TW202246287A - Twelve-membered macrocycle macrocyclic compound - Google Patents

Twelve-membered macrocycle macrocyclic compound Download PDF

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TW202246287A
TW202246287A TW111117242A TW111117242A TW202246287A TW 202246287 A TW202246287 A TW 202246287A TW 111117242 A TW111117242 A TW 111117242A TW 111117242 A TW111117242 A TW 111117242A TW 202246287 A TW202246287 A TW 202246287A
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alkyl
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present
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張楊
付志飛
孫繼奎
陳健
健 黎
曙輝 陳
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大陸商南京明德新藥研發有限公司
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Abstract

The invention discloses a series of twelve-membered macrocyclic compounds, and specifically discloses a compound represented by formula (III) and a pharmaceutically acceptable salt thereof.

Description

十二元大環類化合物Twelve-membered macrocyclic compounds

本發明涉及一系列十二元大環類化合物，具體涉及式(III)所示化合物及其藥學上可接受的鹽。The present invention relates to a series of twelve-membered macrocyclic compounds, in particular to compounds represented by formula (III) and pharmaceutically acceptable salts thereof.

本發明主張如下優先權 ：CN202110492226.8，申請日：2021年05月06日；CN202110502109.5，申請日：2021年05月08日；CN202110545538.0，申請日：2021年05月19日；CN202110738841.2，申請日：2021年06月30日；CN202110825905.2，申請日：2021年07月21日；CN202111131764.0，申請日：2021年09月26日；CN202111162653.6，申請日：2021年09月30日；CN202111389719.5，申請日：2021年11月22日；CN202210452057.X，申請日：2022年04月26日。 The present invention claims the following priority rights : CN202110492226.8, application date: May 06, 2021; CN202110502109.5, application date: May 08, 2021; CN202110545538.0, application date: May 19, 2021; CN202110738841 .2, application date: June 30, 2021; CN202110825905.2, application date: July 21, 2021; CN202111131764.0, application date: September 26, 2021; CN202111162653.6, application date: 2021 September 30; CN202111389719.5, application date: November 22, 2021; CN202210452057.X, application date: April 26, 2022.

RAS蛋白是由RAS基因表達的產物。RAS蛋白可以與鳥嘌呤三核苷酸磷酸(GTP)或鳥嘌呤二核苷酸磷酸(GDP)結合，RAS蛋白的活性狀態對細胞的生長、分化、細胞骨架、蛋白質運輸和分泌等都具有影響，其活性是透過與GTP或GDP的結合進行調節：當RAS蛋白與GDP結合時，它處於休眠狀態，也就是“失活”狀態；當有上游特定的細胞生長因子刺激時，RAS蛋白被誘導交換GDP，與GTP結合，此時稱為“活化”狀態。與GTP結合的RAS蛋白能夠活化下游的蛋白，進行訊號傳遞。RAS蛋白自身具有弱的水解GTP水解活性，能夠水解GTP到GDP。這樣就可以實現從活化狀態到失活狀態的轉化。在這個水解過程中，還需要GAP(GTPase activating proteins, GTP水解酶活化蛋白)參與。它能與RAS蛋白作用，大大促進其水解GTP到GDP的能力。RAS蛋白的突變將影響其與GAP的作用，也就影響了其水解GTP到GDP的能力，使其一直處於活化狀態。活化的RAS蛋白持續的給予下游蛋白生長訊號，最終導致細胞不停的生長和分化，最終產生腫瘤。RAS基因家族成員眾多，其中與各種癌症密切相關的亞家族主要有克爾斯滕大鼠肉瘤病毒致癌基因同源物(KRAS)、哈維大鼠肉瘤病毒致癌同源物(HRAS)和神經母細胞瘤大鼠肉瘤病毒致癌基因同源物(NRAS)。人們發現大約30%的人類腫瘤中都攜帶某些突變的RAS基因，其中以KRAS突變最為顯著，占到所有RAS突變中的86%。對於KRAS突變，最為常見的突變出現在12號甘胺酸(G12)，13號甘胺酸(G13)和61號穀胺醯胺(Q61)殘基上，其中G12突變占到83%。RAS protein is the product expressed by the RAS gene. RAS protein can bind to guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP), and the active state of RAS protein has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc. , its activity is regulated by binding to GTP or GDP: when the RAS protein binds to GDP, it is in a dormant state, that is, in an "inactive" state; when stimulated by specific upstream cell growth factors, the RAS protein is induced Exchanging GDP, combined with GTP, this time is called "activated" state. The RAS protein combined with GTP can activate downstream proteins for signal transmission. RAS protein itself has a weak hydrolysis activity to hydrolyze GTP and can hydrolyze GTP to GDP. This allows for the transition from the active state to the inactive state. In this hydrolysis process, GAP (GTPase activating proteins, GTPase activating proteins) is also required to participate. It can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP. The mutation of RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always in an activated state. The activated RAS protein continuously sends growth signals to downstream proteins, which eventually leads to the continuous growth and differentiation of cells, and finally produces tumors. There are many members of the RAS gene family, among which the subfamilies closely related to various cancers mainly include Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS) and neuroblast Tumor rat sarcoma viral oncogene homologue (NRAS). It has been found that about 30% of human tumors carry certain mutated RAS genes, among which KRAS mutations are the most prominent, accounting for 86% of all RAS mutations. For KRAS mutations, the most common mutations occurred at glycine 12 (G12), glycine 13 (G13) and glutamine 61 (Q61) residues, of which G12 mutations accounted for 83%.

G12C突變是KRAS基因突變中比較常見的一個亞型，它是指12號甘胺酸突變為半胱胺酸。KRAS G12C突變在肺癌中最為常見，根據文獻(Nat Rev Drug Discov 2014;13:828-851)報導的數據推算，KRAS G12C突變占到所有肺癌患者的10%左右。G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine 12 to cysteine. KRAS G12C mutation is the most common in lung cancer. According to the data reported in literature (Nat Rev Drug Discov 2014;13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients.

文獻J Med Chem. 2020 Jan 9; 6 3(1):52-65報導了AMG510(結構如下)與KRAS G12C蛋白的共晶結構(ID:6IOM)。根據文獻報導，AMG510結合在KRAS G12C蛋白的SwichⅡ口袋中，丙烯基和Cys12加成形成共價鍵，羰基與Lys16形成氫鍵，母核嘧啶酮并吡啶分別和Tyr96形成pi-pi作用，異丙基甲基吡啶和母核之間以86.8°的二面角插入疏水口袋，氟苯酚和母核以58.8°的二面角插入疏水口袋，同時酚羥基和Arg68形成氫鍵作用。(見圖1和 圖2，Maestro 2017-2，Pymol 1.8.6)。

Figure 02_image003
Document J Med Chem. 2020 Jan 9; 6 3(1):52-65 reported the co-crystal structure (ID: 6IOM) of AMG510 (structure as follows) and KRAS G12C protein. According to literature reports, AMG510 binds in the Swich II pocket of the KRAS G12C protein, the acryl group and Cys12 add to form a covalent bond, the carbonyl group forms a hydrogen bond with Lys16, and the mother nucleoside pyrimidine ketopyridine forms a pi-pi interaction with Tyr96, isopropyl The dihedral angle between the methylpyridine and the core is 86.8°, and the fluorophenol and the core are inserted into the hydrophobic pocket at a dihedral angle of 58.8°. At the same time, the phenolic hydroxyl group and Arg68 form a hydrogen bond. (See Figures 1 and 2, Maestro 2017-2, Pymol 1.8.6).
Figure 02_image003

本發明提供了式(III)所示化合物或其藥學上可接受的鹽，

Figure 02_image001
其中， T 1、T 2和T 3分別獨立地選自CH和N； T 4選自CR 6和N； 環A選自哌𠯤基、
Figure 02_image005
和
Figure 02_image007
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； 各R 2分別獨立地選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； R 6選自H、F、Cl和CN； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，R a選自CN，R 1被R a取代形成
Figure 02_image013
；或者 2)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，所述
Figure 02_image011
被1、2或3個R a取代，R a選自C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代，各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基。 The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure 02_image001
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; T 4 is selected from CR 6 and N; ring A is selected from piperyl,
Figure 02_image005
with
Figure 02_image007
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
optionally substituted by 1, 2 or 3 R a ; each R independently selected from H and C 1-3 alkyl optionally substituted by 1 , 2 or 3 R ; R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; R 5 is selected from From H and F ; R is selected from H, F, Cl and CN; m is selected from 0, 1, 2 and 3 ; each R is independently selected from H, F, Cl, Br, I , CN, C -3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl and cyclobutenyl are optionally 1, 2 or 3 R substitutions; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; the proviso is that, 1) when T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image011
When, R a is selected from CN, R 1 is replaced by R a to form
Figure 02_image013
; or 2) when T 4 is selected from N, ring A is selected from piperthiol, R 1 is selected from
Figure 02_image011
when the
Figure 02_image011
Substituted by 1, 2 or 3 R a selected from C 1-3 alkyl, -C ( O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl , the C 1-3 alkyl and cyclobutenyl are optionally substituted by 1, 2 or 3 R, each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morphol Linky.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O) OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and ring Butenyl is optionally substituted with 1, 2 or 3 R, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、

Figure 02_image016
和
Figure 02_image018
，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 02_image016
with
Figure 02_image018
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其中，T 4選自N，環A選自哌𠯤基，R 1選自

Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof, wherein T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述各R 2分別獨立地選自H和CH 3，其他變量如本發明所定義。 In some solutions of the present invention, each R 2 is independently selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F和Cl，其他變量如本發明所定義。 In some aspects of the present invention, the R 4 is selected from F and Cl, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image059
、
Figure 02_image061
、
Figure 02_image063
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image059
,
Figure 02_image061
,
Figure 02_image063
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image069
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image069
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
和
Figure 02_image154
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
with
Figure 02_image154
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image156
、
Figure 02_image158
、
Figure 02_image160
、
Figure 02_image162
、
Figure 02_image164
、
Figure 02_image166
、
Figure 02_image168
、
Figure 02_image170
、
Figure 02_image172
、
Figure 02_image174
、
Figure 02_image176
、
Figure 02_image178
、
Figure 02_image180
、
Figure 02_image182
、
Figure 02_image184
、
Figure 02_image186
、
Figure 02_image188
、
Figure 02_image190
和
Figure 02_image192
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image156
,
Figure 02_image158
,
Figure 02_image160
,
Figure 02_image162
,
Figure 02_image164
,
Figure 02_image166
,
Figure 02_image168
,
Figure 02_image170
,
Figure 02_image172
,
Figure 02_image174
,
Figure 02_image176
,
Figure 02_image178
,
Figure 02_image180
,
Figure 02_image182
,
Figure 02_image184
,
Figure 02_image186
,
Figure 02_image188
,
Figure 02_image190
with
Figure 02_image192
, other variables are as defined in the present invention.

本發明提供了式(III)所示化合物或其藥學上可接受的鹽，

Figure 02_image001
其中， T 1、T 2和T 3分別獨立地選自CH和N； T 4選自CR 6和N； 環A選自哌𠯤基、
Figure 02_image005
和
Figure 02_image007
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； 各R 2分別獨立地選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； R 6選自H、F、Cl和CN； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，R a選自CN，R 1被R a取代形成
Figure 02_image013
；或者 2)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，所述
Figure 02_image011
任選被1、2或3個R a取代，R a選自C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代，各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基。 The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure 02_image001
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; T 4 is selected from CR 6 and N; ring A is selected from piperyl,
Figure 02_image005
with
Figure 02_image007
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
optionally substituted by 1, 2 or 3 R a ; each R independently selected from H and C 1-3 alkyl optionally substituted by 1 , 2 or 3 R ; R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; R 5 is selected from From H and F ; R is selected from H, F, Cl and CN; m is selected from 0, 1, 2 and 3 ; each R is independently selected from H, F, Cl, Br, I , CN, C -3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl and cyclobutenyl are optionally 1, 2 or 3 R substitutions; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; the proviso is that, 1) when T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image011
When, R a is selected from CN, R 1 is replaced by R a to form
Figure 02_image013
; or 2) when T 4 is selected from N, ring A is selected from piperthiol, R 1 is selected from
Figure 02_image011
when the
Figure 02_image011
Optionally substituted by 1, 2 or 3 R a selected from C 1-3 alkyl, -C ( O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutyl Alkenyl, the C 1-3 alkyl and cyclobutenyl are optionally substituted by 1, 2 or 3 R, and each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and MoFrinki.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O) OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and ring Butenyl is optionally substituted with 1, 2 or 3 R, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、

Figure 02_image016
和
Figure 02_image018
，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 02_image016
with
Figure 02_image018
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其中，T 4選自N，環A選自哌𠯤基，R 1選自

Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof, wherein T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述各R 2分別獨立地選自H和CH 3，其他變量如本發明所定義。 In some solutions of the present invention, each R 2 is independently selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F和Cl，其他變量如本發明所定義。 In some aspects of the present invention, the R 4 is selected from F and Cl, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
和
Figure 02_image154
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
with
Figure 02_image154
, other variables are as defined in the present invention.

本發明提供了式(III)所示化合物或其藥學上可接受的鹽，

Figure 02_image001
其中， T 1、T 2和T 3分別獨立地選自CH和N； T 4選自CR 6和N； 環A選自哌𠯤基、
Figure 02_image005
和
Figure 02_image007
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； 各R 2分別獨立地選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； R 6選自H、F、Cl和CN； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1）當T 4選自N，環A選自哌𠯤基時，R 1選自
Figure 02_image009
，所述
Figure 02_image009
任選被1、2或3個R a取代；或者 2）當T 4選自N，環A選自哌𠯤基時，R 1選自
Figure 02_image011
和
Figure 02_image013
，所述
Figure 02_image011
被1、2或3個C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基被1、2或3個F、OCH 3、NH 2和嗎福林基取代；或者 3）當T 4選自CR 6，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，R 6選自F、Cl和CN。 The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure 02_image001
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; T 4 is selected from CR 6 and N; ring A is selected from piperyl,
Figure 02_image005
with
Figure 02_image007
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
optionally substituted by 1, 2 or 3 R a ; each R independently selected from H and C 1-3 alkyl optionally substituted by 1 , 2 or 3 R ; R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; R 5 is selected from From H and F ; R is selected from H, F, Cl and CN; m is selected from 0, 1, 2 and 3 ; each R is independently selected from H, F, Cl, Br, I , CN, C -3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl and cyclobutenyl are optionally 1, 2 or 3 R substitutions; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; with the proviso that, 1 ) when T4 is selected from N and ring A is selected from piperyl, R1 is selected from
Figure 02_image009
, the
Figure 02_image009
Optionally substituted by 1, 2 or 3 R a ; or 2) when T 4 is selected from N and ring A is selected from piperyl, R 1 is selected from
Figure 02_image011
with
Figure 02_image013
, the
Figure 02_image011
By 1, 2 or 3 C 1-3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl The group is substituted by 1, 2 or 3 F, OCH 3 , NH 2 and morpholinyl; or 3) when T 4 is selected from CR 6 , ring A is selected from piperyl, and R 1 is selected from
Figure 02_image011
When, R 6 is selected from F, Cl and CN.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O) OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and ring Butenyl is optionally substituted with 1, 2 or 3 R, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、

Figure 02_image016
和
Figure 02_image018
，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 02_image016
with
Figure 02_image018
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其中，當T 4選自N，環A選自哌𠯤基時，R 1選自

Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof, wherein, when T 4 is selected from N, ring A is selected from piperyl, R 1 is selected from
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述各R 2分別獨立地選自H和CH 3，其他變量如本發明所定義。 In some solutions of the present invention, each R 2 is independently selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F和Cl，其他變量如本發明所定義。 In some aspects of the present invention, the R 4 is selected from F and Cl, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
和
Figure 02_image154
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
with
Figure 02_image154
, other variables are as defined in the present invention.

本發明提供了式(III)所示化合物或其藥學上可接受的鹽，

Figure 02_image001
其中， T 1、T 2和T 3分別獨立地選自CH和N； T 4選自CR 6和N； 環A選自哌𠯤基、
Figure 02_image005
和
Figure 02_image007
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； 各R 2分別獨立地選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； R 6選自H、F、Cl和CN； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1）當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image009
時，所述
Figure 02_image009
任選被1、2或3個R a取代； 2）當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 02_image011
時，所述
Figure 02_image011
被1、2或3個C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基被1、2或3個F、OCH 3、NH 2和嗎福林基取代。 The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure 02_image001
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; T 4 is selected from CR 6 and N; ring A is selected from piperyl,
Figure 02_image005
with
Figure 02_image007
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
optionally substituted by 1, 2 or 3 R a ; each R independently selected from H and C 1-3 alkyl optionally substituted by 1 , 2 or 3 R ; R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; R 5 is selected from From H and F ; R is selected from H, F, Cl and CN; m is selected from 0, 1, 2 and 3 ; each R is independently selected from H, F, Cl, Br, I , CN, C -3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl and cyclobutenyl are optionally 1, 2 or 3 R substitutions; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; provided that, 1) when T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image009
when the
Figure 02_image009
Optionally substituted by 1, 2 or 3 R a ; 2) When T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 02_image011
when the
Figure 02_image011
By 1, 2 or 3 C 1-3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl The group is substituted by 1, 2 or 3 F, OCH 3 , NH 2 and morpholinyl.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O) OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and ring Butenyl is optionally substituted with 1, 2 or 3 R, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、

Figure 02_image016
和
Figure 02_image018
，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 02_image016
with
Figure 02_image018
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述各R 2分別獨立地選自H和CH 3，其他變量如本發明所定義。 In some solutions of the present invention, each R 2 is independently selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F，其他變量如本發明所定義。 In some solutions of the present invention, the R 4 is selected from F, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image275
、
Figure 02_image277
、
Figure 02_image279
和
Figure 02_image280
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image275
,
Figure 02_image277
,
Figure 02_image279
with
Figure 02_image280
, other variables are as defined in the present invention.

本發明提供了式(II)所示化合物或其藥學上可接受的鹽，

Figure 02_image281
其中， T 1、T 2和T 3分別獨立地選自CH和N； 環A選自哌𠯤基、
Figure 02_image005
和
Figure 02_image007
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； R 2選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1）當環A選自哌𠯤基，R 1選自
Figure 02_image009
時，所述
Figure 02_image009
任選被1、2或3個R a取代； 2）當環A選自哌𠯤基，R 1選自
Figure 02_image011
時，所述
Figure 02_image011
被1、2或3個C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基被1、2或3個F、OCH 3、NH 2和嗎福林基取代。 The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure 02_image281
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; ring A is selected from piperyl,
Figure 02_image005
with
Figure 02_image007
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
Optionally substituted by 1, 2 or 3 R a ; R 2 is selected from H and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ; R 3 is selected from From C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R is selected from H, F, Cl , Br and I; R is selected from H and F m is selected from 0, 1, 2 and 3; each R a is independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, -C (O)OC 1-3 alkyl , -C(O)NHC 1-3 alkyl and cyclobutenyl, said C 1-3 alkyl and cyclobutenyl are optionally substituted by 1, 2 or 3 R; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; the condition is that, 1) when ring A is selected from Piperyl, R 1 is selected from
Figure 02_image009
when the
Figure 02_image009
Optionally substituted by 1, 2 or 3 R a ; 2) When Ring A is selected from piperyl, R 1 is selected from
Figure 02_image011
when the
Figure 02_image011
By 1, 2 or 3 C 1-3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl The group is substituted by 1, 2 or 3 F, OCH 3 , NH 2 and morpholinyl.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O) OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and ring Butenyl is optionally substituted with 1, 2 or 3 R, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、

Figure 02_image016
和
Figure 02_image018
，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 02_image016
with
Figure 02_image018
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
和
Figure 02_image047
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
with
Figure 02_image047
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 2選自H和CH 3，其他變量如本發明所定義。 In some aspects of the present invention, the R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F，其他變量如本發明所定義。 In some solutions of the present invention, the R 4 is selected from F, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
和
Figure 02_image057
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
with
Figure 02_image057
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
和
Figure 02_image144
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
with
Figure 02_image144
, other variables are as defined in the present invention.

本發明提供了式(I)所示化合物或其藥學上可接受的鹽，

Figure 02_image283
其中， 環A選自哌𠯤基和
Figure 02_image005
； R 1選自
Figure 02_image009
和
Figure 02_image011
，所述
Figure 02_image009
和
Figure 02_image011
任選被1、2或3個R a取代； R 2選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基和-C(O)NHC 1-3烷基，所述C 1-3烷基任選被1、2或3個F取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 條件是，當環A選自哌𠯤基時，R 1選自
Figure 02_image009
，所述
Figure 02_image009
任選被1、2或3個R a取代。 The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure 02_image283
Among them, Ring A is selected from piperyl and
Figure 02_image005
; R 1 is selected from
Figure 02_image009
with
Figure 02_image011
, the
Figure 02_image009
with
Figure 02_image011
Optionally substituted by 1, 2 or 3 R a ; R 2 is selected from H and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ; R 3 is selected from From C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; m is selected from 0, 1, 2 and 3; each R a is independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, -C(O)OC 1-3 alkyl and -C(O)NHC 1 -3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 Fs; each R b is independently selected from H, F, Cl, Br, I and CN; provided that when ring When A is selected from piperthiol, R 1 is selected from
Figure 02_image009
, the
Figure 02_image009
Optionally substituted with 1, 2 or 3 R a .

在本發明的一些方案中，所述各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3和CH(CH 3) 2任選被1、2或3個F取代，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH2CH3 and CH( CH3 ) 2 are optionally substituted with 1, 2 or 3 Fs, other variables are as defined herein.

在本發明的一些方案中，所述各R a分別獨立地選自H、F、CN、CH 2F、-C(O)OCH 3和-C(O)NHCH 3，其他變量如本發明所定義。 In some schemes of the present invention, each R a is independently selected from H, F, CN, CH 2 F, -C(O)OCH 3 and -C(O)NHCH 3 , and other variables are as defined in the present invention definition.

在本發明的一些方案中，所述R 1選自

Figure 02_image020
、
Figure 02_image022
、
Figure 02_image024
、
Figure 02_image013
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
和
Figure 02_image035
，其他變量如本發明所定義。 In some aspects of the present invention, said R 1 is selected from
Figure 02_image020
,
Figure 02_image022
,
Figure 02_image024
,
Figure 02_image013
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
with
Figure 02_image035
, other variables are as defined in the present invention.

在本發明的一些方案中，所述R 2選自H和CH 3，其他變量如本發明所定義。 In some aspects of the present invention, the R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 3選自CH(CH 3) 2，其他變量如本發明所定義。 In some aspects of the present invention, the R 3 is selected from CH(CH 3 ) 2 , and other variables are as defined in the present invention.

在本發明的一些方案中，所述R 4選自F，其他變量如本發明所定義。 In some solutions of the present invention, the R 4 is selected from F, and other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image051
、
Figure 02_image053
和
Figure 02_image055
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image051
,
Figure 02_image053
with
Figure 02_image055
, other variables are as defined in the present invention.

在本發明的一些方案中，所述結構單元

Figure 02_image049
選自
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image289
、
Figure 02_image096
和
Figure 02_image098
，其他變量如本發明所定義。 In some solutions of the present invention, the structural unit
Figure 02_image049
selected from
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image289
,
Figure 02_image096
with
Figure 02_image098
, other variables are as defined in the present invention.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其化合物選自

Figure 02_image292
Figure 02_image294
Figure 02_image296
Figure 02_image298
Figure 02_image300
Figure 02_image302
， 其中， R 1、R 2、R 3、R 4、R 5和m如本發明所定義。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from
Figure 02_image292
Figure 02_image294
Figure 02_image296
Figure 02_image298
Figure 02_image300
Figure 02_image302
, wherein, R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined in the present invention.

本發明還有一些方案由上述變量任意組合而來。Some solutions of the present invention are formed by any combination of the above variables.

本發明還提供了下列化合物或其藥學上可接受的鹽，

Figure 02_image304
Figure 02_image306
Figure 02_image308
Figure 02_image310
Figure 02_image312
Figure 02_image314
Figure 02_image316
Figure 02_image318
Figure 02_image320
Figure 02_image322
Figure 02_image324
Figure 02_image326
Figure 02_image328
Figure 02_image330
Figure 02_image332
Figure 02_image334
Figure 02_image336
Figure 02_image338
Figure 02_image340
Figure 02_image342
Figure 02_image344
Figure 02_image346
Figure 02_image348
Figure 02_image350
Figure 02_image352
Figure 02_image354
Figure 02_image356
。 The present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
Figure 02_image304
Figure 02_image306
Figure 02_image308
Figure 02_image310
Figure 02_image312
Figure 02_image314
Figure 02_image316
Figure 02_image318
Figure 02_image320
Figure 02_image322
Figure 02_image324
Figure 02_image326
Figure 02_image328
Figure 02_image330
Figure 02_image332
Figure 02_image334
Figure 02_image336
Figure 02_image338
Figure 02_image340
Figure 02_image342
Figure 02_image344
Figure 02_image346
Figure 02_image348
Figure 02_image350
Figure 02_image352
Figure 02_image354
Figure 02_image356
.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其化合物選自

Figure 02_image358
Figure 02_image360
Figure 02_image362
Figure 02_image364
Figure 02_image366
Figure 02_image368
Figure 02_image370
Figure 02_image372
Figure 02_image374
Figure 02_image376
Figure 02_image378
Figure 02_image380
Figure 02_image382
Figure 02_image384
Figure 02_image386
Figure 02_image388
Figure 02_image390
Figure 02_image392
Figure 02_image394
Figure 02_image396
Figure 02_image398
Figure 02_image400
Figure 02_image402
Figure 02_image404
Figure 02_image406
Figure 02_image408
Figure 02_image410
Figure 02_image412
Figure 02_image414
Figure 02_image416
Figure 02_image418
Figure 02_image420
Figure 02_image422
Figure 02_image424
Figure 02_image426
Figure 02_image428
Figure 02_image430
Figure 02_image432
Figure 02_image434
Figure 02_image436
Figure 02_image438
Figure 02_image440
Figure 02_image442
Figure 02_image444
Figure 02_image446
Figure 02_image448
Figure 02_image450
Figure 02_image452
Figure 02_image454
Figure 02_image456
Figure 02_image458
。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from
Figure 02_image358
Figure 02_image360
Figure 02_image362
Figure 02_image364
Figure 02_image366
Figure 02_image368
Figure 02_image370
Figure 02_image372
Figure 02_image374
Figure 02_image376
Figure 02_image378
Figure 02_image380
Figure 02_image382
Figure 02_image384
Figure 02_image386
Figure 02_image388
Figure 02_image390
Figure 02_image392
Figure 02_image394
Figure 02_image396
Figure 02_image398
Figure 02_image400
Figure 02_image402
Figure 02_image404
Figure 02_image406
Figure 02_image408
Figure 02_image410
Figure 02_image412
Figure 02_image414
Figure 02_image416
Figure 02_image418
Figure 02_image420
Figure 02_image422
Figure 02_image424
Figure 02_image426
Figure 02_image428
Figure 02_image430
Figure 02_image432
Figure 02_image434
Figure 02_image436
Figure 02_image438
Figure 02_image440
Figure 02_image442
Figure 02_image444
Figure 02_image446
Figure 02_image448
Figure 02_image450
Figure 02_image452
Figure 02_image454
Figure 02_image456
Figure 02_image458
.

在本發明的一些方案中，所述化合物或其藥學上可接受的鹽，其化合物選自

Figure 02_image460
。 In some aspects of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from
Figure 02_image460
.

本發明還提供了上述化合物或其藥學上可接受的鹽在製備治療腫瘤藥物中的應用。The present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.

在本發明的一些方案中，所述腫瘤指KRAS G12C突變相關的腫瘤。 In some aspects of the present invention, the tumor refers to a KRAS G12C mutation-associated tumor.

本發明還提供了下列合成方法： 方法1：

Figure 02_image462
Figure 02_image464
Figure 02_image466
方法2：
Figure 02_image468
Figure 02_image470
Figure 02_image472
方法3：
Figure 02_image474
Figure 02_image476
方法4：
Figure 02_image478
Figure 02_image480
方法5：
Figure 02_image482
Figure 02_image484
Figure 02_image486
方法6：
Figure 02_image488
The present invention also provides the following synthetic methods: Method 1:
Figure 02_image462
Figure 02_image464
Figure 02_image466
Method 2:
Figure 02_image468
Figure 02_image470
Figure 02_image472
Method 3:
Figure 02_image474
Figure 02_image476
Method 4:
Figure 02_image478
Figure 02_image480
Method 5:
Figure 02_image482
Figure 02_image484
Figure 02_image486
Method 6:
Figure 02_image488

本發明還提供了下列測試方法：The present invention also provides following test method:

方法1：MIA-PA-CA-2細胞實驗 實驗材料： DMEM培養基，胎牛血清購自Biosera，馬血清購自Gibco。CellTiter-Glo(細胞活率化學發光檢測試劑)試劑購自Promega。MIA-PA-CA-2細胞系購南京科佰生物科技有限公司。EnVision多標記分析儀(PerkinElmer)。 實驗方法： 將MIA-PA-CA-2細胞種於白色96孔板中，80μL細胞懸液每孔，其中包含1000個MIA-PA-CA-2細胞。細胞板置於二氧化碳培養箱中過夜培養。 將待測化合物用排槍進行5倍稀釋至第8個濃度，即從2mM稀釋至26nM，設置雙複孔實驗。向中間板中加入78 μL培養基，再按照對應位置，轉移2 μL每孔的梯度稀釋化合物至中間板，混勻後轉移20μL每孔到細胞板中。轉移到細胞板中的化合物濃度範圍是10μM至0.13 nM。細胞板置於二氧化碳培養箱中培養3天。另準備一塊細胞板，在加藥當天讀取訊號值作為最大值(下面方程式中Max值)參與數據分析。向此細胞板每孔加入50 μL細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光訊號穩定。採用多標記分析儀讀數。 數據分析： 利用方程式(樣品-最小值)/(最大值-最小值)*100%將原始數據換算成抑制率，IC 50的值即可透過四參數進行曲線擬合得出(GraphPad Prism軟體中"log(抑制劑)/響應 -- 變量作用域" 模式得出)。 Method 1: MIA-PA-CA-2 cell experiment Experimental materials: DMEM medium, fetal bovine serum was purchased from Biosera, and horse serum was purchased from Gibco. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. MIA-PA-CA-2 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. EnVision Multilabel Analyzer (PerkinElmer). Experimental method: MIA-PA-CA-2 cells were planted in a white 96-well plate, 80 μL of cell suspension per well, which contained 1000 MIA-PA-CA-2 cells. Cell plates were cultured overnight in a carbon dioxide incubator. The compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, diluted from 2mM to 26nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 μL of each well to the cell plate after mixing. The concentration of compounds transferred to the cell plate ranged from 10 μM to 0.13 nM. Cell plates were cultured in a carbon dioxide incubator for 3 days. Prepare another cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis. Add 50 μL of cell viability chemiluminescent detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer. Data analysis: Use the equation (sample-minimum value)/(maximum value-minimum value)*100% to convert the original data into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (in GraphPad Prism software "log(inhibitor)/response--variable scope" mode derived).

方法2：體內藥代動力學研究 SD小鼠口服及靜脈注射受試化合物的藥代動力學研究 受試化合物與10%二甲基亞碸/60%聚乙二醇400/30%水溶液混合，渦旋並超聲，製備得到1 mg/mL澄清溶液，微孔濾膜過濾後備用。選取7至10周齡的雄性SD小鼠，靜脈注射給予候選化合物溶液，劑量為2-3 mg/kg。口服給予候選化合物溶液，劑量為10 mg/kg。收集一定時間的全血，製備得到血漿，以LC-MS/MS方法分析藥物濃度，並用Phoenix WinNonlin 軟體(美國Pharsight公司)計算藥代參數。 Method 2: In vivo pharmacokinetic studies Pharmacokinetic Study of Oral and Intravenous Injection of Test Compounds in SD Mice The test compound was mixed with 10% dimethylsulfoxide/60% polyethylene glycol 400/30% aqueous solution, vortexed and sonicated to prepare a 1 mg/mL clear solution, which was filtered through a microporous membrane for use. Select 7- to 10-week-old male SD mice and administer the candidate compound solution intravenously at a dose of 2-3 mg/kg. The candidate compound solution was orally administered at a dose of 10 mg/kg. Whole blood was collected for a certain period of time to prepare plasma, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA).

方法3：體內藥效學研究 人胰腺癌Mia PaCa-2細胞裸小鼠皮下移植腫瘤Balb/c Nude小鼠模型的體內藥效學研究 1. 細胞培養和腫瘤組織準備 細胞培養：人胰腺癌Mia PaCa-2細胞(ATCC-CRL-1420)體外單層培養，培養條件為DMEM/F12培養基中加20％胎牛血清，1% 雙抗，37 ℃ 5%二氧化碳孵箱培養。一周兩次用胰酶-EDTA進行常規消化處理傳代。當細胞飽和度為80%-90%，數量到達要求時，收取細胞，計數，重懸於適量PBS中，1:1加入基質膠，獲取細胞密度為25 x 10 6cells/mL的細胞懸液。 細胞接種：將0.2 mL(5×10 6cells/mouse個)Mia PaCa-2細胞(加基質膠，體積比為1:1)皮下接種於每隻小鼠的右後背，腫瘤平均體積達到190 mm 3時，根據腫瘤體積進行隨機分組，每組6隻，空白組給藥劑量為0，測試組給藥劑量分別為5 mg/kg、10 mg/kg、30mg/kg，給藥體積10µL/g，口服給藥，給藥21天，每天一次。 2. 腫瘤測量和實驗指標 每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。 化合物的抑瘤療效用TGI(%)或相對腫瘤增殖率T/C(%)評價。 相對腫瘤增殖率T/C(%) = TRTV / CRTV × 100 %(TRTV：治療組RTV；CRTV：陰性對照組RTV)。根據腫瘤測量的結果計算出相對腫瘤體積(relative tumor volume，RTV)，計算公式為 RTV = Vt / V0，其中V0是分組給藥時(即D0)測量所得平均腫瘤體積，Vt為某一次測量時的平均腫瘤體積，TRTV與CRTV取同一天數據。 TGI (%)，反映腫瘤生長抑制率。TGI(%)=[(1-(某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積))/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)]×100%。 Method 3: In vivo pharmacodynamic study of human pancreatic cancer Mia PaCa-2 cells subcutaneously transplanted tumor Balb/c Nude mouse model in vivo pharmacodynamic study 1. Cell culture and tumor tissue preparation Cell culture: human pancreatic cancer Mia PaCa-2 cells (ATCC-CRL-1420) were cultured in a monolayer in vitro. The culture conditions were DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, and cultured in a 5% carbon dioxide incubator at 37 °C. 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, resuspend in an appropriate amount of PBS, add Matrigel at 1:1, and obtain a cell suspension with a cell density of 25 x 10 6 cells/mL . Cell inoculation: 0.2 mL (5×10 6 cells/mouse) Mia PaCa-2 cells (plus matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 190 mm At 3 o'clock, they were randomly divided into groups according to tumor volume, with 6 rats in each group. The dose of the blank group was 0, and the doses of the test groups were 5 mg/kg, 10 mg/kg, and 30 mg/kg, and the administration volume was 10 µL/g. , orally administered for 21 days, once a day. 2. Tumor measurement and experimental indicators The tumor diameter was measured with a vernier caliper twice a week. The formula for calculating tumor volume is: V = 0.5a × b 2 , 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 (%). Relative tumor proliferation rate T/C (%) = TRTV / CRTV × 100 % (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV = Vt / V0, where V0 was the average tumor volume measured during group administration (that is, D0), and Vt was a certain measurement The average tumor volume of TRTV and CRTV take the data on the same day. TGI (%), reflecting the rate of tumor growth inhibition. 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 the solvent control group-Start of treatment of the solvent control group Time-average tumor volume)]×100%.

方法4：體內藥效學研究 人非小細胞肺癌NCI-H358細胞裸小鼠皮下移植腫瘤Balb/c Nude小鼠模型的體內藥效學研究 1. 細胞培養和腫瘤組織準備 細胞培養：人非小細胞肺癌NCI-H358體外單層培養，培養條件為DMEM/F12培養基中加20%胎牛血清，1%雙抗，37 ℃ 5%二氧化碳孵箱培養。一周兩次用胰酶-EDTA進行常規消化處理傳代。當細胞飽和度為80%-90%，數量到達要求時，收取細胞，計數，重懸於適量PBS中，1:1加入基質膠，獲取細胞密度為25 × 10 6cells/mL的細胞懸液。 細胞接種： 將0.2 mL(5×10 6cells/mouse個)NCI-H358細胞(加基質膠，體積比為1:1)皮下接種於每隻小鼠的右後背，腫瘤平均體積達到100-150 mm 3時，根據腫瘤體積進行隨機分組，每組8隻，空白組給藥劑量為0，測試組給藥劑量分別為1.5 mg/kg、5 mg/kg、15mg/kg，給藥體積10µL/g，口服給藥，給藥28天，每天一次。 2. 腫瘤測量和實驗指標 每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。 化合物的抑瘤療效用TGI(%)或相對腫瘤增殖率T/C(%)評價。相對腫瘤增殖率T/C(%) = TRTV / CRTV × 100 %(TRTV：治療組RTV；CRTV：陰性對照組RTV)。根據腫瘤測量的結果計算出相對腫瘤體積(relative tumor volume，RTV)，計算公式為 RTV = Vt / V0，其中V0是分組給藥時(即D0)測量所得平均腫瘤體積，Vt為某一次測量時的平均腫瘤體積，TRTV與CRTV取同一天數據。 TGI (%)，反映腫瘤生長抑制率。TGI(%)=[(1-(某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積))/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)] ×100%。 技術效果 本發明化合物對KRAS G12C靶點有抑制作用，在MIA-PA-CA-2和NCI-H358細胞增殖展現出較好的抑制活性。對Mia PaCa-2異種移植和NCI-H358異種移植的腫瘤生長有較好的抑制作用，且本發明化合物具有優異的藥代動力學性質。本發明化合物具有良好的血漿穩定性、全血穩定性和GSH磷酸緩衝溶液穩定性。本發明化合物無PXR陽性活化，無CYP誘導活化。本發明化合物具有顯著的抑瘤作用，無明顯不耐受現象。 Method 4: In vivo pharmacodynamic study In vivo pharmacodynamic study of human non-small cell lung cancer NCI-H358 cells subcutaneously transplanted into nude mice with tumor Balb/c Nude mouse model 1. Cell culture and tumor tissue preparation Cell culture: human non-small cell lung cancer Cell lung cancer NCI-H358 was cultured in a single layer in vitro. The culture conditions were DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, and cultured in a 5% carbon dioxide incubator at 37 °C. 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, resuspend in an appropriate amount of PBS, add Matrigel at 1:1, and obtain a cell suspension with a cell density of 25 × 10 6 cells/mL . Cell inoculation: Subcutaneously inoculate 0.2 mL (5×10 6 cells/mouse) NCI-H358 cells (plus Matrigel, volume ratio 1:1) on the right back of each mouse, and the average tumor volume reaches 100-150 mm3 , they were randomly divided into groups according to the tumor volume, with 8 rats in each group, the administration dose of the blank group was 0, the administration doses of the test groups were 1.5 mg/kg, 5 mg/kg, and 15 mg/kg, and the administration volume was 10 μL/kg. g, oral administration, administration for 28 days, once a day. 2. Tumor measurement and experimental indicators The tumor diameter was measured with a vernier caliper twice a week. The formula for calculating tumor volume is: V = 0.5a × b 2 , 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 (%). Relative tumor proliferation rate T/C (%) = TRTV / CRTV × 100 % (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV = Vt / V0, where V0 was the average tumor volume measured during group administration (that is, D0), and Vt was a certain measurement The average tumor volume of TRTV and CRTV take the data on the same day. TGI (%), reflecting the rate of tumor growth inhibition. 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 the solvent control group-Start of treatment of the solvent control group average tumor volume)] × 100%. Technical Effects The compound of the present invention has an inhibitory effect on the KRAS G12C target, and exhibits better inhibitory activity on the proliferation of MIA-PA-CA-2 and NCI-H358 cells. It has good inhibitory effect on tumor growth of Mia PaCa-2 xenograft and NCI-H358 xenograft, and the compound of the present invention has excellent pharmacokinetic properties. The compound of the present invention has good plasma stability, whole blood stability and GSH phosphate buffer solution stability. The compound of the present invention has no PXR positive activation and no CYP-induced activation. The compound of the present invention has significant antitumor effect without obvious intolerance phenomenon.

相關定義related definition

除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

這裡所採用的術語“藥學上可接受的”，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

術語“藥學上可接受的鹽”是指本發明化合物的鹽，由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時，可以透過在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物接觸的方式獲得鹼加成鹽。當本發明的化合物中含有相對鹼性的官能團時，可以透過在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物接觸的方式獲得酸加成鹽。本發明的某些特定的化合物含有鹼性和酸性的官能團，從而可以被轉換成任一鹼或酸加成鹽。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat or in a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.

本發明的藥學上可接受的鹽可由含有酸根或鹼基的母體化合物透過常規化學方法合成。一般情況下，這樣的鹽的製備方法是：在水或有機溶劑或兩者的混合物中，經由游離酸或鹼形式的這些化合物與化學計量的適當的鹼或酸反應來製備。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

本發明的化合物可以存在特定的幾何或立體異構體形式。本發明設想所有的這類化合物，包括順式和反式異構體、(-)- 和 (+)-對映體、( R)- 和 ( S)-對映體、非對映異構體、( D)-異構體、( L)-異構體，及其外消旋混合物和其他混合物，例如對映異構體或非對映體富集的混合物，所有這些混合物都屬本發明的範圍之內。烷基等取代基中可存在另外的不對稱碳原子。所有這些異構體以及它們的混合物，均包括在本發明的範圍之內。 The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereomers isomers, ( D )-isomers, ( L )-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氫取代氫形成氘代藥物，氘與碳構成的鍵比普通氫與碳構成的鍵更堅固，相比於未氘化藥物，氘代藥物有降低毒副作用、增加藥物穩定性、增強療效、延長藥物生物半衰期等優勢。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

術語“任選”或“任選地”指的是隨後描述的事件或狀況可能但不是必需出現的，並且該描述包括其中所述事件或狀況發生的情況以及所述事件或狀況不發生的情況。The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not occur .

術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代，取代基可以包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為氧(即=O)時，意味著兩個氫原子被取代。氧取代不會發生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

術語“任選被取代的”是指可以被取代，也可以不被取代，除非另有規定，取代基的種類和數目在化學上可以實現的基礎上可以是任意的。The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.

當任何變量(例如R)在化合物的組成或結構中出現一次以上時，其在每一種情況下的定義都是獨立的。因此，例如，如果一個基團被0-2個R所取代，則所述基團可以任選地至多被兩個R所取代，並且每種情況下的R都有獨立的選項。此外，取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

當一個連接基團的數量為0時，比如-(CRR) 0-，表示該連接基團為單鍵。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.

當其中一個變量選自單鍵時，表示其連接的兩個基團直接相連，比如A-L-Z中L代表單鍵時表示該結構實際上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

當所列舉的連接基團沒有指明其連接方向，其連接方向是任意的，例如，

Figure 02_image490
中連接基團L為-M-W-，此時-M-W-既可以按與從左往右的讀取順序相同的方向連接環A和環B構成
Figure 02_image492
，也可以按照與從左往右的讀取順序相反的方向連接環A和環B構成
Figure 02_image494
。所述連接基團、取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。 When the linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure 02_image490
The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form
Figure 02_image492
, can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
Figure 02_image494
. Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

除非另有規定，當某一基團具有一個或多個可連接位點時，該基團的任意一個或多個位點可以透過化學鍵與其他基團相連。當該化學鍵的連接方式是不定位的，且可連接位點存在H原子時，則連接化學鍵時，該位點的H原子的個數會隨所連接化學鍵的個數而對應減少變成相應價數的基團。所述位點與其他基團連接的化學鍵可以用直形實線鍵(

Figure 02_image496
)、直形虛線鍵(
Figure 02_image498
)、或波浪線(
Figure 02_image500
)表示。例如-OCH 3中的直形實線鍵表示透過該基團中的氧原子與其他基團相連；
Figure 02_image502
中的直形虛線鍵表示透過該基團中的氮原子的兩端與其他基團相連；
Figure 02_image504
中的波浪線表示透過該苯基基團中的1和2位碳原子與其他基團相連；
Figure 02_image506
表示該哌啶基上的任意可連接位點可以透過1個化學鍵與其他基團相連，至少包括
Figure 02_image508
、
Figure 02_image510
、
Figure 02_image512
、
Figure 02_image514
這4種連接方式，即使-N-上畫出了H原子，但是
Figure 02_image506
仍包括
Figure 02_image508
這種連接方式的基團，只是在連接1個化學鍵時，該位點的H會對應減少1個變成相應的一價哌啶基。 Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bond that described site is connected with other groups can use straight solid line bond (
Figure 02_image496
), straight dashed key (
Figure 02_image498
), or tilde (
Figure 02_image500
)express. For example, the straight solid-line bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
Figure 02_image502
The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
Figure 02_image504
The wavy line in indicates that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
Figure 02_image506
Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure 02_image508
,
Figure 02_image510
,
Figure 02_image512
,
Figure 02_image514
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure 02_image506
still include
Figure 02_image508
For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.

除非另有規定，術語“C 1-6烷基”用於表示直鏈或支鏈的由1至6個碳原子組成的飽和碳氫基團。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一價(如甲基)、二價(如亞甲基)或者多價(如次甲基)。C 1-6烷基的實例包括但不限於甲基 (Me)、乙基 (Et)、丙基 (包括 n-丙基和異丙基)、丁基 (包括 n-丁基，異丁基， s-丁基和 t-丁基)、戊基 (包括 n-戊基，異戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc.; it can be Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl , s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and so on.

除非另有規定，術語“C 1-3烷基”用於表示直鏈或支鏈的由1至3個碳原子組成的飽和碳氫基團。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一價(如甲基)、二價(如亞甲基)或者多價(如次甲基)。C 1-3烷基的實例包括但不限於甲基 (Me)、乙基 (Et)、丙基 (包括 n-丙基和異丙基) 等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl) and the like.

除非另有規定，C n-n+m或C n-C n+m包括n至n+m個碳的任何一種具體情況，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一個範圍，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示環上原子數為n至n+m個，例如3-12元環包括3元環、4元環、5元環、6元環、7元環、8元環、9元環、10元環、11元環、和12元環，也包括n至n+m中的任何一個範圍，例如3-12元環包括3-6元環、3-9元環、5-6元環、5-7元環、6-7元環、6-8元環、和6-10元環等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, e.g. C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n+ m-membered means that the number of atoms on the ring is from n to n+m. For example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. 10-membered rings, 11-membered rings, and 12-membered rings, including any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, and 5-6-membered rings , 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

本發明的化合物可以透過本發明所屬技術領域具有通常知識者所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本發明所屬技術領域具有通常知識者所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。The compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art of the present invention, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the technology of the present invention There are equivalents known to those of ordinary skill in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

本發明的化合物存在立體構型的，可以透過單晶繞射、旋光、CD等試驗方法確定。The compound of the present invention has a stereo configuration, which can be determined by single crystal diffraction, optical rotation, CD and other test methods.

本發明的化合物可以透過本發明所屬技術領域具有通常知識者所熟知的常規方法來確認結構，如果本發明涉及化合物的絕對構型，則該絕對構型可以透過本領域常規技術手段予以確證。例如單晶X光繞射法(SXRD)，把培養出的單晶用Bruker D8 venture繞射儀收集繞射強度數據，光源為CuKα輻射，掃描方式：φ/ω 掃描，收集相關數據後，進一步採用直接法(Shelxs97)解析晶體結構，便可以確證絕對構型。The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultivated single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data. The light source is CuKα radiation, and the scanning method is φ/ω scanning. After collecting relevant data, further The absolute configuration can be confirmed by solving the crystal structure by the direct method (Shelxs97).

下面透過實施例對本發明進行詳細描述，但並不意味著對本發明任何不利限制。本文已經詳細地描述了本發明，其中也公開了其具體實施例方式，對本發明所屬技術領域具有通常知識者而言，在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。The present invention will be described in detail through examples below, but it does not imply any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments have also been disclosed. For those skilled in the art to which the present invention belongs, various implementations can be made for the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Changes and improvements will be apparent.

計算例1

Figure 02_image516
Figure 02_image518
Figure 02_image520
Figure 02_image522
Figure 02_image524
Figure 02_image526
透過薛定諤公司Maestro軟體的Macromodel 模塊計算AMG510的低能構象。為了鎖定AMG510的活性構象，進一步降低其旋轉能壘，我們透過連接鏈將AMG510的氟苯酚片段和異丙基甲基吡啶片段環合，得到了一系列不同的氟苯酚片段和異丙基甲基吡啶片段以鏈相連接的大環分子，並探索了這些大環分子與AMG510和KRAS G12C蛋白共晶中的活性構象間的結合差異。AMG510和KRAS G12C蛋白的結合模式圖如圖1所示，AMG510和KARS G12C的結合模式2D圖如圖2所示，化合物A~E的低能構象與AMG510活性構象疊合圖如圖3~8所示。 結論：本發明化合物與AMG510的活性構象重合度高。 Calculation example 1
Figure 02_image516
Figure 02_image518
Figure 02_image520
Figure 02_image522
Figure 02_image524
Figure 02_image526
The low-energy conformation of AMG510 was calculated by the Macromodel module of Schrödinger's Maestro software. In order to lock the active conformation of AMG510 and further reduce its rotational energy barrier, we obtained a series of different fluorophenol fragments and isopropylmethylpyridine fragments by ring-closing the fluorophenol fragment and isopropylmethylpyridine fragment of AMG510 through the linker chain. The pyridine fragments are chain-linked macrocycles, and the binding differences between these macrocycles and the active conformations in the co-crystal of AMG510 and KRAS G12C proteins were explored. The binding mode diagram of AMG510 and KRAS G12C protein is shown in Figure 1, the 2D diagram of the binding mode of AMG510 and KARS G12C is shown in Figure 2, and the superposition of the low-energy conformation of compounds A~E and the active conformation of AMG510 is shown in Figure 3~8 Show. Conclusion: The compound of the present invention has a high degree of coincidence with the active conformation of AMG510.

實施例1

Figure 02_image528
合成路線：
Figure 02_image530
Figure 02_image532
步驟1：化合物001-3的合成 在預先乾燥過的5.0 升三口瓶中加入化合物001-1 (300 g, 1.84 mol, 1.00 eq)，001-2(異丙烯基三氟硼酸鉀, 300 g, 2.03 mol, 1.10 eq)，碳酸鉀 (381g, 2.76 mol, 1.5 eq)，1,4-二㗁烷(3.0 升)  和水 (0.3 升)。加完後，置換氮氣三次。然後體系中加入1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(16.40 g, 22.41 mmol, 1.22e-2 eq)。加料完成後，反應體系在90 °C，反應攪拌12 小時。將體系濃縮。向體系中加入水(1.2升)和乙酸乙酯(2.0升)。體系靜置分液。水相用乙酸乙酯(1.0升，1次)萃取。合併有機相，無水硫酸鈉乾燥，過濾。濾液濃縮。粗品用矽膠柱層析(石油醚：乙酸乙酯 = 8:1至5:1)純化得到化合物001-3。 LCMS: MS m/z: 169.0[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 7.91-7.83 (m, 1H), 7.11-7.04 (m, 1H), 5.53-5.45 (m, 1H), 5.34-5.24 (m, 1H), 4.48-4.21 (m, 2H), 2.14 (s, 3H)。 步驟2：化合物001-5的合成 在預先洗乾淨的3.0升單口瓶中加入化合物001-3 (119.3 g, 707.49 mmol, 1.00 eq)，化合物001-4 (300.05 g, 1.41 mol, 2.0 eq)，磷酸鉀 (300.36 g, 1.41 mol, 2.0 eq)，2-甲基四氫呋喃 (1200 mL)和水 (300 mL)。加完後，置換氮氣三次。然後體系中加入1,1'-雙二苯基膦二茂鐵二氯化鈀 (46.11 g, 70.75 mmol, 0.1 eq)。加完後，置換氮氣三次。反應體系在76 °C(體系溫度)，反應攪拌12 小時。將反應體系冷卻至室溫，加入1.5 升水和2.0 升乙酸乙酯稀釋，分液後收集有機相，水相用乙酸乙酯萃取(1.0 升，2 次)。合併有機相，用無水硫酸鈉乾燥，減壓濃縮得到殘餘物。粗產品透過快速柱層析分離(石油醚:乙酸乙酯 = 10:1 至 4:1)純化得到化合物001-5。 LCMS: MS m/z: 219.1[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 7.99 (d, J= 5.2 Hz, 1H), 7.77 (d, J= 16.0 Hz, 1H), 7.08 (d, J= 5.2 Hz, 1H), 6.47 (d, J= 15.6 Hz, 1H), 5.50 (s, 1H), 5.28 (s, 1H), 4.31 (br s, 2H), 3.81 (s, 3H), 2.15 (s, 3H)。 步驟3：化合物001-6的合成 用氬氣置換過的2.0升氫化瓶加入鈀/碳 (17 g, 10%含量)。加完後，將四氫呋喃 (1.5 L)，化合物001-5 (85 g, 389.46 mmol, 1 eq)和碳酸鈉 (41.28 g, 389.46 mmol, 1.0 eq)加入到體系中。加料完畢，將體系用氫氣置換3次。體系氫氣氛圍中在25°C，壓力: 15 psi，攪拌1.0 小時。反應體系經矽藻土過濾，濾餅用乙酸乙酯(200 mL, 3次)洗滌。合併濾液直接濃縮化合物001-6。 LCMS: MS m/z: 223.1[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 7.95 (d, J= 4.8 Hz, 1H), 6.78 (d, J= 5.2 Hz, 1H), 3.90 - 3.77 (m, 2H), 3.67 (s, 3H), 3.08 - 2.97 (m, 1H), 2.80 (t, J= 7.2 Hz, 2H), 2.66 (t, J= 7.2 Hz, 2H), 1.28 (s, 3H), 1.27 (s, 3H)。 步驟4：化合物001-7的合成 向預先乾燥好的3.0 L三口瓶中加入化合物001-6 (150 g, 674.82 mmol, 1 eq) 和四氫呋喃 (1.5 L) 。 然後將體系溫度降到0 ~ 5 °C，向體系中分批加入硼氫化鋰 (29.29 g, 1.34 mol, 1.99 eq)。加完後，溫度恢復到25 °C，並在此溫度下反應1.0小時。將體系緩慢加入到攪拌的飽和氯化銨 4.0升淬滅。加入1.5 升乙酸乙酯稀釋，分液後收集有機相，水相用乙酸乙酯萃取(1.0 L，2次)。合併有機相飽和食鹽水洗滌(300 mL，1次) ，無水硫酸鈉乾燥，減壓濃縮得到化合物001-7，粗品未純化直接用於下一步。 LCMS: MS m/z: 195.1[M+1] +。 步驟5：化合物001-8的合成 向預先乾燥好的3.0 L三口瓶中加入化合物001-7 (130 g, 669.16 mmol, 1.00 eq)，咪唑 (68.33 g, 1.00 mol, 1.5 eq)  和二氯甲烷 (2.00 L)  加完後，體系冷卻到0 ~ 10 °C，向體系中緩慢滴加第三丁基二甲基氯矽烷 (102.63 g, 680.94 mmol, 83.44 mL, 1.02 eq)  的二氯甲烷 (500 mL)。加完後，體系溫度緩慢恢復到25 °C，並在此溫度下反應12小時。向反應體系中小心地加入300 mL飽和氯化銨淬滅反應。體系靜置，分液後收集有機相，水相用二氯甲烷萃取(500 mL，1 次)。合併有機相，用無水硫酸鈉乾燥，減壓濃縮得到殘餘物。粗產品透過快速柱層析分離(石油醚:乙酸乙酯 = 10:1 至6:1)純化。得到化合物001-8。 LCMS: MS m/z: 309.2[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 7.93 (d, J= 4.8 Hz, 1H), 6.81 (d, J= 4.8 Hz, 1H), 3.87 (br s, 2H), 3.63 (t, J= 5.6 Hz, 2H), 3.01 - 2.95 (m, 1H), 2.59 (t, J= 7.2 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H)。 步驟6：化合物001-10的合成 氮氣保護，向預先乾燥好的3.0 L單口瓶中加入化合物001-9 (70 g, 334.92 mmol, 1.00 eq)和二氯甲烷 (0.7 L)。樣品溶解後，保持體系溫度在20 ~ 25 °C，向體系中緩慢滴加草醯氯 (70 g, 551.50 mmol, 48.28 mL, 1.65 eq)。加完後，將體系升溫至40 °C ~ 45 °C, 反應5小時。將反應體系濃縮得到黃色化合物，無需純化直接投入下一步。 氮氣保護，向裝上述黃色化合物的3.0 L單口瓶中加入二氯甲烷 (0.7 L)。樣品溶解後，將體系溫度冷卻到0 °C，保持0 °C，向體系中緩慢滴加化合物001-8 (108.49 g, 351.64 mmol, 1.05 eq)的二氯甲烷 (0.28 L)  溶液。加完後，體系溫度恢復到25 °C，體系在25 °C下反應12小時。反應體系直接濃縮。粗產品透過快速柱層析分離(石油醚:乙酸乙酯 = 5:1 至1:1)純化得到化合物001-10。 LCMS: MS m/z: 543.1[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 10.13 (s, 1H), 9.71 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.82 (d, J= 6.8 Hz, 1H), 7.06 (d, J= 4.8 Hz, 1H), 3.62 (t, J= 6.0 Hz, 2H), 3.27 - 3.12 (m, 1H), 2.68 - 2.57 (m, 2H), 1.81 - 1.72 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H)。 步驟7：化合物001-11的合成 氮氣保護，向預先乾燥好的3.0 L三口瓶中加入化合物001-10 (139 g, 255.73 mmol, 1 eq)，18-冠-6 (33.80 g, 127.87 mmol, 0.5 eq) 和四氫呋喃 (1.39 L)。溶液變澄清後，將體系冷卻到0 ~ 5°C下，向體系中緩慢滴加六甲基二矽基胺基鉀 (1 M, 460.32 mL, 1.8 eq)。加完後，體系回溫到25°C並在此溫度下攪拌12小時。2個平行反應合批後處理和純化。向各自的反應體系中加入飽和氯化銨(1.0 L)淬滅反應。2個體系合併萃取。向體系中加入1.0 L水和1.0 L乙酸乙酯稀釋，靜置分液後收集有機相。水相用乙酸乙酯萃取(600 mL，1次)。合併有機相，用無水硫酸鈉乾燥，減壓濃縮得到殘餘物。粗產品透過快速柱層析分離(石油醚:乙酸乙酯 = 5:1 至2:1)純化得到化合物001-11。 LCMS: MS m/z: 507.2[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 9.24 (br s, 1H), 8.64 (d, J= 5.2 Hz, 1H), 8.23 (d, J= 6.8 Hz, 1H), 7.18 (d, J= 4.8 Hz, 1H), 3.52 (t, J= 6.0 Hz, 2H), 2.71 - 2.62 (m, 1H), 2.41 (t, J= 8.4 Hz, 2H), 1.74 - 1.61 (m, 2H), 1.21 (d, J= 6.8 Hz, 3H), 1.09 (d, J= 6.8 Hz, 3H), 0.79 - 0.73 (m, 9H), -0.11 - -0.05 (m, 6H)。 步驟8：化合物001-12的合成 氮氣保護下，向預先乾燥好的3.0 升三口瓶中加入化合物001-11 (91.85 g, 181.14 mmol, 1.00 eq)，二異丙基乙基胺 (37.46 g, 289.82 mmol, 50.48 mL, 1.6 eq) 和四氫呋喃 (920 mL)。加完後，將體系溫度降到0 ~ 5 °C, 向體系中緩慢加入三氯氧磷 (41.66 g, 271.71 mmol, 25.25 mL, 1.5 eq)。加完後體系緩慢升溫到40°C(體系溫度)，並在此溫度下攪拌2.0小時，得到化合物001-12。反應溶液直接用於下一步 步驟9：化合物001-14的合成 氮氣保護下，將含有化合物001-12 (95.19 g, 181.14 mmol, 1.00 eq)的反應體系降溫到0 ~ 10 °C並保持， 向體系中加入二異丙基乙基胺 (58.52 g, 452.84 mmol, 78.87 mL, 2.5 eq)和預先溶解好的化合物001-13 (72.55 g, 362.27 mmol, 2.0 eq)的四氫呋喃 (210 mL)  溶液。加完後，體系在25 °C 攪拌12.0小時。合併2個平行反應。控制體系溫度20 ~ 25 °C，分別向體系中加入1.0 升飽和氯化鈉淬滅反應。體系靜置分液。水相用乙酸乙酯萃取(0.5 L，2次)。合併有機相，用鹽水洗滌(0.5 L，1次)，無水硫酸鈉乾燥，過濾，濾液濃縮，得到中間體化合物粗品，無需純化直接用於下一步。 LCMS: MS m/z: 689.4[M+1] +。 氮氣保護下，向1.0 L的單口瓶中加入上述中間體化合物，醋酸 (349.65 g, 5.82 mol, 333 mL, 36.16 eq)，四氫呋喃 (111 mL)和水 (111 mL)中。 加完後，體系在25 °C 攪拌12.0小時。向反應體系中加入500 mL水。冷卻到0 ~ 5 °C，用5.0 M 氫氧化鈉(~ 5.0 L)調節體系的pH到7~8。體系靜置分液。水相用乙酸乙酯(1.0 L，3次)萃取。合併有機相，用無水硫酸鈉乾燥，過濾，濾液濃縮。粗品透過快速柱層析分離(二氯甲烷:甲醇 = 40:1至 20:1)純化得到化合物001-14。 LCMS: MS m/z: 575.2[M+1] +。 1H NMR (400MHz, CDCl 3) δ = 8.59 (d, J= 4.8 Hz, 1H), 7.76 (dd, J= 2.0, 8.0 Hz, 1H), 7.17 (d, J= 5.2 Hz, 1H), 4.99 - 4.58 (m, 1H), 4.42 - 3.78 (m, 3H), 3.74 - 3.39 (m, 3H), 3.36 - 2.92 (m, 3H), 2.63 - 2.47 (m, 1H), 2.45 - 2.28 (m, 2H), 1.52 - 1.37 (m, 13H), 1.18 (dd, J= 4.0, 6.8 Hz, 3H), 1.06 (t, J= 6.4 Hz, 3H)。 步驟10：化合物001-16的合成 將化合物001-14 (50 g, 76.30 mmol, 87.76%純度, 1 eq)，化合物001-15 (14.28 g, 91.56 mmol, 1.2 eq) 和無水磷酸鉀 (32.39 g, 152.60 mmol, 2.0 eq) 溶於2-甲基四氫呋喃(250 mL)和水 (100 mL)中，氮氣置換三次，加入[1,1-雙(二第三丁基膦)二茂鐵]二氯化鈀( II ) (2.49 g, 3.81 mmol, 0.05 eq)，反應加熱至75°C，攪拌12小時。反應液冷卻至室溫，過濾，50 mL 2-甲基四氫呋喃洗滌濾餅。收集白色濾餅，減壓濃縮除去溶劑。白色固體在45°C真空乾燥箱乾燥20小時，得到化合物001-16。 LCMS: MS (ESI) m/z: 651.4 [M+1] +。 SFC分析方法 (柱子：Chiralpak IC-3, 50×4.6mm I.D., 3μm；流動相：A (CO2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50~5%，3.0 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.321 min，手性異構體過量95.58%。 1H NMR (400 MHz, CD 3OD) δ ppm 8.44 (d, J= 4.8 Hz, 1H), 8.19 (d, J= 8.8Hz, 1H), 7.29 (d, J= 4.8, 1H), 7.19 (q, J= 7.6Hz, 1H), 6.61 (d, J= 8.4Hz, 1H), 6.51 (t, J= 8.8 Hz, 1H), 5.00 (br s, 1H), 4.40 (br d, J= 13.6 Hz, 1H), 4.07 - 4.20 (m, 1H), 3.99 (br d, J= 13.2Hz, 1H), 3.71 - 3.84 (m, 1H), 3.35 - 3.50 (m, 3H), 3.15 - 3.25 (m, 1H), 2.68-2.86(m, 1H), 2.41 (br t, J= 7.6 Hz, 2H), 1.60 - 1.78 (m, 2H), 1.44-1.58(m, 12H),1.19 (d, J= 6.8 Hz, 3H), 1.02 (d, J= 6.8 Hz, 3H)。 步驟11：化合物001-17的合成 將化合物001-16 (5.00 g, 7.68 mmol, 1 eq) 和三丁基氧膦 (2.64 g, 13.06 mmol, 3.22 mL, 1.7 eq)  溶於無水二氯甲烷 (130 mL)，氮氣置換三次，冷卻至0°C，分批加入1,1-偶氮二甲醯二哌啶 (3.30 g, 13.06 mmol, 1.7 eq) 。加料完畢，15°C，攪拌12小時。反應液減壓濃縮。粗品用150 mL甲基第三丁基醚打漿，過濾，濾液減壓濃縮，得到粗品化合物001-17 。 LCMS: m/z(ESI) = 633.3[M+H] +。 步驟12：化合物001-18的合成 15°C, 將化合物001-17 (9.1 g, 14.38 mmol, 1 eq) 溶於無水二氯甲烷(45 mL)，加入三氟乙酸 (15 mL)，攪拌5小時。反應液減壓濃縮，粗品用甲基第三丁基醚打漿((100mL*4)，過濾，收集固體。固體溶於100 mL二氯甲烷，加入100 mL飽和碳酸氫鈉水溶液，分液。水相用二氯甲烷萃取((40 mL*2)。有機相合併，用飽和食鹽水洗((40 mL))，無水硫酸鈉乾燥，過濾，減壓濃縮，得到化合物001-18。 LCMS: m/z(ESI) = 533.4[M+H] +。 步驟13：化合物001的合成 向預先乾燥的單口瓶中加入001-18 (213 mg, 399.94 μmol, 1 eq) ，(E)-4-氟丁-2-烯酸 (49.95 mg, 479.93 µmol, 1.2 eq) ，二氯甲烷(2 mL)，二異丙基乙胺(129.22 mg, 999.84 µmol, 174.15 µL, 2.5 eq)降溫至0℃加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(187.04 mg, 491.92 µmol, 1.23 eq) ，20℃攪拌16小時。將反應液減壓濃縮至乾，加入甲醇(2mL)，過濾，濾液經高效液相製備色譜(柱子: Phenomenex C18 80*40mm*3µm;流動相: [水(碳酸氫銨)-乙腈]；乙腈%：25%-55%，8min)分離純化。得到化合物001。 LCMS: m/z(ESI) = 619 [M+H] +。 1H NMR (400 MHz, CDCl 3) δ ppm 8.60 (d, J=5.00 Hz, 1 H), 7.83 (d, J=8.50 Hz, 1 H), 7.40 (td, J=8.32, 6.75 Hz, 1 H), 7.15 (d, J=5.13 Hz, 1 H), 6.98 - 7.13 (m, 1 H), 6.94 (d, J=8.25 Hz, 1 H), 6.87 (t, J=8.63 Hz, 1 H), 6.55 - 6.75 (m, 1 H), 5.05 - 5.28 (m, 2 H), 4.53 - 4.99 (m, 3 H), 4.34 - 4.45 (m, 1 H), 3.89 - 4.15 (m, 1 H), 3.42 - 3.84 (m, 3 H), 3.13 - 3.36 (m, 1 H), 2.98 (dt, J=13.38, 6.69 Hz, 1 H), 2.40 - 2.71 (m, 2 H), 2.11 - 2.37 (m, 2 H), 1.65 - 1.77 (m, 3 H), 1.34 (d, J=6.75 Hz, 3 H), 1.08 (d, J=6.75 Hz, 3 H)。 SFC分析方法 (色譜柱：Chiralcel OD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50~5%，3.0 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.332 min，手性異構體過量96.66 %。 Example 1
Figure 02_image528
synthetic route:
Figure 02_image530
Figure 02_image532
Step 1: Synthesis of compound 001-3 Add compound 001-1 (300 g, 1.84 mol, 1.00 eq ), 001-2 (potassium isopropenyl trifluoroborate, 300 g, 2.03 mol, 1.10 eq ), potassium carbonate (381 g, 2.76 mol, 1.5 eq ), 1,4-dioxane (3.0 L) and water (0.3 L). After the addition was complete, nitrogen was replaced three times. Then 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.40 g, 22.41 mmol, 1.22e-2 eq ) was added into the system. After the addition was complete, the reaction system was kept at 90 °C, and the reaction was stirred for 12 hours. The system was concentrated. Water (1.2 L) and ethyl acetate (2.0 L) were added to the system. The system was allowed to stand still for liquid separation. The aqueous phase was extracted with ethyl acetate (1.0 L, once). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1 to 5:1) to obtain compound 001-3. LCMS: MS m/z: 169.0 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 7.91-7.83 (m, 1H), 7.11-7.04 (m, 1H), 5.53-5.45 (m, 1H), 5.34-5.24 (m, 1H), 4.48-4.21 (m, 2H), 2.14 (s, 3H). Step 2: Synthesis of compound 001-5 Add compound 001-3 (119.3 g, 707.49 mmol, 1.00 eq ), compound 001-4 (300.05 g, 1.41 mol, 2.0 eq ) into a pre-washed 3.0-liter one-port bottle, Potassium phosphate (300.36 g, 1.41 mol, 2.0 eq ), 2-methyltetrahydrofuran (1200 mL) and water (300 mL). After the addition was complete, nitrogen was replaced three times. Then 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (46.11 g, 70.75 mmol, 0.1 eq ) was added into the system. After the addition was complete, nitrogen was replaced three times. The reaction system was at 76 °C (system temperature), and the reaction was stirred for 12 hours. The reaction system was cooled to room temperature, diluted with 1.5 liters of water and 2.0 liters of ethyl acetate, the organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (1.0 liter, twice). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 10:1 to 4:1) to obtain compound 001-5. LCMS: MS m/z: 219.1 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 7.99 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 16.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.47 (d , J = 15.6 Hz, 1H), 5.50 (s, 1H), 5.28 (s, 1H), 4.31 (br s, 2H), 3.81 (s, 3H), 2.15 (s, 3H). Step 3: Synthesis of compound 001-6 Palladium/carbon (17 g, 10% content) was added into a 2.0-liter hydrogenation bottle replaced with argon. After the addition was complete, tetrahydrofuran (1.5 L), compound 001-5 (85 g, 389.46 mmol, 1 eq ) and sodium carbonate (41.28 g, 389.46 mmol, 1.0 eq ) were added to the system. After the addition was complete, the system was replaced with hydrogen 3 times. The system was stirred for 1.0 hour at 25°C, pressure: 15 psi in a hydrogen atmosphere. The reaction system was filtered through celite, and the filter cake was washed with ethyl acetate (200 mL, 3 times). The combined filtrates were directly concentrated for compound 001-6. LCMS: MS m/z: 223.1 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 7.95 (d, J = 4.8 Hz, 1H), 6.78 (d, J = 5.2 Hz, 1H), 3.90 - 3.77 (m, 2H), 3.67 (s, 3H) , 3.08 - 2.97 (m, 1H), 2.80 (t, J = 7.2 Hz, 2H), 2.66 (t, J = 7.2 Hz, 2H), 1.28 (s, 3H), 1.27 (s, 3H). Step 4: Synthesis of Compound 001-7 Compound 001-6 (150 g, 674.82 mmol, 1 eq ) and tetrahydrofuran (1.5 L) were added to a pre-dried 3.0 L three-neck flask. Then the temperature of the system was lowered to 0-5 °C, and lithium borohydride (29.29 g, 1.34 mol, 1.99 eq ) was added in batches to the system. After the addition, the temperature was returned to 25 ° C, and reacted at this temperature for 1.0 hour. The system was quenched by slowly adding 4.0 L of stirred saturated ammonium chloride. Add 1.5 L of ethyl acetate for dilution, collect the organic phase after separation, and extract the aqueous phase with ethyl acetate (1.0 L, twice). The combined organic phases were washed with saturated brine (300 mL, once), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 001-7. The crude product was directly used in the next step without purification. LCMS: MS m/z: 195.1 [M+1] + . Step 5: Synthesis of compound 001-8 Add compound 001-7 (130 g, 669.16 mmol, 1.00 eq ), imidazole (68.33 g, 1.00 mol, 1.5 eq ) and dichloromethane into a pre-dried 3.0 L three-neck flask (2.00 L) After the addition, the system was cooled to 0 ~ 10 ° C, and tertiary butyldimethylsilyl chloride (102.63 g, 680.94 mmol, 83.44 mL, 1.02 eq ) was slowly added dropwise in dichloromethane ( 500 mL). After the addition, the temperature of the system was slowly returned to 25 ° C, and reacted at this temperature for 12 hours. Carefully add 300 mL of saturated ammonium chloride to the reaction system to quench the reaction. The system was left to stand, and the organic phase was collected after liquid separation, and the aqueous phase was extracted with dichloromethane (500 mL, once). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 10:1 to 6:1). Compound 001-8 was obtained. LCMS: MS m/z: 309.2 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 7.93 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 3.87 (br s, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.01 - 2.95 (m, 1H), 2.59 (t, J = 7.2 Hz, 2H), 1.85 - 1.72 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H). Step 6: Synthesis of compound 001-10 Under nitrogen protection, compound 001-9 (70 g, 334.92 mmol, 1.00 eq ) and dichloromethane (0.7 L) were added to a pre-dried 3.0 L single-necked bottle. After the sample was dissolved, the temperature of the system was kept at 20-25 °C, and oxalyl chloride (70 g, 551.50 mmol, 48.28 mL, 1.65 eq ) was slowly added dropwise to the system. After the addition, the system was warmed up to 40 °C ~ 45 °C, and reacted for 5 hours. The reaction system was concentrated to obtain a yellow compound, which was directly put into the next step without purification. Under nitrogen protection, dichloromethane (0.7 L) was added to the 3.0 L single-necked bottle containing the above yellow compound. After the sample was dissolved, the temperature of the system was cooled to 0 °C, and kept at 0 °C, a solution of compound 001-8 (108.49 g, 351.64 mmol, 1.05 eq ) in dichloromethane (0.28 L) was slowly added dropwise to the system. After the addition, the temperature of the system was returned to 25 ° C, and the system was reacted at 25 ° C for 12 hours. The reaction system was directly concentrated. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound 001-10. LCMS: MS m/z: 543.1 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 10.13 (s, 1H), 9.71 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 3.62 (t, J = 6.0 Hz, 2H), 3.27 - 3.12 (m, 1H), 2.68 - 2.57 (m, 2H), 1.81 - 1.72 (m, 2H), 1.21 (s, 3H), 1.19 (s, 3H), 0.84 (s, 9H), 0.00 (s, 6H). Step 7: Synthetic nitrogen protection of compound 001-11, add compound 001-10 (139 g, 255.73 mmol, 1 eq ), 18-crown-6 (33.80 g, 127.87 mmol, 0.5 eq ) and tetrahydrofuran (1.39 L). After the solution became clear, the system was cooled to 0-5°C, and potassium hexamethyldisilazide (1 M, 460.32 mL, 1.8 eq ) was slowly added dropwise to the system. After the addition was complete, the system was warmed to 25° C. and stirred at this temperature for 12 hours. 2 parallel reactions combined for batch workup and purification. Saturated ammonium chloride (1.0 L) was added to the respective reaction system to quench the reaction. The two systems were combined for extraction. Add 1.0 L of water and 1.0 L of ethyl acetate to the system for dilution, and collect the organic phase after static separation. The aqueous phase was extracted with ethyl acetate (600 mL, once). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash column chromatography (petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound 001-11. LCMS: MS m/z: 507.2 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 9.24 (br s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 3.52 (t, J = 6.0 Hz, 2H), 2.71 - 2.62 (m, 1H), 2.41 (t, J = 8.4 Hz, 2H), 1.74 - 1.61 (m, 2H), 1.21 (d , J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 0.79 - 0.73 (m, 9H), -0.11 - -0.05 (m, 6H). Step 8: Synthesis of compound 001-12 Under nitrogen protection, compound 001-11 (91.85 g, 181.14 mmol, 1.00 eq ), diisopropylethylamine (37.46 g, 289.82 mmol, 50.48 mL, 1.6 eq ) and tetrahydrofuran (920 mL). After the addition, the temperature of the system was lowered to 0-5 °C, and phosphorus oxychloride (41.66 g, 271.71 mmol, 25.25 mL, 1.5 eq ) was slowly added to the system. After the addition, the system was slowly warmed up to 40°C (system temperature), and stirred at this temperature for 2.0 hours to obtain compound 001-12. The reaction solution was directly used in the next step 9: synthesis of compound 001-14 Under nitrogen protection, the reaction system containing compound 001-12 (95.19 g, 181.14 mmol, 1.00 eq ) was cooled to 0 ~ 10 ° C and maintained, to A solution of diisopropylethylamine (58.52 g, 452.84 mmol, 78.87 mL, 2.5 eq ) and pre-dissolved compound 001-13 (72.55 g, 362.27 mmol, 2.0 eq ) in tetrahydrofuran (210 mL) was added to the system. After the addition was complete, the system was stirred at 25 °C for 12.0 hours. 2 parallel reactions were combined. Control the system temperature at 20-25 °C, and add 1.0 liter of saturated sodium chloride to the system to quench the reaction. The system was allowed to stand still for liquid separation. The aqueous phase was extracted with ethyl acetate (0.5 L, 2 times). The organic phases were combined, washed with brine (0.5 L, once), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude intermediate compound, which was directly used in the next step without purification. LCMS: MS m/z: 689.4[M+1] + . Under nitrogen protection, the above intermediate compound, acetic acid (349.65 g, 5.82 mol, 333 mL, 36.16 eq ), tetrahydrofuran (111 mL) and water (111 mL) were added to a 1.0 L single-necked bottle. After the addition was complete, the system was stirred at 25 °C for 12.0 hours. Add 500 mL of water to the reaction system. Cool to 0 ~ 5 °C, and adjust the pH of the system to 7 ~ 8 with 5.0 M sodium hydroxide (~ 5.0 L). The system was allowed to stand still for liquid separation. The aqueous phase was extracted with ethyl acetate (1.0 L, 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (dichloromethane:methanol=40:1 to 20:1) to obtain compound 001-14. LCMS: MS m/z: 575.2 [M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ = 8.59 (d, J = 4.8 Hz, 1H), 7.76 (dd, J = 2.0, 8.0 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 4.99 - 4.58 (m, 1H), 4.42 - 3.78 (m, 3H), 3.74 - 3.39 (m, 3H), 3.36 - 2.92 (m, 3H), 2.63 - 2.47 (m, 1H), 2.45 - 2.28 (m, 2H), 1.52 - 1.37 (m, 13H), 1.18 (dd, J = 4.0, 6.8 Hz, 3H), 1.06 (t, J = 6.4 Hz, 3H). Step 10: Synthesis of compound 001-16 Compound 001-14 (50 g, 76.30 mmol, 87.76% purity, 1 eq ), compound 001-15 (14.28 g, 91.56 mmol, 1.2 eq ) and anhydrous potassium phosphate (32.39 g , 152.60 mmol, 2.0 eq ) was dissolved in 2-methyltetrahydrofuran (250 mL) and water (100 mL), replaced with nitrogen three times, and added [1,1-bis(di-tert-butylphosphino)ferrocene] di Palladium(II) chloride (2.49 g, 3.81 mmol, 0.05 eq ), the reaction was heated to 75°C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and 50 mL of 2-methyltetrahydrofuran was used to wash the filter cake. The white filter cake was collected and concentrated under reduced pressure to remove the solvent. The white solid was dried in a vacuum oven at 45°C for 20 hours to obtain compound 001-16. LCMS: MS (ESI) m/z: 651.4 [M+1] + . SFC analysis method (column: Chiralpak IC-3, 50×4.6mm ID, 3μm; mobile phase: A (CO2) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50~5%, 3.0 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.321 min, chiral isomer excess 95.58%. 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.44 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 8.8Hz, 1H), 7.29 (d, J = 4.8, 1H), 7.19 (q, J = 7.6Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.51 (t, J = 8.8 Hz, 1H), 5.00 (br s, 1H), 4.40 (br d, J = 13.6 Hz, 1H), 4.07 - 4.20 (m, 1H), 3.99 (br d, J = 13.2Hz, 1H), 3.71 - 3.84 (m, 1H), 3.35 - 3.50 (m, 3H), 3.15 - 3.25 (m, 1H), 2.68-2.86(m, 1H), 2.41 (br t , J = 7.6 Hz, 2H), 1.60 - 1.78 (m, 2H), 1.44-1.58(m, 12H), 1.19 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H) Step 11: Synthesis of Compound 001-17 Compound 001-16 (5.00 g, 7.68 mmol, 1 eq ) and tributylphosphine oxide (2.64 g, 13.06 mmol, 3.22 mL, 1.7 eq ) were dissolved in anhydrous dichloromethane (130 mL), replaced with nitrogen three times, cooled to 0°C, and added 1,1-azobisacyldipiperidine (3.30 g, 13.06 mmol, 1.7 eq ) in batches. Addition was completed, stirred at 15°C for 12 Hour.The reaction solution was concentrated under reduced pressure.The crude product was slurried with 150 mL of methyl tertiary butyl ether, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 001-17.LCMS: m/z (ESI)=633.3[M+H] + . Step 12: Synthesis of compound 001-18 At 15°C, compound 001-17 (9.1 g, 14.38 mmol, 1 eq ) was dissolved in anhydrous dichloromethane (45 m L), added trifluoroacetic acid (15 mL), stirred for 5 hours. The reaction solution was concentrated under reduced pressure, the crude product was slurried with methyl tertiary butyl ether ((100mL*4), filtered, and the solid was collected. The solid was dissolved in 100 mL of dichloromethane, and 100 mL of saturated aqueous sodium bicarbonate solution was added to separate the liquid. The phase was extracted with dichloromethane ((40 mL*2). The combined organic phases were washed with saturated brine ((40 mL)), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 001-18. LCMS: m/ z (ESI) = 533.4[M+H] + .Step 13: Synthesis of Compound 001 Add 001-18 (213 mg, 399.94 μmol, 1 eq ), (E)-4-fluorobutyl -2-enoic acid (49.95 mg, 479.93 µmol, 1.2 eq ), dichloromethane (2 mL), diisopropylethylamine (129.22 mg, 999.84 µmol, 174.15 µL, 2.5 eq ) cooled to 0°C and added O- (7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (187.04 mg, 491.92 µmol, 1.23 eq ), stirred at 20°C for 16 hours. The reaction solution was reduced Concentrate under pressure to dryness, add methanol (2mL), filter, and the filtrate is subjected to high performance liquid chromatography (column: Phenomenex C18 80*40mm*3µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 25% -55%, 8min) separation and purification. Compound 001 was obtained. LCMS: m/z (ESI) = 619 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.60 (d, J =5.00 Hz , 1 H), 7.83 (d, J =8.50 Hz, 1 H), 7.40 (td, J =8.32, 6.75 Hz, 1 H), 7.15 (d, J =5.13 Hz, 1 H), 6.98 - 7.13 ( m, 1 H), 6.94 (d, J =8.25 Hz, 1 H), 6.87 (t, J =8.63 Hz, 1 H), 6.55 - 6.75 (m, 1 H), 5.05 - 5.28 (m, 2 H ), 4.53 - 4.99 (m, 3H), 4.34 - 4.45 (m, 1H), 3.89 - 4.15 (m, 1H), 3.42 - 3.84 (m, 3H), 3.13 - 3.36 (m, 1H ), 2.98 (dt, J =13.38, 6.69 Hz, 1 H), 2. 40 - 2.71 (m, 2H), 2.11 - 2.37 (m, 2H), 1.65 - 1.77 (m, 3H), 1.34 (d, J =6.75 Hz, 3H), 1.08 (d, J =6.75 Hz, 3H). SFC analysis method (column: Chiralcel OD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50~5 %, 3.0 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.332 min, chiral isomer excess 96.66%.

實施例2

Figure 02_image534
Figure 02_image536
步驟1：化合物002-1的合成 將化合物001-17 (3 g, 4.74 mmol, 1 eq) 溶於4N 的鹽酸甲醇溶液中 (30 mL)，20°C攪拌12小時。反應液減壓濃縮，加入乙酸乙酯(30 mL)和飽和碳酸氫鈉水溶液(30 mL)，分液。水相用乙酸乙酯萃取(15 mL*2). 合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析分離，純化(梯度洗脫劑為：二氯甲烷:甲醇=50:1~10:1)，得到化合物002-1。 LCMS: m/z(ESI) =451.1 [M+H] +。 1H NMR (400 MHz, CD 3Cl) δ ppm 9.29 (s, 1H), 8.61 (d, J= 4.8 Hz, 1H), 8.30 (d, J= 8.0 Hz, 1H), 7.31-7.45 (m, 1H), 7.14 (d, J= 5.2 Hz, 1H) , 6.76 - 6.97 (m, 2H), 4.32-4.45 (m, 1H), 3.54 - 3.70 (m, 1H), 2.87-3.01 (m, 1H), 2.60 - 2.71 (m, 2H), 2.16 - 2.32 (m, 2H), 1.33 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 6.8 Hz, 3H)。 步驟2：化合物002-2的合成 20°C將化合物002-1 (2.1 g, 4.66 mmol, 1 eq) 和N,N-二異丙基乙胺 (964.08 mg, 7.46 mmol, 1.30 mL, 1.6 eq) 溶於無水四氫呋喃 (21 mL)，氮氣置換三次，滴加三氯氧磷 (1.07 g, 6.99 mmol, 649.87 µL, 1.5 eq)。加料完畢，加熱至50°C，攪拌1小時，得到化合物002-2。沒有處理，直接用於下一步，產品按理論量計算。 步驟3：化合物002-4的合成 向化合物002-2 (2.19 g, 4.67 mmol, 1 eq) 的四氫呋喃溶液中加入N,N-二異丙基乙胺(1.51 g, 11.68 mmol, 2.03 mL, 2.5 eq)，氮氣置換三次，冷卻至0°C，滴加化合物002-3 (1.20 g, 5.60 mmol, 1.2 eq)  的無水四氫呋喃 (10 mL)  溶液。滴加完畢，自然升至20°C，攪拌12小時。反應液倒入100 mL飽和食鹽水中，乙酸乙酯萃取(15 mL*3)。合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析分離，純化(梯度洗脫劑為：二氯甲烷:甲醇=50:1~10:1)得到化合物002-4。 LCMS: m/z(ESI) = 647.4[M+H] +。 1H NMR (400 MHz, CD 3Cl) δ ppm 8.56 (d, J= 5.2 Hz, 1H), 7.79-7.89 ( m, 1H), 7.29-7.42 (m, 1H), 7.13 (d, J= 4.8 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 4.61 - 4.73 (m, 1H), 4.32 - 4.56 (m, 2H), 3.78 - 4.00 (m, 1H), 3.56 - 3.70 (m, 2H), 3.21 - 3.47 (m, 2H), 2.86-3.02(m, 1H), 2.39 - 2.67 (m, 2H), 2.10 - 2.33 (m, 2H), 1.36 - 1.64 (m, 15H), 1.29 (d, J= 6.8 Hz, 3H), 1.07 (d, J= 6.8 Hz, 3H)。 步驟4：化合物002-5的合成 將化合物002-4 (3.2 g, 4.95 mmol, 1 eq)  溶於無水二氯甲烷 (30 mL)，加入三氟乙酸 (10 mL)，25°C攪拌2小時。反應液減壓濃縮，加入20 mL二氯甲烷和20 mL水，飽和碳酸氫鈉水溶液調pH=8，分液，水相用二氯甲烷萃取(15 mL*2)。合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮。粗品經矽膠柱層析分離純化(梯度洗脫劑為：二氯甲烷:甲醇=30:1~ 5:1), 得到化合物002-5。 LCMS: m/z(ESI) = 547.4[M+H] +。 1H NMR (400 MHz, CDCl 3) δ ppm 8.55 (d, J= 5.2 Hz, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.31-7.46 (m, 1H), 7.11 (d, J= 4.8 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 4.52-4.68(m, 1H), 4.32 - 4.46 (m, 2H), 3.30 - 3.79 (m, 5H), 2.81 - 3.00 (m, 2H), 2.56 - 2.66 (m, 1H), 2.44 - 2.54 (m, 1H), 2.13 - 2.30 (m, 2H), 1.68 (d, J= 6.8 Hz, 3H), 1.42 (d, J= 6.4 Hz, 3H), 1.29 (d, J= 6.8 Hz, 3H), 1.06 (d, J= 6.8 Hz, 3H)。 步驟5：化合物002的合成 氮氣保護，將化合物002-5 (100 mg, 182.95 µmol, 1 eq)和( E)-4-氟丁-2-烯酸 (57.12 mg, 548.84 µmol, 3 eq)溶於二氯甲烷 (4 mL)，然後加入N,N-二異丙基乙胺 (141.86 mg, 1.10 mmol, 191.19 µL, 6 eq)，0°C加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(104.34 mg, 274.42 µmol, 1.5 eq)，升溫至20°C反應2小時。向反應體系中加入飽和碳酸氫鈉溶液(20mL)，分液。水相使用二氯甲烷(20mL*3)萃取，分液。合併有機相，使用和飽和食鹽水(20mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過高效液相色譜分離(色譜柱: Waters Xbridge Prep OBD C18 150*40mm*10µm; 流動相: A(乙腈) 和B(水，含0.04%碳酸氫銨)；梯度：B%: 40%-60%，8 min)，純化得到化合物002。 LCMS: MS m/z: 633.7 [M+1] +. 1H NMR (400 MHz, CD 3OD) δ = 8.49 (d, J = 5.2 Hz, 1H), 8.13 (dd, J = 8.8, 12.0 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 - 6.89 (m, 1H), 6.89 - 6.84 (m, 1H), 6.80 (s, 1H), 5.19 (m, 1H), 5.10 - 4.74 (m, 2H), 4.60 (s, 2H), 4.49 - 4.38 (m, 2H), 3.92 -  3.76 (m, 1H), 3.68 (m, 1H), 3.60 - 3.52 (m, 1H), 3.06 - 2.96 (m, 1H), 2.58 - 2.35 (m, 3H), 2.22 - 2.08 (m, 1H), 1.60 (m, 3H), 1.51 - 1.41 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.02 (dd, J = 3.2, 6.8 Hz, 3H)。 SFC分析方法 (色譜柱：Chiralcel OD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (MeOH，含0.1%異丙胺)；梯度：B%=5~50~5%，3.0 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.256 min，手性異構體過量99.72 %。 Example 2
Figure 02_image534
Figure 02_image536
Step 1: Synthesis of Compound 002-1 Compound 001-17 (3 g, 4.74 mmol, 1 eq ) was dissolved in 4N methanolic hydrochloric acid (30 mL), and stirred at 20° C. for 12 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate (30 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (15 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (gradient eluent: dichloromethane:methanol=50:1~10:1) to obtain compound 002-1. LCMS: m/z (ESI) = 451.1 [M+H] + . 1 H NMR (400 MHz, CD 3 Cl) δ ppm 9.29 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.31-7.45 (m, 1H), 7.14 (d, J = 5.2 Hz, 1H) , 6.76 - 6.97 (m, 2H), 4.32-4.45 (m, 1H), 3.54 - 3.70 (m, 1H), 2.87-3.01 (m, 1H) , 2.60 - 2.71 (m, 2H), 2.16 - 2.32 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). Step 2: Synthesis of compound 002-2 Compound 002-1 (2.1 g, 4.66 mmol, 1 eq ) and N,N-diisopropylethylamine (964.08 mg, 7.46 mmol, 1.30 mL, 1.6 eq ) was dissolved in anhydrous tetrahydrofuran (21 mL), replaced with nitrogen three times, and phosphorus oxychloride (1.07 g, 6.99 mmol, 649.87 µL, 1.5 eq ) was added dropwise. After the addition, the mixture was heated to 50°C and stirred for 1 hour to obtain compound 002-2. Without treatment, it is directly used in the next step, and the product is calculated according to the theoretical amount. Step 3: Synthesis of Compound 002-4 To compound 002-2 (2.19 g, 4.67 mmol, 1 eq ) in tetrahydrofuran was added N,N-diisopropylethylamine (1.51 g, 11.68 mmol, 2.03 mL, 2.5 eq ), replaced with nitrogen three times, cooled to 0°C, and added dropwise a solution of compound 002-3 (1.20 g, 5.60 mmol, 1.2 eq ) in anhydrous tetrahydrofuran (10 mL). After the dropwise addition was completed, it was naturally raised to 20° C. and stirred for 12 hours. The reaction solution was poured into 100 mL saturated brine, and extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (gradient eluent: dichloromethane:methanol=50:1~10:1) to obtain compound 002-4. LCMS: m/z (ESI) = 647.4[M+H] + . 1 H NMR (400 MHz, CD 3 Cl) δ ppm 8.56 (d, J = 5.2 Hz, 1H), 7.79-7.89 (m, 1H), 7.29-7.42 (m, 1H), 7.13 (d, J = 4.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 4.61 - 4.73 (m, 1H), 4.32 - 4.56 (m, 2H), 3.78 - 4.00 (m, 1H), 3.56 - 3.70 (m, 2H), 3.21 - 3.47 (m, 2H), 2.86-3.02(m, 1H), 2.39 - 2.67 (m, 2H), 2.10 - 2.33 (m, 2H) , 1.36 - 1.64 (m, 15H), 1.29 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). Step 4: Synthesis of compound 002-5 Dissolve compound 002-4 (3.2 g, 4.95 mmol, 1 eq ) in anhydrous dichloromethane (30 mL), add trifluoroacetic acid (10 mL), and stir at 25°C for 2 hours . The reaction solution was concentrated under reduced pressure, 20 mL of dichloromethane and 20 mL of water were added, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with dichloromethane (15 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (gradient eluent: dichloromethane:methanol=30:1~5:1) to obtain compound 002-5. LCMS: m/z (ESI) = 547.4[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.55 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.31-7.46 (m, 1H), 7.11 (d, J = 4.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 4.52-4.68(m, 1H), 4.32 - 4.46 (m, 2H), 3.30 - 3.79 (m, 5H), 2.81 - 3.00 (m, 2H), 2.56 - 2.66 (m, 1H), 2.44 - 2.54 (m, 1H), 2.13 - 2.30 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H). Step 5: Synthesis of compound 002 under nitrogen protection, compound 002-5 (100 mg, 182.95 µmol, 1 eq ) and ( E )-4-fluorobut-2-enoic acid (57.12 mg, 548.84 µmol, 3 eq ) were dissolved In dichloromethane (4 mL), then add N,N-diisopropylethylamine (141.86 mg, 1.10 mmol, 191.19 µL, 6 eq ), add O-(7-azobenzotriazole at 0°C )-N,N,N',N'-Tetramethyluronium hexafluorophosphate (104.34 mg, 274.42 µmol, 1.5 eq ), heated to 20°C for 2 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction system, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10µm; mobile phase: A (acetonitrile) and B (water, containing 0.04% ammonium bicarbonate); gradient: B%: 40% -60%, 8 min), purified to obtain compound 002. LCMS: MS m/z: 633.7 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δ = 8.49 (d, J = 5.2 Hz, 1H), 8.13 (dd, J = 8.8, 12.0 Hz , 1H), 7.49 - 7.35 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 - 6.89 (m, 1H), 6.89 - 6.84 (m, 1H), 6.80 (s, 1H), 5.19 (m, 1H), 5.10 - 4.74 (m, 2H), 4.60 (s, 2H), 4.49 - 4.38 (m, 2H), 3.92 - 3.76 (m, 1H), 3.68 (m, 1H), 3.60 - 3.52 (m, 1H), 3.06 - 2.96 (m, 1H), 2.58 - 2.35 (m, 3H), 2.22 - 2.08 (m, 1H), 1.60 (m, 3H), 1.51 - 1.41 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.02 (dd, J = 3.2, 6.8 Hz, 3H). SFC analysis method (chromatographic column: Chiralcel OD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B (MeOH, containing 0.1% isopropylamine); gradient: B%=5~50~5 %, 3.0 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.256 min, chiral isomer excess 99.72%.

實施例3

Figure 02_image538
Figure 02_image540
步驟1：化合物002-2的合成 氮氣保護，將化合物002-1(0.8 g, 1.78 mmol, 1 eq)溶於四氫呋喃(12 mL)，加入N,N-二異丙基乙胺(688.61 mg, 5.33 mmol, 928.05 µL, 3 eq)，然後加入三氯氧磷(680.81 mg, 4.44 mmol, 412.61 µL, 2.5 eq)，40°C反應3小時。得到化合物002-2，該反應體系直接用於下一步。 步驟2：化合物003-2的合成 氮氣保護，0°C下，將化合物002-2 (0.8 g, 1.71 mmol, 1 eq)溶於四氫呋喃(13 mL)，加入N,N-二異丙基乙胺(1.10 g, 8.53 mmol, 1.49 mL, 5 eq)，然後加入化合物003-1 (596.07 mg, 2.22 mmol, 1.3 eq, HCl)，升溫至20°C反應15小時。補加N,N-二異丙基乙胺(1.10 g, 8.53 mmol, 1.49 mL, 5 eq)，20°C反應15小時。因未反應完全，50°C反應15小時。補加N,N-二異丙基乙胺(1.10g, 5eq)，70°C反應30小時。將反應體系加入到冰水(50 mL)中，水相使用乙酸乙酯(50 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(60 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=10:1~1:3，二氯甲烷：甲醇=40:1~30:1)分離純化得到化合物003-2。 LCMS: MS m/z: 665.2 [M+1] +. 1H NMR (400 MHz, CDCl 3) δ = 8.55 (dd, J= 5.2, 2.8 Hz, 1H), 7.81 - 7.71 (m, 1H), 7.41 - 7.32 (m, 6H), 7.09 (d, J= 5.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 5.60 (s, 1H), 5.21 (s, 2H), 4.88 - 4.82 (m, 2H), 4.45 - 4.34 (m, 2H), 4.12 - 4.10 (m, 1H), 3.77 - 3.71 (m, 1H), 3.65 - 3.59 (m, 1H), 2.96 - 2.86 (m, 1H), 2.71 - 2.50 (m, 3H), 2.27 - 2.12 (m, 3H), 1.33 (d, J= 6.8 Hz, 3H), 0.96 (dd, J= 10.8, 6.8 Hz, 3H)。 步驟3：化合物003-3的合成 氮氣保護，將化合物003-2 (0.6 g, 902.66 µmol, 1 eq)溶於四氫呋喃(30 mL)，加入鈀/碳(0.5 g, 902.66 µmol, 10% 含量, 1.00 eq)，氫氣置換三次，然後氫氣氛圍下(15Psi)，25°C反應8小時。將反應體系直接過濾，濾液減壓濃縮得到化合物003-3，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 531.1 [M+1] +. 1H NMR (400 MHz, CDCl 3) δ = 8.55 (dd, J= 5.2, 2.0 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.35 (q, J= 8.0 Hz, 1H), 7.10 (d, J= 5.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 5.63 - 5.57 (m, 1H), 4.96 - 4.80 (m, 1H), 4.67 - 4.59 (m, 1H), 4.37 - 4.35 (m, 1H), 3.77 - 3.74 (m, 2H), 3.67 - 3.62 (m, 1H), 3.59 - 3.49 (m, 1H), 2.93 - 2.84 (m, 1H), 2.61 - 2.51 (m, 3H), 2.27 - 2.14 (m, 2H), 1.88 - 1.84 (m, 2H), 1.32 (dd, J= 6.4, 2.0 Hz, 3H), 0.96 (dd, J= 9.6, 6.8 Hz, 3H)。 步驟4：化合物003和004的合成 氮氣保護，將化合物003-3 (0.1 g, 188.48 µmol, 1 eq)溶於二氯甲烷 (5 mL)，加入N,N-二異丙基乙胺(121.79 mg, 942.39 µmol, 164.14 µL, 5 eq)，然後加入丙烯醯氯(34.12 mg, 376.96 µmol, 30.74 µL, 2 eq)，-60°C反應10分鐘。向反應體系中加入飽和碳酸氫鈉溶液(20 mL)，分液。水相使用二氯甲烷(50 mL*3)萃取，分液。合併有機相，使用和飽和食鹽水(50mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過高效液相色譜分離(色譜柱: Phenomenex Luna 80*30mm*3µm；流動相:A(乙腈) 和B(水，含0.04%鹽酸)；梯度：B%: 5%-35%，8 min)，純化得到產物純品。純品進一步透過SFC拆分(柱子：REGIS(S,S)WHELK-O1(250mm*25mm,10µm)；流動相：A (CO 2) 和B (甲醇，含0.1%氨水)；梯度：B%=60%-60%，7min)，分別得到化合物003和化合物004。 化合物003： LCMS: MS m/z: 585.2 [M+1] +. 1H NMR (400 MHz, CDCl 3) δ = 8.56 (d, J= 5.2 Hz, 1H), 7.81 (d, J= 8.2 Hz, 1H), 7.36 (q, J= 8.0 Hz, 1H), 7.13 (d, J= 5.2 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 6.62 - 6.55 (m, 1H), 6.51 - 6.46 (m, 1H), 5.83 (dd, J= 9.6, 2.0 Hz, 1H), 5.58 (t, J= 5.6 Hz, 1H), 5.09 (s, 1H), 5.01 - 4.95 (m, 1H), 4.46 (d, J= 8.0 Hz, 1H), 4.37 - 4.35 (m, 1H), 4.16 (t, J= 10.0 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.64 - 3.58 (m, 1H), 2.96 - 2.70 (m, 2H), 2.63 - 2.53 (m, 2H), 2.32 - 2.14 (m, 3H), 1.35 (d, J= 6.8 Hz, 3H), 0.97 (d, J= 6.8 Hz, 3H)。 SFC (色譜柱：(S,S)-WHELK-O1，3.5 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (MeOH，含0.1%異丙胺)；梯度：B%=40~40%，4 min；流速: 4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.237 min，手性異構體過量100%。 化合物004： LCMS: MS m/z: 585.2 [M+1] +. 1H NMR (400 MHz, CDCl 3) δ = 8.63 (d, J= 2.4 Hz, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.37 (q, J= 8.0 Hz, 1H), 7.24 (s, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 8.8 Hz, 1H), 6.62 - 6.40 (m, 2H), 5.83 (dd, J= 10.0, 2.0 Hz, 1H), 5.60 (t, J= 4.8 Hz, 1H), 5.09 (s, 1H), 4.98 - 4.95 (m, 1H), 4.48 (d, J= 8.0 Hz, 1H), 4.38 (d, J= 7.6 Hz, 1H), 4.16 (t, J= 9.6 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.60 (t, J= 10.0 Hz, 1H), 3.00 - 2.93 (m, 1H), 2.79 (dd, J= 13.6, 5.2 Hz, 1H), 2.68 - 2.60 (m, 2H), 2.29 - 2.20 (m, 3H), 1.41 (d, J= 6.4 Hz, 3H), 1.06 (d, J= 6.4 Hz, 3H)。 SFC (色譜柱：(S,S)-WHELK-O1，3.5 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (MeOH，含0.1%異丙胺)；梯度：B%=40~40%，4 min；流速: 4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.995 min，手性異構體過量99.80%。 Example 3
Figure 02_image538
Figure 02_image540
Step 1: Synthesis of compound 002-2 under nitrogen protection, compound 002-1 (0.8 g, 1.78 mmol, 1 eq ) was dissolved in tetrahydrofuran (12 mL), and N,N-diisopropylethylamine (688.61 mg, 5.33 mmol, 928.05 µL, 3 eq ), then added phosphorus oxychloride (680.81 mg, 4.44 mmol, 412.61 µL, 2.5 eq ), and reacted at 40°C for 3 hours. Compound 002-2 was obtained, and the reaction system was directly used in the next step. Step 2: Synthesis of compound 003-2 under nitrogen protection, at 0°C, dissolve compound 002-2 (0.8 g, 1.71 mmol, 1 eq ) in tetrahydrofuran (13 mL), add N,N-diisopropylethyl Amine (1.10 g, 8.53 mmol, 1.49 mL, 5 eq ), then compound 003-1 (596.07 mg, 2.22 mmol, 1.3 eq , HCl) was added, and the temperature was raised to 20°C for 15 hours. Add N,N-diisopropylethylamine (1.10 g, 8.53 mmol, 1.49 mL, 5 eq ) and react at 20°C for 15 hours. Because of incomplete reaction, reacted for 15 hours at 50°C. Add N,N-diisopropylethylamine (1.10 g, 5 eq) and react at 70° C. for 30 hours. The reaction system was added into ice water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1~1:3, dichloromethane: methanol = 40:1~30:1) to obtain compound 003-2. LCMS: MS m/z: 665.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.55 (dd, J = 5.2, 2.8 Hz, 1H), 7.81 - 7.71 (m, 1H), 7.41 - 7.32 (m, 6H), 7.09 (d, J = 5.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 5.60 (s, 1H ), 5.21 (s, 2H), 4.88 - 4.82 (m, 2H), 4.45 - 4.34 (m, 2H), 4.12 - 4.10 (m, 1H), 3.77 - 3.71 (m, 1H), 3.65 - 3.59 (m , 1H), 2.96 - 2.86 (m, 1H), 2.71 - 2.50 (m, 3H), 2.27 - 2.12 (m, 3H), 1.33 (d, J = 6.8 Hz, 3H), 0.96 (dd, J = 10.8 , 6.8 Hz, 3H). Step 3: Synthesis of compound 003-3 under nitrogen protection, compound 003-2 (0.6 g, 902.66 µmol, 1 eq ) was dissolved in tetrahydrofuran (30 mL), and palladium/carbon (0.5 g, 902.66 µmol, 10% content, 1.00 eq ), replaced by hydrogen three times, and then reacted at 25°C for 8 hours under hydrogen atmosphere (15Psi). The reaction system was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 003-3, which could be directly used in the next reaction without purification. LCMS: MS m/z: 531.1 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.55 (dd, J = 5.2, 2.0 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.35 (q, J = 8.0 Hz, 1H), 7.10 (d, J = 5.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 5.63 - 5.57 (m, 1H), 4.96 - 4.80 (m, 1H), 4.67 - 4.59 (m, 1H), 4.37 - 4.35 (m, 1H), 3.77 - 3.74 (m, 2H), 3.67 - 3.62 (m, 1H ), 3.59 - 3.49 (m, 1H), 2.93 - 2.84 (m, 1H), 2.61 - 2.51 (m, 3H), 2.27 - 2.14 (m, 2H), 1.88 - 1.84 (m, 2H), 1.32 (dd , J = 6.4, 2.0 Hz, 3H), 0.96 (dd, J = 9.6, 6.8 Hz, 3H). Step 4: Synthesis of compounds 003 and 004 under nitrogen protection, compound 003-3 (0.1 g, 188.48 µmol, 1 eq ) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (121.79 mg, 942.39 µmol, 164.14 µL, 5 eq ), then acryloyl chloride (34.12 mg, 376.96 µmol, 30.74 µL, 2 eq ), and react at -60°C for 10 minutes. Add saturated sodium bicarbonate solution (20 mL) to the reaction system, and separate the layers. The aqueous phase was extracted with dichloromethane (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex Luna 80*30mm*3µm; mobile phase: A (acetonitrile) and B (water, containing 0.04% hydrochloric acid); gradient: B%: 5%-35%, 8 min), purified to obtain pure product. The pure product was further separated by SFC (column: REGIS (S, S) WHELK-O1 (250mm*25mm, 10µm); mobile phase: A (CO 2 ) and B (methanol, containing 0.1% ammonia); gradient: B% =60%-60%, 7min), obtain compound 003 and compound 004 respectively. Compound 003: LCMS: MS m/z: 585.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.56 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 8.2 Hz , 1H), 7.36 (q, J = 8.0 Hz, 1H), 7.13 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H ), 6.62 - 6.55 (m, 1H), 6.51 - 6.46 (m, 1H), 5.83 (dd, J = 9.6, 2.0 Hz, 1H), 5.58 (t, J = 5.6 Hz, 1H), 5.09 (s, 1H), 5.01 - 4.95 (m, 1H), 4.46 (d, J = 8.0 Hz, 1H), 4.37 - 4.35 (m, 1H), 4.16 (t, J = 10.0 Hz, 1H), 3.98 - 3.91 (m , 1H), 3.64 - 3.58 (m, 1H), 2.96 - 2.70 (m, 2H), 2.63 - 2.53 (m, 2H), 2.32 - 2.14 (m, 3H), 1.35 (d, J = 6.8 Hz, 3H ), 0.97 (d, J = 6.8 Hz, 3H). SFC (column: (S,S)-WHELK-O1, 3.5 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (MeOH with 0.1% isopropylamine); gradient: B%= 40~40%, 4 min; flow rate: 4 mL/min; wavelength: 220nm; pressure: 124 bar, Rt=1.237 min, chiral isomer excess 100%. Compound 004: LCMS: MS m/z: 585.2 [ M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.63 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.37 (q, J = 8.0 Hz , 1H), 7.24 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.8 Hz, 1H), 6.62 - 6.40 (m, 2H), 5.83 (dd, J = 10.0, 2.0 Hz, 1H), 5.60 (t, J = 4.8 Hz, 1H), 5.09 (s, 1H), 4.98 - 4.95 (m, 1H), 4.48 (d, J = 8.0 Hz, 1H), 4.38 ( d, J = 7.6 Hz, 1H), 4.16 (t, J = 9.6 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.60 (t, J = 10.0 Hz, 1H), 3.00 - 2.93 (m, 1H ), 2.79 (dd, J = 13.6, 5.2 Hz, 1H), 2.68 - 2.60 (m, 2H), 2.29 - 2.20 (m, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H). SFC (column: (S,S)-WHELK-O1, 3.5 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (MeOH, containing 0.1% iso Propylamine); gradient: B%=40~40%, 4 min; flow rate: 4 mL/min; wavelength: 220nm; pressure: 124 bar, Rt=1.995 min, chiral isomer excess 99.80%.

實施例4

Figure 02_image542
Figure 02_image544
步驟1：化合物005的合成 向預先乾燥的單口瓶中加入001-18 (150 mg, 281.65 µmol, 1 eq)，005-1(41.01 mg, 422.47 µmol, 1.5 eq)，二氯甲烷(3 mL)，二異丙基乙胺(72.80 mg, 563.29 µmol, 98.12 µL, 2 eq)，降溫至0°C加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(128.51 mg, 337.98 µmol, 1.2 eq)，自然回溫至20°C攪拌1小時。將反應液減壓濃縮至乾，加入乙腈(2 mL)溶解，粗品經高效液相製備色譜(色譜柱: Waters Xbridge BEH C18 100*25mm*5µm;流動相: [水(碳酸氫銨)-乙腈];乙腈%: 25%-55%,10min)分離純化，得到化合物005。 LCMS: m/z(ESI) = 612 [M+H] +。 1H NMR (400 MHz, CDCl 3- d) δ ppm 8.59 (d, J=4.88 Hz, 1 H) 7.78 (d, J=8.38 Hz, 1 H) 7.31 - 7.42 (m, 2 H) 7.11 - 7.26 (m, 1 H) 6.80 - 6.95 (m, 2 H) 6.62 (dd, J=15.76, 5.00 Hz, 1 H) 4.47 - 4.95 (m, 3 H) 4.30 - 4.43 (m, 1 H) 3.13 - 4.00 (m, 5 H) 2.87 - 3.04 (m, 1 H) 2.36 - 2.70 (m, 2 H) 2.09 - 2.33 (m, 2 H) 1.61 - 1.69 (m, 3 H) 1.33 (br d, J=6.63 Hz, 3 H) 1.06 (br d, J=6.75 Hz, 3 H). SFC分析方法 (色譜柱：Chiralcel OD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (MeOH，含0.1%異丙胺)；梯度：B%=5~50~5%，3.0 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.405 min，手性異構體過量100 %。 Example 4
Figure 02_image542
Figure 02_image544
Step 1: Synthesis of Compound 005 Add 001-18 (150 mg, 281.65 µmol, 1 eq ), 005-1 (41.01 mg, 422.47 µmol, 1.5 eq ), dichloromethane (3 mL) to a pre-dried single-necked vial , diisopropylethylamine (72.80 mg, 563.29 µmol, 98.12 µL, 2 eq ), cooled to 0°C and added O-(7-azobenzotriazole)-N,N,N',N'- Tetramethyluronium hexafluorophosphate (128.51 mg, 337.98 µmol, 1.2 eq ) was naturally warmed to 20°C and stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, dissolved in acetonitrile (2 mL), and the crude product was subjected to preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5 µm; mobile phase: [water (ammonium bicarbonate)-acetonitrile ]; Acetonitrile%: 25%-55%, 10min) separation and purification to obtain compound 005. LCMS: m/z (ESI) = 612 [M+H] + . 1 H NMR (400 MHz, CDCl 3 - d ) δ ppm 8.59 (d, J =4.88 Hz, 1 H) 7.78 (d, J =8.38 Hz, 1 H) 7.31 - 7.42 (m, 2 H) 7.11 - 7.26 (m, 1H) 6.80 - 6.95 (m, 2H) 6.62 (dd, J =15.76, 5.00 Hz, 1H) 4.47 - 4.95 (m, 3H) 4.30 - 4.43 (m, 1H) 3.13 - 4.00 (m, 5H) 2.87 - 3.04 (m, 1H) 2.36 - 2.70 (m, 2H) 2.09 - 2.33 (m, 2H) 1.61 - 1.69 (m, 3H) 1.33 (br d, J =6.63 Hz, 3 H) 1.06 (br d, J =6.75 Hz, 3 H). SFC analysis method (column: Chiralcel OD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B ( MeOH, containing 0.1% isopropylamine); Gradient: B%=5~50~5%, 3.0 min; Flow rate: 3.4 mL/min; Wavelength: 220nm; Pressure: 1800 psi, Rt=1.405 min, chiral isomer 100% excess.

實施例5

Figure 02_image546
Figure 02_image548
步驟1：化合物006的合成 向預先乾燥的單口瓶中加入002-5 (200 mg, 365.89 µmol, 1 eq)，005-1(53.28 mg, 548.84 µmol, 1.5 eq)  ，二氯甲烷(4 mL)，二異丙基乙胺(94.58 mg, 731.78 µmol, 127.46 µL, 2 eq)，降溫至0°C，加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(166.95 mg, 439.07 µmol, 1.2 eq)，自然回溫至20°C攪拌1小時。將反應液減壓濃縮至乾，加入乙腈(2 mL)溶解，過濾，粗品經高效液相製備色譜(色譜柱: Waters Xbridge BEH C18 100*25mm*5µm;流動相: [水(碳酸氫銨)-乙腈];乙腈%: 30%-60%,10min)分離純化，得到化合物006。 LCMS: m/z(ESI) = 626 [M+H] +。 1H NMR (400 MHz, CDCl 3) δ ppm 8.59 (br d, J=4.88 Hz, 1 H) 7.83 (dd, J=18.26, 8.50 Hz, 1 H) 7.31 - 7.42 (m, 1 H) 7.13 - 7.25 (m, 2 H) 6.79 - 6.95 (m, 2 H) 6.61 (dd, J=15.70, 5.69 Hz, 1 H) 4.78 - 5.21 (m, 2 H) 4.26 - 4.54 (m, 2 H) 3.56 - 3.86 (m, 3 H) 3.22 - 3.37 (m, 1 H) 2.85 - 3.02 (m, 1 H) 2.39 - 2.71 (m, 2 H) 2.06 - 2.35 (m, 2 H) 1.59 - 1.68 (m, 3 H) 1.55 (br s, 3 H) 1.31 (br s, 3 H) 1.09 (br t, J=6.75 Hz, 3 H)。 SFC分析方法 (色譜柱：Chiralcel OD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (MeOH，含0.1%異丙胺)；梯度：B%=5~50~5%，3.0 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.323 min，手性異構體過量96.88 %。 Example 5
Figure 02_image546
Figure 02_image548
Step 1: Synthesis of Compound 006 Add 002-5 (200 mg, 365.89 µmol, 1 eq ), 005-1 (53.28 mg, 548.84 µmol, 1.5 eq ), dichloromethane (4 mL) to a pre-dried single-necked vial , diisopropylethylamine (94.58 mg, 731.78 µmol, 127.46 µL, 2 eq ), cooled to 0°C, added O-(7-azobenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (166.95 mg, 439.07 µmol, 1.2 eq ), naturally warmed to 20°C and stirred for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, dissolved in acetonitrile (2 mL), filtered, and the crude product was subjected to preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100*25mm*5 µm; mobile phase: [water (ammonium bicarbonate) -acetonitrile]; acetonitrile%: 30%-60%, 10min) separation and purification to obtain compound 006. LCMS: m/z (ESI) = 626 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.59 (br d, J =4.88 Hz, 1 H) 7.83 (dd, J =18.26, 8.50 Hz, 1 H) 7.31 - 7.42 (m, 1 H) 7.13 - 7.25 (m, 2H) 6.79 - 6.95 (m, 2H) 6.61 (dd, J =15.70, 5.69 Hz, 1H) 4.78 - 5.21 (m, 2H) 4.26 - 4.54 (m, 2H) 3.56 - 3.86 (m, 3H) 3.22 - 3.37 (m, 1H) 2.85 - 3.02 (m, 1H) 2.39 - 2.71 (m, 2H) 2.06 - 2.35 (m, 2H) 1.59 - 1.68 (m, 3 H) 1.55 (br s, 3 H) 1.31 (br s, 3 H) 1.09 (br t, J =6.75 Hz, 3 H). SFC analysis method (chromatographic column: Chiralcel OD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B (MeOH, containing 0.1% isopropylamine); gradient: B%=5~50~5 %, 3.0 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.323 min, chiral isomer excess 96.88%.

實施例6

Figure 02_image550
合成路線：
Figure 02_image552
Figure 02_image554
步驟1：化合物007-1的合成 氮氣保護，將氰基乙酸(3.64 g, 42.78 mmol, 6 eq)溶於二氯甲烷(35 mL)，加入草醯氯(8.15 g, 64.17 mmol, 5.62 mL, 9 eq)，然後加入N,N-二甲基甲醯胺(104.23 mg, 1.43 mmol, 109.72 µL, 0.2 eq)，25°C反應3小時。待反應完畢後，將反應體系直接減壓濃縮，得到醯氯中間態。氮氣保護，將化合物001-8 (2.2 g, 7.13 mmol, 1 eq)溶於二氯甲烷 (40 mL)，加入三乙胺(2.89 g, 28.52 mmol, 3.97 mL, 4 eq)，0°C緩慢加入醯氯中間態，然後緩慢升溫至25°C反應2小時。向反應體系中加入水(50mL)，分液。水相使用二氯甲烷(30mL*2)萃取，分液。合併有機相，使用飽和食鹽水(50mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=20:1~1:1)分離，純化得到化合物007-1。 LCMS: MS m/z: 376.1 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.47 (d, J= 4.8 Hz, 1H), 7.86 (s, 1H), 7.05 (d, J= 4.8 Hz, 1H), 3.65 (t, J= 5.6 Hz, 2H), 3.58 (s, 2H), 3.19 - 3.12 (m, 1H), 2.65 (t, J= 7.2 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H)。 步驟2：化合物007-2的合成 氮氣保護，將化合物007-1 (2.1 g, 5.59 mmol, 1 eq)溶於四氫呋喃(30 mL)，加入四甲基氟化銨(10.42 g, 111.83 mmol, 20 eq)，20°C反應23小時。向反應體系中加入水(50mL)，水相使用乙酸乙酯(100mL*3)萃取，分液。合併有機相，使用飽和食鹽水(50mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品化合物007-2，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 262.1 [M+1] +。 1H NMR (400 MHz, CD 3OD) δ = 8.37 (d, J= 5.2 Hz, 1H), 7.23 (d, J= 4.8 Hz, 1H), 3.86 - 3.84 (m, 1H), 3.59 (t, J= 6.0 Hz, 2H), 3.28 - 3.19 (m, 2H), 2.67 (t, J= 8.0 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H)。 步驟3：化合物007-3的合成 氮氣保護，將化合物007-2 (1.5 g, 5.74 mmol, 1 eq)溶於二氯甲烷(45 mL)，0°C加入咪唑(1.17 g, 17.22 mmol, 3 eq)和第三丁基二苯基氯矽烷(2.37 g, 8.61 mmol, 2.21 mL, 1.5 eq)，20°C反應6小時。向反應體系中加入水( 100mL)，水相使用二氯甲烷(100mL*3)萃取，分液。合併有機相，使用飽和食鹽水(100mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=30:1~1:1)分離，純化得到化合物007-3。 LCMS: MS m/z: 500.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.47 (d, J= 4.8 Hz, 1H), 7.66 - 7.64 (m, 4H), 7.48 - 7.38 (m, 7H), 7.03 (d, J= 4.8 Hz, 1H), 3.74 (t, J= 6.0 Hz, 2H), 3.36 (s, 2H), 3.18 - 3.12 (m, 1H), 2.70 (t, J= 7.6 Hz, 2H), 1.88 - 1.82 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.09 (s, 9H)。 步驟4：化合物007-5的合成 氮氣保護，將化合物007-4 (961.46 mg, 4.58 mmol, 1.3 eq)溶於氯化亞碸(10.48 g, 88.05 mmol, 6.39 mL, 25 eq)，80°C反應2小時。待反應完畢後，將反應體系直接減壓濃縮，得到醯氯中間態。氮氣保護，將化合物007-3 (1.76 g, 3.52 mmol, 1 eq)溶於四氫呋喃(30 mL)，0°C加入第三丁醇鈉(676.93 mg, 7.04 mmol, 2 eq)，0°C攪拌0.5小時，然後0°C緩慢加入醯氯中間態的四氫呋喃(24 mL)溶液，然後緩慢升溫至25°C反應3小時。向反應體系中加入水( 50mL)，水相使用乙酸乙酯(100mL*2)萃取，分液。合併有機相，使用飽和食鹽水(50mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=50:1~1:1，二氯甲烷：甲醇=80:1~30:1)分離，純化得到化合物007-5。 LCMS: MS m/z: 691.1 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 11.90 (br s, 1H), 8.49 (s, 1H), 7.64 - 7.62 (m, 4H), 7.53 (d, J= 6.8 Hz, 1H), 7.47 - 7.36 (m, 8H), 3.74 (t, J= 6.0 Hz, 2H), 3.50 - 3.42 (m, 1H), 3.01 (t, J= 7.6 Hz, 2H), 1.91 - 1.85 (m, 2H), 1.09 (s, 4H), 1.06 (s, 11H)。 步驟5：化合物007-6的合成 氮氣保護，將化合物007-5 (0.91 g, 1.32 mmol, 1 eq)溶於四氫呋喃(35 mL)，0°C緩慢加入氫化鈉(263.10 mg, 6.58 mmol, 60% 含量, 5 eq)，然後50°C反應4小時。向反應體系中加入飽和氯化銨溶液(50mL)淬滅反應，水相使用乙酸乙酯(3*100mL)萃取，分液。合併有機相，使用飽和食鹽水(100mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：二氯甲烷：甲醇=40:1~8:1)分離，純化得到化合物007-6。 LCMS: MS m/z: 655.2 [M+1] +。 1H NMR (400 MHz, CD 3OD) δ = 8.51 (d, J= 5.2 Hz, 1H), 8.22 (d, J= 8.0 Hz, 1H), 7.53 - 7.49 (m, 4H), 7.43 - 7.32 (m, 7H), 3.64 - 3.55 (m, 2H), 2.79 - 2.72 (m, 1H), 2.58 - 2.46 (m, 2H), 1.81 - 1.66 (m, 2H), 1.23 (d, J= 6.8 Hz, 3H), 1.07 (d, J= 6.8 Hz, 3H), 0.88 (s, 9H)。 步驟6：化合物007-7的合成 氮氣保護，將化合物007-6 (1.17 g, 1.79 mmol, 1 eq)溶於四氫呋喃(18 mL)，加入N,N-二異丙基乙胺(692.32 mg, 5.36 mmol, 933.05 µL, 3 eq)，然後加入三氯氧磷(684.48 mg, 4.46 mmol, 414.83 µL, 2.5 eq)，40°C反應3小時，得到粗產品化合物007-7，該反應體系可直接用於下一步反應。 步驟7：化合物007-8的合成 氮氣保護，0°C下，將化合物007-7 (1.1 g, 1.63 mmol, 1 eq)溶於四氫呋喃(17.2 mL)，加入N,N-二異丙基乙胺(844.11 mg, 6.53 mmol, 1.14 mL, 4 eq)，然後加入化合物001-13 (425.12 mg, 2.12 mmol, 1.3 eq)，升溫至20°C反應16小時。將反應體系加入到水(50mL)中，水相使用乙酸乙酯(50mL*3)萃取，分液。合併有機相，使用飽和食鹽水(60mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：二氯甲烷：甲醇=200:1~12:1)分離，純化得到化合物007-8。 LCMS: MS m/z: 837.3 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.63 - 8.59 (m, 1H), 7.81 - 7.72 (m, 1H), 7.58 - 7.52 (m, 4H), 7.44 - 7.33 (m, 6H), 7.17 - 7.13 (m, 1H), 4.37 - 3.76 (m, 4H), 3.66 - 3.56 (m, 3H), 3.22 - 3.10 (m, 1H), 2.97 - 2.76 (m, 1H), 2.60 - 2.45 (m, 1H), 2.41 - 2.26 (m, 2H), 1.81 - 1.64 (m, 2H), 1.61 (s, 3H), 1.52 - 1.46 (m, 9H), 1.24 - 1.19 (m, 3H), 1.03 (d, J= 6.8 Hz, 3H), 0.95 - 0.92 (m, 9H)。 步驟8：化合物007-9的合成 氮氣保護，將化合物007-8 (0.69 g, 823.89 µmol, 1 eq)和化合物001-15 (256.92 mg, 1.65 mmol, 2 eq)溶於1,4-二㗁烷(14 mL)和水(1.4 mL)，加入碳酸鈉(261.97 mg, 2.47 mmol, 3 eq)和四(三苯基膦)鈀(95.21 mg, 82.39 µmol, 0.1 eq)，80°C反應1小時。向反應體系中加入水(50mL)，水相使用乙酸乙酯(60mL*3)萃取，分液。合併有機相，使用飽和食鹽水(60mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=20:1~2:1)分離，純化得到化合物007-9。 LCMS: MS m/z: 913.3 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 9.18 (d, J= 8.8 Hz, 1H), 8.69 (d, J= 5.2 Hz, 1H), 7.92 (t, J= 6.8 Hz, 1H), 7.58 (d, J= 7.6 Hz, 1H), 7.55 - 7.50 (m, 4H), 7.41 - 7.33 (m, 6H), 7.21 (dd, J= 12.4, 4.8 Hz, 1H), 6.72 - 6.68 (m, 2H), 4.22 - 4.07 (m, 3H), 3.65 - 3.58 (m, 3H), 3.28 - 3.06 (m, 2H), 2.74 - 2.62 (m, 1H), 2.52 - 2.40 (m, 2H), 2.34 (t, J= 8.0 Hz, 1H), 1.86 - 1.66 (m, 2H), 1.53 (s, 9H), 1.38 (d, J= 6.4 Hz, 2H), 1.31 (s, 1H), 1.24 - 1.20 (m, 3H), 1.03 (dd, J= 14.4, 6.4 Hz, 3H), 0.91 (d, J= 7.2 Hz, 9H)。 步驟9：化合物007-10的合成 氮氣保護，將化合物007-9 (0.34 g, 372.34 µmol, 1 eq)溶於四氫呋喃(10 mL)，加入四甲基氟化銨(1.21 g, 13.03 mmol, 35 eq)，20°C反應23小時。向反應體系中加入水(10mL)，水相使用乙酸乙酯(10mL*3)萃取，分液。合併有機相，使用飽和食鹽水(5mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品化合物007-10，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 675.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 9.26 - 9.04 (m, 1H), 8.70 (t, J= 4.8 Hz, 1H), 8.00 (d, J= 9.2 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.30 - 7.29 (m, 1H), 6.72 - 6.67 (m, 2H), 4.30 - 4.18 (m, 2H), 4.16 - 3.99 (m, 2H), 3.65 - 3.49 (m, 3H), 3.47 - 3.41 (m, 1H), 3.30 - 3.23 (m, 2H), 2.76 - 2.62 (m, 1H), 2.48 (t, J= 7.2 Hz, 1H), 2.32 (t, J= 7.6 Hz, 1H), 1.84 - 1.76 (m, 2H), 1.54 (s, 9H), 1.45 - 1.43 (m, 6H), 1.25 - 1.20 (m, 3H)。 步驟10：化合物007-11的合成 氮氣保護，將化合物007-10 (0.34 g, 503.90 µmol, 1 eq)溶於四氫呋喃(21 mL)，加入三苯基膦(462.59 mg, 1.76 mmol, 3.5 eq)，20°C加入偶氮二甲酸二乙酯(307.16 mg, 1.76 mmol, 320.62 µL, 3.5 eq)，20°C反應2小時。向反應體系中加入水(20mL)，水相使用乙酸乙酯(30mL*3)萃取，分液。合併有機相，使用飽和食鹽水(20mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(流動相：石油醚：乙酸乙酯=20:1~2:1)分離，純化得到化合物007-11。 LCMS: MS m/z: 657.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.59 (t, J= 4.4 Hz, 1H), 7.97 - 7.89 (m, 1H), 7.39 - 7.34 (m, 1H), 7.12 (d, J= 5.2 Hz, 1H), 6.89 (t, J= 6.8 Hz, 1H), 6.86 - 6.80 (m, 1H), 4.37 (d, J= 8.8 Hz, 1H), 4.32 - 4.18 (m, 2H), 4.09 - 4.03 (m, 1H), 4.01 - 3.90 (m, 1H), 3.71 - 3.56 (m, 2H), 3.52 - 3.29 (m, 2H), 2.81 - 2.69 (m, 1H), 2.64 - 2.52 (m, 1H), 2.48 - 2.33 (m, 1H), 2.39 - 2.15 (m, 2H), 1.53 (s, 9H), 1.42 (t, J= 6.4 Hz, 3H), 1.31 (dd, J= 6.8, 3.2 Hz, 3H), 1.00 - 0.88 (m, 3H)。 步驟11：化合物007-12的三氟乙酸鹽的合成 氮氣保護，將化合物007-11 (0.33 g, 402.00 µmol, 1 eq)溶於二氯甲烷(13 mL)，加入三氟乙酸(2.29 g, 20.10 mmol, 1.49 mL, 50 eq)，20°C反應2小時。將反應體系直接減壓濃縮得到化合物007-12的三氟乙酸鹽，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 557.2 [M+1] +。 步驟12：化合物007和008的合成 氮氣保護，將化合物007-12的三氟乙酸鹽 (0.5 g, 351.33 µmol, 1 eq)溶於二氯甲烷(12 mL)，加入N,N-二異丙基乙胺(681.08 mg, 5.27 mmol, 917.90 µL, 15 eq)，然後加入丙烯醯氯(63.60 mg, 702.65 µmol, 57.29 µL, 2 eq)，-60°C反應10分鐘。向反應體系中加入飽和碳酸氫鈉溶液(20mL)，分液。水相使用二氯甲烷(50mL*3)萃取，分液。合併有機相，使用和飽和食鹽水(50mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過高效液相色譜分離(色譜柱: Waters Xbridge BEH C18 250*50mm*10µm；流動相:A(乙腈) 和B(水，含10mM碳酸氫銨)；梯度：B%: 40%-70%，10 min)分離，再進一步透過SFC(柱子：DAICEL CHIRALCEL OJ(250mm*30mm,10µm)；流動相：A (CO 2) 和B (乙醇，含0.1%氨水)；梯度：B%=37%-37%，18min)拆分，分別得到化合物007和化合物008。 化合物007：LCMS: MS m/z: 611.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.60 (d, J= 4.8 Hz, 1H), 7.96 (d, J= 9.2 Hz, 1H), 7.38 (q, J= 8.0 Hz, 1H), 7.16 (d, J= 4.8 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.85 (t, J= 8.8 Hz, 1H), 6.75 - 6.52 (m, 1H), 6.42 (dd, J= 16.4, 1.2 Hz, 1H), 5.84 (d, J= 10.0 Hz, 1H), 4.46 - 4.27 (m, 3H), 4.14 - 3.95 (m, 2H), 3.79 - 3.53 (m, 4H), 2.74 - 2.67 (m, 1H), 2.66 - 2.59 (m, 1H), 2.57 - 2.49 (m, 1H), 2.31 - 2.15 (m, 2H), 1.43 (d, J= 6.4 Hz, 3H), 1.32 (d, J= 6.8 Hz, 3H), 0.91 (d, J= 6.8 Hz, 3H)。 SFC (柱子：Chiralcel OJ-3，3 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.278 min，手性異構體過量100%。 化合物008：LCMS: MS m/z: 611.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.59 (d, J= 5.2 Hz, 1H), 7.90 (d, J= 6.8 Hz, 1H), 7.37 (q, J= 7.6 Hz, 1H), 7.12 (d, J= 5.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 8.8 Hz, 1H), 6.73 - 6.56 (m, 1H), 6.43 (dd, J= 16.4, 1.2 Hz, 1H), 5.84 (d, J= 11.2 Hz, 1H), 4.67 - 4.52 (m, 1H), 4.44 - 4.36 (m, 2H), 4.27 - 3.99 (m, 2H), 3.65 - 3.60 (m, 1H), 3.58 - 3.26 (m, 3H), 2.79 - 2.71 (m, 1H), 2.58 - 2.52 (m, 1H), 2.43 - 2.35 (m, 1H), 2.24 - 2.15 (m, 2H), 1.41 (d, J= 6.8 Hz, 3H), 1.31 (d, J= 6.8 Hz, 3H), 0.98 (d, J= 6.8 Hz, 3H)。 SFC (柱子：Chiralcel OJ-3，3 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.501 min，手性異構體過量98.48%。 Example 6
Figure 02_image550
synthetic route:
Figure 02_image552
Figure 02_image554
Step 1: Synthesis of compound 007-1 under nitrogen protection, cyanoacetic acid (3.64 g, 42.78 mmol, 6 eq ) was dissolved in dichloromethane (35 mL), and oxalyl chloride (8.15 g, 64.17 mmol, 5.62 mL, 9 eq ), then N,N-dimethylformamide (104.23 mg, 1.43 mmol, 109.72 µL, 0.2 eq ) was added and reacted at 25°C for 3 hours. After the reaction is completed, the reaction system is directly concentrated under reduced pressure to obtain an intermediate state of acyl chloride. Under nitrogen protection, compound 001-8 (2.2 g, 7.13 mmol, 1 eq ) was dissolved in dichloromethane (40 mL), triethylamine (2.89 g, 28.52 mmol, 3.97 mL, 4 eq ) was added, and slowly heated at 0°C Add acidic chloride intermediate state, then slowly warming up to 25 DEG C of reaction 2 hours. Water (50 mL) was added to the reaction system, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL*2), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1~1:1), and purified to obtain compound 007-1. LCMS: MS m/z: 376.1 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.47 (d, J = 4.8 Hz, 1H), 7.86 (s, 1H), 7.05 (d, J = 4.8 Hz, 1H), 3.65 (t, J = 5.6 Hz, 2H), 3.58 (s, 2H), 3.19 - 3.12 (m, 1H), 2.65 (t, J = 7.2 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H). Step 2: Synthesis of compound 007-2 under nitrogen protection, compound 007-1 (2.1 g, 5.59 mmol, 1 eq ) was dissolved in tetrahydrofuran (30 mL), and tetramethylammonium fluoride (10.42 g, 111.83 mmol, 20 eq ), 20 DEG C of reaction 23 hours. Water (50 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (100 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 007-2, which was directly used in the next reaction without purification. LCMS: MS m/z: 262.1 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δ = 8.37 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 4.8 Hz, 1H), 3.86 - 3.84 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.28 - 3.19 (m, 2H), 2.67 (t, J = 8.0 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H ). Step 3: Synthesis of compound 007-3 under nitrogen protection, compound 007-2 (1.5 g, 5.74 mmol, 1 eq ) was dissolved in dichloromethane (45 mL), and imidazole (1.17 g, 17.22 mmol, 3 eq ) and tert-butyldiphenylchlorosilane (2.37 g, 8.61 mmol, 2.21 mL, 1.5 eq ), react at 20°C for 6 hours. Water (100 mL) was added to the reaction system, the aqueous phase was extracted with dichloromethane (100 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1~1:1), and purified to obtain compound 007-3. LCMS: MS m/z: 500.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.47 (d, J = 4.8 Hz, 1H), 7.66 - 7.64 (m, 4H), 7.48 - 7.38 (m, 7H), 7.03 (d, J = 4.8 Hz , 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.36 (s, 2H), 3.18 - 3.12 (m, 1H), 2.70 (t, J = 7.6 Hz, 2H), 1.88 - 1.82 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 1.09 (s, 9H). Step 4: Synthesis of compound 007-5 under nitrogen protection, compound 007-4 (961.46 mg, 4.58 mmol, 1.3 eq ) was dissolved in argon oxychloride (10.48 g, 88.05 mmol, 6.39 mL, 25 eq ), 80°C React for 2 hours. After the reaction is completed, the reaction system is directly concentrated under reduced pressure to obtain an intermediate state of acyl chloride. Under nitrogen protection, compound 007-3 (1.76 g, 3.52 mmol, 1 eq ) was dissolved in tetrahydrofuran (30 mL), and sodium tert-butoxide (676.93 mg, 7.04 mmol, 2 eq ) was added at 0°C, stirred at 0°C After 0.5 hour, a solution of tetrahydrofuran (24 mL) in the intermediate state of acyl chloride was slowly added at 0°C, and then the temperature was slowly raised to 25°C for 3 hours. Water (50 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (100 mL*2), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 50:1~1:1, dichloromethane: methanol = 80:1~30:1), and purified to obtain compound 007-5. LCMS: MS m/z: 691.1 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 11.90 (br s, 1H), 8.49 (s, 1H), 7.64 - 7.62 (m, 4H), 7.53 (d, J = 6.8 Hz, 1H), 7.47 - 7.36 (m, 8H), 3.74 (t, J = 6.0 Hz, 2H), 3.50 - 3.42 (m, 1H), 3.01 (t, J = 7.6 Hz, 2H), 1.91 - 1.85 (m, 2H), 1.09 (s, 4H), 1.06 (s, 11H). Step 5: Synthesis of compound 007-6 under nitrogen protection, compound 007-5 (0.91 g, 1.32 mmol, 1 eq ) was dissolved in tetrahydrofuran (35 mL), and sodium hydride (263.10 mg, 6.58 mmol, 60 % content, 5 eq ), then reacted at 50°C for 4 hours. A saturated ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction, the aqueous phase was extracted with ethyl acetate (3*100 mL), and the layers were separated. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: dichloromethane: methanol = 40:1~8:1), and purified to obtain compound 007-6. LCMS: MS m/z: 655.2 [M+1] + . 1 H NMR (400 MHz, CD 3 OD) δ = 8.51 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.53 - 7.49 (m, 4H), 7.43 - 7.32 ( m, 7H), 3.64 - 3.55 (m, 2H), 2.79 - 2.72 (m, 1H), 2.58 - 2.46 (m, 2H), 1.81 - 1.66 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H). Step 6: Synthesis of compound 007-7 under nitrogen protection, compound 007-6 (1.17 g, 1.79 mmol, 1 eq ) was dissolved in tetrahydrofuran (18 mL), and N,N-diisopropylethylamine (692.32 mg, 5.36 mmol, 933.05 µL, 3 eq ), then add phosphorus oxychloride (684.48 mg, 4.46 mmol, 414.83 µL, 2.5 eq ), and react at 40°C for 3 hours to obtain the crude product compound 007-7, which can be directly for the next reaction. Step 7: Synthesis of compound 007-8 under nitrogen protection, at 0°C, dissolve compound 007-7 (1.1 g, 1.63 mmol, 1 eq ) in tetrahydrofuran (17.2 mL), add N,N-diisopropylethyl Amine (844.11 mg, 6.53 mmol, 1.14 mL, 4 eq ), then compound 001-13 (425.12 mg, 2.12 mmol, 1.3 eq ) was added, and the temperature was raised to 20°C for 16 hours. The reaction system was added into water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: dichloromethane: methanol = 200:1~12:1), and purified to obtain compound 007-8. LCMS: MS m/z: 837.3 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.63 - 8.59 (m, 1H), 7.81 - 7.72 (m, 1H), 7.58 - 7.52 (m, 4H), 7.44 - 7.33 (m, 6H), 7.17 - 7.13 (m, 1H), 4.37 - 3.76 (m, 4H), 3.66 - 3.56 (m, 3H), 3.22 - 3.10 (m, 1H), 2.97 - 2.76 (m, 1H), 2.60 - 2.45 (m, 1H ), 2.41 - 2.26 (m, 2H), 1.81 - 1.64 (m, 2H), 1.61 (s, 3H), 1.52 - 1.46 (m, 9H), 1.24 - 1.19 (m, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.95 - 0.92 (m, 9H). Step 8: Nitrogen protection for the synthesis of compound 007-9, compound 007-8 (0.69 g, 823.89 µmol, 1 eq ) and compound 001-15 (256.92 mg, 1.65 mmol, 2 eq ) were dissolved in 1,4-bis Alkanes (14 mL) and water (1.4 mL), add sodium carbonate (261.97 mg, 2.47 mmol, 3 eq ) and tetrakis (triphenylphosphine) palladium (95.21 mg, 82.39 µmol, 0.1 eq ), 80 ° C reaction 1 Hour. Water (50 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (60 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1~2:1), and purified to obtain compound 007-9. LCMS: MS m/z: 913.3 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 9.18 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 5.2 Hz, 1H), 7.92 (t, J = 6.8 Hz, 1H), 7.58 ( d, J = 7.6 Hz, 1H), 7.55 - 7.50 (m, 4H), 7.41 - 7.33 (m, 6H), 7.21 (dd, J = 12.4, 4.8 Hz, 1H), 6.72 - 6.68 (m, 2H) , 4.22 - 4.07 (m, 3H), 3.65 - 3.58 (m, 3H), 3.28 - 3.06 (m, 2H), 2.74 - 2.62 (m, 1H), 2.52 - 2.40 (m, 2H), 2.34 (t, J = 8.0 Hz, 1H), 1.86 - 1.66 (m, 2H), 1.53 (s, 9H), 1.38 (d, J = 6.4 Hz, 2H), 1.31 (s, 1H), 1.24 - 1.20 (m, 3H ), 1.03 (dd, J = 14.4, 6.4 Hz, 3H), 0.91 (d, J = 7.2 Hz, 9H). Step 9: Synthesis of compound 007-10 under nitrogen protection, compound 007-9 (0.34 g, 372.34 µmol, 1 eq ) was dissolved in tetrahydrofuran (10 mL), and tetramethylammonium fluoride (1.21 g, 13.03 mmol, 35 eq ), 20 DEG C of reaction 23 hours. Water (10 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 007-10, which was directly used in the next reaction without purification. LCMS: MS m/z: 675.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 9.26 - 9.04 (m, 1H), 8.70 (t, J = 4.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.60 - 7.50 (m , 1H), 7.30 - 7.29 (m, 1H), 6.72 - 6.67 (m, 2H), 4.30 - 4.18 (m, 2H), 4.16 - 3.99 (m, 2H), 3.65 - 3.49 (m, 3H), 3.47 - 3.41 (m, 1H), 3.30 - 3.23 (m, 2H), 2.76 - 2.62 (m, 1H), 2.48 (t, J = 7.2 Hz, 1H), 2.32 (t, J = 7.6 Hz, 1H), 1.84 - 1.76 (m, 2H), 1.54 (s, 9H), 1.45 - 1.43 (m, 6H), 1.25 - 1.20 (m, 3H). Step 10: Synthesis of compound 007-11 under nitrogen protection, compound 007-10 (0.34 g, 503.90 µmol, 1 eq ) was dissolved in tetrahydrofuran (21 mL), and triphenylphosphine (462.59 mg, 1.76 mmol, 3.5 eq ) was added , add diethyl azodicarboxylate (307.16 mg, 1.76 mmol, 320.62 µL, 3.5 eq ) at 20°C, and react at 20°C for 2 hours. Water (20 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1~2:1), and purified to obtain compound 007-11. LCMS: MS m/z: 657.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.59 (t, J = 4.4 Hz, 1H), 7.97 - 7.89 (m, 1H), 7.39 - 7.34 (m, 1H), 7.12 (d, J = 5.2 Hz , 1H), 6.89 (t, J = 6.8 Hz, 1H), 6.86 - 6.80 (m, 1H), 4.37 (d, J = 8.8 Hz, 1H), 4.32 - 4.18 (m, 2H), 4.09 - 4.03 ( m, 1H), 4.01 - 3.90 (m, 1H), 3.71 - 3.56 (m, 2H), 3.52 - 3.29 (m, 2H), 2.81 - 2.69 (m, 1H), 2.64 - 2.52 (m, 1H), 2.48 - 2.33 (m, 1H), 2.39 - 2.15 (m, 2H), 1.53 (s, 9H), 1.42 (t, J = 6.4 Hz, 3H), 1.31 (dd, J = 6.8, 3.2 Hz, 3H) , 1.00 - 0.88 (m, 3H). Step 11: Synthesis of trifluoroacetic acid salt of compound 007-12 under nitrogen protection, compound 007-11 (0.33 g, 402.00 µmol, 1 eq ) was dissolved in dichloromethane (13 mL), and trifluoroacetic acid (2.29 g, 20.10 mmol, 1.49 mL, 50 eq ), react at 20°C for 2 hours. The reaction system was directly concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 007-12, which could be directly used in the next reaction without purification. LCMS: MS m/z: 557.2 [M+1] + . Step 12: Synthesis of compounds 007 and 008 under nitrogen protection, the trifluoroacetic acid salt of compound 007-12 (0.5 g, 351.33 µmol, 1 eq ) was dissolved in dichloromethane (12 mL), and N,N-diisopropyl Diethylethylamine (681.08 mg, 5.27 mmol, 917.90 µL, 15 eq ), and then acryloyl chloride (63.60 mg, 702.65 µmol, 57.29 µL, 2 eq ), were reacted at -60°C for 10 minutes. Saturated sodium bicarbonate solution (20 mL) was added to the reaction system, and the layers were separated. The aqueous phase was extracted with dichloromethane (50mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50mm*10µm; mobile phase: A (acetonitrile) and B (water, containing 10mM ammonium bicarbonate); gradient: B%: 40%-70 %, 10 min), and further separated by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10µm); mobile phase: A (CO 2 ) and B (ethanol, containing 0.1% ammonia); gradient: B%=37 %-37%, 18min) resolution to obtain compound 007 and compound 008, respectively. Compound 007: LCMS: MS m/z: 611.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.60 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.38 (q, J = 8.0 Hz, 1H), 7.16 ( d, J = 4.8 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 8.8 Hz, 1H), 6.75 - 6.52 (m, 1H), 6.42 (dd, J = 16.4 , 1.2 Hz, 1H), 5.84 (d, J = 10.0 Hz, 1H), 4.46 - 4.27 (m, 3H), 4.14 - 3.95 (m, 2H), 3.79 - 3.53 (m, 4H), 2.74 - 2.67 ( m, 1H), 2.66 - 2.59 (m, 1H), 2.57 - 2.49 (m, 1H), 2.31 - 2.15 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). SFC (column: Chiralcel OJ-3, 3 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50%, 3 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 124 bar, Rt=1.278 min, chiral isomer excess 100%. Compound 008: LCMS: MS m/z: 611.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.59 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.37 (q, J = 7.6 Hz, 1H), 7.12 ( d, J = 5.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.8 Hz, 1H), 6.73 - 6.56 (m, 1H), 6.43 (dd, J = 16.4 , 1.2 Hz, 1H), 5.84 (d, J = 11.2 Hz, 1H), 4.67 - 4.52 (m, 1H), 4.44 - 4.36 (m, 2H), 4.27 - 3.99 (m, 2H), 3.65 - 3.60 ( m, 1H), 3.58 - 3.26 (m, 3H), 2.79 - 2.71 (m, 1H), 2.58 - 2.52 (m, 1H), 2.43 - 2.35 (m, 1H), 2.24 - 2.15 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). SFC (Column: Chiralcel OJ-3, 3 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50%, 3 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure : 124 bar, Rt=1.501 min, chiral isomer excess 98.48%.

實施例7

Figure 02_image556
合成路線：
Figure 02_image558
Figure 02_image560
步驟1：化合物009-2的合成 向預先乾燥的單口瓶中加入化合物009-1 (20 g, 121.96 mmol, 1 eq)，異丙烯基三氟硼酸鉀001-2(21.66 g, 146.35 mmol, 1.2 eq)，碳酸鈉(38.78 g, 365.87 mmol, 3 eq)，二㗁烷(200 mL)，水(50 mL)，1,1-雙(二苯基磷)二茂鐵氯化鈀(4.46 g, 6.10 mmol, 0.05 eq)充分氮氣置換，100 °C攪拌5小時。將反應液減壓濃縮，加入甲基第三丁基醚(200 mL)，過濾，濾餅使用甲基第三丁基醚充分淋洗至無產品殘留。濾液用甲基第三丁基醚(200 mL*3)萃取，收集合併有機相加入飽和氯化鈉水溶液(40 mL)，分離有機相加入無水硫酸鈉乾燥過濾，濾液減壓濃縮。粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 4:0 – 4:1)，得到化合物009-2。 LCMS: MS m/z: 170.1[M+H] +。 步驟2：化合物009-3的合成 向預先乾燥的單口瓶中加入化合物009-2 (5.15 g, 30.36 mmol, 1 eq)，001-4 (9.01 g, 42.51 mmol, 1.4 eq)，二㗁烷 (60 mL)，水 (15 mL)，磷酸鉀(12.89 g, 60.73 mmol, 2 eq)，充分氮氣置換加入[1,1-雙(二第三丁基膦)二茂鐵]二氯化鈀(1.98 g, 3.04 mmol, 0.1 eq)，100°C攪拌12小時。將反應液減壓濃縮後，加入甲基第三丁基醚(60 mL)充分攪拌過濾，濾餅使用甲基第三丁基醚淋洗至無產品殘留，收集濾液有機相加入飽和食鹽水(50 mL)洗，分離有機相加入無水硫酸鈉乾燥過濾，濾液減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 9:0 – 9:1)，得到化合物009-3。 LCMS: MS m/z: 220.1[M+H] +。 步驟3：化合物009-4的合成 充分氬氣置換後，向預先乾燥的單口瓶中加入鈀/碳 (750 mg, 10%含量)，四氫呋喃(30 mL)，化合物009-3 (3 g, 13.68 mmol, 1 eq)，20°C通入15 psi 氫氣氛圍下攪拌2小時。合併體系透過矽藻土過濾，濾餅使用乙酸乙酯(500 mL)充分淋洗至無產品殘留，收集濾液減壓濃縮。粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 7:0 – 7:3)，得到化合物009-4。 LCMS: MS m/z: 224.2[M+H]+。 1H NMR (400 MHz, CDCl3) δ =  8.57 (s, 1 H) 3.70 (s, 3 H) 3.02 (dt, J=13.52, 6.73 Hz, 1 H) 2.88 - 2.96 (m, 4 H) 1.30 (d, J=6.78 Hz, 6 H)。 步驟4：化合物009-5的合成 平行設置兩批反應：向預先乾燥的三口瓶中加入四氫鋁鋰(169.99 mg, 4.48 mmol, 2 eq)，四氫呋喃(5 mL)，降溫至0°C加入化合物009-4 (500 mg, 2.24 mmol, 1 eq)的四氫呋喃(1 mL)溶液，加畢，自然回溫至20°C攪拌1小時。分別向兩反應中加入水(0.17 mL)，15%氫氧化鈉水溶液(0.17 mL)，水(0.51 mL)，加入無水硫酸鈉乾燥，充分攪拌過濾，減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 1:0 – 1:1)，得到化合物009-5。 LCMS: MS m/z: 196.2[M+H] +。 步驟5：化合物009-6的合成 向預先乾燥的單口瓶中加入化合物009-5(323 mg, 1.65 mmol, 1 eq)，二氯甲烷(4 mL)，咪唑(337.84 mg, 4.96 mmol, 3 eq)，降溫至0 °C加入第三丁基二甲基氯矽烷(498.65 mg, 3.31 mmol, 405.40 µL, 2 eq) 的二氯甲烷(1 mL)溶液，加畢，立即轉移至20°C，攪拌2小時。加入水(15 mL)，二氯甲烷(10 mL*3)萃取，收集合併有機相加入無水硫酸鈉乾燥過濾，減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 4:0 – 4:1)，得到化合物009-6。 LCMS: MS m/z: 310.2[M+H] +。 步驟6：化合物009-7的合成 向預先乾燥的單口瓶中加入001-9 (345 mg, 1.65 mmol, 1 eq)，二氯甲烷(4 mL)，草醯氯(419.04 mg, 3.30 mmol, 288.99 µL, 2 eq)，45 °C攪拌4小時。將兩批反應液減壓濃縮至乾，得到異氰酸酯活性中間體化合物，直接進行下一步。 向預先裝有上述異氰酸酯活性中間體化合物的反應瓶中氮氣置換，氮氣氛圍下加入二氯甲烷(1 mL)  ，降溫至0°C加入化合物 009-6 (357.65 mg, 1.16 mmol, 0.7 eq) 的二氯甲烷(1 mL) 溶液，自然回溫至20 °C攪拌1小時。立即向反應液中分別加入飽和碳酸氫鈉水溶液(20 mL)淬滅，於20 °C下充分攪拌後，用二氯甲烷(10 mL*3)萃取，收集有機相，加入無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到粗品化合物009-7。 LCMS: MS m/z: 545.9[M+1] +。 步驟7：化合物009-8的合成 向預先乾燥的單口瓶中加入化合物009-7 (500 mg, 918.24 µmol, 1 eq) ，四氫呋喃 (10 mL)，降溫至0°C後加入雙(三甲基矽)胺基鉀四氫呋喃溶液(1 M, 1.84 mL, 2 eq)，加畢，撤出冰浴，20 °C攪拌1小時。向體系中加入飽和氯化銨水溶液(30 mL)，加入乙酸乙酯(20 mL*3)萃取，收集合併有機相，加入無水硫酸鈉乾燥過濾，濾液減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 7:0 – 7:3)，得到化合物009-8。 LCMS: MS m/z: 508.2 [M+H] +。 步驟8：化合物009-9的合成 向預先乾燥的反應瓶中加入化合物009-8(100 mg, 196.83 µmol, 1 eq)，四氫呋喃(1.2 mL)，二異丙基乙胺(76.32 mg, 590.48 µmol, 102.85 µL, 3 eq)，三氯氧磷(69.41 mg, 452.70 µmol, 42.07 µL, 2.3 eq)，45 °C攪拌2小時，得到化合物009-9，反應溶液直接用於下一步。 步驟9：化合物009-10的合成 向預先裝有化合物009-9 (103.63 mg, 196.83 µmol, 1 eq) 的反應瓶中加入二異丙基乙胺(50.88 mg, 393.66 µmol, 68.57 µL, 2 eq)，降溫至0°C後加入化合物002-3 (50.62 mg, 236.20 µmol, 1.2 eq)的四氫呋喃(0.5 mL)，保持0 °C攪拌5分鐘，體系中加入足量的飽和碳酸氫鈉水溶液(10 mL)將合併體系淬滅，加入乙酸乙酯(10 mL*4)萃取，收集有機相加入，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到粗品化合物009-10，可直接用於下一步反應。 LCMS: MS m/z: 704.6[M+1] +。 步驟10：化合物009-11的合成 向預先乾燥的單口瓶中加入化合物009-10(200 mg, 283.95 µmol, 1 eq)，四氫呋喃(4 mL)，乙酸(12 mL)，水(4 mL)，20 °C攪拌20分鐘。將合併體系加入飽和碳酸氫鈉水溶液調節pH值至8，乙酸乙酯(20 mL*3)萃取，收集有機相，加入無水硫酸鈉乾燥，過濾，濾液減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 100:0 – 0:100)，得到化合物009-11。 LCMS: MS m/z: 590.3[M+1] +。 步驟11：化合物009-12的合成 向預先乾燥的單口瓶中加入化合物009-11 (223 mg, 377.91 µmol, 1 eq)，001-15(88.39 mg, 566.86 µmol, 1.5 eq)，二㗁烷(4 mL)，水(1 mL)，磷酸鉀(160.43 mg, 755.82 µmol, 2 eq)，充分氮氣置換後加入[1,1-雙(二第三丁基膦)二茂鐵]二氯化鈀(24.63 mg, 37.79 µmol, 0.1 eq)，100 °C攪拌3小時。體系中加入飽和氯化鈉水溶液(10 mL)，乙酸乙酯(10 mL*3)萃取，收集有機相加入無水硫酸鈉乾燥，過濾，濾液減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 100:0 – 0:100)，得到化合物009-12。 LCMS: MS m/z: 666.6[M+1] +。 步驟12：化合物009-13的合成 向預先乾燥的單口瓶中加入化合物009-12(248 mg, 372.52 µmol, 1 eq)，二氯甲烷(5 mL)，正三丁基膦 (296.95 mg, 1.47 mmol, 3.94 eq)，1,1-偶氮二甲醯二哌啶(371.27 mg, 1.47 mmol, 3.95 eq)，20 °C攪拌18小時。加入水(10 mL)，二氯甲烷(10 mL*2)萃取，收集合併有機相，加入無水硫酸鈉乾燥，過濾，濾液加入矽膠(0.5 g)，減壓濃縮。粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 7:0 – 7:3)，得到化合物009-13。 LCMS: MS m/z: 648.4[M+1] +。 步驟13：化合物009-14的合成 向預先乾燥的單口瓶中加入化合物009-13(870 mg, 1.34 mmol, 1 eq)，二氯甲烷(8 mL)，三氟乙酸(3.06 g, 26.86 mmol, 1.99 mL, 20 eq)，20°C攪拌16小時。反應液中加入飽和碳酸氫鈉水溶液(10mL)將pH調至8，二氯甲烷(5 mL*3)萃取，收集有機相，加入無水硫酸鈉乾燥，過濾，濾液減壓濃縮，粗品用矽膠柱層析分離純化(石油醚：乙酸乙酯 = 1:1 – 0:1)，得到化合物009-14。 LCMS: MS m/z: 548.3[M+1] +。 步驟14：化合物009和010的合成 向預先乾燥的單口瓶中加入化合物009-14(100 mg, 182.62 µmol, 1 eq)，( E)-4-氟丁-2-烯酸(28.51 mg, 273.92 µmol, 1.5 eq)，二氯甲烷 (2.5 mL)，二異丙基乙胺(47.20 mg, 365.23 µmol, 63.62 µL, 2 eq)，降溫至0°C加入O-(7-氮雜苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦鹽(83.32 mg, 219.14 µmol, 1.2 eq)，加畢，轉移至20 °C攪拌1小時。向反應液中加入水(10 mL)，二氯甲烷(10 mL*3)萃取，收集有機相加入無水硫酸鈉乾燥過濾，濾液減壓濃縮。粗品透過薄層層析矽膠板純化(展開劑，二氯甲烷：甲醇 = 40:1)，得到化合物009和010。 化合物009：LCMS: MS m/z: 634.4 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 9.10 (s, 1H), 7.92 - 7.82 (m, 1H), 7.42 - 7.34 (m, 1H), 7.11 - 6.96 (m, 1H), 6.93 (d, J= 8.5 Hz, 1H), 6.83 (t, J= 8.7 Hz, 1H), 6.71 - 6.52 (m, 1H), 5.20 (br d, J= 9.1 Hz, 1H), 5.11 - 5.07 (m, 1H), 4.97 - 4.77 (m, 2H), 4.57 - 4.37 (m, 3H), 3.78 - 3.59 (m, 3H), 2.99 - 2.89 (m, 1H), 2.64 - 2.59 (m, 2H), 1.63 (br d, J= 6.8 Hz, 2H), 1.55 - 1.50 (m, 6H), 1.31 (dd, J= 2.5, 6.8 Hz, 3H), 1.07 (t, J= 6.8 Hz, 3H)。 SFC分析方法 (柱子：Chiralpak AD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.182 min，手性異構體過量93.9 %。 化合物010：LCMS: MS m/z: 634.4 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 9.10 (s, 1H), 7.85 - 7.76 (m, 1H), 7.43 - 7.34 (m, 1H), 7.07 - 6.98 (m, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.83 (t, J= 8.6 Hz, 1H), 6.66 - 6.52 (m, 1H), 5.20 (br d, J= 2.3 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.47 - 4.34 (m, 2H), 4.17 - 3.91 (m, 3H), 3.78 - 3.58 (m, 3H), 3.01 - 2.87 (m, 1H), 2.67 - 2.60 (m, 2H), 1.43 (d, J= 7.0 Hz, 2H), 1.40 - 1.33 (m, 3H), 1.31 (d, J= 6.6 Hz, 3H), 1.26 - 1.21 (m, 3H), 1.02 (d, J= 6.8 Hz, 3H)。 SFC分析方法 (柱子：Chiralpak AD-3, 50×4.6mm I.D., 3µm；流動相：A (CO 2) 和 B (EtOH，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 1800 psi，Rt=1.398 min，手性異構體過量98.62 %。 Example 7
Figure 02_image556
synthetic route:
Figure 02_image558
Figure 02_image560
Step 1: Synthesis of compound 009-2 Add compound 009-1 (20 g, 121.96 mmol, 1 eq ), potassium isopropenyl trifluoroborate 001-2 (21.66 g, 146.35 mmol, 1.2 eq ), sodium carbonate (38.78 g, 365.87 mmol, 3 eq ), dioxane (200 mL), water (50 mL), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (4.46 g , 6.10 mmol, 0.05 eq ) was fully replaced with nitrogen, and stirred at 100 °C for 5 hours. The reaction solution was concentrated under reduced pressure, methyl tertiary butyl ether (200 mL) was added, filtered, and the filter cake was fully rinsed with methyl tertiary butyl ether until no product remained. The filtrate was extracted with methyl tertiary butyl ether (200 mL*3), the combined organic phase was added to saturated aqueous sodium chloride solution (40 mL), the organic phase was separated, added to anhydrous sodium sulfate, dried and filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:0-4:1) to obtain compound 009-2. LCMS: MS m/z: 170.1 [M+H] + . Step 2: Synthesis of compound 009-3 Add compound 009-2 (5.15 g, 30.36 mmol, 1 eq ), 001-4 (9.01 g, 42.51 mmol, 1.4 eq ), dioxane ( 60 mL), water (15 mL), potassium phosphate (12.89 g, 60.73 mmol, 2 eq ), and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium dichloride was added for full nitrogen replacement ( 1.98 g, 3.04 mmol, 0.1 eq ), stirred at 100° C. for 12 hours. After the reaction solution was concentrated under reduced pressure, methyl tertiary butyl ether (60 mL) was added and stirred and filtered, the filter cake was rinsed with methyl tertiary butyl ether until no product remained, and the organic phase of the filtrate was collected and added to saturated brine ( 50 mL), separated the organic phase and added anhydrous sodium sulfate to dry and filter, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9:0-9:1) to obtain compound 009-3 . LCMS: MS m/z: 220.1 [M+H] + . Step 3: Synthesis of compound 009-4 After sufficient argon replacement, palladium/carbon (750 mg, 10% content), tetrahydrofuran (30 mL), compound 009-3 (3 g, 13.68 mmol, 1 eq ), stirred for 2 hours at 20 ° C under a hydrogen atmosphere of 15 psi. The combined system was filtered through diatomaceous earth, and the filter cake was fully rinsed with ethyl acetate (500 mL) until no product remained, and the collected filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:0-7:3) to obtain compound 009-4. LCMS: MS m/z: 224.2 [M+H]+. 1 H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1 H) 3.70 (s, 3 H) 3.02 (dt, J=13.52, 6.73 Hz, 1 H) 2.88 - 2.96 (m, 4 H) 1.30 ( d, J=6.78 Hz, 6H). Step 4: Synthesis of compound 009-5 Two batches of reactions were set up in parallel: Add lithium aluminum hydride (169.99 mg, 4.48 mmol, 2 eq ) and tetrahydrofuran (5 mL) to a pre-dried three-neck flask, cool to 0°C and add Compound 009-4 (500 mg, 2.24 mmol, 1 eq ) was dissolved in tetrahydrofuran (1 mL). After the addition was completed, it was naturally warmed to 20°C and stirred for 1 hour. Add water (0.17 mL), 15% aqueous sodium hydroxide solution (0.17 mL), and water (0.51 mL) to the two reactions respectively, add anhydrous sodium sulfate to dry, stir and filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography Purification (petroleum ether: ethyl acetate = 1:0 - 1:1) gave compound 009-5. LCMS: MS m/z: 196.2 [M+H] + . Step 5: Synthesis of compound 009-6 Add compound 009-5 (323 mg, 1.65 mmol, 1 eq ), dichloromethane (4 mL), imidazole (337.84 mg, 4.96 mmol, 3 eq ), cooled to 0 °C and added tertiary butyldimethylchlorosilane (498.65 mg, 3.31 mmol, 405.40 µL, 2 eq ) in dichloromethane (1 mL) solution, after addition, immediately transferred to 20 °C, Stir for 2 hours. Add water (15 mL), extract with dichloromethane (10 mL*3), collect and combine organic phases, add anhydrous sodium sulfate, dry and filter, concentrate under reduced pressure, and separate and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 4 :0-4:1), to obtain compound 009-6. LCMS: MS m/z: 310.2 [M+H] + . Step 6: Synthesis of compound 009-7 Add 001-9 (345 mg, 1.65 mmol, 1 eq ), dichloromethane (4 mL), oxalyl chloride (419.04 mg, 3.30 mmol, 288.99 µL, 2 eq ), stirred at 45 °C for 4 hours. The two batches of reaction solution were concentrated to dryness under reduced pressure to obtain an isocyanate active intermediate compound, which was directly carried out to the next step. Nitrogen replacement was carried out in the reaction flask pre-installed with the above-mentioned isocyanate-reactive intermediate compound, dichloromethane (1 mL) was added under nitrogen atmosphere, the temperature was lowered to 0°C, and compound 009-6 (357.65 mg, 1.16 mmol, 0.7 eq ) was added Dichloromethane (1 mL) solution was naturally warmed to 20 °C and stirred for 1 hour. Immediately add saturated sodium bicarbonate aqueous solution (20 mL) to the reaction solution to quench, stir well at 20 °C, extract with dichloromethane (10 mL*3), collect the organic phase, add anhydrous sodium sulfate to dry, After filtration, the filtrate was concentrated under reduced pressure to obtain crude compound 009-7. LCMS: MS m/z: 545.9 [M+1] + . Step 7: Synthesis of compound 009-8 Add compound 009-7 (500 mg, 918.24 μmol, 1 eq ), tetrahydrofuran (10 mL) to a pre-dried single-necked bottle, add bis(trimethyl Si) Amide potassium tetrahydrofuran solution (1 M, 1.84 mL, 2 eq ), after the addition was completed, the mixture was removed from the ice bath and stirred at 20 °C for 1 hour. Add saturated ammonium chloride aqueous solution (30 mL) to the system, add ethyl acetate (20 mL*3) for extraction, collect and combine the organic phases, add anhydrous sodium sulfate to dry and filter, the filtrate is concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography Purification (petroleum ether: ethyl acetate = 7:0 - 7:3) gave compound 009-8. LCMS: MS m/z: 508.2 [M+H] + . Step 8: Synthesis of compound 009-9 Add compound 009-8 (100 mg, 196.83 µmol, 1 eq ), tetrahydrofuran (1.2 mL), diisopropylethylamine (76.32 mg, 590.48 µmol , 102.85 µL, 3 eq ), phosphorus oxychloride (69.41 mg, 452.70 µmol, 42.07 µL, 2.3 eq ), stirred at 45 °C for 2 hours to obtain compound 009-9, and the reaction solution was directly used in the next step. Step 9: Synthesis of Compound 009-10 Add diisopropylethylamine (50.88 mg, 393.66 µmol, 68.57 µL, 2 eq ), added compound 002-3 (50.62 mg, 236.20 μmol, 1.2 eq) in tetrahydrofuran (0.5 mL) after cooling to 0 ° C, kept stirring at 0 ° C for 5 minutes, and added a sufficient amount of saturated aqueous sodium bicarbonate ( 10 mL) to quench the combined system, add ethyl acetate (10 mL*4) for extraction, collect the organic phase and add, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude compound 009-10, which can be directly used in the following One step reaction. LCMS: MS m/z: 704.6 [M+1] + . Step 10: Synthesis of compound 009-11 Add compound 009-10 (200 mg, 283.95 µmol, 1 eq ), tetrahydrofuran (4 mL), acetic acid (12 mL), water (4 mL) to a pre-dried single-necked vial, Stir at 20°C for 20 minutes. Add saturated aqueous sodium bicarbonate solution to the combined system to adjust the pH to 8, extract with ethyl acetate (20 mL*3), collect the organic phase, add anhydrous sodium sulfate to dry, filter, concentrate the filtrate under reduced pressure, and separate the crude product by silica gel column chromatography Purification (petroleum ether: ethyl acetate = 100:0 - 0:100) gave compound 009-11. LCMS: MS m/z: 590.3 [M+1] + . Step 11: Synthesis of compound 009-12 Add compound 009-11 (223 mg, 377.91 µmol, 1 eq ), 001-15 (88.39 mg, 566.86 µmol, 1.5 eq ), dioxane ( 4 mL), water (1 mL), potassium phosphate (160.43 mg, 755.82 µmol, 2 eq ), and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium dichloride was added after full nitrogen replacement (24.63 mg, 37.79 µmol, 0.1 eq ), stirred at 100 °C for 3 hours. Add saturated sodium chloride aqueous solution (10 mL) to the system, extract with ethyl acetate (10 mL*3), collect the organic phase and add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum Ether: ethyl acetate = 100:0 - 0:100), yielding compound 009-12. LCMS: MS m/z: 666.6[M+1] + . Step 12: Synthesis of compound 009-13 Add compound 009-12 (248 mg, 372.52 µmol, 1 eq ), dichloromethane (5 mL), n-tributylphosphine (296.95 mg, 1.47 mmol , 3.94 eq ), 1,1-azobisacyldipiperidine (371.27 mg, 1.47 mmol, 3.95 eq ), stirred at 20 °C for 18 hours. Add water (10 mL), extract with dichloromethane (10 mL*2), collect and combine organic phases, add anhydrous sodium sulfate to dry, filter, add silica gel (0.5 g) to the filtrate, and concentrate under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:0-7:3) to obtain compound 009-13. LCMS: MS m/z: 648.4[M+1] + . Step 13: Synthesis of compound 009-14 Add compound 009-13 (870 mg, 1.34 mmol, 1 eq ), dichloromethane (8 mL), trifluoroacetic acid (3.06 g, 26.86 mmol, 1.99 mL, 20 eq ), stirred at 20°C for 16 hours. Add saturated aqueous sodium bicarbonate solution (10 mL) to the reaction solution to adjust the pH to 8, extract with dichloromethane (5 mL*3), collect the organic phase, add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure. Chromatographic separation and purification (petroleum ether: ethyl acetate = 1:1 - 0:1) gave compound 009-14. LCMS: MS m/z: 548.3 [M+1] + . Step 14: Synthesis of compounds 009 and 010 Add compound 009-14 (100 mg, 182.62 µmol, 1 eq ), ( E )-4-fluorobut-2-enoic acid (28.51 mg, 273.92 µmol, 1.5 eq ), dichloromethane (2.5 mL), diisopropylethylamine (47.20 mg, 365.23 µmol, 63.62 µL, 2 eq ), cooled to 0°C and added O-(7-azabenzotri Azolazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (83.32 mg, 219.14 µmol, 1.2 eq ), after addition, transferred to 20 °C and stirred for 1 hour. Water (10 mL) was added to the reaction solution, dichloromethane (10 mL*3) was extracted, the organic phase was collected, added to anhydrous sodium sulfate, dried and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on a silica gel plate (developing solvent, dichloromethane: methanol = 40:1) to obtain compounds 009 and 010. Compound 009: LCMS: MS m/z: 634.4 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 9.10 (s, 1H), 7.92 - 7.82 (m, 1H), 7.42 - 7.34 (m, 1H), 7.11 - 6.96 (m, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 8.7 Hz, 1H), 6.71 - 6.52 (m, 1H), 5.20 (br d, J = 9.1 Hz, 1H), 5.11 - 5.07 (m, 1H) , 4.97 - 4.77 (m, 2H), 4.57 - 4.37 (m, 3H), 3.78 - 3.59 (m, 3H), 2.99 - 2.89 (m, 1H), 2.64 - 2.59 (m, 2H), 1.63 (br d , J = 6.8 Hz, 2H), 1.55 - 1.50 (m, 6H), 1.31 (dd, J = 2.5, 6.8 Hz, 3H), 1.07 (t, J = 6.8 Hz, 3H). SFC analysis method (column: Chiralpak AD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50%, 3 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.182 min, chiral isomer excess 93.9 %. Compound 010: LCMS: MS m/z: 634.4 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 9.10 (s, 1H), 7.85 - 7.76 (m, 1H), 7.43 - 7.34 (m, 1H), 7.07 - 6.98 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.83 (t, J = 8.6 Hz, 1H), 6.66 - 6.52 (m, 1H), 5.20 (br d, J = 2.3 Hz, 1H), 5.11 - 5.06 (m, 1H) , 4.47 - 4.34 (m, 2H), 4.17 - 3.91 (m, 3H), 3.78 - 3.58 (m, 3H), 3.01 - 2.87 (m, 1H), 2.67 - 2.60 (m, 2H), 1.43 (d, J = 7.0 Hz, 2H), 1.40 - 1.33 (m, 3H), 1.31 (d, J = 6.6 Hz, 3H), 1.26 - 1.21 (m, 3H), 1.02 (d, J = 6.8 Hz, 3H). SFC analysis method (column: Chiralpak AD-3, 50×4.6mm ID, 3µm; mobile phase: A (CO 2 ) and B (EtOH, containing 0.1% isopropylamine); gradient: B%=5~50%, 3 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 1800 psi, Rt=1.398 min, chiral isomer excess 98.62%.

實施例8

Figure 02_image562
合成路線：
Figure 02_image564
步驟1：化合物011-1的合成 氮氣保護，將化合物007-6(1.8 g, 2.75 mmol, 1 eq)溶於四氫呋喃(27 mL)，加入N,N-二異丙基乙胺(1.07 g, 8.24 mmol, 1.44 mL, 3 eq)，然後加入氧氯化磷(1.05 g, 6.87 mmol, 638.21 µL, 2.5 eq)，40°C反應3小時。得到化合物011-1，該反應體系直接用於下一步。 步驟2：化合物011-3的合成 氮氣保護，0°C下，將化合物011-1 (1.8 g, 2.67 mmol, 1 eq)溶於四氫呋喃(26 mL)，加入N,N-二異丙基乙胺(1.38 g, 10.68 mmol, 1.86 mL, 4 eq)，然後加入化合物011-2 (646.94 mg, 3.47 mmol, 1.3 eq)，升溫至20 °C反應1小時。補加化合物011-2 (248.64 mg, 1.34 mmol, 0.5 eq)，20°C反應1小時。將反應體系加入到水(50 mL)中，水相使用乙酸乙酯(50 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(60 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(二氯甲烷：甲醇=200:1~30:1)分離純化，得到化合物011-3。 LCMS: MS m/z: 823.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.62 (d, J= 5.2 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.56 - 7.51 (m, 4H), 7.43 - 7.32 (m, 6H), 7.14 (d, J= 5.2 Hz, 1H), 3.66 - 3.62 (m, 4H), 3.49 - 3.43 (m, 4H), 3.23 - 3.18 (m, 2H), 2.50 - 2.43 (m, 1H), 2.42 - 2.35 (m, 2H), 1.81 - 1.66 (m, 2H), 1.52 (s, 9H), 1.21 (d, J= 6.8 Hz, 3H), 1.06 (d, J= 6.4 Hz, 3H), 0.94 (s, 9H)。 步驟3：化合物011-4的合成 氮氣保護，將化合物011-3 (1.92 g, 2.33 mmol, 1 eq)和化合物001-15 (727.08 mg, 4.66 mmol, 2 eq)溶於1,4-二㗁烷(40 mL)和水(4 mL)，加入碳酸鈉(741.38 mg, 6.99 mmol, 3 eq)和四(三苯基膦)鈀(269.43 mg, 233.16 µmol, 0.1 eq)，80°C反應1小時。向反應體系中加入水(50 mL)，水相使用乙酸乙酯(60 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(60 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(石油醚：乙酸乙酯=20:1~1:1)分離純化，得到化合物011-4。 LCMS: MS m/z: 899.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 9.22 (s, 1H), 8.69 (d, J= 5.2 Hz, 1H), 7.86 (d, J= 9.6 Hz, 1H), 7.54 (t, J= 1.2 Hz, 1H), 7.52 (d, J= 1.2 Hz, 2H), 7.50 (d, J= 1.6 Hz, 1H), 7.40 (d, J= 3.2 Hz, 1H), 7.38 - 7.29 (m, 6H), 7.21 (d, J= 5.2 Hz, 1H), 6.72 - 6.68 (m, 2H), 3.69 (d, J= 3.6 Hz, 4H), 3.65 - 3.59 (m, 6H), 2.64 - 2.57 (m, 1H), 2.44 - 2.40 (m, 2H), 1.85 - 1.77 (m, 1H), 1.71 - 1.67 (m, 1H), 1.53 (s, 9H), 1.23 (d, J= 6.8 Hz, 3H), 1.02 (d, J= 6.4 Hz, 3H), 0.91 (s, 9H)。 步驟4：化合物011-5的合成 氮氣保護，將化合物011-4(1.6 g, 1.78 mmol, 1 eq)溶於四氫呋喃(48 mL)，加入四甲基氟化銨(5.80 g, 62.28 mmol, 35 eq)，20°C反應23小時。向反應體系中加入水(40 mL)，水相使用乙酸乙酯(50 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(50 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物011-5，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 661.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.71 (d, J= 5.2 Hz, 1H), 7.97 (d, J= 9.6 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.31 (d, J= 7.2 Hz, 1H), 7.26 - 7.24 (m, 1H), 6.70 - 6.65 (m, 2H), 3.80 (s, 8H), 3.53 (t, J= 5.6 Hz, 2H), 3.36 - 3.26 (m, 1H), 2.65 - 2.59 (m, 1H), 2.41 (t, J= 7.6 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.53 (s, 9H), 1.23 (d, J= 6.4 Hz, 3H), 1.03 (d, J= 6.8 Hz, 3H)。 步驟5：化合物011-6的合成 氮氣保護，將化合物011-5(1.6 g, 2.42 mmol, 1 eq)溶於四氫呋喃(96 mL)，加入三苯基膦(2.22 g, 8.48 mmol, 3.5 eq)，20°C加入偶氮二甲酸二乙酯(1.48 g, 8.48 mmol, 1.54 mL, 3.5 eq)，20°C反應1小時。向反應體系中加入水(20 mL)，水相使用乙酸乙酯(30 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(20 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過柱層析(石油醚：乙酸乙酯=25:1~1:4)分離純化，分別得到化合物011-6。 LCMS: MS m/z: 643.1 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.58 (d, J= 5.2 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.11 (d, J= 5.2 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 3.95 - 3.88 (m, 2H), 3.85 - 3.79 (m, 3H), 3.77 - 3.60 (m, 5H), 2.81 - 2.74 (m, 1H), 2.58 - 2.51 (m, 1H), 2.46 - 2.38 (m, 1H), 2.28 - 2.11 (m, 2H), 1.53 (s, 9H), 1.31 (d, J= 6.8 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H)。 步驟6：化合物011-7的合成 氮氣保護，將化合物011-6 (0.5 g, 777.98 µmol, 1 eq)溶於二氯甲烷 (15 mL)，加入三氟乙酸(3.55 g, 31.12 mmol, 2.30 mL, 40 eq)，20°C反應1小時。將反應體系直接減壓濃縮得到化合物011-7，無需純化，可直接用於下一步反應。 LCMS: MS m/z: 543.2 [M+1] +。 步驟7：化合物011和012的合成 氮氣保護，將化合物011-7 (0.96 g, 692.47 µmol, 1 eq)溶於二氯甲烷(24 mL)，加入N,N-二異丙基乙胺(1.34 g, 10.39 mmol, 1.81 mL, 15 eq)，然後加入丙烯醯氯(125.35 mg, 1.38 mmol, 112.93 µL, 2 eq)，-60°C反應10分鐘。向反應體系中加入飽和碳酸氫鈉溶液(20 mL)，分液。水相使用二氯甲烷(50 mL*3)萃取，分液。合併有機相，使用飽和食鹽水(50 mL)清洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到粗產品。粗產品透過高效液相色譜分離(色譜柱: Waters Xbridge BEH C18 250*50mm*10µm；流動相:A(乙腈) 和B(水，含10mM碳酸氫銨)；梯度：B%: 35%-55%，10 min)，再透過SFC(柱子：DAICEL CHIRALPAK AD(250mm*30mm,10µm)；流動相：A (CO 2) 和B (異丙醇，含0.1%氨水)；梯度：B%=35%-35%，10min)拆分，純化得到化合物011和化合物012。 化合物011: LCMS: MS m/z: 597.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.58 (d, J= 5.2 Hz, 1H), 7.89 (d, J= 8.8 Hz, 1H), 7.36 (q, J= 8.4 Hz, 1H), 7.12 (d, J= 5.2 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 6.64 (dd, J= 16.8, 10.4 Hz, 1H), 6.40 (dd, J= 16.8, 1.2 Hz, 1H), 5.83 (dd, J= 10.4, 1.2 Hz, 1H), 4.37 (d, J= 8.4 Hz, 1H), 4.07 - 3.78 (m, 6H), 3.75 - 3.66 (m, 2H), 3.65 - 3.59 (m, 1H), 2.80 - 2.73 (m, 1H), 2.60 - 2.50 (m, 1H), 2.45 - 2.34 (m, 1H), 2.28 - 2.11 (m, 2H), 1.30 (d, J= 6.8 Hz, 3H), 0.96 (d, J= 6.4 Hz, 3H)。 SFC 分析(柱子：Chiralpak AD-3，3 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (IPA，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.383 min，手性異構體過量100%。 化合物012: LCMS: MS m/z: 597.2 [M+1] +。 1H NMR (400 MHz, CDCl 3) δ = 8.58 (d, J= 4.8Hz, 1H), 7.89 (d, J= 8.8 Hz, 1H), 7.36 (q, J= 8.0 Hz, 1H), 7.12 (d, J= 5.2 Hz, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.82 (t, J= 8.8 Hz, 1H), 6.64 (dd, J= 16.8, 10.4 Hz, 1H), 6.40 (dd, J= 16.4, 1.2 Hz, 1H), 5.83 (dd, J= 10.8, 1.6 Hz, 1H), 4.36 (d, J= 8.4 Hz, 1H), 4.10 - 3.79 (m, 6H), 3.76 - 3.67 (m, 2H), 3.65 - 3.57 (m, 1H), 2.82 - 2.73 (m, 1H), 2.60 - 2.50 (m, 1H), 2.45 - 2.37 (m, 1H), 2.28 - 2.11 (m, 2H), 1.30 (d, J= 6.8 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H)。 SFC分析(柱子：Chiralpak AD-3，3 µm，0.46 cm id × 5cm L；流動相：A (CO 2) 和 B (IPA，含0.1%異丙胺)；梯度：B%=5~50%，3 min；流速: 3.4 mL/min；波長: 220nm；壓力: 124 bar，Rt=1.562 min，手性異構體過量96.28%。 Example 8
Figure 02_image562
synthetic route:
Figure 02_image564
Step 1: Synthesis of compound 011-1 under nitrogen protection, compound 007-6 (1.8 g, 2.75 mmol, 1 eq ) was dissolved in tetrahydrofuran (27 mL), and N,N-diisopropylethylamine (1.07 g, 8.24 mmol, 1.44 mL, 3 eq ), then added phosphorus oxychloride (1.05 g, 6.87 mmol, 638.21 µL, 2.5 eq ), and reacted at 40°C for 3 hours. Compound 011-1 was obtained, and the reaction system was directly used in the next step. Step 2: Synthesis of compound 011-3 under nitrogen protection, at 0°C, dissolve compound 011-1 (1.8 g, 2.67 mmol, 1 eq ) in tetrahydrofuran (26 mL), add N,N-diisopropylethyl Amine (1.38 g, 10.68 mmol, 1.86 mL, 4 eq ), then compound 011-2 (646.94 mg, 3.47 mmol, 1.3 eq ) was added, and the temperature was raised to 20 °C for 1 hour. Compound 011-2 (248.64 mg, 1.34 mmol, 0.5 eq ) was added and reacted at 20°C for 1 hour. The reaction system was added into water (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol=200:1~30:1) to obtain compound 011-3. LCMS: MS m/z: 823.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.62 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 - 7.51 (m, 4H), 7.43 - 7.32 (m , 6H), 7.14 (d, J = 5.2 Hz, 1H), 3.66 - 3.62 (m, 4H), 3.49 - 3.43 (m, 4H), 3.23 - 3.18 (m, 2H), 2.50 - 2.43 (m, 1H ), 2.42 - 2.35 (m, 2H), 1.81 - 1.66 (m, 2H), 1.52 (s, 9H), 1.21 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H) , 0.94 (s, 9H). Step 3: Synthesis of compound 011-4 under nitrogen protection, compound 011-3 (1.92 g, 2.33 mmol, 1 eq ) and compound 001-15 (727.08 mg, 4.66 mmol, 2 eq ) were dissolved in 1,4-bis Alkanes (40 mL) and water (4 mL), add sodium carbonate (741.38 mg, 6.99 mmol, 3 eq ) and tetrakis (triphenylphosphine) palladium (269.43 mg, 233.16 µmol, 0.1 eq ), 80 ° C reaction 1 Hour. Water (50 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (60 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1~1:1) to obtain compound 011-4. LCMS: MS m/z: 899.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 9.22 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.54 (t, J = 1.2 Hz, 1H), 7.52 (d, J = 1.2 Hz, 2H), 7.50 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 3.2 Hz, 1H), 7.38 - 7.29 (m, 6H), 7.21 (d, J = 5.2 Hz, 1H), 6.72 - 6.68 (m, 2H), 3.69 (d, J = 3.6 Hz, 4H), 3.65 - 3.59 (m, 6H), 2.64 - 2.57 (m, 1H) , 2.44 - 2.40 (m, 2H), 1.85 - 1.77 (m, 1H), 1.71 - 1.67 (m, 1H), 1.53 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.02 (d , J = 6.4 Hz, 3H), 0.91 (s, 9H). Step 4: Synthesis of compound 011-5 under nitrogen protection, compound 011-4 (1.6 g, 1.78 mmol, 1 eq ) was dissolved in tetrahydrofuran (48 mL), and tetramethylammonium fluoride (5.80 g, 62.28 mmol, 35 eq ), 20 DEG C of reaction 23 hours. Water (40 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 011-5, which was directly used in the next reaction without further purification. LCMS: MS m/z: 661.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.71 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.26 - 7.24 (m, 1H), 6.70 - 6.65 (m, 2H), 3.80 (s, 8H), 3.53 (t, J = 5.6 Hz, 2H), 3.36 - 3.26 (m, 1H), 2.65 - 2.59 (m, 1H), 2.41 (t, J = 7.6 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.53 (s, 9H), 1.23 (d, J = 6.4 Hz, 3H ), 1.03 (d, J = 6.8 Hz, 3H). Step 5: Synthesis of compound 011-6 Nitrogen protection, compound 011-5 (1.6 g, 2.42 mmol, 1 eq ) was dissolved in tetrahydrofuran (96 mL), and triphenylphosphine (2.22 g, 8.48 mmol, 3.5 eq ) was added , diethyl azodicarboxylate (1.48 g, 8.48 mmol, 1.54 mL, 3.5 eq ) was added at 20°C, and reacted at 20°C for 1 hour. Water (20 mL) was added to the reaction system, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 25:1~1:4) to obtain compound 011-6 respectively. LCMS: MS m/z: 643.1 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.58 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.11 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 3.95 - 3.88 (m, 2H), 3.85 - 3.79 (m, 3H), 3.77 - 3.60 (m, 5H), 2.81 - 2.74 (m, 1H), 2.58 - 2.51 (m, 1H), 2.46 - 2.38 (m, 1H), 2.28 - 2.11 (m, 2H), 1.53 (s, 9H) , 1.31 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). Step 6: Synthesis of compound 011-7 under nitrogen protection, compound 011-6 (0.5 g, 777.98 µmol, 1 eq ) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3.55 g, 31.12 mmol, 2.30 mL , 40 eq ), react at 20°C for 1 hour. The reaction system was directly concentrated under reduced pressure to obtain compound 011-7, which can be directly used in the next reaction without purification. LCMS: MS m/z: 543.2 [M+1] + . Step 7: Synthesis of compounds 011 and 012 under nitrogen protection, compound 011-7 (0.96 g, 692.47 µmol, 1 eq ) was dissolved in dichloromethane (24 mL), and N,N-diisopropylethylamine (1.34 g, 10.39 mmol, 1.81 mL, 15 eq ), then added acryloyl chloride (125.35 mg, 1.38 mmol, 112.93 µL, 2 eq ), and reacted at -60°C for 10 minutes. Add saturated sodium bicarbonate solution (20 mL) to the reaction system, and separate the layers. The aqueous phase was extracted with dichloromethane (50 mL*3), and the layers were separated. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column: Waters Xbridge BEH C18 250*50mm*10µm; mobile phase: A (acetonitrile) and B (water, containing 10mM ammonium bicarbonate); gradient: B%: 35%-55 %, 10 min), and then passed through SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10µm); mobile phase: A (CO 2 ) and B (isopropanol, containing 0.1% ammonia); gradient: B%=35 %-35%, 10min) resolution, purification to obtain compound 011 and compound 012. Compound 011: LCMS: MS m/z: 597.2 [M+1] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.58 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.36 (q, J = 8.4 Hz, 1H), 7.12 ( d, J = 5.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 6.64 (dd, J = 16.8, 10.4 Hz, 1H), 6.40 ( dd, J = 16.8, 1.2 Hz, 1H), 5.83 (dd, J = 10.4, 1.2 Hz, 1H), 4.37 (d, J = 8.4 Hz, 1H), 4.07 - 3.78 (m, 6H), 3.75 - 3.66 (m, 2H), 3.65 - 3.59 (m, 1H), 2.80 - 2.73 (m, 1H), 2.60 - 2.50 (m, 1H), 2.45 - 2.34 (m, 1H), 2.28 - 2.11 (m, 2H) , 1.30 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H). SFC analysis (column: Chiralpak AD-3, 3 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (IPA, containing 0.1% isopropylamine); gradient: B%=5~50%, 3 min; flow rate: 3.4 mL/min; wavelength: 220nm; pressure: 124 bar, Rt=1.383 min, chiral isomer excess 100%. Compound 012: LCMS: MS m/z: 597.2 [M+1] + .1 H NMR (400 MHz, CDCl 3 ) δ = 8.58 (d, J = 4.8Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.36 (q, J = 8.0 Hz, 1H), 7.12 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 8.8 Hz, 1H), 6.64 (dd, J = 16.8, 10.4 Hz, 1H), 6.40 (dd, J = 16.4, 1.2 Hz, 1H), 5.83 (dd, J = 10.8, 1.6 Hz, 1H), 4.36 (d, J = 8.4 Hz, 1H), 4.10 - 3.79 (m, 6H), 3.76 - 3.67 (m, 2H), 3.65 - 3.57 (m, 1H), 2.82 - 2.73 (m, 1H), 2.60 - 2.50 (m, 1H), 2.45 - 2.37 (m, 1H), 2.28 - 2.11 (m, 2H ), 1.30 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). SFC analysis (column: Chiralpak AD-3, 3 µm, 0.46 cm id × 5cm L; mobile phase: A (CO 2 ) and B (IPA, containing 0.1% isopropylamine); Gradient: B%=5~50%, 3 min; Flow rate: 3.4 mL/min; Wavelength: 220nm; Pressure: 124 bar, Rt=1.562 min, Chiral isomer excess 96.28%.

測試例1：MIA-PA-CA-2細胞實驗 實驗材料： DMEM培養基，胎牛血清購自Biosera，馬血清購自Gibco。CellTiter-Glo(細胞活率化學發光檢測試劑)試劑購自Promega。MIA-PA-CA-2細胞系購南京科佰生物科技有限公司。EnVision多標記分析儀(PerkinElmer)。 實驗方法： 將MIA-PA-CA-2細胞種於白色96孔板中，80μL細胞懸液每孔，其中包含1000個MIA-PA-CA-2細胞。細胞板置於二氧化碳培養箱中過夜培養。 將待測化合物用排槍進行5倍稀釋至第8個濃度，即從2mM稀釋至26nM，設置雙複孔實驗。向中間板中加入78 μL培養基，再按照對應位置，轉移2 μL每孔的梯度稀釋化合物至中間板，混勻後轉移20μL每孔到細胞板中。轉移到細胞板中的化合物濃度範圍是10μM至0.13 nM。細胞板置於二氧化碳培養箱中培養3天。另準備一塊細胞板，在加藥當天讀取訊號值作為最大值(下面方程式中Max值)參與數據分析。向此細胞板每孔加入50 μL細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光訊號穩定。採用多標記分析儀讀數。 數據分析： 利用方程式(樣品-最小值)/(最大值-最小值)*100%將原始數據換算成抑制率，IC 50的值即可透過四參數進行曲線擬合得出(GraphPad Prism軟體中"log(抑制劑)/響應 -- 變量作用域" 模式得出)。表1提供了本發明的化合物對MIA-PA-CA-2細胞增殖的抑制活性。 表1. 本發明受試化合物體外篩選試驗結果 化合物 MIA-PA-CA-2 IC 50(nM) 001 19 002 17 005 1.1 006 0.5 009 24 012 18 結論：本發明化合物對MIA-PA-CA-2細胞增殖展現出較好的抑制活性。 Test Example 1: MIA-PA-CA-2 cell experiment Experimental materials: DMEM medium, fetal bovine serum was purchased from Biosera, and horse serum was purchased from Gibco. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. MIA-PA-CA-2 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. EnVision Multilabel Analyzer (PerkinElmer). Experimental method: MIA-PA-CA-2 cells were planted in a white 96-well plate, 80 μL of cell suspension per well, which contained 1000 MIA-PA-CA-2 cells. Cell plates were cultured overnight in a carbon dioxide incubator. The compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, diluted from 2mM to 26nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 20 μL of each well to the cell plate after mixing. The concentration of compounds transferred to the cell plate ranged from 10 μM to 0.13 nM. Cell plates were cultured in a carbon dioxide incubator for 3 days. Prepare another cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis. Add 50 μL of cell viability chemiluminescent detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read using a multi-label analyzer. Data analysis: Use the equation (sample-minimum value)/(maximum-minimum value)*100% to convert the original data into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (in the GraphPad Prism software "log(inhibitor)/response--variable scope" mode derived). Table 1 provides the inhibitory activity of the compounds of the present invention on the proliferation of MIA-PA-CA-2 cells. Table 1. In vitro screening test results of test compounds of the present invention compound MIA-PA-CA-2 IC 50 (nM) 001 19 002 17 005 1.1 006 0.5 009 twenty four 012 18 Conclusion: the compound of the present invention exhibits better inhibitory activity on the proliferation of MIA-PA-CA-2 cells.

測試例2：體內藥代動力學研究 實驗目的：SD小鼠口服及靜脈注射受試化合物的藥代動力學研究 實驗操作：受試化合物與10%二甲基亞碸/60%聚乙二醇400/30%水溶液混合，渦旋並超聲，製備得到1 mg/mL澄清溶液，微孔濾膜過濾後備用。選取7至10周齡的雄性SD小鼠，靜脈注射給予候選化合物溶液，劑量約2 mg/kg。口服給予候選化合物溶液，劑量約10 mg/kg。收集一定時間的全血，製備得到血漿，以LC-MS/MS方法分析藥物濃度，並用Phoenix WinNonlin 軟體(美國Pharsight公司)計算藥代參數。 實驗結果如表2所示： 表2. 受試化合物的藥代動力學結果 給藥途徑 藥代動力學參數 化合物002 化合物009 靜脈注射給藥 劑量 Dose(mg/kg) 2.4 2.0 半衰期 T 1/2(h) 0.58 0.9 清除率 CL (ml/min/kg) 13.9 20.4 表觀分佈容積 Vd ss(L/kg) 0.58 1.3 血漿濃度-時間曲線下面積 AUC 0-last(nM.h) 3796 2582 口服給藥 劑量 Dose(mg/kg) 12 10 達峰時間 T max(h) 0.33 0.4 達峰濃度 C max(nM) 16833 4200 血漿濃度-時間曲線下面積 AUC 0-last(nM.h) 27573 10651 生物利用度 F (%) 147 83.7 結果結論： 本發明化合物口服給藥後有優異的系統總暴露量、達峰濃度和生物利用度，展現優異的藥代動力學特性。 Test Example 2: In Vivo Pharmacokinetic Study Experiment Purpose: Pharmacokinetic study of SD mice orally and intravenously injected test compound Experimental operation: test compound with 10% dimethyl sulfide/60% polyethylene glycol 400/30% aqueous solution was mixed, vortexed and sonicated to prepare a 1 mg/mL clear solution, which was filtered through a microporous membrane and used for later use. Male SD mice aged 7 to 10 weeks were selected, and the candidate compound solution was administered intravenously at a dose of about 2 mg/kg. The candidate compound solution was orally administered at a dose of about 10 mg/kg. Whole blood was collected for a certain period of time to prepare plasma, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 2: Table 2. Pharmacokinetic results of test compounds Route of administration Pharmacokinetic parameters Compound 002 Compound 009 intravenous administration Dose(mg/kg) 2.4 2.0 Half-life T 1/2 (h) 0.58 0.9 Clearance CL (ml/min/kg) 13.9 20.4 Apparent volume of distribution Vd ss (L/kg) 0.58 1.3 Area under the plasma concentration-time curve AUC 0-last (nM.h) 3796 2582 Oral administration Dose(mg/kg) 12 10 Peak time T max (h) 0.33 0.4 Peak concentration C max (nM) 16833 4200 Area under the plasma concentration-time curve AUC 0-last (nM.h) 27573 10651 Bioavailability F (%) 147 83.7 Results and conclusions: After oral administration, the compound of the present invention has excellent systemic total exposure, peak concentration and bioavailability, and exhibits excellent pharmacokinetic properties.

測試例3：血漿穩定性研究 實驗目的：評定受試化合物分別在CD-1小鼠、SD大鼠、米格魯犬、食蟹猴、人的血漿穩定性 實驗操作：將凍存的血漿解凍10~20分鐘，待血漿完全解凍後，將其置於離心機中以3220×g離心5分鐘，去除其中存在的懸浮物和沉澱物。準備96孔孵育板，分別命名為T0、T10、T30、T60、T120。將孵育板中對應的加入98 μL的小鼠、大鼠、犬、猴和人空白血漿，然後加入2 μL化合物或對照化合物的工作液加入到對應的孵育板中，每個樣品準備兩個平行孔。所有的樣品在37˚C水浴鍋中進行孵育。化合物和對照化合物比沙可啶、馬來酸依那普利、普魯卡因和普魯本辛的最終孵育濃度為2 μM，最終有機相含量為2.0%。每一個孵育時間點結束時，取出相應的孵育板，向每個對應的樣品孔中加入400 μL含有200 ng/mL甲苯磺丁脲和拉貝諾爾的乙腈溶液沉澱蛋白。所有樣品板封膜並搖勻後，3220×g離心20 分鐘。取50 µL上清液加入100 µL超純水稀釋，所有樣品混勻後用LC/MS/MS的方法分析。實驗結果如表3所示。 表3. 受試化合物CD-1小鼠、SD大鼠、米格魯犬、食蟹猴和人的血漿穩定性 化合物 種屬 120min下受試化合物含量檢測 002 CD-1小鼠 92.8 % SD大鼠 87.2 % 米格魯犬 78.9 % 食蟹猴 82.2 % 人 79.4 % 009 CD-1小鼠 86.3 % SD大鼠 100.3 % 米格魯犬 93.6 % 食蟹猴 84.5 % 人 87.7 % 實驗結論：本發明化合物在CD-1小鼠、SD大鼠、米格魯犬、食蟹猴和人血漿中的穩定性良好。 Test Example 3: Plasma stability study Experiment purpose: To evaluate the plasma stability of the test compound in CD-1 mice, SD rats, Beagle dogs, cynomolgus monkeys, and humans Experimental operation: Thaw the frozen plasma After 10-20 minutes, after the plasma is completely thawed, place it in a centrifuge and centrifuge at 3220×g for 5 minutes to remove the suspended solids and sediments present therein. Prepare 96-well incubation plates and name them T0, T10, T30, T60, T120 respectively. Add 98 μL of mouse, rat, dog, monkey and human blank plasma to the corresponding incubation plate, and then add 2 μL of compound or control compound working solution to the corresponding incubation plate, prepare two parallels for each sample hole. All samples were incubated in a 37˚C water bath. Compounds and control compounds bisacodyl, enalapril maleate, procaine and propensine were incubated at a final concentration of 2 μM and a final organic phase content of 2.0%. At the end of each incubation time point, the corresponding incubation plate was taken out, and 400 μL of acetonitrile solution containing 200 ng/mL tolbutamide and Rabenol was added to each corresponding sample well to precipitate proteins. After all sample plates were sealed and shaken well, they were centrifuged at 3220×g for 20 minutes. Take 50 µL of supernatant and add 100 µL of ultrapure water to dilute, mix all samples and analyze by LC/MS/MS. The experimental results are shown in Table 3. Table 3. Plasma stability of test compounds in CD-1 mice, SD rats, Beagle dogs, cynomolgus monkeys and humans compound species Content detection of the test compound under 120min 002 CD-1 mouse 92.8% SD rat 87.2% Beagle 78.9% cynomolgus monkey 82.2% people 79.4% 009 CD-1 mouse 86.3 % SD rat 100.3% Beagle 93.6% cynomolgus monkey 84.5% people 87.7% Experimental conclusion: the compound of the present invention has good stability in plasma of CD-1 mice, SD rats, Beagle dogs, cynomolgus monkeys and humans.

測試例4：全血穩定性研究 實驗目的：評定受試化合物分別在評定受試化合物分別在CD-1小鼠、SD大鼠、米格魯犬、食蟹猴的全血穩定性 實驗操作：在實驗當天或實驗的前一天，採用抗凝劑EDTA-K2採集新鮮的CD-1小鼠、SD大鼠、米格魯犬、食蟹猴全血。在實驗開始前，將全血與PBS進行1：1（v：v）混合，放置於37℃水浴鍋中預熱10~20分鐘。準備96孔孵育板，分別命名為T0、T30、T60、T240。在對應的孵育板中，包括T0、T30、T60和T240孵育板，將2 μL化合物或對照化合物的工作液與98 μL的小鼠、大鼠、犬、猴和人空白全血混合，每個樣品準備兩個平行孔。所有的樣品在37˚C水浴鍋中進行孵育。化合物的最終孵育濃度為5 μM，對照化合物的最終孵育濃度為2 μM。每一個時間點孵育結束時，取出相應的孵育板，立即向對應的樣品孔中加入100 μL超純水，混勻，然後加入800 μL含有200 ng/mL甲苯磺丁脲和拉貝諾爾的乙腈溶液沉澱蛋白。樣品板封膜並搖勻後，4000轉/分鐘離心20 分鐘。取150 µL上清液用LC/MS/MS的方法分析。實驗結果如表4所示。 表4. 受試化合物CD-1小鼠、SD大鼠、米格魯犬、食蟹猴的全血穩定性 化合物 種屬 120 min下受試化合物含量檢測 002 CD-1小鼠 88.9 % SD大鼠 88.4 % 食蟹猴 89.1 % 米格魯犬 86.5 % 人 106 % 009 CD-1小鼠 119 % SD大鼠 98.4 % 食蟹猴 86.6 % 米格魯犬 104 % 人 101 % 實驗結論：多種屬全血穩定性研究顯示本發明化合物在全血中的穩定性良好。 Test Example 4: Whole Blood Stability Study Experimental Purpose: To evaluate the test compounds in CD-1 mice, SD rats, Beagle dogs, and cynomolgus monkeys in the whole blood stability test operation: On the day of the experiment or the day before the experiment, the anticoagulant EDTA-K2 was used to collect fresh whole blood from CD-1 mice, SD rats, Beagle dogs, and cynomolgus monkeys. Before the experiment started, the whole blood was mixed with PBS 1:1 (v:v), and placed in a 37°C water bath to preheat for 10-20 minutes. Prepare 96-well incubation plates and name them T0, T30, T60, and T240 respectively. In the corresponding incubation plates, including T0, T30, T60 and T240 incubation plates, mix 2 μL of working solution of compound or control compound with 98 μL of mouse, rat, dog, monkey and human blank whole blood, each Samples are prepared in two parallel wells. All samples were incubated in a 37˚C water bath. Compounds were incubated at a final concentration of 5 μM and control compounds were incubated at a final concentration of 2 μM. At the end of the incubation at each time point, take out the corresponding incubation plate, immediately add 100 μL of ultrapure water to the corresponding sample well, mix well, and then add 800 μL of acetonitrile containing 200 ng/mL tolbutamide and Rabenol solution to precipitate protein. After the sample plate was sealed and shaken well, it was centrifuged at 4000 rpm for 20 minutes. Take 150 µL of the supernatant and analyze it by LC/MS/MS. The experimental results are shown in Table 4. Table 4. Whole blood stability of test compound CD-1 mice, SD rats, Beagle dogs, and cynomolgus monkeys compound species Content detection of test compound under 120 min 002 CD-1 mouse 88.9% SD rat 88.4% cynomolgus monkey 89.1% Beagle 86.5% people 106% 009 CD-1 mouse 119% SD rat 98.4% cynomolgus monkey 86.6% Beagle 104 % people 101% Experimental conclusion: the whole blood stability study of various genera shows that the compound of the present invention has good stability in whole blood.

測試例5：GSH加成穩定性研究 實驗目的：評定受試化合物在GSH緩衝溶液中加成穩定性 實驗操作：準備96孔孵育板，分別命名為T0、T60、T120、T240、NGSH。將孵育板中對應的加入1500 μL的GSH -磷酸鉀緩衝溶液(最終測試GSH濃度為5 μM)，然後加入受試化合物或對照化合物的工作液加入到對應的孵育板中，每個樣品準備兩個平行孔。所有的樣品在37˚C水浴鍋中進行孵育。受試化合物和對照化合物阿法替尼、依魯替尼的最終孵育濃度分別為1 μM和10 μM 。每一個孵育時間點結束時，加入600 μL/孔200 ng/mL甲苯磺丁脲和拉貝諾爾的乙腈溶液作為終止液，凍存在-80 oC冰箱中直到最後一個時間點的樣品處理完成。所有樣品板封膜並搖勻5分鐘，4000轉/分鐘離心20分鐘。取50 µL上清液加入100 µL超純水稀釋，所有樣品混勻後用LC/MS/MS的方法分析。實驗結果如表5所示。 表5. 受試化合物GSH加成穩定性 化合物 120min下受試化合物含量檢測 002 84.3 % 009 91.3 % 實驗結論：本發明化合物在GSH磷酸緩衝溶液的穩定性良好。 Test Example 5: GSH Addition Stability Study Experimental Purpose: To evaluate the addition stability of the test compound in GSH buffer solution Experimental operation: Prepare 96-well incubation plates and name them T0, T60, T120, T240, NGSH respectively. Add 1500 μL of GSH-potassium phosphate buffer solution (the final test GSH concentration is 5 μM) to the corresponding incubation plate, and then add the working solution of the test compound or control compound to the corresponding incubation plate, prepare two samples for each parallel holes. All samples were incubated in a 37˚C water bath. The final incubation concentrations of the test compound and the reference compound afatinib and ibrutinib were 1 μM and 10 μM, respectively. At the end of each incubation time point, 600 μL/well of 200 ng/mL tolbutamide and Rabenol acetonitrile solution was added as a stop solution, and frozen in a -80 o C refrigerator until the sample processing at the last time point was completed. All sample plates were sealed and shaken for 5 minutes, and centrifuged at 4000 rpm for 20 minutes. Take 50 µL of supernatant and add 100 µL of ultrapure water to dilute, mix all samples and analyze by LC/MS/MS. The experimental results are shown in Table 5. Table 5. GSH addition stability of test compounds compound Content detection of the test compound under 120min 002 84.3 % 009 91.3 % Experimental conclusion: the compound of the present invention has good stability in GSH phosphate buffer solution.

測試例6：雙向滲透性和外排率研究 實驗目的：採用MDR1-MDCKII單層細胞模型測定了受試化合物的雙向滲透性和外排率。 實驗操作：實驗中將MDR1-MDCK II細胞(第11代)接種到96孔細胞培養板中，連續培養4-7天後用於轉運實驗。測試化合物用運輸緩衝液(含10 mM Hepes的HBSS, pH 7.4)從原液稀釋至2 µM濃度(DMSO ＜ 1%)，並應用於細胞單層的頂端或基底外側。分別用加P-gp抑制劑(GF120918, 10 µM)和不加P-gp抑制劑(GF120918, 10 µM)重複測定試驗化合物從A向B方向或B向A方向的滲透度。在10 μM GF120918存在或不存在的情況下，對地高辛進行10 μM的雙向測試，而在沒有GF120918的情況下，對納多洛爾和美托洛爾進行2 μM的雙向測試。平板在37±1 oC二氧化碳培養箱中，飽和濕度5%二氧化碳，不震動培養2.5小時。此外，還測定了各化合物的射流比。根據分析物/IS的峰面積比，採用LC-MS/MS分析方法對試驗品和參比化合物進行定量。實驗結果如表6所示。 表6. 受試化合物雙向滲透性和外排率研究 化合物 A到B滲透速率 (10 -6cm/s) 外排比 009 1.3 18.0 實驗結論：化合物009具備中等的滲透速率和外排比。 Test Example 6: Research on Bi-directional Permeability and Efflux Rate Experimental Purpose: The bi-directional permeability and efflux rate of the test compound were determined using the MDR1-MDCKII monolayer cell model. Experimental operation: In the experiment, MDR1-MDCK II cells (11th generation) were inoculated into 96-well cell culture plates, and used for transport experiments after continuous culture for 4-7 days. Test compounds were diluted from stock solutions to 2 µM concentrations (DMSO < 1%) in shipping buffer (HBSS with 10 mM Hepes, pH 7.4) and applied to the apical or basolateral cell monolayer. The permeability of the test compound from A to B direction or B to A direction was repeatedly measured with P-gp inhibitor (GF120918, 10 µM) and without P-gp inhibitor (GF120918, 10 µM). Digoxin was bidirectionally tested at 10 μM in the presence or absence of 10 μM GF120918 and nadolol and metoprolol were bidirectionally tested at 2 μM in the absence of GF120918. Plates were cultured in a carbon dioxide incubator at 37±1 o C, saturated with 5% carbon dioxide, for 2.5 hours without shaking. In addition, the jet ratio of each compound was also measured. The test and reference compounds were quantified by LC-MS/MS analysis based on the analyte/IS peak area ratio. The experimental results are shown in Table 6. Table 6. Bidirectional Permeability and Efflux Studies of Test Compounds compound A to B penetration rate (10 -6 cm/s) OUTRATIO 009 1.3 18.0 Experimental conclusion: Compound 009 has moderate penetration rate and efflux ratio.

測試例7：孕烷X核受體(PXR)研究 實驗目的：測定受試化合物是否能活化孕烷X核受體(PXR) 實驗操作：細胞接種及PXR受體活化孵育：實驗管中加入凍存PXR報告細胞，每管添加6.4 mL細胞復甦液(最終體積為7 mL/管)，在37 oC水浴中復甦5 - 10分鐘。細胞培養板中，每孔添加200 µL細胞分散液，活細胞多重檢測空白孔中不加入細胞，將接種後的細胞置於飽和濕度5%二氧化碳、37 oC培養箱中孵育4-6個小時。準備測試化合物(TA)，空白(VC)和陽參化合物(PC)的給藥溶液，並在37 oC水浴中預熱。從培養箱中取回細胞並吸取細胞培養板中每個孔的培養液。加入200 µL受試化合物或對照化合物的給藥溶液至對應的孔中，空白對照工作液加入到活細胞多重檢測空白孔中，每個樣品三個平行孔。所有的樣品在飽和濕度5%二氧化碳、37˚C培養箱中孵育22-24小時。 PXR受體及活細胞多重檢測(活性): 準備活細胞多重檢測試劑，添加6.7 µL 300x活細胞多重檢測底物到2 mL活細胞多重檢測緩衝液中，室溫條件下保存。從培養箱中取出細胞，吸取給藥溶液，室溫下用200 µL活細胞多重檢測緩衝液沖洗一次。每孔中添加50 µL活細胞多重檢測試劑，左右傾斜2-3次，孵育板在黑暗室溫條件下孵育15分鐘。 準備螢光素酶檢測試劑：加2 mL檢測底物到2 mL檢測緩衝液中。15分鐘孵化結束後，吸出活細胞多重檢測試劑，每孔添加100 µL螢光素酶檢測試劑，至少孵育5分鐘。在SpectraMax M4讀板器中，讀取螢光值(螢光相對單位在485 nm / 535 nm，活度)。在添加螢光素酶檢測試劑並孵育至少5分鐘後，讀取發光(螢光相對單位，PXR活化)，SpectraMax M4讀板器讀板時間為500 ms /孔。 實驗結果如表7所示： 表7. 受試化合物PXR活化 測試化合物 PXR陽性活化倍數 活度% 10 µM 10 µM 002 1.48 98.9 009 1.52 97.5 實驗結論：化合物002和化合物009無PXR陽性活化(PXR陽性活化的閾值為2倍)。 Test Example 7: Research on Pregnane X Nuclear Receptor (PXR) Experimental Purpose: To determine whether the test compound can activate Pregnane X Nuclear Receptor (PXR) Experimental operation: Cell inoculation and PXR receptor activation incubation: add frozen Store the PXR reporter cells, add 6.4 mL of cell recovery solution to each tube (the final volume is 7 mL/tube), and recover in a 37 o C water bath for 5 - 10 minutes. In the cell culture plate, add 200 µL of cell dispersion solution to each well, and do not add cells to the blank wells for live cell multiplex detection, and incubate the inoculated cells in a 37 o C incubator with a saturated humidity of 5% carbon dioxide for 4-6 hours . Prepare dosing solutions of test compound (TA), blank (VC) and genus compound (PC), and preheat in a 37 o C water bath. Retrieve the cells from the incubator and pipette the medium from each well of the cell culture plate. Add 200 µL of the administration solution of the test compound or the control compound to the corresponding wells, and add the blank control working solution to the multiple detection blank wells of live cells, with three parallel wells for each sample. All samples were incubated for 22-24 hours in a 37˚C incubator with a saturated humidity of 5% carbon dioxide. PXR receptor and live cell multiplex detection (activity): Prepare live cell multiplex detection reagent, add 6.7 µL 300x live cell multiplex detection substrate to 2 mL live cell multiplex detection buffer, store at room temperature. Take out the cells from the incubator, pipette the dosing solution, and wash once with 200 µL live cell multiplex detection buffer at room temperature. Add 50 µL live cell multiplex detection reagent to each well, tilt left and right 2-3 times, and incubate the plate at room temperature in the dark for 15 minutes. Prepare Luciferase Assay Reagent: Add 2 mL of Assay Substrate to 2 mL of Assay Buffer. After the 15-minute incubation, aspirate the Live Cell Multiplex Detection Reagent, add 100 µL Luciferase Detection Reagent to each well, and incubate for at least 5 minutes. In the SpectraMax M4 plate reader, read the fluorescence value (relative fluorescence unit at 485 nm / 535 nm, activity). After adding the luciferase detection reagent and incubating for at least 5 minutes, the luminescence (relative units of fluorescence, PXR activation) was read with a SpectraMax M4 plate reader at 500 ms/well. The experimental results are shown in Table 7: Table 7. PXR activation of test compounds test compound PXR positive activation fold activity% 10 µM 10 µM 002 1.48 98.9 009 1.52 97.5 Experimental conclusion: compound 002 and compound 009 have no PXR positive activation (the threshold of PXR positive activation is 2 times).

測試例8：CYP誘導實驗 實驗目的：測定受試化合物是否能誘導CYP酶過表達 實驗操作： 肝細胞孵育 所有孵育均在37±1℃、5% CO 2和飽和濕度條件的培養箱中進行。 待培養體系建立好後，棄去三明治培養基的上層培養液，於每個細胞培養孔中加入200 µL已預熱至37℃並新鮮配製的給藥工作液（包含供試品、陽性對照和基質對照），將細胞培養板放置於培養箱中繼續培養24小時。培養24小時後，更換新鮮配製的給藥工作液並繼續培養24小時。整個孵育時間為48小時。每個藥物濃度及對照濃度分別做三個平行。 待細胞與給藥工作液孵育48小時後，棄去板中剩餘的藥物溶液，用0.5 mL預熱至37℃的HBSS溶液清洗細胞孔2次，於每孔加入100 µL已預熱至37℃的酶活標記底物工作液孵育30分鐘。孵育30分鐘後，每孔取出75.0 µL上清樣品加入到含有150 µL終止液的96孔深孔板中。搖板10分鐘，於4℃、3220 g離心20分鐘，然後取上清溶液按1:4的比例用含有0.1%甲酸的水溶液稀釋。稀釋後的樣品搖板10分鐘後，用液相色譜-串聯質譜（LC-MS/MS）方法對代謝產物的生成量進行檢測。 酶活性檢測反應結束之後，棄去上清剩餘溶液，並用0.5 mL預熱的HBSS清洗細胞。於每孔加入280 μL含有1% β-巰基乙醇的裂解液，封板，搖板10分鐘後，轉移至低於-60℃冰箱內保存。 樣品分析檢測 利用液相色譜-串聯質譜（LC-MS/MS）方法測定經蛋白沉澱後肝細胞中三個CYP酶底物的代謝產物（對乙醯胺基酚、羥基安非他酮以及1’-羥基咪達唑侖）的濃度。 細胞毒性實驗 供試品的潛在毒性由肝細胞中乳酸脫氫酶(LDH)的釋放量來評估。將與肝細胞孵育24小時和48小時後的給藥工作液各自取出100 μL，用商品化LDH試劑盒對其乳酸脫氫酶的濃度進行檢測。細胞裂解溶液作為實驗陽性對照，孵育培養液作為空白對照。 RNA分析檢測 室溫化凍樣品板，將所有樣品轉移至新的96孔板中。應用核酸提取純化設備抽提RNA。在樣品板的不同位置隨機抽取超過樣品總量10%的樣品，運用ND2000微量分光光度計測定260 nm與280 nm的OD值，透過計算兩者的比值來判斷總RNA的純度。反轉錄以得到cDNA。用實時螢光定量PCR儀實時定量分析選擇的基因。按如下程序設置反應條件：50℃兩分鐘；95℃十分鐘；以下兩步做40個循環：95℃十五秒，60℃一分鐘。內源性對照18S rRNA作為內標。 數據分析 酶活性數據分析 實驗數據顯示了CYP1A2、CYP2B6和CYP3A4的酶代謝產物的生成量。酶活性的改變是透過比較在化合物存在或不存在的條件下相應細胞色素酶的誘導倍數來表現的。誘導倍數的計算方法及與對照化合物的誘導比率的計算方法如下： 誘導倍數=供試品（或對照化合物）處理過的樣品中的酶活性/基質對照處理過的樣品中的酶活性 與對照化合物的誘導比率（%）=（供試品處理過的樣品的誘導倍數-1）/（對照化合物處理過的樣品的誘導倍數-1）× 100 基因表達數據分析 該項目採用ΔCt相對定量的方法來比較不同處理組間基因表達的差異，以18S rRNA為內參基因來校正每個樣品的基因表達量。目的基因的Ct值減去內參基因的Ct值則為ΔCt，即Ct目的基因 – Ct18S = ΔCt。用處理組的ΔCt值減去基質對照組的ΔCt值則為ΔΔCt，即ΔCt處理組 –ΔCt基質對照組 = ΔΔCt。最後以2-ΔΔCt的方法進行統計分析，比較處理組與基質對照組間的倍數的變化。供試品與對照化合物的誘導比率的計算方法如下： 與對照化合物的誘導比率（%）=（供試品處理過的樣品的誘導倍數-1）/（對照化合物處理過的樣品的誘導倍數-1）× 100 實驗結果如表8所示： 表8. 受試化合物CYP誘導實驗 測試化合物編號. 測試化合物濃度 （μM） CYP酶活性 CYP基因表達 LDH釋放 陽性對照的百分比 基質對照的倍數 陽性對照的百分比 基質對照的百分比 1A2 2B6 3A4 1A2 2B6 3A4 1A2 2B6 3A4 24 hrs 48 hrs 009 10.0 -3.5 -4.5 -5.0 0.881 0.745 1.80 -0.5 -2.5 5.7 95.1 117.2 實驗結論：化合物009無CYP誘導活化。 Test Example 8: CYP induction experiment Experimental purpose: To determine whether the test compound can induce the overexpression of CYP enzymes Experimental operation: Hepatocyte incubation All incubations were performed in an incubator at 37±1°C, 5% CO 2 and saturated humidity. After the culture system was established, the supernatant medium of the sandwich medium was discarded, and 200 µL of freshly prepared drug administration solution (including the test product, positive control and matrix) was added to each cell culture well. Control), the cell culture plate was placed in the incubator to continue culturing for 24 hours. After culturing for 24 hours, replace the freshly prepared working solution for administration and continue culturing for 24 hours. The entire incubation time was 48 hours. Three parallels were performed for each drug concentration and control concentration. After the cells were incubated with the drug administration solution for 48 hours, the remaining drug solution in the plate was discarded, the cell wells were washed twice with 0.5 mL of HBSS solution preheated to 37°C, and 100 µL of HBSS solution preheated to 37°C was added to each well. Enzyme-labeled substrate working solution was incubated for 30 minutes. After 30 minutes of incubation, 75.0 µL of supernatant samples were taken from each well and added to a 96-well deep-well plate containing 150 µL of stop solution. Shake the plate for 10 minutes, centrifuge at 4 °C and 3220 g for 20 minutes, then take the supernatant solution and dilute it with an aqueous solution containing 0.1% formic acid at a ratio of 1:4. After the diluted sample was shaken for 10 minutes, the production of metabolites was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After the enzyme activity detection reaction was completed, the remaining supernatant solution was discarded, and the cells were washed with 0.5 mL of preheated HBSS. Add 280 μL of lysate solution containing 1% β-mercaptoethanol to each well, seal the plate, shake the plate for 10 minutes, and transfer to a refrigerator below -60°C for storage. Sample analysis and detection The metabolites of three CYP enzyme substrates (paracetamol, hydroxybupropion and 1 '-hydroxymidazolam) concentration. Cytotoxicity test The potential toxicity of the test article was evaluated by the release of lactate dehydrogenase (LDH) in hepatocytes. 100 μL of the administration solution after incubation with hepatocytes for 24 hours and 48 hours were taken out respectively, and the concentration of lactate dehydrogenase was detected with a commercial LDH kit. The cell lysis solution was used as the positive control of the experiment, and the incubation medium was used as the blank control. RNA Analysis Detection Thaw the sample plate at room temperature and transfer all samples to a new 96-well plate. Use nucleic acid extraction and purification equipment to extract RNA. Samples exceeding 10% of the total sample were randomly selected from different positions on the sample plate, and the OD values at 260 nm and 280 nm were measured with an ND2000 micro-spectrophotometer, and the purity of the total RNA was judged by calculating the ratio of the two. Reverse transcription to obtain cDNA. The selected genes were quantitatively analyzed in real time with a real-time fluorescent quantitative PCR instrument. Set the reaction conditions as follows: 50°C for two minutes; 95°C for ten minutes; do 40 cycles of the following two steps: 95°C for fifteen seconds, 60°C for one minute. Endogenous control 18S rRNA was used as internal standard. Data Analysis Enzyme Activity Data Analysis Experimental data show the production of enzyme metabolites of CYP1A2, CYP2B6 and CYP3A4. Changes in enzyme activity are expressed by comparing the fold induction of the corresponding cytochrome enzymes in the presence or absence of compounds. The calculation method of the induction multiple and the induction ratio with the reference compound are as follows: Induction ratio (%) = (Induction fold of samples treated with test substance - 1) / (Induction fold of samples treated with control compound - 1) × 100 Gene expression data analysis The differences in gene expression among different treatment groups were compared, and 18S rRNA was used as an internal reference gene to correct the gene expression of each sample. The Ct value of the target gene minus the Ct value of the internal reference gene is ΔCt, that is, Ct target gene – Ct18S = ΔCt. Subtract the ΔCt value of the matrix control group from the ΔCt value of the treatment group to obtain ΔΔCt, that is, ΔCt treatment group – ΔCt matrix control group = ΔΔCt. Finally, statistical analysis was carried out with the method of 2-ΔΔCt, and the fold change between the treatment group and the matrix control group was compared. The calculation method of the induction ratio of the test product and the control compound is as follows: The induction ratio of the control compound (%)=(the induction multiple of the sample treated by the test product-1)/(the induction multiple of the sample treated by the reference compound- 1) × 100 The experimental results are shown in Table 8: Table 8. CYP induction experiments of test compounds Test compound number. Test compound concentration (μM) CYP enzyme activity CYP gene expression LDH release % of positive control multiple of matrix control % of positive control % of matrix control 1A2 2B6 3A4 1A2 2B6 3A4 1A2 2B6 3A4 24 hrs 48 hrs 009 10.0 -3.5 -4.5 -5.0 0.881 0.745 1.80 -0.5 -2.5 5.7 95.1 117.2 Experimental conclusion: Compound 009 has no CYP-induced activation.

測試例9：人胰腺癌Mia PaCa-2細胞裸小鼠皮下移植腫瘤Balb/c Nude小鼠模型的體內藥效學研究 細胞培養和腫瘤組織準備 細胞培養：人胰腺癌Mia PaCa-2細胞（ATCC-CRL-1420）體外單層培養，培養條件為DMEM/F12培養基中加20%胎牛血清，1% 雙抗，37 ℃ 5%二氧化碳孵箱培養。一周兩次用胰酶-EDTA進行常規消化處理傳代。當細胞飽和度為80%-90%，數量到達要求時，收取細胞，計數，重懸於適量PBS中，1:1加入基質膠，獲取細胞密度為25 × 10 6cells/mL的細胞懸液。 細胞接種： 將0.2 mL（5×10 6cells/鼠）Mia PaCa-2細胞（加基質膠，體積比為1:1）皮下接種於每隻小鼠的右後背，腫瘤平均體積達到190 mm 3時，根據腫瘤體積進行隨機分組，按照表9中的方案開始給藥。 表9實驗動物分組及給藥方案 組別 動物數 化合物治療 劑量 (mg/kg) 給藥體積(µL/g) 給藥途徑 給藥 頻率 1 8 空白組 -- 10 PO QD ×25 2 8 002 1.5 10 PO QD ×25 3 8 002 5 10 PO QD ×25 4 8 009 1.5 10 PO QD ×25 5 8 009 5 10 PO QD ×25 注： PO代表口服；QD代表每日一次。 腫瘤測量和實驗指標 每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。 化合物的抑瘤療效用TGI(%)或相對腫瘤增殖率T/C(%)評價。相對腫瘤增殖率T/C（%） = TRTV / CRTV × 100 %（TRTV：治療組RTV；CRTV：陰性對照組RTV）。根據腫瘤測量的結果計算出相對腫瘤體積（relative tumor volume，RTV），計算公式為 RTV = Vt / V0，其中V0是分組給藥時（即D0）測量所得平均腫瘤體積，Vt為某一次測量時的平均腫瘤體積，TRTV與CRTV取同一天數據。 TGI (%)，反映腫瘤生長抑制率。TGI(%)=[(1-(某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積))/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)]×100%。 實驗結果 實驗結果如圖8、9所示。 結果表明： 給藥25天時，溶劑對照組荷瘤鼠的瘤體積達到2275 mm 3，待測物化合物002 (1.5 mg/kg)和化合物002 (5 mg/kg)的腫瘤體積均值分別為1675 mm 3和534 mm 3；T/C 分別為74.23 %和23.93%；TGI分別為 28.02% 和81.32 %，在兩個濃度下均能顯著地抑制腫瘤生長(p值均小於0.001)。待測物化合物009 (1.5 mg/kg)和化合物009 (5 mg/kg)的腫瘤體積均值分別為1325 mm 3和506 mm 3；T/C 分別為56.99 %和21.89%；TGI分別為 44.37% 和82.59 %，在兩個濃度下均能顯著地抑制腫瘤生長(p值均小於0.001)。受試物AMG510 (5 mg/kg)的腫瘤體積均值為963 mm 3，T/C為41.78 %，TGI為61.28 %，p值均＜0.001，同樣具有顯著的抑瘤作用，且小鼠各個劑量組的體重平穩，無明顯不耐受現象。 Test Example 9: In vivo pharmacodynamic study of human pancreatic cancer Mia PaCa-2 cells subcutaneously transplanted into nude mice with tumor Balb/c Nude mouse model Cell culture and tumor tissue preparation Cell culture: Human pancreatic cancer Mia PaCa-2 cells (ATCC -CRL-1420) in vitro monolayer culture, the culture conditions are DMEM/F12 medium plus 20% fetal bovine serum, 1% double antibody, 37 ℃ 5% carbon dioxide incubator 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, resuspend in an appropriate amount of PBS, add Matrigel at 1:1, and obtain a cell suspension with a cell density of 25 × 10 6 cells/mL . Cell inoculation: 0.2 mL (5×10 6 cells/mouse) of Mia PaCa-2 cells (plus Matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached 190 mm 3 , randomized grouping was performed according to the tumor volume, and the administration was started according to the scheme in Table 9. Table 9 Experimental Animal Grouping and Dosing Scheme group number of animals compound therapy Dose (mg/kg) Dosing volume (µL/g) Route of administration Dosing frequency 1 8 blank group -- 10 PO QD ×25 2 8 002 1.5 10 PO QD ×25 3 8 002 5 10 PO QD ×25 4 8 009 1.5 10 PO QD ×25 5 8 009 5 10 PO QD ×25 Note: PO stands for oral; QD stands for once daily. Tumor Measurement and Experimental Index Tumor diameter was measured twice a week with a vernier caliper. The formula for calculating tumor volume is: V = 0.5a × b 2 , 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 (%). Relative tumor proliferation rate T/C (%) = TRTV / CRTV × 100 % (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV = Vt / V0, where V0 was the average tumor volume measured during group administration (that is, D0), and Vt was a certain measurement The average tumor volume of TRTV and CRTV take the data on the same day. TGI (%), reflecting the rate of tumor growth inhibition. 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 the solvent control group-Start of treatment of the solvent control group Time-average tumor volume)]×100%. Experimental Results The experimental results are shown in Figures 8 and 9. The results showed that: after 25 days of administration, the tumor volume of the tumor-bearing mice in the solvent control group reached 2275 mm 3 , and the average tumor volumes of the test compound 002 (1.5 mg/kg) and compound 002 (5 mg/kg) were 1675 mm 3 , respectively. mm 3 and 534 mm 3 ; T/C were 74.23 % and 23.93 %; TGI were 28.02 % and 81.32 %, and both concentrations could significantly inhibit tumor growth (all p values were less than 0.001). The mean tumor volumes of test compound 009 (1.5 mg/kg) and compound 009 (5 mg/kg) were 1325 mm 3 and 506 mm 3 ; T/C were 56.99 % and 21.89 %; TGI were 44.37 % and 82.59 %, both concentrations can significantly inhibit tumor growth (p values are less than 0.001). The average tumor volume of the test substance AMG510 (5 mg/kg) was 963 mm 3 , the T/C was 41.78 %, the TGI was 61.28 %, and the p values were all <0.001. It also had a significant tumor inhibitory effect, and each dose of the mouse The body weight of the group was stable, and there was no obvious intolerance phenomenon.

無none

圖1是 AMG510和KRASG12C蛋白的結合模式(活性構象：6IOM) 。 圖2是 AMG510和KARSG12C的結合模式2D圖。 圖3是化合物A的低能構象與AMG510活性構象疊合圖。 圖4是化合物B的低能構象與AMG510活性構象疊合圖。 圖5是化合物C的低能構象與AMG510活性構象疊合圖。 圖6是化合物D的低能構象與AMG510活性構象疊合圖。 圖7是化合物E的低能構象與AMG510活性構象疊合圖。 圖8是人胰腺癌Mia PaCa-2細胞裸小鼠皮下移植腫瘤Balb/c Nude小鼠模型研究的腫瘤體積圖。 圖9是人胰腺癌Mia PaCa-2細胞裸小鼠皮下移植腫瘤Balb/c Nude小鼠模型研究的體重變化圖。 Fig. 1 is the binding mode (active conformation: 61OM) of AMG510 and KRASG12C protein. Figure 2 is a 2D diagram of the binding mode of AMG510 and KARSG12C. Figure 3 is the overlay of the low-energy conformation of compound A and the active conformation of AMG510. Figure 4 is the overlay of the low-energy conformation of compound B and the active conformation of AMG510. Figure 5 is the overlay of the low-energy conformation of compound C and the active conformation of AMG510. Figure 6 is the overlay of the low-energy conformation of compound D and the active conformation of AMG510. Figure 7 is the overlay of the low-energy conformation of compound E and the active conformation of AMG510. Fig. 8 is a diagram of the tumor volume of human pancreatic cancer Mia PaCa-2 cells transplanted subcutaneously in nude mice with Balb/c Nude mouse model. Fig. 9 is a graph showing the body weight change of human pancreatic cancer Mia PaCa-2 cell subcutaneously implanted tumor Balb/c Nude mouse model in nude mice.

Claims (19)

一種式(III)所示化合物或其藥學上可接受的鹽，
Figure 03_image001
其中， T 1、T 2和T 3分別獨立地選自CH和N； T 4選自CR 6和N； 環A選自哌𠯤基、
Figure 03_image005
和
Figure 03_image007
； R 1選自
Figure 03_image009
和
Figure 03_image011
，所述
Figure 03_image009
和
Figure 03_image011
任選被1、2或3個R a取代； 各R 2分別獨立地選自H和C 1-3烷基，所述C 1-3烷基任選被1、2或3個R b取代； R 3選自C 1-6烷基，所述C 1-6烷基任選被1、2或3個R b取代； R 4選自H、F、Cl、Br和I； R 5選自H和F； R 6選自H、F、Cl和CN； m選自0、1、2和3； 各R a分別獨立地選自H、F、Cl、Br、I、CN、C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代； 各R b分別獨立地選自H、F、Cl、Br、I和CN； 各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基； 條件是， 1)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 03_image011
時，R a選自CN，R 1被R a取代形成
Figure 03_image013
；或者 2)當T 4選自N，環A選自哌𠯤基，R 1選自
Figure 03_image011
時，所述
Figure 03_image011
被1、2或3個R a取代，R a選自C 1-3烷基、-C(O)OC 1-3烷基、-C(O)NHC 1-3烷基和環丁烯基，所述C 1-3烷基和環丁烯基任選被1、2或3個R取代，各R分別獨立地選自F、OCH 3、N(CH 3) 2、NH 2和嗎福林基。 A compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure 03_image001
Wherein, T 1 , T 2 and T 3 are independently selected from CH and N; T 4 is selected from CR 6 and N; ring A is selected from piperyl,
Figure 03_image005
with
Figure 03_image007
; R 1 is selected from
Figure 03_image009
with
Figure 03_image011
, the
Figure 03_image009
with
Figure 03_image011
optionally substituted by 1, 2 or 3 R a ; each R independently selected from H and C 1-3 alkyl optionally substituted by 1 , 2 or 3 R ; R 3 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by 1, 2 or 3 R b ; R 4 is selected from H, F, Cl, Br and I; R 5 is selected from From H and F ; R is selected from H, F, Cl and CN; m is selected from 0, 1, 2 and 3 ; each R is independently selected from H, F, Cl, Br, I , CN, C -3 alkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl, the C 1-3 alkyl and cyclobutenyl are optionally 1, 2 or 3 R substitutions; each R b is independently selected from H, F, Cl, Br, I and CN; each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morpholinyl; the proviso is that, 1) when T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 03_image011
When, R a is selected from CN, R 1 is replaced by R a to form
Figure 03_image013
; or 2) when T 4 is selected from N, ring A is selected from piperthiol, R 1 is selected from
Figure 03_image011
when the
Figure 03_image011
Substituted by 1, 2 or 3 R a selected from C 1-3 alkyl, -C ( O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl and cyclobutenyl , the C 1-3 alkyl and cyclobutenyl are optionally substituted by 1, 2 or 3 R, each R is independently selected from F, OCH 3 , N(CH 3 ) 2 , NH 2 and morphol Linky. 如請求項1所述化合物或其藥學上可接受的鹽，其中，各R a分別獨立地選自H、F、Cl、Br、I、CN、CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基，所述CH 3、CH 2CH 3、CH(CH 3) 2、-C(O)OCH 3、-C(O)NHCH 3和環丁烯基任選被1、2或3個R取代。 The compound or pharmaceutically acceptable salt thereof as claimed in item 1, wherein each R a is independently selected from H, F, Cl, Br, I, CN, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , -C(O)NHCH 3 and cyclobutenyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , -C(O)OCH 3 , - C(O) NHCH3 and cyclobutenyl are optionally substituted with 1, 2 or 3 Rs. 如請求項1或2所述化合物或其藥學上可接受的鹽，其中，各R a分別獨立地選自H、F、CN、CHF 2、CH 2F、CH 2OCH 3、CH 2N(CH 3) 2、CH 2NH 2、-C(O)OCH 3、-C(O)NHCH 3、
Figure 03_image016
和
Figure 03_image018
。 The compound or pharmaceutically acceptable salt thereof as claimed in item 1 or 2, wherein each R a is independently selected from H, F, CN, CHF 2 , CH 2 F, CH 2 OCH 3 , CH 2 N( CH 3 ) 2 , CH 2 NH 2 , -C(O)OCH 3 , -C(O)NHCH 3 ,
Figure 03_image016
with
Figure 03_image018
. 如請求項1所述化合物或其藥學上可接受的鹽，其中，R 1選自
Figure 03_image020
、
Figure 03_image022
、
Figure 03_image024
、
Figure 03_image013
、
Figure 03_image027
、
Figure 03_image029
、
Figure 03_image031
、
Figure 03_image033
、
Figure 03_image035
、
Figure 03_image037
、
Figure 03_image039
、
Figure 03_image041
、
Figure 03_image043
、
Figure 03_image045
和
Figure 03_image047
。 The compound or pharmaceutically acceptable salt thereof as claimed in item 1 , wherein, R is selected from
Figure 03_image020
,
Figure 03_image022
,
Figure 03_image024
,
Figure 03_image013
,
Figure 03_image027
,
Figure 03_image029
,
Figure 03_image031
,
Figure 03_image033
,
Figure 03_image035
,
Figure 03_image037
,
Figure 03_image039
,
Figure 03_image041
,
Figure 03_image043
,
Figure 03_image045
with
Figure 03_image047
. 如請求項1所述化合物或其藥學上可接受的鹽，其中，T 4選自N，環A選自哌𠯤基，R 1選自
Figure 03_image024
、
Figure 03_image013
、
Figure 03_image027
、
Figure 03_image029
、
Figure 03_image031
、
Figure 03_image033
、
Figure 03_image035
、
Figure 03_image037
、
Figure 03_image039
、
Figure 03_image041
、
Figure 03_image043
、
Figure 03_image045
和
Figure 03_image047
。 The compound as claimed in item 1 or a pharmaceutically acceptable salt thereof, wherein T 4 is selected from N, ring A is selected from piperyl, and R 1 is selected from
Figure 03_image024
,
Figure 03_image013
,
Figure 03_image027
,
Figure 03_image029
,
Figure 03_image031
,
Figure 03_image033
,
Figure 03_image035
,
Figure 03_image037
,
Figure 03_image039
,
Figure 03_image041
,
Figure 03_image043
,
Figure 03_image045
with
Figure 03_image047
. 如請求項1所述化合物或其藥學上可接受的鹽，其中，各R 2分別獨立地選自H和CH 3。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from H and CH 3 . 如請求項1所述化合物或其藥學上可接受的鹽，其中，R 3選自CH(CH 3) 2。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from CH(CH 3 ) 2 . 如請求項1所述化合物或其藥學上可接受的鹽，其中，R 4選自F和Cl。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from F and Cl. 如請求項1所述化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image049
選自
Figure 03_image051
、
Figure 03_image053
、
Figure 03_image055
和
Figure 03_image057
。 The compound or pharmaceutically acceptable salt thereof as claimed in item 1, wherein the structural unit
Figure 03_image049
selected from
Figure 03_image051
,
Figure 03_image053
,
Figure 03_image055
with
Figure 03_image057
. 如請求項9所述化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image049
選自
Figure 03_image059
、
Figure 03_image061
、
Figure 03_image063
、
Figure 03_image053
、
Figure 03_image055
和
Figure 03_image057
。 The compound or pharmaceutically acceptable salt thereof as claimed in item 9, wherein the structural unit
Figure 03_image049
selected from
Figure 03_image059
,
Figure 03_image061
,
Figure 03_image063
,
Figure 03_image053
,
Figure 03_image055
with
Figure 03_image057
. 如請求項1、9或10任意一項所述化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image049
選自
Figure 03_image069
、
Figure 03_image070
、
Figure 03_image072
、
Figure 03_image053
、
Figure 03_image055
和
Figure 03_image057
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1, 9 or 10, wherein the structural unit
Figure 03_image049
selected from
Figure 03_image069
,
Figure 03_image070
,
Figure 03_image072
,
Figure 03_image053
,
Figure 03_image055
with
Figure 03_image057
. 如請求項1、9或10任意一項所述化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image049
選自
Figure 03_image074
、
Figure 03_image076
、
Figure 03_image078
、
Figure 03_image080
、
Figure 03_image082
、
Figure 03_image084
、
Figure 03_image086
、
Figure 03_image088
、
Figure 03_image090
、
Figure 03_image092
、
Figure 03_image094
、
Figure 03_image096
、
Figure 03_image098
、
Figure 03_image100
、
Figure 03_image102
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image108
、
Figure 03_image110
、
Figure 03_image112
、
Figure 03_image114
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image120
、
Figure 03_image122
、
Figure 03_image124
、
Figure 03_image126
、
Figure 03_image128
、
Figure 03_image130
、
Figure 03_image132
、
Figure 03_image134
、
Figure 03_image136
、
Figure 03_image138
、
Figure 03_image140
、
Figure 03_image142
、
Figure 03_image144
、
Figure 03_image146
、
Figure 03_image580
、
Figure 03_image582
、
Figure 03_image152
和
Figure 03_image154
。 The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1, 9 or 10, wherein the structural unit
Figure 03_image049
selected from
Figure 03_image074
,
Figure 03_image076
,
Figure 03_image078
,
Figure 03_image080
,
Figure 03_image082
,
Figure 03_image084
,
Figure 03_image086
,
Figure 03_image088
,
Figure 03_image090
,
Figure 03_image092
,
Figure 03_image094
,
Figure 03_image096
,
Figure 03_image098
,
Figure 03_image100
,
Figure 03_image102
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image108
,
Figure 03_image110
,
Figure 03_image112
,
Figure 03_image114
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image120
,
Figure 03_image122
,
Figure 03_image124
,
Figure 03_image126
,
Figure 03_image128
,
Figure 03_image130
,
Figure 03_image132
,
Figure 03_image134
,
Figure 03_image136
,
Figure 03_image138
,
Figure 03_image140
,
Figure 03_image142
,
Figure 03_image144
,
Figure 03_image146
,
Figure 03_image580
,
Figure 03_image582
,
Figure 03_image152
with
Figure 03_image154
. 如請求項12所述化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image049
選自
Figure 03_image156
、
Figure 03_image158
、
Figure 03_image160
、
Figure 03_image162
、
Figure 03_image164
、
Figure 03_image166
、
Figure 03_image168
、
Figure 03_image170
、
Figure 03_image172
、
Figure 03_image174
、
Figure 03_image176
、
Figure 03_image178
、
Figure 03_image180
、
Figure 03_image182
、
Figure 03_image184
、
Figure 03_image186
、
Figure 03_image188
、
Figure 03_image190
和
Figure 03_image192
。 The compound or pharmaceutically acceptable salt thereof as claimed in item 12, wherein the structural unit
Figure 03_image049
selected from
Figure 03_image156
,
Figure 03_image158
,
Figure 03_image160
,
Figure 03_image162
,
Figure 03_image164
,
Figure 03_image166
,
Figure 03_image168
,
Figure 03_image170
,
Figure 03_image172
,
Figure 03_image174
,
Figure 03_image176
,
Figure 03_image178
,
Figure 03_image180
,
Figure 03_image182
,
Figure 03_image184
,
Figure 03_image186
,
Figure 03_image188
,
Figure 03_image190
with
Figure 03_image192
. 如請求項1~2、4~10或13任意一項所述化合物或其藥學上可接受的鹽，其化合物選自
Figure 03_image292
Figure 03_image294
Figure 03_image296
Figure 03_image298
Figure 03_image603
Figure 03_image302
， 其中， R 1、R 2、R 3、R 4、R 5和m如請求項1~2、4~10或13任意一項所定義。 The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1~2, 4~10 or 13, the compound is selected from
Figure 03_image292
Figure 03_image294
Figure 03_image296
Figure 03_image298
Figure 03_image603
Figure 03_image302
, wherein, R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined in any one of claim items 1~2, 4~10 or 13. 一種下列化合物或其藥學上可接受的鹽，
Figure 03_image304
Figure 03_image306
Figure 03_image308
Figure 03_image310
Figure 03_image312
Figure 03_image314
Figure 03_image316
Figure 03_image318
Figure 03_image605
Figure 03_image322
Figure 03_image324
Figure 03_image326
Figure 03_image609
Figure 03_image330
Figure 03_image332
Figure 03_image334
Figure 03_image336
Figure 03_image612
Figure 03_image340
Figure 03_image342
Figure 03_image344
Figure 03_image346
Figure 03_image348
Figure 03_image350
Figure 03_image352
Figure 03_image354
Figure 03_image356
。 A compound or a pharmaceutically acceptable salt thereof,
Figure 03_image304
Figure 03_image306
Figure 03_image308
Figure 03_image310
Figure 03_image312
Figure 03_image314
Figure 03_image316
Figure 03_image318
Figure 03_image605
Figure 03_image322
Figure 03_image324
Figure 03_image326
Figure 03_image609
Figure 03_image330
Figure 03_image332
Figure 03_image334
Figure 03_image336
Figure 03_image612
Figure 03_image340
Figure 03_image342
Figure 03_image344
Figure 03_image346
Figure 03_image348
Figure 03_image350
Figure 03_image352
Figure 03_image354
Figure 03_image356
. 如請求項15所述化合物或其藥學上可接受的鹽，其化合物選自
Figure 03_image358
Figure 03_image360
Figure 03_image362
Figure 03_image364
Figure 03_image366
Figure 03_image368
Figure 03_image370
Figure 03_image372
Figure 03_image374
Figure 03_image376
Figure 03_image378
Figure 03_image380
Figure 03_image382
Figure 03_image384
Figure 03_image386
Figure 03_image388
Figure 03_image620
Figure 03_image392
Figure 03_image394
Figure 03_image396
Figure 03_image398
Figure 03_image400
Figure 03_image402
Figure 03_image404
Figure 03_image406
Figure 03_image408
Figure 03_image410
Figure 03_image412
Figure 03_image414
Figure 03_image416
Figure 03_image418
Figure 03_image420
Figure 03_image422
Figure 03_image424
Figure 03_image426
Figure 03_image428
Figure 03_image430
Figure 03_image432
Figure 03_image434
Figure 03_image436
Figure 03_image438
Figure 03_image628
Figure 03_image442
Figure 03_image444
Figure 03_image446
Figure 03_image448
Figure 03_image450
Figure 03_image452
Figure 03_image454
Figure 03_image456
Figure 03_image458
。 Compound or pharmaceutically acceptable salt thereof as described in claim item 15, its compound is selected from
Figure 03_image358
Figure 03_image360
Figure 03_image362
Figure 03_image364
Figure 03_image366
Figure 03_image368
Figure 03_image370
Figure 03_image372
Figure 03_image374
Figure 03_image376
Figure 03_image378
Figure 03_image380
Figure 03_image382
Figure 03_image384
Figure 03_image386
Figure 03_image388
Figure 03_image620
Figure 03_image392
Figure 03_image394
Figure 03_image396
Figure 03_image398
Figure 03_image400
Figure 03_image402
Figure 03_image404
Figure 03_image406
Figure 03_image408
Figure 03_image410
Figure 03_image412
Figure 03_image414
Figure 03_image416
Figure 03_image418
Figure 03_image420
Figure 03_image422
Figure 03_image424
Figure 03_image426
Figure 03_image428
Figure 03_image430
Figure 03_image432
Figure 03_image434
Figure 03_image436
Figure 03_image438
Figure 03_image628
Figure 03_image442
Figure 03_image444
Figure 03_image446
Figure 03_image448
Figure 03_image450
Figure 03_image452
Figure 03_image454
Figure 03_image456
Figure 03_image458
. 如請求項16所述化合物或其藥學上可接受的鹽，其化合物選自
Figure 03_image460
。 Compound or pharmaceutically acceptable salt thereof as described in claim item 16, its compound is selected from
Figure 03_image460
. 如請求項1~17任意一項所述的化合物或其藥學上可接受的鹽在製備治療腫瘤藥物中的應用。 Application of the compound described in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors. 如請求項18所述應用，其中腫瘤指KRAS G12C突變相關的腫瘤。 Use as described in Claim 18, wherein the tumor refers to a tumor related to KRAS G12C mutation.
TW111117242A 2021-05-06 2022-05-06 Twelve-membered macrocycle macrocyclic compound TW202246287A (en)

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CN202110545538.0 2021-05-19
CN202110738841.2 2021-06-30
CN202110738841 2021-06-30
CN202110825905 2021-07-21
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