5H). 495.3 [M+H ⁺]. 197

(400 MHz, DMSO- d ₆) δ 13.28 (s, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.16 (s, 1H), 7.72 (m, 3H), 7.55 (s, 2H), 7.46 - 7.19 (m, 4H), 4.57 (s, 2H), 4.14 (s, 2H), 3.83 (t, J= 5.1 Hz, 2H), 3.46 (s, 2H), 3.28 (t, J= 5.1 Hz, 2H), 2.56 (m, 2H), 2.12 - 1.79 (m, 4H). 469.3 [M+H ⁺]. 198

(400 MHz, CD ₃OD) δ 8.14 (d, J= 8.4 Hz, 1H), 7.78 (d, J= 8.2 Hz, 2H), 7.57 - 7.56 (m, 3H), 7.55 - 7.49 (m, 3H), 7.26 (d, J= 8.0 Hz, 1H), 4.42 (s, 2H), 4.03 (q, J= 10.7 Hz, 4H), 3.67 - 3.58 (m, 4H), 3.22 (s, 2H), 2.17 - 2.06 (m, 2H), 1.89 - 1.86 (m, 4H), 1.81 - 1.66 (m, 6H). 509.4 [M+H ⁺]. 199

(400 MHz, DMSO- d ₆ ) δ 12.72 (br s, 1H), 7.99 (dd, J= 8.4, 3.0 Hz, 1H), 7.58- 7.47 (m, 4H), 7.46 (d, J= 2.8 Hz, 1H), 7.40 (s, 2H), 7.30 (dd, J= 8.0, 2.8 Hz, 2H), 7.20 (dd, J= 8.4, 2.8 Hz, 1H), 4.64 (d, J= 2.8 Hz, 2H), 4.24 (d, J= 2.8 Hz, 2H), 3.88 (dd, J= 6.0, 4.0 Hz, 2H), 3.34 (dd, J= 6.0, 4.0Hz, 2H), 3.17 (s, 2H), 2.11 - 2.06 (m, 2H), 1.78-1.67 (m, 6H). 483.0 [M+H ⁺]. 200

(400 MHz, CD ₃OD) δ 7.95 (d, J= 8.6 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 2.2 Hz, CD ₃OD 1H), 7.56 - 7.48 (m, 5H), 7.33 - 7.24 (m, 5H), 7.20 (m, 1H), 4.78 (m, 1H), 4.40 (s, 2H), 4.01 (m, 1H), 3.82 (s, 2H), 3.66 - 3.52 (m, 4H), 3.01 (s, 3H). 518.4 [M+H ⁺]. 201

(400 MHz, CD ₃OD) δ 7.93 (d, J= 8.5 Hz, 1H), 7.74 (d, J= 7.8 Hz, 2H), 7.62 (d, J= 2.2 Hz, 1H), 7.56 - 7.49 (m, 3H), 7.47 (s, 2H), 7.32 - 7.23 (m, 5H), 7.22 - 7.15 (m, 1H), 4.77 (m, 1H), 4.44 (s, 2H), 4.01 (m, 1H), 3.85 (s, 2H), 3.60 (s, 4H), 3.29 (m, 1H), 2.75 (m, 3.4 Hz, 1H), 1.41 - 1.21 (m, 2H), 0.95 - 0.82 (m, 2H). 544.3 [M+H ⁺]. 202

(400 MHz, CD ₃OD) δ 7.64 - 7.44 (m, 5H), 7.36 - 7.27 (m, 6H), 7.24 (m, 1H), 7.12 (s, 1H), 6.45 (s, 1H), 4.81 - 4.73 (m, 1H), 4.63 (s, 2H), 4.20 (s, 2H), 4.00 (m, 1H), 3.89 - 3.83 (m, 2H), 3.34 (m, 2H), 3.27 (m, 1H). 535.2 [M+H ⁺]. 203

(400 MHz, CD ₃OD) δ 7.72 - 7.60 (m, 4H), 7.56 - 7.48 (m, 3H), 7.33 (m, 4H), 7.24 (m, 1H), 7.14 (s, 1H), 6.51 - 6.46 (m, 1H), 4.79 (m, 1H), 4.41 (s, 2H), 4.01 (m, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 3.60 - 3.48 (m, 4H), 3.27 (m, 1H). 534.1 [M+H ⁺]. 204

(400 MHz, CD ₃OD) δ 7.69 - 7.48 (m, 7H), 7.32 (m, 4H), 7.24 (m, 1H), 7.14 (s, 1H), 6.49 (m, 1H), 4.77 (m, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 4.06 - 3.95 (m, 1H), 3.73 - 3.64 (m, 3H), 3.64 - 3.51 (m, 1H), 3.28 - 3.16 (m, 2H), 2.06 - 1.67 (m, 4H), 1.62 (m, 5H), 1.42 (m, 3H). 547.3 [M+H ⁺].    205

(400 MHz, CD ₃OD) δ 7.67 - 7.59 (m, 4H), 7.54 - 7.46 (m, 3H), 7.33 (m, 4H), 7.24 (m, 1H), 7.13 (s, 1H), 6.48 (s, 1H), 4.78 (m, 1H), 4.35 (m, 2H), 4.01 (m, 1H), 3.84 (m, 3H), 3.68 (s, 3H), 3.63 - 3.33 (m, 3H), 3.29 - 3.16 (m, 2H), 3.15 - 2.84 (m, 3H). 547.4 [M+H ⁺]. 206

(400 MHz, CD ₃OD) δ 7.79 (m, 1H), 7.70 - 7.54 (m, 3H), 7.37 - 7.19 (m, 5H), 7.10 (m, 2H), 7.04 (d, J= 7.8 Hz, 1H), 6.38 (s, 1H), 4.75 - 4.66 (m, 1H), 4.24 (s, 2H), 4.15 (q, J= 7.0 Hz, 2H), 3.98 (m, 1H), 3.60 (s, 3H), 3.46 (m, 2H), 3.25 (m, 1H), 3.03 - 2.86 (m, 2H), 1.93 (m, 2H), 1.88 - 1.67 (m, 3H), 1.51 (m, 4H). 563.4 [M+H ⁺]. 207

(400 MHz, CD ₃OD) δ 8.00 (m, 1H), 7.76 - 7.70 (m, 2H), 7.60 - 7.41 (m, 5H), 7.20 (s, 1H), 4.31 (s, 2H), 3.55 - 3.44 (m, 2H), 3.17 (s, 2H), 2.98 (m, 2H), 2.03 - 1.64 (m, 6H), 1.29 (s, 6H). 475.4 [M+H ⁺]. 208

(400 MHz, CD ₃OD) δ 7.83 - 7.64 (m, 3H), 7.59 - 7.24 (m, 5H), 6.93 (s, 1H), 4.29 (s, 2H), 3.46 (m, 2H), 3.22 - 3.07 (m, 2H), 2.97 (m, 2H), 2.86 - 2.66 (m, 3H), 2.05 - 1.39 (m, 6H), 1.37 - 1.20 (m, 6H). 455.4 [M+H ⁺].    209

(400 MHz, CD ₃OD) δ 7.81 - 7.67 (m, 3H), 7.63 - 7.46 (m, 4H), 7.10 (s, 1H), 6.58 (s, 1H), 4.30 (s, 2H), 4.05 (s, 3H), 3.48 (m, 2H), 3.17 (s, 2H), 2.98 (m, 2H), 1.96 (m, 2H), 1.90 - 1.67 (m, 3H), 1.58 - 1.47 (m, 1H), 1.32 (s, 6H). 471.3 [M+H ⁺]. 210

(400 MHz, CD ₃OD) δ 7.97 (m, 1H), 7.78 - 7.71 (m, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.55 - 7.48 (m, 5H), 7.33 - 7.25 (m, 5H), 7.23 - 7.16 (m, 1H), 4.79 (m, 1H), 4.38 (s, 2H), 4.01 (m, 1H), 3.57 - 3.45 (m, 2H), 3.21 (s, 2H), 2.10 (m, 4H). 475.5 [M+H ⁺]. 211

(400 MHz, CD ₃OD) δ 7.96 (dd, J= 8.6, 3.5 Hz, 1H), 7.76 (dd, J= 8.6, 2.6 Hz, 2H), 7.64 (d, J= 2.1 Hz, 1H), 7.56 - 7.43 (m, 5H), 7.36 - 7.23 (m, 5H), 7.21-7.16 (m, 1H), 4.78 (d, J= 8.1 Hz, 1H), 4.58 - 4.38 (m, 1H), 4.32 - 4.19 (m, 2H), 4.17 - 4.09 (m, 2H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.85 (dd, J= 11.4, 6.3 Hz, 1H), 3.73 (d, J= 8.4 Hz, 1H), 2.76 (s, 3H), 2.52 - 2.22 (m, 2H). 505.5 [M+H ⁺]. 212

(400 MHz, CD ₃OD) δ 7.96 (d, J= 8.4 Hz, 1H), 7.72 (d, J= 8.0 Hz, 2H), 7.65 (s, 1H), 7.53 - 7.45 (m, 5H), 7.34-7.16 (m, 6H), 5.40 - 5.28 (m, 1H), 4.36 (s, 2H), 4.15 - 4.05 (m, 2H), 2.66 - 2.37 (m, 2H), 2.28 - 2.12 (m, 2H), 1.70 - 1.50 (m, 2H). 461.5 [M+H ⁺]. 213

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.2 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.57 - 7.46 (m, 5H), 7.33 - 7.24 (m, 5H), 7.19 (m, 1H), 4.82 - 4.76 (m, 1H), 4.60 (d, J= 13.5 Hz, 1H), 4.24 (d, J= 13.6 Hz, 1H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.62 (m, 2H), 2.10 (m, 1H), 1.89 - 1.59 (m, 5H), 1.45 (dd, J= 12.3, 6.7 Hz, 6H). 517.5 [M+H ⁺]. 214

(400 MHz, CD ₃OD) δ 8.14 (dd, J= 8.3, 3.3 Hz, 1H), 7.78 (dd, J= 11.6, 8.2 Hz, 2H), 7.62 - 7.53 (m, 6H), 7.27 - 7.25 (m, 1H), 4.62 (s, 1H), 4.36 (s, 1H), 3.63 - 3.52 (m, 1H), 3.25 - 3.22 (m, 3H), 2.17 - 2.06 (m, 2H), 2.05 - 1.68 (m, 10H), 1.64 - 1.61 (m, 5H), 1.44 (d, J= 6.7 Hz, 3H). 495.4 [M+H ⁺]. 215

(400 MHz, CD ₃OD) δ 8.18 (s, 1H), 7.78 (s, 2H), 7.71 (s, 1H), 7.64 - 7.50 (m, 5H), 7.40 (d, J= 7.8 Hz, 1H), 4.62 (t, J= 3.8 Hz, 1H), 4.35 (s, 1H), 3.61-3.54 (m, 3H), 3.34 - 3.25 (m, 1H), 2.64 (s, 2H), 2.04 (m, 4H), 1.83 (m, 4H), 1.67-1.58 (m, 5H), 1.43 (s, 3H). 481.4 [M+H ⁺]. 216

(400 MHz, CD ₃OD) δ 8.17 (m, 1H), 7.80 (m, 2H), 7.66 - 7.53 (m, 6H), 7.32 - 7.26 (m, 1H), 4.65 (s, 1H), 4.38 (s, 1H), 3.58 (m, 1H), 3.28 (m, 1H), 3.19 (s, 2H), 2.07 - 1.76 (m, 4H), 1.66 (m, 5H), 1.46 (d, J= 6.7 Hz, 3H), 1.33 (s, 6H). 468.9 [M+H ⁺]. 217

(400 MHz, CD3OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.56 - 7.47 (m, 5H), 7.31 - 7.26 (m, 5H), 7.20 (m, 1H), 4.83 - 4.70 (m, 2H), 4.12 - 3.95 (m, 2H), 3.19 (m, 1H), 2.87 (m, 1H), 2.12 - 1.52 (m, 9H). 503.3 [M+H ⁺]. 218

(400 MHz, CD ₃OD) δ 7.99 (d, J= 8.6 Hz, 1H), 7.77 (d, J= 8.1 Hz, 2H), 7.67 (d, J= 2.2 Hz, 1H), 7.62 - 7.49 (m, 5H), 7.36 - 7.26 (m, 5H), 7.31 - 7.18 (m, 1H), 4.85 - 4.72 (m, 2H), 4.14 - 3.99 (m, 2H), 3.32-3.14 (m, 3H), 2.89 (t, J= 12.2 Hz, 1H), 2.11-1.81 (m, 3H), 1.73 - 1.48 (m, 6H). 503.6 [M+H ⁺]. 219

(400 MHz, CD ₃OD) δ 7.97 - 7.94 (m, 1H), 7.79 - 7.74 (m, 2H), 7.64 (s, 1H), 7.58 (d, J= 7.6 Hz, 2H), 7.51 (m, 3H), 7.34 - 7.23 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.74 (m, 1H), 4.66 (s, 2H), 4.06 - 3.95 (m, 4H), 3.57 - 3.46 (m, 2H), 3.42 - 3.34 (m, 2H), 1.50 (d, J= 6.3 Hz, 6H). 519.6 [M+H ⁺]. 220

(400 MHz, CD ₃OD) δ 7.97 (d, J= 8.5 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.65 (d, J= 2.2 Hz, 1H), 7.58 - 7.48 (m, 5H), 7.33 - 7.25 (m, 5H), 7.19 (m, 1H), 4.82 - 4.76 (m, 1H), 4.44 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.65 (q, J= 6.5 Hz, 2H), 3.29 (s, 1H), 2.34 - 2.21 (m, 2H), 1.81 - 1.69 (m, 2H), 1.36 (d, J= 6.6 Hz, 6H). 503.6 [M+H ⁺]. 221

(400 MHz, CD ₃OD) δ 7.95 (d, J= 8.5 Hz, 1H), 7.72 (d, J= 8.1 Hz, 2H), 7.64 (d, J= 2.3 Hz, 1H), 7.54 - 7.44 (m, 5H), 7.33 - 7.24 (m, 5H), 7.19 (m, 1H), 4.78 (m, 1H), 4.25 (m, 1H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.29 (m, 1H), 3.26 - 3.12 (m, 1H), 2.17 - 1.91 (m, 4H), 1.90 - 1.69 (m, 2H). 475.4 [M+H ⁺]. 222

(400 MHz, CD ₃OD) δ 7.95 (s, 1H), 7.76-7.13 (m, 14H), 4.01 (s, 1H), 3.52-2.91 (m, 6H), 2.69 (s, 1H), 2.17 - 1.75 (m, 4H). 475.4 [M+H ⁺].    223

(400 MHz, CD ₃OD) δ 7.92 (d, J= 8.5 Hz, 1H), 7.70 (d, J= 7.9 Hz, 2H), 7.62 (d, J= 2.2 Hz, 1H), 7.53 - 7.48 (m, 3H), 7.44 (s, 2H), 7.31 - 7.25 (m, 5H), 7.21 - 7.18 (m, 1H), 4.76 (dt, J= 8.2, 2.3 Hz, 1H), 4.64 (t, J= 8.0 Hz, 1H), 4.00 (dd, J= 10.1, 7.9 Hz, 1H), 3.47 - 3.45 (m, 2H), 2.51 - 2.47 (m, 1H), 2.37 - 2.13 (m, 4H). 461.5 [M+H ⁺].    224

(400 MHz, CD ₃OD) δ 7.94 (d, J= 8.6 Hz, 1H), 7.64 (d, J= 2.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.51 (s, 1H), 7.41 (m, 2H), 7.32 - 7.23 (m, 7H), 7.19 (m, 1H), 4.78 (m, 1H), 4.01 (dd, J= 10.1, 8.0 Hz, 1H), 3.56 - 3.46 (m, 2H), 3.29 (m, 1H), 3.15 (m, 2H), 2.98 - 2.87 (m, 1H), 2.10 (m, 2H), 1.91 (m, 2H). 475.5 [M+H ⁺]. 225

(400 MHz, CD ₃OD) δ 7.90 (dd, J= 8.5, 4.3 Hz, 1H), 7.69 (dd, J= 11.8, 8.2 Hz, 2H), 7.60 (d, J= 2.2 Hz, 1H), 7.54 (d, J= 8.1 Hz, 1H), 7.52 - 7.38 (m, 4H), 7.17 (ddd, J= 8.1, 4.8, 2.8 Hz, 2H), 7.00 (d, J= 8.1 Hz, 2H), 6.74 (t, J= 7.5 Hz, 1H), 4.93-4.88 (m, 1H), 4.56 (s, 1H), 4.29 (s, 1H), 4.00 - 3.94 (m, 1H), 3.91 (s, 3H), 3.51 (q, J= 7.0 Hz, 1H), 3.24-3.126 (m, 2H), 2.00 - 1.91 (m, 1H), 1.90 - 1.61 (m, 4H), 1.58 (d, J= 6.3 Hz, 4H), 1.38 (d, J= 6.6 Hz, 3H). 547.2 [M+H ⁺]. 226

(400 MHz, CD ₃OD) δ 7.95 - 7.89 (m, 1H), 7.73 - 7.69 (m, 2H), 7.61 (s, 1H), 7.51(d, J= 7.7 Hz, 2H), 7.47 - 7.44 (m, 2H), 7.42 (s, 1H), 7.20 - 7.15 (m, 2H), 7.03 - 6.99 (m, 2H), 6.77 - 6.72 (m, 1H), 5.06 - 4.87 (m, 1H), 4.40 (s, 2H), 4.00 - 3.90 (m, 4H), 3.64 - 3.59 (m, 2H), 3.21-3.11 (m, 1H), 2.27 - 2.14 (m, 2H), 1.79 - 1.62 (m, 2H), 1.32 (d, J= 6.6 Hz, 6H). 533.1 [M+H ⁺]. 227

(400 MHz, CD ₃OD) δ 8.20 (s, 1H), 7.98 (d, J= 8.3 Hz, 1H), 7.77 - 7.68 (m, 4H), 7.55 - 7.46 (m, 7H), 7.23 (d, J= 8.4 Hz, 1H), 5.17 (s, 1H), 4.30 (s, 2H), 4.16 - 4.04 (m, 1H), 3.47 (d, J= 12.6 Hz, 2H), 3.38 (dd, J= 10.4, 2.7 Hz, 1H), 2.97 (td, J= 12.6, 3.0 Hz, 2H), 2.00 - 1.90 (m, 2H), 1.88 - 1.44 (m, 4H). 490.4 [M+H ⁺]. 228

(400 MHz, CD ₃OD) δ 7.95 (dd, J= 8.5, 4.4 Hz, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J= 8.1 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.26 - 7.07 (m, 4H), 7.00 (t, J= 7.5 Hz, 1H), 5.10 - 4.98 (m, 1H), 4.61 (s, 1H), 4.34 (s, 1H), 4.09 - 3.97 (m, 1H), 3.56 (q, J= 7.0 Hz, 1H), 3.28 - 3.14 (m, 2H), 2.04 - 1.96 (m, 1H), 1.93 - 1.71 (m, 3H), 1.62 (d, J= 6.3 Hz, 5H), 1.43 (d, J= 6.7 Hz, 3H). 535.4 [M+H ⁺]. 229

(400 MHz, CD ₃OD) δ 7.86 (d, J= 8.5 Hz, 1H), 7.68 (d, J= 7.8 Hz, 2H), 7.61 (s, 1H), 7.51 (d, J= 7.8 Hz, 2H), 7.46 - 7.34 (m, 3H), 7.26 - 7.07 (m, 4H), 6.99 (t, J= 7.5 Hz, 1H), 5.02 - 4.93 (m, 2H), 4.38 (s, 2H), 4.03 (t, J= 9.2 Hz, 1H), 3.94 - 3.73 (m, 3H), 3.55 (d, J= 9.7 Hz, 2H), 3.37 - 3.22 (m, 3H), 3.09 (s, 1H), 2.96 - 2.81 (m, 1H). 535.4 [M+H ⁺]. 230

(400 MHz, CD ₃OD) δ 7.79 - 7.67 (m, 3H), 7.67 - 7.54 (m, 2H), 7.51 - 7.34 (m, 3H), 7.24 - 7.08 (m, 6H), 4.72 (d, J= 8.1 Hz, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 3.99 (dd, J= 10.1, 8.3 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.29 - 3.19 (m, 2H), 2.04 - 1.64 (m, 5H), 1.65 (d, J= 6.3 Hz, 4H), 1.45 (d, J= 6.7 Hz, 3H). 535.5 [M+H ⁺]. 231

(400 MHz, CD ₃OD) δ 7.79-7.68 (m, 3H), 7.67 - 7.44 (m, 4H), 7.24 - 7.07 (m, 7H), 4.77 - 4.69 (m, 1H), 4.42 - 4.31 (m, 2H), 4.00 (dd, J= 10.2, 8.3 Hz, 1H), 3.97 - 3.46 (m, 7H), 3.38 - 3.33 (m, 1H), 3.14 - 2.88 (m, 3H). 535.5 [M+H ⁺]. 232

(400 MHz, CD ₃OD) δ 7.90 (dd, J= 8.6, 4.2 Hz, 1H), 7.73 - 7.60 (m, 4H), 7.54 (d, J= 8.3 Hz, 1H), 7.51 - 7.37 (m, 4H), 7.19 - 7.07 (m, 4H), 5.08 (d, J= 8.1 Hz, 1H), 4.57 (s, 1H), 4.30 (s, 1H), 4.04 (dd, J= 10.3, 8.2 Hz, 1H), 3.51 (h, J= 6.7 Hz, 1H), 3.30 - 3.21 (m, 2H), 2.00-1.68 (m, 4H), 1.58 (d, J= 6.3 Hz, 4H), 1.57 -1.41 (m, 2H), 1.39 (d, J= 6.6 Hz, 2H). 597.5 [M+H ⁺]. 233

(400 MHz, CD ₃OD) δ 7.94 (d, J= 7.3 Hz, 1H), 7.76 - 7.53 (m, 4H), 7.51 - 7.40 (m, 5H), 7.31 (d, J= 8.0 Hz, 1H), 7.26 - 7.16 (m, 3H), 4.79 (d, J= 8.0 Hz, 1H), 4.58 (s, 1H), 4.31 (s, 1H), 3.98 (t, J= 9.2 Hz, 1H), 3.53 (q, J= 6.9 Hz, 1H), 3.29 - 3.14 (m, 2H), 2.01 - 1.66 (m, 5H), 1.61 (d, J= 6.3 Hz, 4H), 1.40 (d, J= 6.6 Hz, 3H). 595.4 [M+H ⁺]. 234

(400 MHz, CD ₃OD) δ 8.71 (s, 1H), 8.53 (d, J= 5.5 Hz, 1H), 8.35 (d, J= 8.1 Hz, 1H), 7.99 (d, J= 8.5 Hz, 1H), 7.82 - 7.71 (m, 3H), 7.58 - 7.46 (m, 4H), 7.24 (dd, J= 8.6, 1.4 Hz, 1H), 5.25 - 5.18 (m, 1H), 4.31 (s, 2H), 4.12 (dd, J= 10.5, 8.5 Hz, 1H), 3.98 (s, 1H), 3.53 - 3.44 (m, 2H), 3.40 (dd, J= 10.5, 3.2 Hz, 1H), 3.35 (s, 1H), 3.06 - 2.91 (m, 2H), 2.02 - 1.91 (m, 2H), 1.90 - 1.81 (m, 1H), 1.80 - 1.67 (m, 2H), 1.60 - 1.45 (m, 1H). 490.4 [M+H ⁺]. 235

(400 MHz, CD ₃OD) δ 8.69 (s, 1H), 8.52 (s, 1H), 8.32 (d, J= 8.2 Hz, 1H), 7.99 (d, J= 8.5 Hz, 1H), 7.80 - 7.70 (m, 3H), 7.57 - 7.45 (m, 4H), 7.24 (dd, J= 8.6, 1.4 Hz, 1H), 5.24 - 5.15 (m, 1H), 4.30 (s, 2H), 4.12 (dd, J= 10.5, 8.5 Hz, 2H), 3.98 (s, 1H), 3.52 - 3.44 (m, 2H), 3.40 (dd, J= 10.5, 3.2 Hz, 1H), 3.04 - 2.91 (m, 2H), 2.03 - 1.91 (m, 2H), 1.84 (d, J= 13.6 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.57 - 1.46 (m, 1H). 490.4 [M+H ⁺]. 236

¹H NMR (400 MHz, CD ₃OD) δ 7.85 (dd, J= 8.4, 3.1 Hz, 1H), 7.76 (dd, J= 11.7, 8.3 Hz, 2H), 7.61 (d, J= 8.2 Hz, 1H), 7.58 – 7.44 (m, 3H), 7.42 (s, 1H), 7.33 (d, J= 2.9 Hz, 1H), 7.18 (dt, J= 8.7, 1.6 Hz, 1H), 7.02 (t, J= 8.4 Hz, 1H), 6.49 (s, 2H), 5.29 (dt, J= 7.7, 3.6 Hz, 1H), 4.64 (s, 1H), 4.37 (s, 1H), 4.01-3.52 (m, 8H), 3.27 (dd, J= 9.8, 4.1 Hz, 2H), 2.07-1.68 (m, 6H), 1.65 (d, J= 6.3 Hz, 3H), 1.46 (d, J= 6.7 Hz, 3H). 577.4 [M+H] ⁺ 237

¹H NMR (400 MHz, CD ₃OD) δ 7.94 – 7.87 (m, 1H), 7.83 – 7.72 (m, 2H), 7.66 – 7.61 (m, 1H), 7.61 – 7.40 (m, 5H), 7.24 – 7.14 (m, 1H), 7.09 – 6.99 (m, 1H), 6.68 – 6.60 (m, 1H), 6.60 – 6.51 (m, 1H), 5.29 – 5.20 (m, 1H), 4.64 (s, 2H), 4.42 – 4.34 (m, 1H), 3.96 (t, J = 9.5 Hz, 1H), 3.83 (s, 3H), 3.64 – 3.46 (m, 1H), 3.17 – 3.12 (m, 1H), 2.11 – 1.56 (m, 9H), 1.46 (d, J = 6.7 Hz, 3H). 565.5 [M+H] ⁺ 238

¹H NMR (400 MHz, CD ₃OD) δ 8.30 (d, J= 8.3 Hz, 1H), 7.91 (d, J= 8.9 Hz, 2H), 7.83 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 1.3 Hz, 2H), 7.57 (dd, J= 12.8, 8.4 Hz, 3H), 7.28 (s, 1H), 6.88 (d, J= 1.9 Hz, 2H), 4.45 (s, 2H), 4.06 (q, J= 10.7 Hz, 4H), 3.66 (s, 3H), 3.69-3.60 (m, 4H), 1.93-1.88 (m, 4H). 533.1 [M+H] ⁺ Example 92-238: Example number structure ^1H NMR MS (ESI) M/Z 92

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.52 - 7.48 (m, 5H) , 7.30 - 7.23 (m, 5H), 7.19 - 7.14 (m, 1H), 4.77 (dt, J = 8.0, 2.4 Hz, 1H), 4.30 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz , 1H), 3.44 (d, J = 12.4 Hz, 2H), 3.33 - 3.17 (m, 2H), 3.07 (t, J = 12.4 Hz, 1H), 2.38 (d, J = 14.4Hz, 1H), 2.15 - 2.02 (m, 1H), 1.98 - 1.95 (m, 1H), 1.66 (t, J = 13.2 Hz, 1H), 1.25 (s, 3H) 546.3 [M+H] ⁺ . 93

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.57 - 7.50 (m , 5H), 7.31 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.43 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.61 (d, J = 13.3 Hz, 2H), 3.29 - 3.22 (m, 3H), 2.33 - 2.23 (m, 2H), 1.87 - 1.71 (m, 2H), 1.47 (s, 3H) . 528.0 [M+H] ⁺ . 94

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.63 (s, 1H), 7.57 - 7.39 (m, 5H), 7.35 - 7.23 ( m, 5H), 7.23 - 7.15 (m, 1H), 4.77 (d, J = 7.8 Hz, 1H), 4.24 (s, 2H), 4.07 - 3.97 (m, 1H), 3.23 - 3.11 (m, 1H) , 2.94 - 2.80 (m, 1H), 2.38 - 2.24 (m, 3H), 2.21 - 2.11 (m, 2H), 1.61 - 1.43 (m, 4H). 547.2 [M+H] ⁺ . 95

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.53 - 7.47 (m , 5H), 7.32 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.82 - 4.75 (m, 1H), 4.22 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H ), 3.29 - 3.28 (m, 1H), 3.24 - 3.15 (m, 1H), 2.74 - 2.66 (m, 1H), 2.31 - 2.23 (m, 2H), 2.14 - 2.04 (m, 2H), 1.71 - 1.63 (m, 4H). 547.1 [M+H] ⁺ . 96

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 10.8 Hz, 6H), 7.26 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 4.15 (br, 1H), 3.79 (br, 2H), 3.62 (br, 1H), 3.43 (br, 1H), 2.95 (s, 6H), 2.61 (br, 1H), 2.36 (br, 1H), 1.84 - 1.77 (m, 2H), 1.65 - 1.57 (m, 5H), 1.42 - 1.22 (m, 4H), 1.04 - 1.10 (m, 1H). 510.3 [M+H] ⁺ . 97

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.62 - 7.51 (m, 6H), 7.25 (d, J = 8.4 Hz , 1H), 4.49 (s, 2H), 4.25 - 4.12 (m, 1H), 3.95 - 3.78 (m, 2H), 3.71 - 3.59 (m, 1H), 3.54 - 3.44 (m, 1H), 3.31 (s , 2H), 2.97 (s, 6H), 2.70 - 2.58 (m, 1H), 2.48 - 2.33 (m, 1H), 1.86 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H), 1.39 - 1.27 (m, 2H), 1.11 - 0.99 (m, 1H). 510.3 [M+H] ⁺ . 98

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.61 - 7.50 (m, 6H), 7.26 (d, J = 8.5 Hz , 1H), 4.49 - 4.35 (m, 2H), 4.23 - 4.14 (m, 1H), 3.70 - 3.51 (m, 2H), 3.38 (s, 2H), 3.31 (s, 3H), 3.30 - 3.23 (m , 2H), 2.45 - 2.30 (m, 1H), 2.21 - 2.03 (m, 1H), 1.87 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H), 1.42 - 1.27 (m, 2H), 1.13 - 1.01 (m, 1H). 497.3 [M+H] ⁺ . 99

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.64 - 7.50 (m, 6H), 7.26 (d, J = 8.6 Hz , 1H), 4.52 - 4.32 (m, 2H), 4.25 - 4.13 (m, 1H), 3.71 - 3.50 (m, 2H), 3.39 (s, 2H), 3.32 (s, 3H), 3.30 - 3.22 (m , 2H), 2.49 - 2.30 (m, 1H), 2.21 - 2.03 (m, 1H), 1.88 - 1.72 (m, 2H), 1.70 - 1.55 (m, 5H), 1.40 - 1.27 (m, 2H), 1.16 - 0.95 (m, 1H). 497.3 [M+H] ⁺ . 100

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.67 - 7.46 (m, 6H), 7.27 (d, J = 8.4 Hz , 1H), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.51 - 3.40 (m, 2H), 3.17 (s, 2H), 3.08 - 2.94 (m, 2H), 2.49 - 2.16 (m, 2H), 2.00 - 1.83 (m, 2H), 1.30 (s, 6H). 483.1 [M+H] ⁺ . 101

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.58 - 7.47 (m, 6H), 7.26 (d, J = 8.4 Hz , 1H), 4.38 (s, 2H), 4.07 (s, 4H), 3.61 (s, 2H), 3.54 (s, 2H), 3.16 (s, 2H), 1.30 (s, 6H). 455.2 [M+H] ⁺ . 102

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.5 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.63 (d, J = 2.2 Hz, 1H), 7.54 - 7.49 (m , 3H), 7.45 (s, 2H), 7.34 - 7.22 (m, 5H), 7.19 (m, 1H), 4.78 (dt, J = 8.1, 2.3 Hz, 1H), 4.42 (s, 2H), 4.08 - 3.96 (m, 5H), 3.61 (dt, J = 20.3, 5.3 Hz, 4H), 3.30-3.27 (m, 1H), 1.89 (dt, J = 16.1, 5.4 Hz, 4H). 531.2 [M+H] ⁺ . 103

(400 MHz, CD ₃ OD) δ 8.14 (dd, J = 8.4, 1.8 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.59 - 7.51 (m, 6H), 7.26 (d, J = 8.4 Hz, 1H), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.52 - 3.44 (m, 2H), 3.08 - 2.95 (m, 2H), 2.38 (m, 2H), 1.92 (m, 2H), 1.80 (m, 6.9 Hz, 3H), 1.61 (m, 6H), 1.34 (m, 3H), 1.07 (m, 1H). 523.1 [M+H] ⁺ . 104

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.3 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.61 - 7.52 (m, 6H), 7.27 (d, J = 8.2 Hz, 1H) , 4.41 (s, 2H), 3.95 - 3.75 (m, 4H), 3.30 (s, 2H), 3.13 - 3.00 (m, 2H), 2.99 - 2.84 (m, 2H), 1.86 - 1.75 (m, 2H) , 1.71 - 1.53 (m, 6H), 1.44 - 1.22 (m, 3H), 1.12 - 1.02 (m, 1H). 509.3 [M+H] ⁺ . 105

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.63 - 7.47 (m, 6H), 7.26 (d, J = 8.5Hz, 1H) , 4.27 (s, 2H), 4.10 - 4.02 (m, 2H), 3.51 - 3.42 (m, 3H), 3.32 (s, 2H), 2.17 - 2.06 (m, 2H), 1.85 - 1.57 (m, 9H) , 1.40 - 1.28 (m, 2H), 1.14 - 0.99 (m, 1H). 497.2 [M+H] ⁺ . 106

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.89 - 7.76 (m, 2H), 7.67 - 7.33 (m, 6H), 7.27 (d, J = 8.3 Hz, 1H) , 4.46 (s, 2H), 3.85 (s, 2H), 3.70 - 3.49 (m, 4H), 3.30 (s, 2H), 1.87 - 1.76 (m, 2H), 1.73 - 1.46 (m, 5H), 1.36 - 1.28 (m, 2H), 1.12 - 1.03 (m, 1H). 496.1 [M+H] ⁺ . 107

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.64 - 7.43 (m, 6H), 7.26 (d, J = 8.4 Hz, 1H) , 4.50 - 4.35 (m, 2H), 4.08 (s, 3H), 3.31 - 3.25 (m, 6H), 1.88 - 1.73 (m, 2H), 1.70 - 1.45 (m, 8H), 1.41 - 1.25 (m, 2H), 1.13 - 0.98 (m, 1H) 497.1 [M+H] ⁺ 108

(400 MHz, CD ₃ OD) δ 8.18 - 8.10 (m, 1H), 7.84 - 7.74 (m, 2H), 7.72 - 7.46 (m, 6H), 7.30 - 7.22 (m, 1H), 4.73 - 4.58 (m , 1H), 4.38 - 4.26 (m, 1H), 4.15 - 3.98 (m, 1H), 3.77 - 3.43 (m, 3H), 3.40 - 3.31 (m, 2H), 2.94 (s, 6H), 2.62 - 2.51 (m, 1H), 2.29 - 1.99 (m, 3H), 1.87 - 1.70 (m, 2H), 1.67 - 1.46 (m, 5H), 1.41 - 1.25 (m, 2H), 1.13 - 0.99 (m, 1H) 524.2 [M+H] ⁺ 109

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.67 - 7.47 (m, 6H), 7.26 (d, J = 8.5 Hz, 1H) , 4.42 (s, 2H), 4.09 - 3.97 (m, 4H), 3.68 - 3.55 (m, 4H), 3.32 (s, 2H), 1.93 - 1.75 (m, 6H), 1.68 - 1.55 (m, 5H) , 1.39 - 1.27 (m, 2H), 1.11 - 1.01 (m, 1H) 523.2 [M+H] ⁺ 110

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.3, 2.0 Hz, 2H), 7.58 - 7.53 (m, 4H), 7.49 (m, 2H) , 7.26 (dd, J = 8.5, 1.2 Hz, 1H), 4.80 (m, 3H), 4.47 - 4.24 (m, 5H), 4.07 (s, 1H), 3.57 (m, 1H), 1.81 (m, 2H ), 1.61 (m, 5H), 1.34 (m, 2H), 1.07 (m, 1H). 495.1 [M+H] ⁺ . 111

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.67 - 7.47 (m, 6H), 7.26 (d, J = 8.5 Hz, 1H) , 4.38 (s, 2H), 3.40 - 3.31 (m, 6H), 2.01 - 1.71 (m, 6H), 1.70 - 1.51 (m, 5H), 1.42 - 1.32 (m, 2H), 1.28 (s, 3H) , 1.14 - 0.98 (m, 1H). 511.2 [M+H] ⁺ 112

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.65 - 7.49 (m, 6H), 7.26 (d, J = 8.8 Hz, 1H) , 4.29 (s, 2H), 3.68 - 3.55 (m, 4H), 3.45 - 3.36 (m, 4H), 3.31 (s, 2H), 1.85 - 1.75 (m, 2H), 1.68 - 1.55 (m, 5H) , 1.39 - 1.28 (m, 2H), 1.12 - 1.03 (m, 1H) 531.1 [M+H] ⁺ . 113

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.66 - 7.50 (m, 6H), 7.26 (d, J = 9.0 Hz , 1H), 4.26 (s, 2H), 4.10 - 4.02 (m, 2H), 4.00 - 3.95 (m, 1H), 3.88 - 3.83 (m, 1H), 3.78 - 3.72 (m, 1H), 3.32 (s , 2H), 2.48 - 2.40 (m, 1H), 2.14 - 2.07 (m, 1H), 1.85 - 1.77 (m, 2H), 1.68 - 1.55 (m, 5H), 1.39 - 1.29 (m, 2H), 1.10 - 1.03 (m, 1H). 483.2 [M+H] ⁺ . 114

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.65 - 7.51 (m, 6H), 7.27 (d, J = 7.2 Hz , 1H), 4.61 (d, J = 12.9 Hz, 1H), 4.29 (d, J = 13.0 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.58 (d, J = 5.1 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.43 (s, 3H), 3.32 - 3.31 (m, 3H), 2.32 - 2.24 (m, 1H), 2.17 - 2.09 (m, 1H), 2.01 - 1.88 (m, 2H) , 1.85 - 1.76 (m, 2H), 1.70 - 1.56 (m, 5H), 1.40 - 1.30 (m, 2H), 1.12 - 1.03 (m, 1H). 511.4 [M+H] ⁺ 115

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (d, J = 7.3 Hz , 1H), 4.61 (d, J = 13.0 Hz, 1H), 4.29 (d, J = 13.0 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.58 (d, J = 5.1 Hz, 2H), 3.50 - 3.43 (m, 1H), 3.42 (s, 3H), 3.31 - 3.30 (m, 3H), 2.36 - 2.23 (m, 1H), 2.19 - 2.08 (m, 1H), 2.03 - 1.87 (m, 2H) , 1.86 - 1.76 (m, 2H), 1.69 - 1.54 (m, 5H), 1.39 - 1.28 (m, 2H), 1.12 - 1.01 (m, 1H). 511.3 [M+H] ⁺ 116

(400 MHz, CD ₃ OD) δ 8.16 (d, J = 8.5 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.70 - 7.53 (m, 6H), 7.28 (d, J = 8.6 Hz, 1H) , 4.38 (s, 2H), 3.92 - 3.80 (m, 2H), 3.43 - 3.36 (m, 2H), 3.32 (s, 2H), 2.88 - 2.73 (m, 2H), 1.89 - 1.77 (m, 2H) , 1.71 - 1.57 (m, 5H), 1.42 - 1.31 (m, 2H), 1.30 - 1.20 (m, 6H), 1.13 - 1.05 (m, 1H). 511.3 [M+H] ⁺ 117

(400 MHz, CD ₃ OD) δ 8.17 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.65 - 7.54 (m, 6H), 7.29 (d, J = 7.3 Hz , 1H), 4.41 (s, 2H), 4.13 - 3.98 (m, 2H), 3.86 - 3.71 (m, 2H), 3.51 - 3.34 (m, 4H), 3.30 - 3.17 (m, 2H), 1.88 - 1.79 (m, 2H), 1.71 - 1.59 (m, 5H), 1.43 - 1.32 (m, 2H), 1.14 - 1.06 (m, 1H) 531.1 [M+H] ⁺ 118

(400 MHz, DMSO- d ₆ ) δ 13.21 (s, 1H), 8.26 - 8.13 (m, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.60 - 7.50 (m, 3H), 7.36 (s , 1H), 7.31 - 7.21 (m, 3H), 4.52 (s, 2H), 3.24 - 3.13 (m, 4H), 2.38 - 2.29 (m, 2H), 1.81 - 1.68 (m, 6H), 1.62 - 1.47 (m, 5H), 1.34 - 1.25 (m, 2H), 1.09 - 1.00 (m, 1H). 495.3 [M+H] ⁺ 119

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.58 - 7.49 (m, 4H), 7.34 (d, J = 7.9 Hz , 2H), 7.25 (d, J = 8.4 Hz, 1H), 4.66 (s, 2H), 4.22 (s, 2H), 3.88 (t, J = 5.1 Hz, 2H), 3.37 - 3.35 (m, 4H) , 1.85 - 1.81 (m, 2H), 1.65 - 1.62 (m, 5H), 1.37 - 1.27 (m, 2H), 1.11-1.05 (m, 1H). 497.1 [M+H] ⁺ 120

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.66 - 7.50 (m, 6H), 7.26 (d, J = 7.3 Hz , 1H), 4.27 (s, 2H), 4.11 - 4.01 (m, 2H), 4.01 - 3.94 (m, 1H), 3.89 - 3.82 (m, 1H), 3.79 - 3.71 (m, 1H), 3.32 (s , 2H), 2.50 - 2.38 (m, 1H), 2.14 - 2.06 (m, 1H), 1.87 - 1.76 (m, 2H), 1.69 - 1.54 (m, 5H), 1.40 - 1.29 (m, 2H), 1.12 - 1.02 (m, 1H) 483.2 [M+H] ⁺ 121

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.64 - 7.45 (m, 6H), 7.26 (d, J = 8.5 Hz , 1H), 4.37 (s, 2H), 4.26 - 4.18 (m, 2H), 4.15 - 4.07 (m, 2H), 3.32 (s, 2H), 2.61 - 2.54 (m, 1H), 2.50 - 2.44 (m , 1H), 1.84 - 1.76 (m, 2H), 1.70 - 1.53 (m, 5H), 1.39 - 1.30 (m, 2H), 1.10 - 1.03 (m, 1H). 453.0 [M+H] ⁺ 122

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.66 - 7.49 (m, 6H), 7.26 (d, J = 8.4 Hz , 1H), 4.40 (s, 2H), 3.59 - 3.45 (m, 2H), 3.30 - 3.17 (m, 4H), 2.25 - 2.02 (m, 4H), 1.86 - 1.75 (m, 2H), 1.70 - 1.54 (m, 5H), 1.39 - 1.29 (m, 2H), 1.10 - 1.01 (m, 1H) 467.3 [M+H] ⁺ 123

(400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.68 - 7.49 (m, 6H), 7.27 (d, J = 7.4 Hz , 1H), 4.34 (s, 2H), 3.32 (s, 2H), 2.89 (s, 6H), 1.85 - 1.76 (m, 2H), 1.69 - 1.53 (m, 5H), 1.38 - 1.28 (m, 2H ), 1.11 - 1.03 (m, 1H). 441.2 [M+H] ⁺ 124

(400 MHz, CD ₃ OD) δ 7.83 - 7.69 (m, 3H), 7.67 - 7.48 (m, 4H), 7.14 (s, 1H), 6.61 (s, 1H), 4.33 (s, 2H), 4.08 ( s, 3H), 3.56 - 3.45 (m, 2H), 3.34 (s, 2H), 3.07 - 2.94 (m, 2H), 2.03 - 1.52 (m, 13H), 1.42 - 1.31 (m, 2H), 1.16 - 1.05 (m, 1H). 511.1 [M+H] ⁺ 125

(400 MHz, CD ₃ OD) δ 7.84 - 7.70 (m, 3H), 7.67 - 7.50 (m, 4H), 7.14 (s, 1H), 6.61 (s, 1H), 4.38 (s, 2H), 4.08 ( s, 3H), 3.90 - 3.80 (m, 2H), 3.43 - 3.36 (m, 2H), 3.32 (s, 2H), 2.86 - 2.74 (m, 2H), 1.94 - 1.84 (m, 2H), 1.74 - 1.55 (m, 5H), 1.43 - 1.32 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.15 - 1.06 (m, 1H). 541.1 [M+H] ⁺ 126

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.55 (m, 6H), 7.27 (d, J = 8.4 Hz, 1H ), 4.56 (s, 2H), 4.42 (s, 2H), 4.30 (s, 2H), 3.46 (d, J = 12.8 Hz, 2H), 3.17 (s, 2H), 3.01 (m, 2H), 2.39 (d, J = 13.6 Hz, 2H), 1.97- 1.85 (m, 2H), 1.30 (s, 6H). 483.1 [M+H] ⁺ 127

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.0, 1.9 Hz, 2H), 7.60 - 7.50 (m, 6H), 7.26 (d, J = 8.4 Hz, 1H), 4.38 (m, 2H), 3.93-3.77 (m, 3H), 3.73 - 3.21 (m, 4H), 3.17 (s, 2H), 3.08-2.95 (m, 3H), 1.30 (s , 6H). 553.1 [M+H] ⁺ 128

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.66 - 7.48 (m, 6H), 7.26 (d, J = 9.9 Hz , 1H), 4.27 (s, 2H), 4.06 (dd, J = 11.8, 4.6 Hz, 2H), 3.54 - 3.42 (m, 3H), 3.17 (s, 2H), 2.16 - 2.07 (m, 2H), 1.78 - 1.65 (m, 2H), 1.30 (s, 6H). 457.3 [M+H] ⁺ 129

(400 MHz, CD ₃ OD) δ 8.04 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.55 - 7.38 (m, 6H), 7.16 (d, J = 9.7 Hz , 1H), 4.33 (s, 2H), 3.72 (s, 2H), 3.54 - 3.38 (m, 4H), 3.07 (s, 2H), 1.20 (s, 6H). 456 [M+H] ⁺ 130

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.63 - 7.49 (m, 6H), 7.26 (d, J = 9.9 Hz , 1H), 4.44 (d, J = 17.7 Hz, 2H), 4.17 - 4.03 (m, 4H), 3.29 (d, J = 3.6 Hz, 3H), 3.17 (s, 2H), 1.54 (d, J = 15.4 Hz, 3H), 1.30 (s, 6H). 457.1 [M+H] ⁺ 131

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.67 - 7.50 (m, 6H), 7.26 (d, J = 9.9 Hz , 1H), 4.56 (d, J = 12.8 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.51 - 3.39 (m, 2H), 3.30 - 3.21 ( m, 2H), 3.17 (s, 2H), 2.84 (s, 6H), 2.54 - 2.44 (m, 1H), 2.25 - 2.13 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.90 ( m, 1H), 1.30 (s, 6H). 484.2 [M+H] ⁺ 132

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.62 - 7.49 (m, 6H), 7.26 (d, J = 10.0 Hz , 1H), 4.41 (s, 2H), 4.02 (s, 4H), 3.62 (t, J = 5.2 Hz, 4H), 3.17 (s, 2H), 1.88 (t, J = 5.3 Hz, 4H), 1.30 (s, 6H). 483.3 [M+H] ⁺ 133

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.67 - 7.50 (m, 6H), 7.26 (d, J = 8.6 Hz, 1H) , 4.35 (s, 2H), 3.39 - 3.31 (m, 4H), 3.17 (s, 2H), 1.89 - 1.72 (m, 4H), 1.30 (s, 6H), 1.28 (s, 3H). 471.3 [M+H] ⁺ 134

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.62 - 7.45 (m, 6H), 7.26 (d, J = 10.0 Hz , 1H), 4.24 (s, 2H), 3.60 - 3.51 (m, 4H), 3.43 - 3.36 (m, 4H), 3.16 (s, 2H), 1.30 (s, 6H). 491.1 [M+H] ⁺ 135

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.63 - 7.50 (m, 6H), 7.26 (d, J = 10.0 Hz , 1H), 4.26 (s, 2H), 4.10 - 4.02 (m, 2H), 3.99 - 3.94 (m, 1H), 3.88 - 3.82 (m, 1H), 3.78 - 3.72 (m, 1H), 3.17 (s , 2H), 2.47 - 2.40 (m, 1H), 2.13 - 2.07 (m, 1H), 1.30 (s, 6H). 443.2 [M+H] ⁺ 136

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.67 - 7.50 (m, 6H), 7.27 (d, J = 9.9 Hz , 1H), 4.60 (d, J = 12.9 Hz, 1H), 4.29 (d, J = 13.0 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.58 (d, J = 5.0 Hz, 2H), 3.42 (s, 3H), 3.35 - 3.31 (m, 2H), 3.17 (s, 2H), 2.34 - 2.25 (m, 1H), 2.17 - 2.09 (m, 1H), 2.02 - 1.87 (m, 2H), 1.30 (s, 6H). 471.3 [M+H] ⁺ 137

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.69 - 7.49 (m, 6H), 7.26 (d, J = 9.8 Hz , 1H), 4.61 - 4.48 (m, 1H), 4.30 - 4.14 (m, 1H), 3.83 - 3.68 (m, 1H), 3.57 (d, J = 5.1 Hz, 2H), 3.42 (s, 3H), 3.40 - 3.31 (m, 2H), 3.17 (s, 2H), 2.32 - 2.19 (m, 1H), 2.16 - 2.03 (m, 1H), 2.00 - 1.84 (m, 2H), 1.30 (s, 6H). 472.2 [M+H] ⁺ 138

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.61 - 7.52 (m, 6H), 7.27 (d, J = 7.6 Hz , 1H), 4.36 (s, 2H), 3.91 - 3.78 (m, 2H), 3.38 (d, J = 12.2 Hz, 2H), 3.17 (s, 2H), 2.78 (t, J = 11.7 Hz, 2H) , 1.30 (s, 6H), 1.24 (s, 3H), 1.23 (s, 3H). 471.2 [M+H] ⁺ 139

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.27 (d, J = 7.3 Hz , 1H), 4.39 (s, 2H), 4.13 - 4.01 (m, 2H), 3.72 (t, J = 12.6 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.28 - 3.20 (m, 2H), 3.17 (s, 2H), 1.30 (s, 6H). 443.0 [M+H] ⁺ 140

(400 MHz, DMSO- d ₆ ) δ 13.18 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.56 - 7.49 (m, 3H), 7.35 (s, 1H), 7.30 - 7.18 (m, 3H), 4.52 (s, 2H), 3.24 - 3.16 (m, 2H), 3.04 (s, 2H), 2.37 - 2.28 ( m, 2H), 1.76 - 1.68 (m, 4H), 1.24 (s, 6H). 455.2 [M+H] ⁺ 141

(400 MHz, CD ₃ OD) δ 8.10 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 -7.40 (m, 5H), 7.31 (d, J = 8.0 Hz , 2H), 7.23 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 4.20 (s, 2H), 3.85 (t, J = 5.2 Hz, 2H), 3.33 (t, J = 5.2 Hz , 2H), 3.14 (s, 2H), 1.28 (s, 6H). 457.1 [M+H] ⁺ 142

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (d, J = 8.4 Hz , 1H), 4.26 (s, 2H), 4.11 - 4.01 (m, 2H), 4.01 - 3.92 (m, 1H), 3.90 - 3.83 (m, 1H), 3.75 (q, J = 8.1 Hz, 1H), 3.17 (s, 2H), 2.48 - 2.38 (m, 1H), 2.16 - 2.06 (m, 1H), 1.30 (s, 6H). 443.3 [M+H] ⁺ 143

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.57 - 7.54 (m, 6H), 7.27 (d, J = 8.4Hz , 1H), 4.41 (s, 2H), 4.14 - 4.11 (m, 1H), 3.75-3.73(m, 2H), 3.65 - 3.52 (m, 1H), 3.31-3.30 (m, 1H), 3.17 (s , 2H), 2.94 (s, 6H), 2.59 (m, 1H), 2.34 (m, 1H), 1.30 (s, 6H). 470.2 [M+H] ⁺ 144

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.60 - 7.51 (m, 6H), 7.27 (d, J = 8.4 Hz ,1H), 4.42 (s, 2H), 4.13 (t, J = 8.4 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.59 (m, 1H), 3.41 (m, 2H), 3.17 (s, 2H), 2.95 (s, 6H), 2.61 (m, 1H), 2.36 (q,7.2, 6.8 Hz, 1H), 1.30 (s, 6H). 470.3 [M+H] ⁺ 145

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.64 - 7.51 (m, 6H), 7.26 (d, J = 8.0 Hz , 1H), 4.43 - 4.39 (m, 2H), 4.19 (s, 1H), 3.63 (m, 1H), 3.55 (d, J = 11.6 Hz, 1H), 3.39 (s, 3H), 3.26 - 3.20 ( m, 1H), 3.17 (s, 2H), 2.37 (m, 1H), 2.17-2.14 (m, 1H), 1.30 (s, 6H). 457.3 [M+H] ⁺ 146

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.58 - 7.54 (m, 6H), 7.27 (d, J = 8.4 Hz , 1H), 4.42 (dd, J = 20.0, 8.0 Hz, 2H), 4.19 (s, 1H), 3.68 - 3.58 (m, 1H), 3.55 (d, J = 12.4 Hz, 1H), 3.17 (s, 2H), 2.38 (m, 1H), 2.20 -2.11 (m, 1H), 1.30 (s, 6H). 457.1 [M+H] ⁺ 147

(400 MHz, CD ₃ OD) δ 8.13 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.58 - 7.52 (m, 4H), 7.48 (d, J = 8.3 Hz , 2H), 7.26 (d, J = 7.2 Hz, 1H), 4.37 (s, 2H), 4.26 - 4.17 (m, 2H), 4.15 - 4.06 (m, 2H), 3.17 (s, 2H), 2.64 - 2.53 (m, 1H), 2.52 - 2.41 (m, 1H), 1.30 (s, 6H). 412.9 [M+H] ⁺ 148

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.5, 2H), 7.60 - 7.50 (m, 6H), 7.26 (dd, J = 8.5, 1.5 Hz, 1H), 4.39 (s, 2H), 3.55 - 3.48 (m, 2H), 3.25-3.18 (m, 2H), 3.16 (s, 2H), 2.20 (s, 2H), 2.06 - 1.97 (m, 2H), 1.30 (s, 6H). 427.0 [M+H] ⁺ 149

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.59 (s, 2H), 7.56 - 7.50 (m, 4H), 7.27 (d, J = 9.4 Hz, 1H), 4.33 (s, 2H), 3.17 (s, 2H), 2.89 (s, 6H), 1.30 (s, 6H). 401.1 [M+H] ⁺ 150

(400 MHz, CD ₃ OD) δ 8.19 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 8.7 Hz, 3H), 7.53 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 4.31 (s, 2H), 3.59 (s, 2H), 3.54 - 3.45 (m , 2H), 2.99 (m, 2H), 2.64 (m, 2H), 2.12 - 1.93 (m, 5H), 1.90 - 1.47 (m, 5H). 453.3 [M+H] ⁺ 151

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.61 - 7.51 (m, 6H), 7.26 (dd, J = 8.7, 1.4 Hz, 1H), 4.31 (s, 2H), 3.48 (d, J = 12.2 Hz, 2H), 3.22 (s, 2H), 3.05 - 2.93 (m, 2H), 2.13 - 2.09 (m, 2H), 1.98 - 1.95 (m, 2H), 1.86 - 171 (m, 9H), 1.53 - 1.50 (m, 1H). 467.3 [M+H] ⁺ 152

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 3.1 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.4, 6.1 Hz, 1H), 4.31 (s, 2H), 3.48 (d, J = 12.2 Hz, 2H ), 3.32 (s, 2H), 3.04 - 2.93 (m, 2H), 1.97 (d, J = 14.5 Hz, 2H), 1.87 - 1.52 (m, 11H), 1.31 (d, J = 16.1 Hz, 2H) , 1.01 - 0.88 (m, 1H). 499.2 [M+H ⁺ ]. 153

(400 MHz, CD ₃ OD) δ 8.07 (d, J = 8.4 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.62 - 7.52 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H) , 7.18 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 4.31 (s, 2H), 4.02 (s, 3H), 3.52 - 3.47 (m, 2H), 3.33 (s, 2H), 3.00 (t, J = 12.4 Hz, 2H), 2.03 - 1.94 (m, 2H), 1.90 - 1.68 (m, 6H), 1.67 - 1.59 (m, 5H), 1.35 - 1.29 (m, 2H), 1.13 - 1.01 (m, 1H). 511.3 [M+H ⁺ ]. 154

(400 MHz, CD ₃ OD) δ 7.77 - 7.67 (m, 3H), 7.62 - 7.55 (m, 1H), 7.54 - 7.48 (m, 3H), 7.11 (s, 1H), 6.58 (s, 1H), 4.42 (s, 2H), 4.06 (s, 3H), 4.05 - 3.96 (m, 4H), 3.65 - 3.56 (m, 4H), 3.33 (s, 2H), 1.93 - 1.82 (m, 6H), 1.68 - 1.58 (m, 5H), 1.39 - 1.29 (m, 2H), 1.14 - 1.02 (m, 1H). 553.2 [M+H ⁺ ]. 155

(400 MHz, CD ₃ OD) δ 7.77 - 7.67 (m, 3H), 7.58 (d, J = 16.5 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.10 (s, 1H), 6.58 (s, 1H), 4.42 (s, 2H), 4.05 (s, 3H), 4.05 - 3.97 (m, 4H), 3.71 - 3.53 (m, 4H), 3.17 (s, 2H), 1.95 - 1.80 (m, 4H) , 1.32 (s, 6H). 513.0 [M+H ⁺ ]. 156

(400 MHz, CD ₃ OD) δ 8.19 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.71 (s, 1H), 7.57 (s, 2H), 7.56 - 7.50 (m, 3H), 7.27 - 7.20 (m, 1H), 4.43 (s, 2H), 4.03 (d, J = 6.3 Hz, 4H), 3.69 - 3.54 (m, 4H), 3.47 (s, 2H), 3.28 - 3.22 (m, 2H), 3.05 (t, J = 13.2 Hz, 2H), 2.16 (td, J = 14.1, 4.3 Hz, 2H), 1.95 - 1.85 (m, 6H). 524.1 [M+H ⁺ ]. 157

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.64 (q, J = 1.0 Hz, 1H ), 7.58 (s, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.30 - 7.24 (m, 1H), 4.31 (s, 2H), 3.58 (d, J = 2.1 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.41 - 3.39 (m, 2H), 3.37 - 3.35 (m, 2H), 3.19 (s, 3H), 3.02 - 2.96 (m, 2H), 1.98 - 1.93 (m, 2H) , 1.86 - 1.69 (m, 3H), 1.57 - 1.50 (m, 1H). 487.2 [M+H ⁺ ]. 158

(400 MHz, CD ₃ OD) δ 8.34 (d, J = 9.5 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H ), 7.53 (s, 1H), 7.49-7.34 (m, 3H), 7.34 - 7.23 (m, 5H), 7.28 - 7.14 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.37 ( s, 2H), 4.01 (dd, J = 10.1, 7.9 Hz, 1H), 3.30-3.27 (m, 1H), 2.09-1.77 (m, 5H), 1.66 (s, 1H), 1.32 (s, 6H) . 504.1 [M+H ⁺ ] 159

(400 MHz, CD ₃ OD) δ 8.12 - 8.04 (m, 2H), 8.01 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.67 - 7.53 (m, 4H) , 7.36 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J = 7.9 Hz, 1H), 4.49 (s, 2H), 4.07 - 3.96 (m, 1H), 3.53 (d , J = 12.4 Hz, 2H), 3.13 (t, J = 12.3 Hz, 2H), 1.99 - 1.95 (m, 2H), 1.91 - 1.68 (m, 4H), 1.58 - 1.55 (m, 1H). 557.2 [M+H ⁺ ]. 160

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.67 - 7.58 (m, 2H) , 7.57 - 7.42 (m, 3H), 7.35 - 7.25 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 4.01 (dd , J = 10.1, 8.0 Hz, 1H), 3.54 (d, J = 12.4 Hz, 2H), 3.13 (t, J = 12.2 Hz, 2H), 1.90 - 1.48 (d, J = 14.5 Hz, 2H), 1.90 - 1.48 (m, 5H). 523.0 [M+H ⁺ ]. 161

(400 MHz, CD ₃ OD) δ 7.98 - 7.91 (m, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.4, 2.3 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.54 (d, J = 4.5 Hz, 1H), 7.50 (d, J = 5.3 Hz, 2H), 7.31 - 7.24 (m, 5H), 7.23 - 7.15 (m, 1H), 4.82 - 4.74 (m, 1H), 4.50 (s, 2H), 4.06 - 3.96 (m, 1H), 3.61 - 3.51 (m, 2H), 3.33 (m, 1H), 3.22 - 3.09 (m, 2H), 2.05 - 1.92 (m, 2H), 1.87 - 1.73 (m, 3H), 1.63 - 1.50 (m, 1H). 523.1 [M+H ⁺ ]. 162

(400 MHz, CD ₃ OD) δ 9.12 (s, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 16.8 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H ), 7.55 (s, 1H), 7.47 (d, J = 16.8 Hz, 1H), 7.32 - 7.27 (m, 5H), 7.21 - 7.16 (m, 1H), 4.81 - 4.75 (m, 1H), 4.58 ( s, 2H), 4.01 (dd, J = 10.1, 7.9 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.29 - 3.28 (m, 1H), 3.18 - 3.11 (m, 2H), 2.04 - 1.87 ( m, 5H), 1.65 - 1.53 (m, 1H). 491.3 [M+H ⁺ ]. 163

(400 MHz, CD ₃ OD) δ 7.90 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.55 (s, 1H ), 7.42 (d, J = 1.1 Hz, 2H), 7.34 - 7.19 (m, 6H), 6.71 (d, J = 2.4 Hz, 1H), 5.52 (s, 1H), 4.81 (d, J = 8.1 Hz , 1H), 4.62 (t, J = 6.0 Hz, 2H), 4.04 (dd, J = 10.1, 8.0 Hz, 1H), 3.71 - 3.60 (m, 4H), 3.06 (t, J = 12.1 Hz, 2H) , 2.01 (m, 2H), 1.90 - 1.78 (m, 3H), 1.57 (m, 1H). 493.1 [M+H ⁺ ]. 164

(400 MHz, CD ₃ OD) δ 7.86 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.75 (d, J = 4.7 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.32 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 7.13 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.81 - 4.75 (m, 1H), 4.27 (s, 2H), 4.21 (q, J = 6.9 Hz, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.53 - 3.43 (m , 2H), 3.29 - 3.28 (m, 1H), 3.04 - 2.92 (m, 2H), 2.00 - 1.92 (m, 2H), 1.89 - 1.81 (m, 1H), 1.79 - 1.68 (m, 2H), 1.59 - 1.49 (m, 4H). 533.1 [M+H ⁺ ]. 165

(400 MHz, CD ₃ OD) δ 7.85 (d, J = 8.6 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.54 - 7.45 (m, 2H) , 7.34 - 7.23 (m, 5H), 7.23 - 7.15 (m, 2H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.28 (s, 2H), 4.01 (m, 1H), 3.53 - 3.44 (m, 2H), 3.05 - 2.92 (m, 2H), 1.97 (m, 2H), 1.85 (m, 1H), 1.74 (m, 2H), 1.52 (m, 1H ), 1.45 (dd, J = 6.1, 1.5 Hz, 6H). 547.4 [M+H ⁺ ]. 166

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.7 Hz, 2H), 7.54 (dd, J = 17.5, 7.7 Hz, 6H), 7.26 (d , J = 8.5 Hz, 1H), 4.43 (d, J = 14.8 Hz, 2H), 4.20 - 4.04 (m, 4H), 3.84 (s, 2H), 3.75 - 3.65 (m, 2H), 1.85 - 1.77 ( m, 2H), 1.65 - 1.58 (m, 5H), 1.39 - 1.29 (m, 2H), 1.14 - 0.99 (m, 1H). 531.1 [M+H ⁺ ]. 167

(400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 13.1 Hz, 5H), 7.34 - 7.25 (m, 5H), 7.19 (dd, J = 5.7, 3.0 Hz, 1H), 4.78 (d, J = 7.8 Hz, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 4.29 (s, 2H), 4.07 - 3.96 (m, 1H), 3.45 (d, J = 13.0 Hz, 2H), 3.00 (t, J = 13.1 Hz, 2H), 2.37 (d, J = 14.5 Hz, 2H), 2.02 (d, J = 7.1 Hz, 1H), 1.92 (t, J = 12.9 Hz, 2H). 531.3 [M+H ⁺ ]. 168

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 7.9 Hz, 2H), 7.65 (s, 1H), 7.58 - 7.46 (m, 5H), 7.34 - 7.24 (m, 5H), 7.24 - 7.15 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.43 - 4.30 (m, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H ), 3.93 - 3.63 (m, 4H), 3.61 - 3.45 (m, 2H), 3.41 - 3.34 (m, 1H), 3.27 - 3.19 (m, 1H), 3.15 - 2.84 (m, 3H). 517.2 [M+H] ⁺ . 169

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.57 - 7.48 (m , 5H), 7.34 - 7.26 (m, 5H), 7.23 - 7.16 (m, 1H), 4.81 - 4.75 (m, 1H), 4.44 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H ), 3.83 (s, 2H), 3.56 (s, 4H), 3.29 - 3.28 (m, 1H). 504.1 [M+H ⁺ ]. 170

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.54 - 7.45 (m , 5H), 7.32 - 7.27 (m, 5H), 7.22 - 7.16 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.41 (d, J = 27.1 Hz, 2H), 4.14 (d, J = 11.2 Hz, 1H), 4.06 (s, 3H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.29 - 3.26 (m, 4H), 1.52 (d, J = 9.9 Hz, 3H). 505.2 [M+H ⁺ ]. 171

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H ), 7.46 - 7.44 (m, 4H), 7.32 - 7.26 (m, 5H), 7.21 - 7.17 (m, 1H), 4.86 - 4.68 (m, 6H), 4.35 - 4.33 (m, 6H), 4.01 (dd , J = 10.1, 8.0 Hz, 1H). 503.0 [M+H ⁺ ]. 172

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.55 - 7.47 (m , 5H), 7.32 - 7.26 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.73 (m, 1H), 4.33 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H ), 3.37 - 3.32 (m, 4H), 3.29 - 3.27 (m, 1H), 1.85 - 1.74 (m, 4H), 1.28 (s, 3H). 519.3 [M+H ⁺ ]. 173

(400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H ), 7.50 - 7.44 (m, 4H), 7.33 - 7.25 (m, 5H), 7.19 (m, 1H), 4.78 (m, 1H), 4.17 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.48 (m, 4H), 3.35 (m, 4H). 539.1 [M+H ⁺ ]. 174

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.56 - 7.46 (m , 5H), 7.34 - 7.25 (m, 5H), 7.23 - 7.15 (m, 1H), 4.81 - 4.75 (m, 1H), 4.25 (s, 2H), 4.10 - 3.93 (m, 4H), 3.88 - 3.82 (m, 1H), 3.79 - 3.70 (m, 1H), 3.29 - 3.27 (m, 1H), 2.48 - 2.36 (m, 1H), 2.15 - 2.03 (m, 1H). 491.3 [M+H ⁺ ]. 175

(400 MHz, DMSO- d ₆ ) δ 13.24 (s, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.57 ( s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 1.4 Hz, 2H), 7.35-7.14 (m, 8H), 4.76 (d, J = 7.6 Hz, 1H), 4.56 (s, 2H), 4.13 (s, 2H), 3.89 (dd, J = 9.8, 7.8 Hz, 1H), 3.82 (dd, J = 6.0, 4.4 Hz, 2H), 3.27 (t, J = 5.2 Hz , 2H), 3.16 - 3.08 (m, 1H). 505.0 [M+H ⁺ ]. 176

(400 MHz, CD ₃ OD) δ 7.98 -7.94 (m, 1H), 7.78 - 7.70 (m, 2H), 7.64 (t, J = 2.5 Hz, 1H), 7.54 - 7.49 (m, 5H), 7.34 - 7.23 (m, 5H), 7.22 - 7.15 (m, 1H), 4.82 - 4.74 (m, 1H), 4.35 (s, 2H), 4.01 (dd, J = 10.2, 7.8 Hz, 1H), 3.65 - 3.54 ( m, 2H), 3.37 (d, J = 12.1 Hz, 2H), 3.28 (m, 1H), 2.81 (t, J = 11.7 Hz, 2H), 1.56 (p, J = 7.3 Hz, 4H), 0.99 ( t, J = 7.4 Hz, 6H). 547.2 [M+H ⁺ ]. 177

(400 MHz, CD ₃ O) δ 7.95 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.55 - 7.46 (m , 5H), 7.33 - 7.24 (m, 5H), 7.23 - 7.16 (m, 1H), 4.78 (dt, J = 8.1, 2.3 Hz, 1H), 4.34 (s, 2H), 4.01 (dd, J = 10.1 , 8.0 Hz, 1H), 3.44 (d, J = 12.5 Hz, 2H), 3.30 - 3.28 (m, 1H), 3.25 - 2.98 (m, 2H), 2.38 (d, J = 14.7 Hz, 2H), 1.65 (td, J = 14.5, 14.0, 3.8 Hz, 2H), 1.25 (s, 3H). 546.2 [M+H ⁺ ]. 178

(400 MHz, CD ₃ OD) δ 8.17 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.58 - 7.48 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 4.03 (s, 4H), 3.66 - 3.57 (m, 4H), 3.46 (s, 2H), 3.37 (d, J = 13.3 Hz, 2H), 3.14 - 2.99 (m, 2H), 2.76 (s, 3H), 2.33 - 2.14 (m, 2H), 1.98 - 1.88 (m, 4H), 1.38 - 1.24 (m, 2H). 538.4 [M+H ⁺ ]. 179

(400 MHz, CD ₃ OD) δ 8.12 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H), 7.59 - 7.46 (m, 5H), 7.21 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 4.42 - 4.33 (m, 1H), 4.08 - 3.97 (m, 4H), 3.83 - 3.72 (m, 1H), 3.67 - 3.53 (m , 4H), 3.51 - 3.41 (m, 2H), 3.22 - 3.10 (m, 1H), 2.73 - 2.60 (m, 1H), 2.03 - 1.97 (m, 2H), 1.96 (s, 3H), 1.92 - 1.84 (m, 4H), 1.74 - 1.64 (m, 2H). 566.3 [M+H ⁺ ]. 180

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.56 - 7.52 (m , 3H), 7.51 (s, 2H), 7.32 - 7.26 (m, 5H), 7.22 - 7.16 (m, 1H), 4.78 (d, J = 8.1 Hz, 1H), 4.42 (s, 2H), 4.01 ( dd, J = 10.0, 8.0 Hz, 1H), 3.68 - 3.54 (m, 2H), 3.29 - 3.20 (m, 3H), 2.33 - 2.22 (m, 2H), 1.80 (t, J = 14.2 Hz, 2H) , 1.47 (s, 3H). 528.2 [M+H ⁺ ]. 181

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.56-7.47 (m , 5H), 7.34 - 7.24 (m, 5H), 7.28 - 7.15 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.32 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.40-3.07 (m, 8H), 2.06 (d, J = 14.8 Hz, 2H), 1.76 - 1.63 (m, 2H), 1.22 (s, 3H). 533.3 [M+H ⁺ ]. 182

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 11.6 Hz, 5H), 7.37 - 7.24 (m, 5H), 7.28 - 7.15 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.56 (dt, J = 15.6, 7.6 Hz, 2H) , 4.36 - 4.29 (m, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.51 - 3.36 (m, 3H), 3.21 - 3.03 (m, 2H), 2.54 - 2.46 (m, 2H) , 2.43 - 2.32 (m, 2H), 1.96 - 1.83 (m, 2H). 531.2 [M+H ⁺ ]. 183

(400 MHz, CD ₃ OD) δ 8.19 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.66 (s, 1H), 7.61 - 7.51 (m, 5H), 7.30 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 4.11 - 4.00 (m, 4H), 3.68 - 3.59 (m, 6H), 3.43 (s, 2H), 2.87 - 2.79 (m, 2H ), 2.77 (s, 3H), 2.25 - 2.13 (m, 2H), 1.95 - 1.89 (m, 4H), 1.81 - 1.74 (m, 2H). 601.9 [M+H ⁺ ]. 184

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.55 - 7.49 (m , 5H), 7.30 - 7.26 (m, 5H), 7.21 - 7.18 (m, 1H), 4.78 (d, J = 7.9 Hz, 1H), 4.59 (d, J = 13.0 Hz, 1H), 4.28 (d, J = 13.0 Hz, 1H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.86 - 3.83 (m, 1H), 3.57 (d, J = 5.0 Hz, 2H), 3.49 - 3.38 (m, 5H ), 2.31 - 2.24 (m, 1H), 2.18 - 2.07 (m, 1H), 2.02 - 1.85 (m, 2H). 519.2 [M+H ⁺ ]. 185

(400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.55 - 7.50 (m , 3H), 7.48 (s, 2H), 7.34 - 7.24 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.74 (m, 1H), 4.23 (s, 2H), 4.06 - 3.90 (m , 3H), 3.49 - 3.37 (m, 2H), 3.29 - 3.28 (m, 1H), 2.97 (d, J = 7.1 Hz, 2H), 2.08 - 1.94 (m, 1H), 1.75 - 1.66 (m, 2H ), 1.44 - 1.32 (m, 2H). 519.2 [M+H ⁺ ]. 186

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.52 (m, 5H ), 7.32 - 7.26 (m, 5H), 7.20 (m, 1H), 4.78 (m, 1H), 4.34 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.66 - 3.46 ( m, 2H), 3.04 (m, 2H), 2.53 (m, 1H), 2.13 - 1.85 (m, 4H). 532.4 [M+H ⁺ ]. 187

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.56 - 7.48 (m , 5H), 7.32 - 7.26 (m, 5H), 7.20 - 7.18 (m, 1H), 4.78 (d, J = 8.0 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.18 (br, 1H), 4.18 (dd, J = 10.1, 8.0 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.38 (s, 3H), 2.43 - 2.36 (m, 1H), 2.17 - 2.15 (m, 1H). 505.2 [M+H ⁺ ]. 188

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.55 - 7.48 (m , 5H), 7.32 - 7.26 (m, 5H), 7.21 - 7.18 (m, 1H), 4.78 (d, J = 7.8 Hz, 1H), 4.44 - 4.34 (m, 2H), 4.18 (br, 1H), 4.01 (dd, J = 10.0, 8.0 Hz, 1H), 3.67 - 3.51 (m, 2H), 3.38 (s, 3H), 2.44 - 2.32 (m, 1H), 2.21 - 2.00 (m, 1H). 505.1 [M+H ⁺ ]. 189

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.57 - 7.44 (m , 5H), 7.37 - 7.23 (m, 5H), 7.19 (m, 1H), 4.77 (m, 1H), 4.56 - 4.25 (m, 2H), 4.01 (m, 1H), 3.81 - 3.39 (m, 2H ), 3.29 - 3.08 (m, 2H), 2.31 - 1.91 (m, 2H), 1.44 (s, 3H). 505.4 [M+H ⁺ ]. 190

(400 MHz, CD ₃ OD) δ 7.98 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.54 (s, 3H ), 7.48 (m, 2H), 7.32 - 7.27 (m, 5H), 7.19 (m, 1H), 5.23 - 5.16 (m, 4H), 5.14 - 5.07 (m, 1H), 4.79 (m, 1H), 4.02 (m, 1H), 3.64 (m, 2H), 2.54 (m, 2H), 1.97 - 1.78 (m, 6H). 531.2 [M+H ⁺ ]. 191

(400 MHz, CD ₃ OD) δ 7.69 - 7.61 (m, 4H), 7.56 - 7.47 (m, 3H), 7.33 (m, 4H), 7.28 - 7.20 (m, 1H), 7.14 (s, 1H), 6.50 (s, 1H), 4.84 - 4.76 (m, 1H), 4.29 (s, 2H), 4.01 (m, 1H), 3.70 (s, 3H), 3.50 - 3.44 (m, 2H), 3.03 - 2.92 ( m, 2H), 1.95 (m, 2H), 1.84 (m, 1H), 1.73 (m, 2H), 1.51 (m, 1H). 519.4 [M+H ⁺ ]. 192

(400 MHz, CD ₃ OD) δ 7.65 (m, 4H), 7.55 - 7.46 (m, 3H), 7.34 - 7.31 (m, 4H), 7.24 (m, 1H), 7.15 (s, 1H), 6.50 ( s, 1H), 4.79 (m, 1H), 4.56 (s, 2H), 4.41 (s, 2H), 4.28 (s, 2H), 4.02 (m, 1H), 3.70 (s, 3H), 3.51 - 3.42 (m, 2H), 2.99 (m, 2H), 2.38 (m, 2H), 1.89 (m, 2H). 561.4 [M+H ⁺ ]. 193

(400 MHz, CD ₃ OD) δ 7.65 - 7.54 (m, 4H), 7.51 - 7.44 (m, 3H), 7.36 - 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 7.10 (s, 1H ), 6.43 (s, 1H), 4.80 - 4.70 (m, 1H), 4.40 (s, 2H), 4.09 - 3.95 (m, 5H), 3.71 - 3.55 (m, 7H), 3.27 (m, 1H), 1.88 (m, 4H). 561.3 [M+H ⁺ ]. 194

(400 MHz, CD ₃ OD) δ 7.99 - 7.91 (m, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.54 - 7.43 (m, 5H) , 7.25 - 7.18 (m, 2H), 7.09 - 7.03 (m, 2H), 6.78 (m, 1H), 5.02 - 4.94 (m, 1H), 4.29 (s, 2H), 4.02 - 3.97 (m, 1H) , 3.95 (s, 3H), 3.47 (m, 2H), 3.21 (dd, J = 10.2, 2.2 Hz, 1H), 2.97 (m, 2H), 2.01 - 1.43 (m, 6H). 519.5 [M+H ⁺ ]. 195

(400 MHz, DMSO- d ₆ ) δ 13.26 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.53 (s, 2H), 7.40 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 4.27 (s, 4H), 3.46 (s, 2H), 3.42 (s, 2H), 2.62 - 2.53 (m, 2H), 2.21 (m, 4H), 2.08 - 1.93 (m, 3H), 1.92 - 1.69 (m, 5H). 495.3 [M+H ⁺ ]. 196

(400 MHz, CD ₃ OD) δ 8.18 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 1.2 Hz, 1H), 7.61 - 7.56 (m , 3H), 7.53 (d, J = 8.1 Hz, 2H), 7.39 (dd, J = 8.5, 1.4 Hz, 1H), 4.43 (s, 2H), 4.03 (m, 4H), 3.61 (m, 6H) , 2.73 - 2.59 (m, 2H), 2.12 - 2.00 (m, 3H), 1.89 (m, 5H). 495.3 [M+H ⁺ ]. 197

(400 MHz, DMSO- d ₆ ) δ 13.28 (s, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.72 (m, 3H), 7.55 (s, 2H), 7.46 - 7.19 (m, 4H), 4.57 (s, 2H), 4.14 (s, 2H), 3.83 (t, J = 5.1 Hz, 2H), 3.46 (s, 2H), 3.28 (t, J = 5.1 Hz , 2H), 2.56 (m, 2H), 2.12 - 1.79 (m, 4H). 469.3 [M+H ⁺ ]. 198

(400 MHz, CD ₃ OD) δ 8.14 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.57 - 7.56 (m, 3H), 7.55 - 7.49 (m, 3H) , 7.26 (d, J = 8.0 Hz, 1H), 4.42 (s, 2H), 4.03 (q, J = 10.7 Hz, 4H), 3.67 - 3.58 (m, 4H), 3.22 (s, 2H), 2.17 - 2.06 (m, 2H), 1.89 - 1.86 (m, 4H), 1.81 - 1.66 (m, 6H). 509.4 [M+H ⁺ ]. 199

(400 MHz, DMSO- d ₆ ) δ 12.72 (br s, 1H), 7.99 (dd, J = 8.4, 3.0 Hz, 1H), 7.58- 7.47 (m, 4H), 7.46 (d, J = 2.8 Hz, 1H), 7.40 (s, 2H), 7.30 (dd, J = 8.0, 2.8 Hz, 2H), 7.20 (dd, J = 8.4, 2.8 Hz, 1H), 4.64 (d, J = 2.8 Hz, 2H), 4.24 (d, J = 2.8 Hz, 2H), 3.88 (dd, J = 6.0, 4.0 Hz, 2H), 3.34 (dd, J = 6.0, 4.0Hz, 2H), 3.17 (s, 2H), 2.11 - 2.06 (m, 2H), 1.78-1.67 (m, 6H). 483.0 [M+H ⁺ ]. 200

(400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.2 Hz, CD ₃ OD 1H), 7.56 - 7.48 (m, 5H), 7.33 - 7.24 (m, 5H), 7.20 (m, 1H), 4.78 (m, 1H), 4.40 (s, 2H), 4.01 (m, 1H), 3.82 (s, 2H) , 3.66 - 3.52 (m, 4H), 3.01 (s, 3H). 518.4 [M+H ⁺ ]. 201

(400 MHz, CD ₃ OD) δ 7.93 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.56 - 7.49 (m , 3H), 7.47 (s, 2H), 7.32 - 7.23 (m, 5H), 7.22 - 7.15 (m, 1H), 4.77 (m, 1H), 4.44 (s, 2H), 4.01 (m, 1H), 3.85 (s, 2H), 3.60 (s, 4H), 3.29 (m, 1H), 2.75 (m, 3.4 Hz, 1H), 1.41 - 1.21 (m, 2H), 0.95 - 0.82 (m, 2H). 544.3 [M+H ⁺ ]. 202

(400 MHz, CD ₃ OD) δ 7.64 - 7.44 (m, 5H), 7.36 - 7.27 (m, 6H), 7.24 (m, 1H), 7.12 (s, 1H), 6.45 (s, 1H), 4.81 - 4.73 (m, 1H), 4.63 (s, 2H), 4.20 (s, 2H), 4.00 (m, 1H), 3.89 - 3.83 (m, 2H), 3.34 (m, 2H), 3.27 (m, 1H) . 535.2 [M+H ⁺ ]. 203

(400 MHz, CD ₃ OD) δ 7.72 - 7.60 (m, 4H), 7.56 - 7.48 (m, 3H), 7.33 (m, 4H), 7.24 (m, 1H), 7.14 (s, 1H), 6.51 - 6.46 (m, 1H), 4.79 (m, 1H), 4.41 (s, 2H), 4.01 (m, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 3.60 - 3.48 (m, 4H) , 3.27 (m, 1H). 534.1 [M+H ⁺ ]. 204

(400 MHz, CD ₃ OD) δ 7.69 - 7.48 (m, 7H), 7.32 (m, 4H), 7.24 (m, 1H), 7.14 (s, 1H), 6.49 (m, 1H), 4.77 (m, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 4.06 - 3.95 (m, 1H), 3.73 - 3.64 (m, 3H), 3.64 - 3.51 (m, 1H), 3.28 - 3.16 (m, 2H), 2.06 - 1.67 (m, 4H), 1.62 (m, 5H), 1.42 (m, 3H). 547.3 [M+H ⁺ ]. 205

(400 MHz, CD ₃ OD) δ 7.67 - 7.59 (m, 4H), 7.54 - 7.46 (m, 3H), 7.33 (m, 4H), 7.24 (m, 1H), 7.13 (s, 1H), 6.48 ( s, 1H), 4.78 (m, 1H), 4.35 (m, 2H), 4.01 (m, 1H), 3.84 (m, 3H), 3.68 (s, 3H), 3.63 - 3.33 (m, 3H), 3.29 - 3.16 (m, 2H), 3.15 - 2.84 (m, 3H). 547.4 [M+H ⁺ ]. 206

(400 MHz, CD ₃ OD) δ 7.79 (m, 1H), 7.70 - 7.54 (m, 3H), 7.37 - 7.19 (m, 5H), 7.10 (m, 2H), 7.04 (d, J = 7.8 Hz, 1H), 6.38 (s, 1H), 4.75 - 4.66 (m, 1H), 4.24 (s, 2H), 4.15 (q, J = 7.0 Hz, 2H), 3.98 (m, 1H), 3.60 (s, 3H ), 3.46 (m, 2H), 3.25 (m, 1H), 3.03 - 2.86 (m, 2H), 1.93 (m, 2H), 1.88 - 1.67 (m, 3H), 1.51 (m, 4H). 563.4 [M+H ⁺ ]. 207

(400 MHz, CD ₃ OD) δ 8.00 (m, 1H), 7.76 - 7.70 (m, 2H), 7.60 - 7.41 (m, 5H), 7.20 (s, 1H), 4.31 (s, 2H), 3.55 - 3.44 (m, 2H), 3.17 (s, 2H), 2.98 (m, 2H), 2.03 - 1.64 (m, 6H), 1.29 (s, 6H). 475.4 [M+H ⁺ ]. 208

(400 MHz, CD ₃ OD) δ 7.83 - 7.64 (m, 3H), 7.59 - 7.24 (m, 5H), 6.93 (s, 1H), 4.29 (s, 2H), 3.46 (m, 2H), 3.22 - 3.07 (m, 2H), 2.97 (m, 2H), 2.86 - 2.66 (m, 3H), 2.05 - 1.39 (m, 6H), 1.37 - 1.20 (m, 6H). 455.4 [M+H ⁺ ]. 209

(400 MHz, CD ₃ OD) δ 7.81 - 7.67 (m, 3H), 7.63 - 7.46 (m, 4H), 7.10 (s, 1H), 6.58 (s, 1H), 4.30 (s, 2H), 4.05 ( s, 3H), 3.48 (m, 2H), 3.17 (s, 2H), 2.98 (m, 2H), 1.96 (m, 2H), 1.90 - 1.67 (m, 3H), 1.58 - 1.47 (m, 1H) , 1.32 (s, 6H). 471.3 [M+H ⁺ ]. 210

(400 MHz, CD ₃ OD) δ 7.97 (m, 1H), 7.78 - 7.71 (m, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.55 - 7.48 (m, 5H), 7.33 - 7.25 ( m, 5H), 7.23 - 7.16 (m, 1H), 4.79 (m, 1H), 4.38 (s, 2H), 4.01 (m, 1H), 3.57 - 3.45 (m, 2H), 3.21 (s, 2H) , 2.10 (m, 4H). 475.5 [M+H ⁺ ]. 211

(400 MHz, CD ₃ OD) δ 7.96 (dd, J = 8.6, 3.5 Hz, 1H), 7.76 (dd, J = 8.6, 2.6 Hz, 2H), 7.64 (d, J = 2.1 Hz, 1H), 7.56 - 7.43 (m, 5H), 7.36 - 7.23 (m, 5H), 7.21-7.16 (m, 1H), 4.78 (d, J = 8.1 Hz, 1H), 4.58 - 4.38 (m, 1H), 4.32 - 4.19 (m, 2H), 4.17 - 4.09 (m, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.85 (dd, J = 11.4, 6.3 Hz, 1H), 3.73 (d, J = 8.4 Hz, 1H), 2.76 (s, 3H), 2.52 - 2.22 (m, 2H). 505.5 [M+H ⁺ ]. 212

(400 MHz, CD ₃ OD) δ 7.96 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.53 - 7.45 (m, 5H), 7.34 -7.16 (m, 6H), 5.40 - 5.28 (m, 1H), 4.36 (s, 2H), 4.15 - 4.05 (m, 2H), 2.66 - 2.37 (m, 2H), 2.28 - 2.12 (m, 2H) , 1.70 - 1.50 (m, 2H). 461.5 [M+H ⁺ ]. 213

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.57 - 7.46 (m , 5H), 7.33 - 7.24 (m, 5H), 7.19 (m, 1H), 4.82 - 4.76 (m, 1H), 4.60 (d, J = 13.5 Hz, 1H), 4.24 (d, J = 13.6 Hz, 1H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.62 (m, 2H), 2.10 (m, 1H), 1.89 - 1.59 (m, 5H), 1.45 (dd, J = 12.3, 6.7 Hz , 6H). 517.5 [M+H ⁺ ]. 214

(400 MHz, CD ₃ OD) δ 8.14 (dd, J = 8.3, 3.3 Hz, 1H), 7.78 (dd, J = 11.6, 8.2 Hz, 2H), 7.62 - 7.53 (m, 6H), 7.27 - 7.25 ( m, 1H), 4.62 (s, 1H), 4.36 (s, 1H), 3.63 - 3.52 (m, 1H), 3.25 - 3.22 (m, 3H), 2.17 - 2.06 (m, 2H), 2.05 - 1.68 ( m, 10H), 1.64 - 1.61 (m, 5H), 1.44 (d, J = 6.7 Hz, 3H). 495.4 [M+H ⁺ ]. 215

(400 MHz, CD ₃ OD) δ 8.18 (s, 1H), 7.78 (s, 2H), 7.71 (s, 1H), 7.64 - 7.50 (m, 5H), 7.40 (d, J = 7.8 Hz, 1H) , 4.62 (t, J = 3.8 Hz, 1H), 4.35 (s, 1H), 3.61-3.54 (m, 3H), 3.34 - 3.25 (m, 1H), 2.64 (s, 2H), 2.04 (m, 4H ), 1.83 (m, 4H), 1.67-1.58 (m, 5H), 1.43 (s, 3H). 481.4 [M+H ⁺ ]. 216

(400 MHz, CD ₃ OD) δ 8.17 (m, 1H), 7.80 (m, 2H), 7.66 - 7.53 (m, 6H), 7.32 - 7.26 (m, 1H), 4.65 (s, 1H), 4.38 ( s, 1H), 3.58 (m, 1H), 3.28 (m, 1H), 3.19 (s, 2H), 2.07 - 1.76 (m, 4H), 1.66 (m, 5H), 1.46 (d, J = 6.7 Hz , 3H), 1.33 (s, 6H). 468.9 [M+H ⁺ ]. 217

(400 MHz, CD3OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.56 - 7.47 (m, 5H ), 7.31 - 7.26 (m, 5H), 7.20 (m, 1H), 4.83 - 4.70 (m, 2H), 4.12 - 3.95 (m, 2H), 3.19 (m, 1H), 2.87 (m, 1H), 2.12 - 1.52 (m, 9H). 503.3 [M+H ⁺ ]. 218

(400 MHz, CD ₃ OD) δ 7.99 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.62 - 7.49 (m , 5H), 7.36 - 7.26 (m, 5H), 7.31 - 7.18 (m, 1H), 4.85 - 4.72 (m, 2H), 4.14 - 3.99 (m, 2H), 3.32-3.14 (m, 3H), 2.89 (t, J = 12.2 Hz, 1H), 2.11-1.81 (m, 3H), 1.73 - 1.48 (m, 6H). 503.6 [M+H ⁺ ]. 219

(400 MHz, CD ₃ OD) δ 7.97 - 7.94 (m, 1H), 7.79 - 7.74 (m, 2H), 7.64 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.51 (m, 3H), 7.34 - 7.23 (m, 5H), 7.22 - 7.16 (m, 1H), 4.82 - 4.74 (m, 1H), 4.66 (s, 2H), 4.06 - 3.95 (m, 4H), 3.57 - 3.46 ( m, 2H), 3.42 - 3.34 (m, 2H), 1.50 (d, J = 6.3 Hz, 6H). 519.6 [M+H ⁺ ]. 220

(400 MHz, CD ₃ OD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.58 - 7.48 (m, 5H) , 7.33 - 7.25 (m, 5H), 7.19 (m, 1H), 4.82 - 4.76 (m, 1H), 4.44 (s, 2H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.65 (q , J = 6.5 Hz, 2H), 3.29 (s, 1H), 2.34 - 2.21 (m, 2H), 1.81 - 1.69 (m, 2H), 1.36 (d, J = 6.6 Hz, 6H). 503.6 [M+H ⁺ ]. 221

(400 MHz, CD ₃ OD) δ 7.95 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.54 - 7.44 (m , 5H), 7.33 - 7.24 (m, 5H), 7.19 (m, 1H), 4.78 (m, 1H), 4.25 (m, 1H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.29 (m, 1H), 3.26 - 3.12 (m, 1H), 2.17 - 1.91 (m, 4H), 1.90 - 1.69 (m, 2H). 475.4 [M+H ⁺ ]. 222

(400 MHz, CD ₃ OD) δ 7.95 (s, 1H), 7.76-7.13 (m, 14H), 4.01 (s, 1H), 3.52-2.91 (m, 6H), 2.69 (s, 1H), 2.17 - 1.75 (m, 4H). 475.4 [M+H ⁺ ]. 223

(400 MHz, CD ₃ OD) δ 7.92 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.53 - 7.48 (m , 3H), 7.44 (s, 2H), 7.31 - 7.25 (m, 5H), 7.21 - 7.18 (m, 1H), 4.76 (dt, J = 8.2, 2.3 Hz, 1H), 4.64 (t, J = 8.0 Hz, 1H), 4.00 (dd, J = 10.1, 7.9 Hz, 1H), 3.47 - 3.45 (m, 2H), 2.51 - 2.47 (m, 1H), 2.37 - 2.13 (m, 4H). 461.5 [M+H ⁺ ]. 224

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.51 (s, 1H), 7.41 (m, 2H), 7.32 - 7.23 (m, 7H), 7.19 (m, 1H), 4.78 (m, 1H), 4.01 (dd, J = 10.1, 8.0 Hz, 1H), 3.56 - 3.46 (m, 2H ), 3.29 (m, 1H), 3.15 (m, 2H), 2.98 - 2.87 (m, 1H), 2.10 (m, 2H), 1.91 (m, 2H). 475.5 [M+H ⁺ ]. 225

(400 MHz, CD ₃ OD) δ 7.90 (dd, J = 8.5, 4.3 Hz, 1H), 7.69 (dd, J = 11.8, 8.2 Hz, 2H), 7.60 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.52 - 7.38 (m, 4H), 7.17 (ddd, J = 8.1, 4.8, 2.8 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.74 ( t, J = 7.5 Hz, 1H), 4.93-4.88 (m, 1H), 4.56 (s, 1H), 4.29 (s, 1H), 4.00 - 3.94 (m, 1H), 3.91 (s, 3H), 3.51 (q, J = 7.0 Hz, 1H), 3.24-3.126 (m, 2H), 2.00 - 1.91 (m, 1H), 1.90 - 1.61 (m, 4H), 1.58 (d, J = 6.3 Hz, 4H), 1.38 (d, J = 6.6 Hz, 3H). 547.2 [M+H ⁺ ]. 226

(400 MHz, CD ₃ OD) δ 7.95 - 7.89 (m, 1H), 7.73 - 7.69 (m, 2H), 7.61 (s, 1H), 7.51(d, J = 7.7 Hz, 2H), 7.47 - 7.44 ( m, 2H), 7.42 (s, 1H), 7.20 - 7.15 (m, 2H), 7.03 - 6.99 (m, 2H), 6.77 - 6.72 (m, 1H), 5.06 - 4.87 (m, 1H), 4.40 ( s, 2H), 4.00 - 3.90 (m, 4H), 3.64 - 3.59 (m, 2H), 3.21-3.11 (m, 1H), 2.27 - 2.14 (m, 2H), 1.79 - 1.62 (m, 2H), 1.32 (d, J = 6.6 Hz, 6H). 533.1 [M+H ⁺ ]. 227

(400 MHz, CD ₃ OD) δ 8.20 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.77 - 7.68 (m, 4H), 7.55 - 7.46 (m, 7H), 7.23 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 4.30 (s, 2H), 4.16 - 4.04 (m, 1H), 3.47 (d, J = 12.6 Hz, 2H), 3.38 (dd, J = 10.4 , 2.7 Hz, 1H), 2.97 (td, J = 12.6, 3.0 Hz, 2H), 2.00 - 1.90 (m, 2H), 1.88 - 1.44 (m, 4H). 490.4 [M+H ⁺ ]. 228

(400 MHz, CD ₃ OD) δ 7.95 (dd, J = 8.5, 4.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (s , 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.26 - 7.07 (m, 4H), 7.00 (t, J = 7.5 Hz, 1H), 5.10 - 4.98 ( m, 1H), 4.61 (s, 1H), 4.34 (s, 1H), 4.09 - 3.97 (m, 1H), 3.56 (q, J = 7.0 Hz, 1H), 3.28 - 3.14 (m, 2H), 2.04 - 1.96 (m, 1H), 1.93 - 1.71 (m, 3H), 1.62 (d, J = 6.3 Hz, 5H), 1.43 (d, J = 6.7 Hz, 3H). 535.4 [M+H ⁺ ]. 229

(400 MHz, CD ₃ OD) δ 7.86 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2H), 7.61 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H ), 7.46 - 7.34 (m, 3H), 7.26 - 7.07 (m, 4H), 6.99 (t, J = 7.5 Hz, 1H), 5.02 - 4.93 (m, 2H), 4.38 (s, 2H), 4.03 ( t, J = 9.2 Hz, 1H), 3.94 - 3.73 (m, 3H), 3.55 (d, J = 9.7 Hz, 2H), 3.37 - 3.22 (m, 3H), 3.09 (s, 1H), 2.96 - 2.81 (m, 1H). 535.4 [M+H ⁺ ]. 230

(400 MHz, CD ₃ OD) δ 7.79 - 7.67 (m, 3H), 7.67 - 7.54 (m, 2H), 7.51 - 7.34 (m, 3H), 7.24 - 7.08 (m, 6H), 4.72 (d, J = 8.1 Hz, 1H), 4.60 (s, 1H), 4.33 (s, 1H), 3.99 (dd, J = 10.1, 8.3 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.29 - 3.19 (m, 2H), 2.04 - 1.64 (m, 5H), 1.65 (d, J = 6.3 Hz, 4H), 1.45 (d, J = 6.7 Hz, 3H). 535.5 [M+H ⁺ ]. 231

(400 MHz, CD ₃ OD) δ 7.79-7.68 (m, 3H), 7.67 - 7.44 (m, 4H), 7.24 - 7.07 (m, 7H), 4.77 - 4.69 (m, 1H), 4.42 - 4.31 (m , 2H), 4.00 (dd, J = 10.2, 8.3 Hz, 1H), 3.97 - 3.46 (m, 7H), 3.38 - 3.33 (m, 1H), 3.14 - 2.88 (m, 3H). 535.5 [M+H ⁺ ]. 232

(400 MHz, CD ₃ OD) δ 7.90 (dd, J = 8.6, 4.2 Hz, 1H), 7.73 - 7.60 (m, 4H), 7.54 (d, J = 8.3 Hz, 1H), 7.51 - 7.37 (m, 4H), 7.19 - 7.07 (m, 4H), 5.08 (d, J = 8.1 Hz, 1H), 4.57 (s, 1H), 4.30 (s, 1H), 4.04 (dd, J = 10.3, 8.2 Hz, 1H ), 3.51 (h, J = 6.7 Hz, 1H), 3.30 - 3.21 (m, 2H), 2.00-1.68 (m, 4H), 1.58 (d, J = 6.3 Hz, 4H), 1.57 -1.41 (m, 2H), 1.39 (d, J = 6.6 Hz, 2H). 597.5 [M+H ⁺ ]. 233

(400 MHz, CD ₃ OD) δ 7.94 (d, J = 7.3 Hz, 1H), 7.76 - 7.53 (m, 4H), 7.51 - 7.40 (m, 5H), 7.31 (d, J = 8.0 Hz, 1H) , 7.26 - 7.16 (m, 3H), 4.79 (d, J = 8.0 Hz, 1H), 4.58 (s, 1H), 4.31 (s, 1H), 3.98 (t, J = 9.2 Hz, 1H), 3.53 ( q, J = 6.9 Hz, 1H), 3.29 - 3.14 (m, 2H), 2.01 - 1.66 (m, 5H), 1.61 (d, J = 6.3 Hz, 4H), 1.40 (d, J = 6.6 Hz, 3H ). 595.4 [M+H ⁺ ]. 234

(400 MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H ), 7.82 - 7.71 (m, 3H), 7.58 - 7.46 (m, 4H), 7.24 (dd, J = 8.6, 1.4 Hz, 1H), 5.25 - 5.18 (m, 1H), 4.31 (s, 2H), 4.12 (dd, J = 10.5, 8.5 Hz, 1H), 3.98 (s, 1H), 3.53 - 3.44 (m, 2H), 3.40 (dd, J = 10.5, 3.2 Hz, 1H), 3.35 (s, 1H) , 3.06 - 2.91 (m, 2H), 2.02 - 1.91 (m, 2H), 1.90 - 1.81 (m, 1H), 1.80 - 1.67 (m, 2H), 1.60 - 1.45 (m, 1H). 490.4 [M+H ⁺ ]. 235

(400 MHz, CD ₃ OD) δ 8.69 (s, 1H), 8.52 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.80 - 7.70 (m, 3H), 7.57 - 7.45 (m, 4H), 7.24 (dd, J = 8.6, 1.4 Hz, 1H), 5.24 - 5.15 (m, 1H), 4.30 (s, 2H), 4.12 (dd, J = 10.5, 8.5 Hz, 2H), 3.98 (s, 1H), 3.52 - 3.44 (m, 2H), 3.40 (dd, J = 10.5, 3.2 Hz, 1H), 3.04 - 2.91 (m, 2H), 2.03 - 1.91 (m, 2H), 1.84 (d, J = 13.6 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.57 - 1.46 (m, 1H). 490.4 [M+H ⁺ ]. 236

¹ H NMR (400 MHz, CD ₃ OD) δ 7.85 (dd, J = 8.4, 3.1 Hz, 1H), 7.76 (dd, J = 11.7, 8.3 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H ), 7.58 – 7.44 (m, 3H), 7.42 (s, 1H), 7.33 (d, J = 2.9 Hz, 1H), 7.18 (dt, J = 8.7, 1.6 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.49 (s, 2H), 5.29 (dt, J = 7.7, 3.6 Hz, 1H), 4.64 (s, 1H), 4.37 (s, 1H), 4.01-3.52 (m, 8H), 3.27 (dd, J = 9.8, 4.1 Hz, 2H), 2.07-1.68 (m, 6H), 1.65 (d, J = 6.3 Hz, 3H), 1.46 (d, J = 6.7 Hz, 3H). 577.4 [M+H] ⁺ 237

¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 – 7.87 (m, 1H), 7.83 – 7.72 (m, 2H), 7.66 – 7.61 (m, 1H), 7.61 – 7.40 (m, 5H), 7.24 – 7.14 (m, 1H), 7.09 – 6.99 (m, 1H), 6.68 – 6.60 (m, 1H), 6.60 – 6.51 (m, 1H), 5.29 – 5.20 (m, 1H), 4.64 (s, 2H), 4.42 – 4.34 (m, 1H), 3.96 (t, J = 9.5 Hz, 1H), 3.83 (s, 3H), 3.64 – 3.46 (m, 1H), 3.17 – 3.12 (m, 1H), 2.11 – 1.56 ( m, 9H), 1.46 (d, J = 6.7 Hz, 3H). 565.5 [M+H] ⁺ 238

¹ H NMR (400 MHz, CD ₃ OD) δ 8.30 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.64 ( d, J = 1.3 Hz, 2H), 7.57 (dd, J = 12.8, 8.4 Hz, 3H), 7.28 (s, 1H), 6.88 (d, J = 1.9 Hz, 2H), 4.45 (s, 2H), 4.06 (q, J = 10.7 Hz, 4H), 3.66 (s, 3H), 3.69-3.60 (m, 4H), 1.93-1.88 (m, 4H). 533.1 [M+H] ⁺

Biological activity test

其中：Conversion%_sample是樣品孔的比值讀數；Conversion%_min：沒有加化合物只有DMSO的孔信號比值，代表沒有抑制時讀數；Conversion%_max：加入最高濃度陽性化合物的實驗孔信號比值，代表完全抑制時讀數。 擬合量效曲線 以濃度的log值作為X軸，百分比抑制率為Y軸，採用分析軟件GraphPad Prism 5的log(inhibitor) vs. response -Variable slope擬合量效曲線，從而得出各個化合物對酶活性的結合活性值。 計算公式：Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。 實驗結果：當結合活性≤10nM時，以字母A表示；當10nM ＜結合活性≤50nM時，以字母B表示；當結合活性＞50nM時，以字母C表示。實驗結果參見表1。 結果表明本發明化合物對PLK4激酶具有較好的結合活性，具有潛在藥物開發價值。 Experimental example 1. In vitro binding experiment of the compound of the present invention to PLK4 In this experiment, LanthaScreen method was used to test the competitive inhibitory effect of the compound on the binding of ATP analog Tracer to PLK4, and the binding activity of the compound to PLK4 was obtained. 1. Experimental materials GST-labeled PLK4 protein, fluorescently-labeled GST antibody, fluorescently-labeled ATP analog Tracer were purchased from ThermoFisher, DMSO was purchased from Sigma, 384-well plates were purchased from Perkinelemer, surfactant Brij-35, HEPES , EGTA and magnesium chloride were purchased from Sigma. 2. Experimental method: (1) Prepare 1×Kinase buffer with ultrapure water. Follow-up operations to avoid direct light or sunlight. (2) Add PLK4 protein and GST antibody to the reaction concentration in 1×Kinase buffer. (3) Pipette to mix well and add to 384-well plate, 16uL per well. (4) Centrifuge the microplate at 1500rpm for 1 minute. (5) Prepare 125 times the highest concentration of the test compound and positive control compound (CFI-400945), dissolved in DMSO. (6) Prepare a 500-fold Tracer fluorescent substrate and dissolve in DMSO. (7) Add the prepared compound, Tracer, and DMSO into the sampling tank of the TECAN D300E injector. (8) Add the sample according to the pre-set sampling position, the positive control is the positive compound with the highest concentration, the negative control is DMSO, and all the test compounds are diluted three times, and nine concentrations are tested. The final concentration of DMSO in the experimental wells used was 1%. (9) Centrifuge the microplate at 1500rpm for 1 minute. (10) Stand at room temperature in the dark for 60 minutes. (11) Use Perkinelmer's microplate reader Envision to read the readings of the two fluorescent bands, and use the ratio of 615nm/665nm to calculate the inhibition rate of the compound. Calculation formula:

Among them: Conversion%_sample is the ratio reading of the sample well; Conversion%_min: the signal ratio of the well with no compound and only DMSO, representing the reading without inhibition; Conversion%_max: the signal ratio of the experimental well with the highest concentration of positive compound, representing complete inhibition time reading. The fitted dose-effect curve takes the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis. The log(inhibitor) vs. response -Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve, so as to obtain the Binding activity value for enzyme activity. Calculation formula: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)). Experimental results: when the binding activity is ≤10nM, it is represented by the letter A; when 10nM<binding activity≤50nM, it is represented by the letter B; when the binding activity>50nM, it is represented by the letter C. See Table 1 for the experimental results. The results show that the compound of the present invention has good binding activity to PLK4 kinase and has potential drug development value.

其中：RLU：樣品的化學發光值；Mean (NC)：陰性對照孔均值；Mean (PC)：陽性對照孔均值。 擬合量效曲線 以濃度的log值作為X軸，百分比抑制率為Y軸，採用分析軟件GraphPad Prism 5的log(inhibitor) vs. response -Variable slope擬合量效曲線，從而得出各個化合物對酶活性的IC50值。 計算公式：Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 2.2 Lance Ultra方法反應過程 (1) 配製1×Kinase buffer。 (2) 化合物濃度梯度的配製：受試化合物測試濃度為10 μM起始，3倍稀釋，10個濃度，單孔檢測。在384孔板中稀釋成100倍終濃度的溶液。用Echo轉移50 nl到384孔板的化合物孔；陰性對照孔和陽性對照孔中分別加50 nl的DMSO。 (3) 用1×Kinase buffer配製2倍終濃度的激酶溶液。 (4) 在化合物孔和陽性對照孔加5 μl的2倍終濃度的激酶溶液；在陰性對照孔中加2.5 μl的1×Kinase buffer。 (5) 1000 rpm離心30秒，振盪混勻後室溫孵育10分鐘。 (6) 用1×Kinase buffer配製2倍終濃度的ATP和基質的混合溶液。 (7) 加入5 μl的2倍終濃度的ATP和基質的混合溶液，起始反應。 (8) 將384孔板離心，振盪混勻後室溫反應一定時間。 (9) 加入10 μl 檢測試劑，離心後振盪混勻，室溫孵育60分鐘。 (10) 加入10 μl Kinase Detection Reagent，1000 rpm離心30秒，振盪混勻後室溫孵育30分鐘。 (11) 用Envision酶標儀讀取發光值RFU。 計算公式： Percent inhibition = (max- sample ratio)/(max-min)*100 擬合量效曲線 以濃度的log值作為X軸，百分比抑制率為Y軸，採用分析軟件GraphPad Prism 5的log(inhibitor) vs. response -Variable slope擬合量效曲線，從而得出各個化合物對酶活性的IC50值。 計算公式：Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 實驗結果：當IC ₅₀≤50nM時，以字母A表示；當50nM ＜IC ₅₀≤100nM時，以字母B表示；當IC ₅₀＞100nM時，以字母C表示。實驗結果參見表1。 結果顯示本發明化合物對PLK4酶具有較好的抑制活性，對其他激酶無有效抑制活性，表明本發明化合物對PLK4具有較好的選擇性，具備藥物開發價值。 Experimental example 2, in vitro enzymatic experiment of the compound of the present invention on PLK kinase In this experiment, the method of ADP-Glo was used to test the inhibitory effect of the compound on the activity of PLK3 and PLK4 kinase, and the method of Lance Ultra was used to test the inhibition of the compound to the activity of PLK1 and PLK2 kinase Effect, and obtained the compound pair and the half inhibitory concentration IC ₅₀ of the compound on the kinase activity of PLK1, PLK2, PLK3, PLK4. 1. Experimental materials PLK1 and PLK2 were purchased from BPS Company, PLK3 was purchased from Carna Company, PLK4 was purchased from Thermofisher Company, Carliper Matrix 21/Matrix 18/Matrix 8/Peptid-RK were purchased from GL Company, Lance Ultra Kit was purchased from PE Company , Danusertib was purchased from Selleckchem, DMSO was purchased from Sigma, and 384-well plates were purchased from Corning. 2. Experimental method 2.1 Reaction process of ADP-Glo method (1) Prepare 1×Kinase buffer. (2) Preparation of compound concentration gradient: the test compound test concentration is 10 μM starting, 3-fold dilution, 10 concentrations, single-hole detection. Dilute the solution to 100 times the final concentration in a 384-well plate. Use Echo to transfer 50 nl to the compound wells of the 384-well plate; add 50 nl of DMSO to the negative control wells and positive control wells respectively. (3) Use 1×Kinase buffer to prepare 2-fold final concentration of kinase solution. (4) Add 2.5 μl of 2-fold final concentration of kinase solution to compound wells and positive control wells; add 2.5 μl of 1×Kinase buffer to negative control wells. (5) Centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 10 minutes. (6) Use 1×Kinase buffer to prepare a mixed solution of ATP and matrix with 2 times the final concentration. (7) Add 2.5 μl of the mixed solution of ATP and substrate at 2 times the final concentration to start the reaction. (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix well, and react at room temperature for 3 hours. (9) Add 5 μl ADP-Glo Reagent, centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 60 minutes. (10) Add 10 μl Kinase Detection Reagent, centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 30 minutes. (11) Read the luminescence value RLU with an Envision microplate reader. Calculation formula:

Among them: RLU: chemiluminescence value of sample; Mean (NC): mean value of negative control well; Mean (PC): mean value of positive control well. The fitted dose-effect curve takes the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis. The log(inhibitor) vs. response -Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve, so as to obtain the IC50 value of enzyme activity. Calculation formula: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 2.2 Lance Ultra method reaction process (1) Prepare 1×Kinase buffer. (2) Preparation of compound concentration gradient: the test compound test concentration is 10 μM starting, 3-fold dilution, 10 concentrations, single-hole detection. Dilute the solution to 100 times the final concentration in a 384-well plate. Use Echo to transfer 50 nl to the compound wells of the 384-well plate; add 50 nl of DMSO to the negative control wells and positive control wells respectively. (3) Use 1×Kinase buffer to prepare 2-fold final concentration of kinase solution. (4) Add 5 μl of 2-fold final concentration of kinase solution to compound wells and positive control wells; add 2.5 μl of 1×Kinase buffer to negative control wells. (5) Centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 10 minutes. (6) Use 1×Kinase buffer to prepare a mixed solution of ATP and matrix with 2 times the final concentration. (7) Add 5 μl of the mixed solution of ATP and substrate at 2 times the final concentration to start the reaction. (8) Centrifuge the 384-well plate, vortex and mix well, and then react at room temperature for a certain period of time. (9) Add 10 μl detection reagent, centrifuge, shake and mix well, and incubate at room temperature for 60 minutes. (10) Add 10 μl Kinase Detection Reagent, centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 30 minutes. (11) Read the luminescence value RFU with an Envision microplate reader. Calculation formula: Percent inhibition = (max- sample ratio)/(max-min)*100 The fitted dose-effect curve takes the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis, using the log( inhibitor) vs. response -Variable slope to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity. Calculation formula: Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) Experimental results: When IC ₅₀ ≤50nM, denote by letter A; when 50nM <IC ₅₀ ≤100nM When IC 50 >100nM, it is represented by letter B; when IC ₅₀ >100nM, it is represented by letter C. See Table 1 for the experimental results. The results show that the compound of the present invention has good inhibitory activity on PLK4 enzyme, but has no effective inhibitory activity on other kinases, indicating that the compound of the present invention has good selectivity to PLK4 and has drug development value.

Experimental Example 3. Cell Proliferation Inhibition Experiment HCC1806/MDA-MB-468 Cell Proliferation Inhibition Experiment In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of compounds on HCC1806/MDA-MB-468 cell proliferation, and it was concluded that the compound inhibited cell growth Half the concentration IC50. 1. Experimental materials HCC1806 is a human breast squamous cell carcinoma cell, which was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; MDA-MB-468 is a human breast cancer cell, which was purchased from ATCC Cell Bank in the United States. 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO. CellTiter-Glo reagent was purchased from Promega Company. 2. Experimental method 1) Inoculate HCC1806/NIH:OVCAR-3 cells in a 96-well culture plate at a density of 600/1500 cells per well, 100 μL per well. 2) Day 0: Use TECAN to add 100 nL of the compound to be tested in a gradient dilution to the culture plate cells, the final concentration of DMSO is 0.5%, and place the culture plate in a cell culture incubator for 168 hours (37 ℃, 5% CO ₂ ) . For the blank control, 30 nL of DMSO was added to each well. 3) Day 7: Add 30 μL of Cell Titer-Glo reagent to each well, and incubate at room temperature for 30 minutes in the dark. 4) Envision microplate reader (PerkinElmer) detects chemiluminescent signals. Data analysis was performed using GraphPad Prism 6 software to obtain the IC50 of the compound. Experimental results: when IC ₅₀ ≤50nM, it is represented by letter A; when 50nM<IC ₅₀ ≤100nM, it is represented by letter B; when IC ₅₀ >100nM, it is represented by letter C. See Table 1 for the experimental results. It can be seen from the experimental results in Table 1 that the compound of the present invention has a good inhibitory effect on the cell proliferation of the HCC1806/MDA-MB-468 cell line, and has good cell activity and selectivity. Table 1: Compound biological activity test results Example No. Binding Assay (nM) PLK4 Enzyme Activity Test IC ₅₀ (nM) MDA-MB-468 _IC50 (nM) HCC1806 IC ₅₀ (nM) Example 4 C C C / Example 5 A A C / Example 6 A B C / Example 7 B B C / Example 8 A A C / Example 9 C / / / Example 10 C / / / Example 11 A A B B Example 12 A A A A Example 13 A A / / Example 14 A A C / Example 15 A A B B Example 16 A A A A Example 17 A A A A Example 18 A A A Example 19 A A C C Example 20 A A B B Example 21 A / / / Example 22 B / / / Example 23 A A / / Example 24 A / / / Example 25 A A C B Example 26 A A B B Example 27 B / / / Example 28 A A C B Example 29 A A / / Example 30 A A B B Example 31 A A Example 32 A A A A Example 33 A A A A Example 34 B B C C Example 35 A A A A Example 36 A A / A Example 37 A A C C Example 38 B B C C Example 39 A A C A Example 40 A A A A Example 41 A A C C Example 42 A / C C Example 43 A / B A Example 44 A / C C Example 45 A / C C Example 46 A A A A Example 47 A A A A Example 48 A A B A Example 49 A A A A Example 50 A A A A Example 51 A A B A Example 52 A A A A Example 53 A A B A Example 54 A A A A Example 55 A A A A Example 56 A A A A Example 57 A A A A Example 58 A A A A Example 59 A A A A Example 60 A / A A Example 61 A / A A Example 62 A / A / Example 63 A A A A Example 64 A / A A Example 65 A A A A Example 66 A A A A Example 67 A A A A Example 68 A / A A Example 69 A / C C Example 70 C / / / Example 71 A / C C Example 72 A A A A Example 73 A / B B Example 74 A / A A Example 75 A / A A Example 76 A / A A Example 77 A / C C Example 78 A / A A Example 79 A / A A Example 80 A / A A Example 81 A / A A Example 82 A / A A Example 83 A A B A Example 84 A A A A Example 85 A A C C Example 86 C / / / Example 87 B / / / Example 88 A A / / Example 89 A A / / Example 90 A A / / Example 91 A A A A Example 92 A / A A Example 93 A / C C Example 94 A / B A Example 95 A / C C Example 96 A / B A Example 97 A / C B Example 98 A / A A Example 99 A / A A Example 100 A / C A Example 101 A / C B Example 102 A A A A Example 103 A / A A Example 104 A / A A Example 105 A / A A Example 106 A / C B Example 107 A / B A Example 108 A / B A Example 109 A A A A Example 110 A / A A Example 111 A / A A Example 112 A / C C Example 113 A / B A Example 114 A / A A Example 115 A / A A Example 116 A / C B Example 117 A / B A Example 118 A / C C Example 119 A / C B Example 120 A / A A Example 121 A / A A Example 122 A A A A Example 123 A / A A Example 124 A A A A Example 125 A A A A Example 126 A / C A Example 127 A / A A Example 128 A / B A Example 129 A / C B Example 130 A / C B Example 131 A / B A Example 132 A A A A Example 133 A / A A Example 134 A / B A Example 135 A / B B Example 136 A / B A Example 137 A / A A Example 138 A / C C Example 139 A / B A Example 140 A / C C Example 141 A / C A Example 142 A / A A Example 143 A / B A Example 144 A / C A Example 145 A / B A Example 146 A / B A Example 147 A / A A Example 148 A / A A Example 149 A / B A Example 150 A / A A Example 151 A A A A Example 152 A / A A Example 153 A A A A Example 154 A / A A Example 155 A / A A Example 156 A A C C Example 157 A / C B Example 158 A / C C Example 159 A / C C Example 160 A / C B Example 161 A / C C Example 162 A / C B Example 163 A / C B Example 164 A / A A Example 165 A / C C Example 166 A / A A Example 167 A / A A Example 168 A A A A Example 169 A A A A Example 170 A / A A Example 171 A A A A Example 172 A / A A Example 173 A / A A Example 174 A / A A Example 175 A A A A Example 176 A / C C Example 177 A / A A Example 178 A / B B Example 179 A / C C Example 180 A / C B Example 181 A / A A Example 182 A / A A Example 183 A / B B Example 184 A / A A Example 185 A / A A Example 186 A / A A Example 187 A / A A Example 188 A / A A Example 189 A / A A Example 190 A / B A Example 191 A / A A Example 192 A / A A Example 193 A / A A Example 194 A / A A Example 195 A / B A Example 196 A / A A Example 197 A / A A Example 198 A / A A Example 199 A / B A Example 200 A / B A Example 201 A / B A Example 202 A / A A Example 203 A / A A Example 204 A / A A Example 205 A / A A Example 206 A / C B Example 207 B / C C Example 208 B / C C Example 209 A / A A Example 210 A / A A Example 211 A / A A Example 212 A / A A Example 213 A / A A Example 214 A / A A Example 215 A / A A Example 216 A / A A Example 217 A / A A Example 218 A / A A Example 219 A / A A Example 220 A / A A Example 221 A / A A Example 222 A / A A Example 223 A / A A Example 224 A / A A Example 225 A / A A Example 226 A / A A Example 227 A / A A Example 228 A / A A Example 229 A / A A Example 230 A / A A Example 231 A / A A Example 232 A / A A Example 233 A / B B Example 234 A / A A Example 235 A / A A Example 236 A A A A Example 237 A A A A Example 238 A / A A

PLK4蛋白序列： 序列名稱 序列    PLK4 Homo sapiens Uniprot: O00444 #2-275    ATCIGEKIEDFKVGNLLGKGSFAGVYRAESIHTGLEVAIKMIDKKAMYKAGMVQRVQNEVKIHCQLKHPSILELYNYFEDSNYVYLVLEMCHNGEMNRYLKNRVKPFSENEARHFMHQIITGMLYLHSHGILHRDLTLSNLLLTRNMNIKIADFGLATQLKMPHEKHYTLCGTPNYISPEIATRSAHGLESDVWSLGCMFYTLLIGRPPFDTDTVKNTLNKVVLADYEMPSFLSIEAKDLIHQLLRRNPADRLSLSSVLDHPFMSRNSSTKSKD PLK4蛋白的表達： PLK4與λ-磷酸酶在大腸桿菌中共表達，挑單克隆接種至100 mL含有Kana抗性的LB培養基中，37℃培養過夜。次日轉接10 mL種子培養物到1 L培養基並在37℃搖床中培養至OD600達到0.4，然後降溫到16℃培養30分鐘。在OD 600達到0.6時，用終濃度0.2 mM IPTG誘導過夜。次日離心後收集細胞存於-80℃。 PLK4蛋白的純化： 細胞裂解：重懸菌體，並加終濃度1mM的 PMSF，超聲破碎，8500 RPM離心兩次，每次30 min。 Ni柱純化：將上清加入預平衡的10 mL Ni柱中；用緩衝液清洗負載的Ni柱；最後洗脫蛋白；4℃透析酶切過夜。次日將切後的樣品上樣至預平衡的25 mL Ni-NTA beads柱子中；收集流穿。 分子篩過濾：預平衡Superdex 75 16/600柱；用3000 mwco濃縮管將二次Ni的流穿濃縮至5mL，並用5 mL上樣環上樣。 離子交換柱層析：將分子篩洗下來的樣品的NaCl濃度稀釋至20 mM。將樣品加載到5 mL預平衡SP- HP色譜柱上，清洗至基線平穩，再線性梯度洗脫，總體積為100mL，每管收集1mL。 PLK4蛋白的結晶： PLK4蛋白（7.7mg/mL）與實施例168分子（0.8 mM）在冰浴中共孵20小時。之後用懸滴法（hanging drop）在18℃下生長晶體，晶體在2至3天后長出。 晶體數據採集在法國的ESRF ID30A1，在PILATUS3 2M探測器上以0.96546的波長完成。使用XDS對數據集進行索引、處理和縮放。採用PDB結構4JXF作為分子置換模型，模型構建在Coot中完成，並使用Refmac5進行修正。 PLK4與實施例168複合物的晶體解析並修正至2.21 Å，實施例168與PLK4形成1:1的複合物。共晶顯示實施例168結合在PLK4的催化口袋內（圖1A），與基質ATP競爭達到抑制效果。實施例168分子通過1H-吲唑與PLK4鉸鏈區的Cys92以及Glu90的骨架形成氫鍵（圖1B），另一側通過吡咯烷-2-酮與Lys41的側鏈以及Thr159的骨架羰基形成雙氫鍵（圖1C）。共晶中可以確認吡咯烷-2-酮上的苯環取代手性中心為 R-構型，化合物中的雙鍵均為反式。 Experimental example 4, the co-crystal structure of the complex of PLK4 kinase and Example 168 The structure of Example 168:

PLK4 protein sequence: sequence name sequence PLK4 Homo sapiens Uniprot: O00444 #2-275 ATCIGEKIEDFKVGNLLGKGSFAGVYRAESIHTGLEVAIKMIDKKAMYKAGMVQRVQNEVKIHCQLKHPSILELYNYFEDSNYVYLVLEMCHNGEMNRYLKNRVKPFSENEARHFMHQIITGMLYLHSHGILHRDLTLSNLLLTRNMNIKIADFGLATQLKMPHEKHYTLCGTPNYISPEIATRSAHGLESDVWSLGCMFYTLLIGRPPFDTDTVKNTLNKVVLADYEMPSFLSIEAKDLIHQLLRRNPADRLSLSSVLDHPFMSRNSSTKSKD Expression of PLK4 protein: PLK4 and λ-phosphatase were co-expressed in Escherichia coli, and a single clone was picked and inoculated into 100 mL LB medium containing Kana resistance, and cultured overnight at 37°C. The next day, 10 mL of seed culture was transferred to 1 L of medium and cultured in a shaker at 37°C until the OD600 reached 0.4, and then cooled to 16°C for 30 minutes. When the OD600 reached 0.6, induce overnight with a final concentration of 0.2 mM IPTG. The next day, the cells were collected by centrifugation and stored at -80°C. Purification of PLK4 protein: Cell lysis: resuspend the cells, add PMSF at a final concentration of 1 mM, sonicate, and centrifuge twice at 8500 RPM, each time for 30 min. Ni column purification: add the supernatant to a pre-equilibrated 10 mL Ni column; wash the loaded Ni column with buffer; finally elute the protein; dialyze at 4°C overnight. The next day, the excised samples were loaded onto a pre-equilibrated 25 mL Ni-NTA beads column; the flow-through was collected. Molecular sieve filtration: Pre-equilibrated Superdex 75 16/600 column; Concentrate the secondary Ni flow-through to 5 mL with a 3000 mwco concentrator tube and load with a 5 mL loading loop. Ion exchange column chromatography: dilute the NaCl concentration of the sample washed by the molecular sieve to 20 mM. Load the sample onto a 5 mL pre-equilibrated SP-HP chromatographic column, wash until the baseline is stable, and then elute with a linear gradient. The total volume is 100 mL, and 1 mL is collected in each tube. Crystallization of PLK4 protein: PLK4 protein (7.7 mg/mL) was co-incubated with Example 168 molecule (0.8 mM) in an ice bath for 20 hours. Crystals were then grown at 18° C. by hanging drop method, and the crystals grew out after 2 to 3 days. Crystal data collection was done at the ESRF ID30A1 in France at a wavelength of 0.96546 on a PILATUS3 2M detector. Datasets are indexed, processed and scaled using XDS. The PDB structure 4JXF was used as the molecular replacement model, and the model was built in Coot and corrected using Refmac5. The crystal of PLK4 in complex with Example 168 was resolved and corrected to 2.21 Å, and Example 168 forms a 1:1 complex with PLK4. Co-crystals showed that Example 168 binds within the catalytic pocket of PLK4 (Fig. 1A), competing with substrate ATP for inhibitory effect. The molecule of Example 168 forms hydrogen bonds with the skeleton of Cys92 and Glu90 in the hinge region of PLK4 through 1H-indazole (Figure 1B), and the other side forms dihydrogen bonds with the side chain of Lys41 and the skeleton carbonyl of Thr159 through pyrrolidin-2-one key (Fig. 1C). It can be confirmed in the co-crystal that the chiral center substituted by the benzene ring on the pyrrolidin-2-one is in the R -configuration, and the double bonds in the compound are all trans.

Experimental example 5, pharmacokinetic determination of the compounds of the present invention in CD-1 male mice Taking CD-1 male mice as the test animals, the compound of the present invention was studied at 1 mg/kg or 2 mg/kg intravenous injection and Pharmacokinetic behavior of plasma in mice after oral administration of 5 mg/kg or 10 mg/kg. 1. Experimental scheme 1.1 Experimental drugs: some compounds of the present invention. 1.2 Experimental animals CD-1 mice (3 mice/group), male, are supplied by Shanghai Jihui Experimental Animal Breeding Co., Ltd. and Weitong Lihua Experimental Animal Technology Co., Ltd. 1.3 Administration IV and PO experimental groups are 3 mice, IV administration dose is 1 mg/kg or 2 mg/kg, administration volume is 5 mL/kg; PO administration dose is 5 mg/kg or 10 mg/kg, the dosing volume is 10 mL/kg. The administration vehicle is 10% DMSO/50% PEG400/40% Water. 1.4 Experimental Equipment The centrifuge was purchased from Eppendorf Company, and the pipette was purchased from Eppendorf Company. 1.5 Sample collection After the administration of mice, 0.02 mL of venous blood was collected at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, placed in EDTA-K2 test tubes, at 4 °C, 4600 The plasma was separated by centrifugation at rpm for 5 min and stored at -80 °C. 1.6 Sample processing 1) Add 200 μL acetonitrile to 10 μL plasma sample for precipitation, vortex and centrifuge for 15 minutes. 2) Take the treated supernatant and dilute it with water to analyze the concentration of the compound to be tested by LC/MS/MS. 1.7 Liquid phase conditions for biological analysis: Shimadzu LC-30AD Mass spectrometry conditions: AB Sciex API 5500 Column: Phenomenex Kinetex 2.6 µm C18 Mobile phase: A: 5 mM ammonium acetate aqueous solution (containing 0.05% formic acid); B: acetonitrile (containing 0.1% formic acid) Flow rate: 0.5 mL/min Elution gradient: Time (min) A (%) B (%) 0.00 85.0 10.0 0.50 85.0 10.0 2.00 5.00 95.0 2.20 5.00 95.0 2.21 85.0 10.0 2.50 85.0 10.0 2. Experimental results and analysis The pharmacokinetic parameters were calculated with WinNonlin 8.0. The pharmacokinetic parameters of intravenous and oral administration of drugs in mice are shown in Table 2 and Table 3 below. Table 2. The pharmacokinetic parameters of mouse intravenous injection of some compounds of the present invention Example Dose CL Vss T _1/2 MRT _Inf AUC (mg/kg) (L/hr/kg) (L/kg) (hr) (hr) (hr*ng/mL) 217 1 1.58 1.75 1.14 1.12 643 218 1 1.84 1.71 1.03 0.93 539 226 1 1.38 1.11 1.12 0.809 739 228 1 1 2.05 1.9 2.04 955 230 1 1.23 3.88 2.92 3.21 807 232 1 0.732 2.73 2.89 3.77 255 Table 3. The pharmacokinetic parameters of oral administration of some compounds of the present invention in mice Example Dose _Cmax AUC T _1/2 MRT _Inf f (mg/kg) (ng/mL) (hr*ng/mL) (hr) (hr) (%) 217 5 73.8 316 2.69 3.92 10.9 218 5 144 400 1.42 2.2 16.7 226 5 218 617 1.32 2.28 16.9 228 5 233 1260 2.32 3.69 25.8 230 5 139 1235 3.84 6.53 30 232 5 228 2003 3.24 5.84 31.6 Dose: dose; CL: clearance rate; Vss: intravenous infusion of steady-state distribution solvent; C _max : maximum plasma concentration; AUC: concentration-area under the curve; T _1/2 : half-life; MRT _inf : average residence time; F: The result of bioavailability shows that the compound of the present invention has good pharmacokinetic properties and has the value of being a medicine.

Experimental example 6. In vivo pharmacodynamics study of the tested drug in MDA-MB-468 transplanted tumor model tumor-bearing mice 1. Experimental animal species: mouse strain: CB17 SCID mouse age and body weight: body weight 19-24 G Sex: Female Quantity: 75 (including the rest of the group) Supplier: Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Animal qualification certificate number: 20170011007031 2. Experimental method Human breast cancer MDA-MB-468 cells were cultured in vitro , the culture conditions are Leibovitz's L-15 medium plus 10% fetal bovine serum, 1% double antibody (penicillin, streptomycin), 37 ° C without CO ₂ culture. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, collect the cells, count and inoculate. PBS containing 10×10 ⁶ MDA-MB-468 cells was mixed with Matrigel at a ratio of 1:1 (final volume 200 µL) and inoculated subcutaneously in the right forelimb armpit of each mouse, on the 26th day after cell inoculation , when the average tumor volume of the enrolled animals reached 150 mm ³ , group administration began (PG-D0). Animal health and mortality were monitored daily. Routine checks included observation of tumor growth and effects of drug treatment on animal behavior such as behavioral activity, food and water intake (visual inspection only), and body weight changes (measured three times a week or once a day) ), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group. 3. Tumor measurement and experimental indicators The experimental indicators are to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured twice a week with vernier calipers. The formula for calculating the tumor volume is: V = 0.5a × b2, where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of solvent control group- The average tumor volume at the beginning of treatment in the solvent control group)]×100%. Relative tumor proliferation rate T/C (%): The calculation formula is as follows: T/C% = TRTV average value/CRTV average value × 100 % (TRTV average value: the average value of RTV in the treatment group; CRTV average value: RTV in the negative control group average of). According to the results of tumor measurement, the relative tumor volume (relative tumor volume, RTV) was calculated, and the calculation formula was RTV = Vt /V0, where V0 was the tumor volume of each mouse measured during group administration (ie d0), and Vt was Tumor volume per mouse at a given measurement. Then calculate the average value for each group. V0 and Vt take the tumor volume data of the same mouse. After the end of the experiment, the tumor weight will be detected, and the Tweight/Cweight percentage will be calculated. Tweight and Cweight represent the tumor weights of the administration group and the solvent control group respectively. Statistical analysis, including the mean and standard error (SEM) of tumor volume at each time point for each group. Comparisons between the two groups were analyzed using a T-test. P<0.05 considered significant difference. 4. Experimental results The drug efficacy test results show that the compound of the present invention has a good tumor inhibitory effect. References: (1) Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 2005, 7(11), 1140–1146. (2) WO2011123946A1, publication date: 2011.10 .13.

Although the present invention has been disclosed above with the embodiments, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field of the present invention can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be defined by the scope of the appended patent application.

none

Figure 1 is a schematic diagram of the eutectic structure of the complex of PLK4 and Example 168.

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              50 55 60
          Gln Leu Lys His Pro Ser Ile Leu Glu Leu Tyr Asn Tyr Phe Glu Asp
          65 70 75 80
          Ser Asn Tyr Val Tyr Leu Val Leu Glu Met Cys His Asn Gly Glu Met
                          85 90 95
          Asn Arg Tyr Leu Lys Asn Arg Val Lys Pro Phe Ser Glu Asn Glu Ala
                      100 105 110
          Arg His Phe Met His Gln Ile Ile Thr Gly Met Leu Tyr Leu His Ser
                  115 120 125
          His Gly Ile Leu His Arg Asp Leu Thr Leu Ser Asn Leu Leu Leu Thr
              130 135 140
          Arg Asn Met Asn Ile Lys Ile Ala Asp Phe Gly Leu Ala Thr Gln Leu
          145 150 155 160
          Lys Met Pro His Glu Lys His Tyr Thr Leu Cys Gly Thr Pro Asn Tyr
                          165 170 175
          Ile Ser Pro Glu Ile Ala Thr Arg Ser Ala His Gly Leu Glu Ser Asp
                      180 185 190
          Val Trp Ser Leu Gly Cys Met Phe Tyr Thr Leu Leu Ile Gly Arg Pro
                  195 200 205
          Pro Phe Asp Thr Asp Thr Val Lys Asn Thr Leu Asn Lys Val Val Leu
              210 215 220
          Ala Asp Tyr Glu Met Pro Ser Phe Leu Ser Ile Glu Ala Lys Asp Leu
          225 230 235 240
          Ile His Gln Leu Leu Arg Arg Asn Pro Ala Asp Arg Leu Ser Leu Ser
                          245 250 255
          Ser Val Leu Asp His Pro Phe Met Ser Arg Asn Ser Ser Thr Lys Ser
                      260 265 270
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Claims (29)

A compound represented by formula (I),

Formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate thereof, wherein, X is selected from N or C (R ⁷ ); Ring A is selected from 5-6 membered cycloalkyl, 5 -6-membered heterocyclic group, 8-14-membered condensed heterocyclic group, 7-11-membered spiroheterocyclic group, wherein each of the heterocyclic rings independently contains one or more C(O), N(R ⁵ )x, O and/or S(O)y; Ring B is selected from phenyl or 5-6 membered heteroaryl; L ^is selected from C _1-6 alkylene optionally substituted by one or more S1, C _2-6 alkenylene, C _2-6 alkynylene; wherein, said S1 is independently selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkane R ^is selected from hydrogen, halogen, hydroxyl or C _1-6 alkyl; each ^R is independently selected from hydrogen, halogen, cyano, hydroxyl or the following groups optionally substituted by one or more S2 : C _1-6 alkyl, C _1-6 alkyl-C(O)-, C _1-6 alkyl-S(O) ₂ -, C _1-6 alkoxy, phenyl, 5-6 members Heteroaryl; wherein, said S2 is independently selected from hydroxyl, halogen, C _1-6 alkyl or C _1-6 alkoxy; each R ³ is independently selected from hydrogen, halogen, cyano, hydroxyl , C _1-6 alkyl, halogenated C _1-6 alkyl or C _1-6 alkoxy; each R ⁴ is independently selected from R ^4a and/or R ^4b ; each R ^4a is independently selected from Hydrogen, halogen, cyano, hydroxyl, or the following groups optionally substituted by one or more S3: C _1-6 alkyl, C _1-6 alkylcarbonyl, (R ⁵ )(R ⁶ )N-, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, (C _1-6 alkyl)-S(O)-, (C _1-6 alkyl)-S(O) _2- ; each R ^4b is independently selected from

, wherein ring C is selected from the following groups optionally substituted by one or more S3: 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 6-10 membered fused heterocyclic group, 7-12 membered spiro Heterocyclic group or 6-8 membered bridged heterocyclic group; Wherein, said S3 is independently selected from halogen, hydroxyl, cyano, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyl C _1-6 alkyl, (R ⁵ )(R ⁶ ) N-, (R ⁵ )(R ⁶ )NC(O)-, C _1-6 alkoxy, C _1-6 alkoxy-C _{1- 6} alkyl-, (R ⁵ )(R ⁶ )NC _1-6 alkyl- or 3-6 membered cycloalkyl; L ² is selected from chemical bonds, or C _1-6 optionally substituted by one or more S4 Alkylene; wherein, one or more carbon atoms in C _1-6 alkylene are optionally substituted by C(O), NR ⁵ , S(O)y and/or O; wherein, said S4 is independently is selected from halogen, cyano group, hydroxyl group, amino group, _C1-6 alkyl group, or any two S4 and the substituted atoms to which it is connected form a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; Moreover, said S4 can be located on the same or different substituting atoms; each R ⁵ , R ⁶ , and R ⁷ are independently selected from hydrogen, cyano, carboxyl, hydroxyl, and C _1-6 alkyl; x is selected from 0 or 1; y is selected from 0, 1 or 2; m, n, p are independently selected from 0, 1, 2, 3, 4 or 5. The compound as claimed in item 1, wherein, X is selected from N; Ring A is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclic group, 8-14 membered fused heterocyclic group, 7-10 membered spiro Heterocyclyl; wherein, each heterocycle independently contains 1-3 C(O), N(R ⁵ )x, S(O)y and/or O; Ring B is selected from phenyl or 5 -6-membered heteroaryl; L ¹ is selected from C _2-4 alkenylene optionally substituted by 1-3 S 1 , said S 1 is independently selected from fluorine, methyl or ethyl; R ¹ is selected from hydrogen , hydroxyl or methyl; each R ² is independently selected from hydrogen, halogen, cyano, hydroxyl or the following groups optionally substituted by 1-3 S2: C _1-4 alkyl, C _1-4 alkane Oxygen, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S(O) ₂ -, phenyl, pyridyl, pyrimidinyl, wherein said S2 is independently selected from halogen , hydroxyl, C _1-4 alkyl or C _1-4 alkoxy; each R ³ is independently selected from hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; each R ⁴ are independently selected from R ^4a and/or R ^4b ; each R ^4a is independently selected from hydrogen, halogen, cyano, hydroxyl, or the following groups optionally substituted by 1-3 S3: C _1-4 alkane radical, (R ⁵ )(R ⁶ )N- or C _1-4 alkoxy; each R ^4b is independently selected from

, wherein ring C is selected from the following groups optionally substituted by 1-3 S3: 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 6-8 membered fused heterocyclyl, 7-11 membered spiro Heterocyclyl or 6-8 member bridged heterocyclyl; Wherein, said S3 is independently selected from halogen, hydroxyl, cyano, carboxyl, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxyl C _1-4 alkyl, (R ⁵ )(R ⁶ )N-, (R ⁵ )(R ⁶ )NC(O)-, C _1-4 alkoxy, C _1-4 alkoxy-C _{1- 4} alkyl-, (R ⁵ )(R ⁶ )NC _1-4 alkyl- or 3-6 membered cycloalkyl; L ² is selected from chemical bonds, or C _1-4 optionally substituted by 1-3 S4 Alkylene group; wherein, the carbon atoms in the C _1-4 alkylene group are optionally substituted by 1-3 C(O), NR ⁵ , S, S(O), S(O) ₂ and/or O; Wherein, said S4 is independently selected from fluorine, hydroxyl, methyl, ethyl, or any two S4 located on the same atom and the substituted atom to which it is connected together form a 3-4 membered cycloalkyl group or a 3-4 membered heterocyclic group; each R ⁵ , R ⁶ are independently selected from hydrogen, C _1-4 alkyl; x is selected from 0 or 1; y is selected from 0, 1 or 2; m, n, p are independently selected Choose from 0, 1, 2, 3. The compound according to claim 1 or 2, wherein ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl. The compound according to any one of claims 1-3, wherein ^L is selected from C _2-4 alkenylene. The compound according to any one of claims 1-3, wherein L ¹ is selected from -CH ₂ -CH ₂ - or -CH ₂ ═CH ₂ -. The compound as claimed in any one of claims 1-5, wherein R ¹ is selected from hydrogen or hydroxyl. The compound as claimed in any one of claims 1-6, wherein each R ³ is independently selected from hydrogen, fluorine, chlorine, methyl or methoxy. The compound according to any one of claims 1-7, wherein each R ⁵ and R ⁶ are independently selected from hydrogen, methyl and ethyl. The compound as described in any one of claim items 1-8, wherein,

selected from

or

, Y is selected from CH or N, pa is selected from 0, 1 or 2. The compound as claimed in any one of claims 1-9, wherein each R ⁴ is independently selected from R ^4a and/or R ^4b ; each R ^4a is independently selected from hydrogen, fluorine, methyl, methoxy Base, ethoxy, isopropoxy, trifluoromethyl, N,N-dimethylaminomethyl; each R ^4b is independently selected from

, where the structural unit

Selected from cyclopropyl-L ² -, cyclobutanyl-L ^2- , cyclopentyl-L ^2- , cyclohexyl-L ^2- , aziridine-L ^2- , oxirane- L ² -, azetidinyl, oxetanyl-L ² -, pyrrolidinyl-L ² -, imidazolidinyl-L ² -, tetrahydrofuranyl-L ² -, piperidinyl-L ² -, piperyl-L ² -, morpholinyl-L ² -, tetrahydropyranyl-L ² -,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

; wherein, K ¹ and K ² are independently selected from CH ₂ , O, or NH; each S3 is independently selected from fluorine, hydroxyl, cyano, carboxyl, methyl, ethyl, methoxy, ethoxy , Isopropoxy, CF ₃ CH ₂ -, Cyclopropyl, H ₂ NC(O)-, N,N-Dimethylamino, N,N-Dimethylaminomethyl, Methoxymethyl group, ClCH ₂ -, HOCH ₂ -; w is selected from 0, 1, or 2; L ² is selected from chemical bonds, -CH ₂ -, -CF ₂ -,

,

,

,

, -CH ₂ -CH ₂ -, -CH ₂ -O-, -CH ₂ -C(O)-, -CH ₂ -NR ⁵ -, -C(O)-NR ⁵ -, -C(O)- O-, -C(O)-, -S(O)-, -S(O) ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -NH-CH ₂ -, -CH ₂ - _CH2 - _CH2 - _CH2- ,

,

,

,

,

or

. The compound as claimed in claim 10, wherein R ^4a is selected from hydrogen; R ^4b is independently selected from

, where the structural unit

selected from azetidinyl-L ² -, pyrrolidinyl-L ^{2 -, piperidinyl-L 2} -, morpholinyl- ^{L 2 -} ; L ² is selected from -CH ₂ -; each S3 are independently selected from methyl; w is selected from 0, 1 or 2. The compound as described in any one of claim items 1-10, wherein, R ⁴ is selected from R ^4a and/or R ^4b ; R ^4a is selected from hydrogen, fluorine, methyl, methoxy, ethoxy, trifluoromethane Base, N,N-dimethylaminomethyl; R ^4b is selected from

,

,

,

,

,

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,

,

,

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,

,

,

,

,

,

,

,

,

,

,

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,

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,

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,

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,

,

,

p is selected from 1, 2 or 3. The compound as claimed in item 12, wherein, R ^4a is selected from hydrogen, R ^4b is selected from

,

,

,

,

,

. A compound represented by formula (I),

Formula (I) or its pharmaceutically acceptable salts, esters, isomers, and solvates thereof, wherein X is N; ring A is selected from 5-6 membered heterocyclic groups, wherein the heterocyclic independently contain 1 C(O) and/or 1 N(R ⁵ )x; each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl, hydroxy C _1-4 alkyl,

,

,

; Wherein, S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1; m is selected from 1 or 2; R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , L ¹ , ring B, m, n, p, x are as described in any one of claim items 1-11. The compound as claimed in item 14, wherein,

selected from

,

,

,

,

or

; each R ² is independently selected from hydrogen, fluorine, chlorine, methyl, CH ₃ OCH ₂ -, HOCH ₂ -,

,

; S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1. The compound as claimed in item 15, wherein,

selected from

, ^R2 is selected from

, S2 is selected from methyl, methoxy, fluorine, bromine; t is selected from 0 or 1. A compound represented by formula (I),

Formula (I) or its pharmaceutically acceptable salts, esters, isomers, and solvates thereof, wherein ring A is selected from 7-10 membered spiro heterocyclic groups, wherein the spiro heterocyclic rings independently contain 1-3 C(O), N(R ⁵ )x, S(O)y and/or O; each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 Alkoxy, C _1-4 alkoxy-C _1-4 alkyl-, C _1-4 alkyl-C(O)-, C _1-4 alkyl-S(O) ₂ -; X, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , L ¹ , ring B, m, n, p, x, y are as described in any one of claims 1-11. The compound as claimed in item 17, wherein X is N; Ring A is selected from

,

,

,

,

,

,

,

, wherein, Z ² is selected from CH ₂ , C(O), NR ⁵ , S, S(O), S(O) ₂ or O; R ² is selected from fluorine, chlorine, methyl, ethyl, methoxy , ethoxy, methoxymethyl, acetyl, methylsulfonyl, m is selected from 0 or 1. The compound as described in any one of claims 1-18, its pharmaceutically acceptable salt, its ester, solvate or its isomer, which has the structure shown in the following general formula:

Wherein, pa is selected from 0, 1 or 2; w is selected from 0, 1 or 2; Y is selected from N or CH; R ² , R ³ , R ⁴ , R ^4a , L ² , S3, ring B, ring C, m, n, p are as defined in any one of claim items 1-11. The compound as described in any one of claims 1-18, its pharmaceutically acceptable salt, its ester, its isomer, and solvate, which have the structure shown in the following general formula:

Wherein, w is selected from 0, 1 or 2; t is selected from 0 or 1; pa is selected from 0, 1 or 2; n is selected from 0 or 1; m is selected from 0, 1 or 2; K ^is selected from N or CH ; K ² is selected from N-S3, NH, O or CH ₂ ; R ² , R ³ , R ⁴ , R ^4a , ring C, S2, S3, L ² , Z ² are as described in any one of claims 1-15 definition. A compound represented by formula (I), its pharmaceutically acceptable salt, its ester, its isomer, solvate,

Formula (I) wherein, X is selected from N or C(R ⁷ ); ring A is selected from 9-13 membered fused heterocyclic groups, wherein the fused heterocyclic rings independently contain 1-3 C(O) , O and/or N(R ⁵ )x; each R ² is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; Ring B, R ¹ , R ³ , R ⁴ , R ⁵ , ring B, R ⁷ , L ¹ , m, n, p are as described in any one of claims 1-11; preferably, ring A is selected as

When, n is 1; and/or, preferably, ring A is

When, R ¹ is not hydrogen; and/or, preferably, Ring A is

hour,

not for

. The compound as claimed in item 21, wherein Ring A is selected from

,

,

,

,

,

,

,

,

,

,

,

or

. The compound as described in Claim 21, its pharmaceutically acceptable salt, its ester, its isomer, and its solvate have the structure shown in the following general formula (IV-1),

Formula (IV-1) wherein, ring A is selected from

,

,

,

,

or

; R ² is selected from hydrogen, fluorine, methyl or methoxy; R ¹ , R ³ , m, n are as defined in any one of claims 1-13; Preferably, ring A is selected as

When, n is 1; and/or, preferably, ring A is

, R ¹ is not hydrogen. The compound as described in Claim 21, its pharmaceutically acceptable salt, its ester, its isomer, and its solvate have the structures shown in the following general formulas (IV-2)-(IV-4),

,

Among them, Ring C is selected from the spiroheterocyclyl as defined by R ^4b in any one of claim items 10-13; Ring B is selected from any one of claim items 1-13 as defined; R ^4a is selected from any one of claim items 10-13 defined in the term; w is selected from 0, 1 or 2; pa is selected from 0, 1 or 2; K ¹ is selected from N or CH; K ² is selected from N-S3, NH, O or CH ₂ ; R ² , L ^2. S3 and m are as defined in any one of claim items 1-13. The compound as described in Claim 21, its pharmaceutically acceptable salt, its ester, its isomer, its solvate, which has the structure shown in the following general formula (IV-5) or (IV-6),

,

Ring A is selected from

,

,

or

; R ² is selected from fluorine, methyl, methoxy; Wherein, ring C is selected from heterocyclic group as defined in any one of claim items 10-13; R ^4a is as defined in any one of claim items 10-13 ; K ¹ is selected from N or CH; K ² is selected from N-S3, NH, O or CH ₂ ; pa is selected from 0, 1 or 2; w is selected from 0, 1 or 2; L ² , S3, m are as requested as defined in any one of items 1-13. The compound as described in Claim 1, its pharmaceutically acceptable salt, its ester, its isomer, and solvate are selected from:

. A pharmaceutical composition containing the compound described in any one of Claims 1-26, its pharmaceutically acceptable salt, its ester, its isomer, and solvate; preferably, the pharmaceutical composition further comprises one or A variety of pharmaceutically acceptable excipients. A pharmaceutical composition, containing the compound described in any one of claims 1-26, its pharmaceutically acceptable salt, its ester, its isomer, solvate or the pharmaceutical composition described in claim 27 and one or a plurality of second therapeutically active agents; Preferably, the second therapeutic agent is an antineoplastic agent; More preferably, the anti-tumor agent is selected from antibody drugs, cytotoxic drugs, hormonal drugs, biological response regulators (such as enhancing immune function), cell differentiation inducers, apoptosis inducers, angiogenesis inhibitors One or more of agents, epidermal growth factor receptor inhibitors. A compound described in any one of claims 1-26, a pharmaceutically acceptable salt thereof, an ester thereof, an isomer, a solvate thereof, a pharmaceutical composition described in claim 27, and a drug described in claim 28 Application of the composition in the preparation of medicaments for preventing and/or treating related diseases mediated by PLK4 in subjects; Preferably, the related disease mediated by PLK4 is a cell abnormal proliferation disease; More preferably, the abnormal cell proliferation disease is cancer; More preferably, the abnormal cell proliferation disease is cancer, selected from the group consisting of lung cancer, breast cancer, colon cancer, brain cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, head and neck cancer, neuroblastoma, Prostate cancer, melanoma, glioblastoma multiforme, ovarian cancer, cervical cancer, lymphoma, leukemia, sarcoma, with tumor effector, osteosarcoma, germ cell tumor, glioma, or mesothelioma. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer.

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