TW202227441A - Quinazoline compound and pharmaceutical composition thereof - Google Patents

Quinazoline compound and pharmaceutical composition thereof Download PDF

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TW202227441A
TW202227441A TW110138961A TW110138961A TW202227441A TW 202227441 A TW202227441 A TW 202227441A TW 110138961 A TW110138961 A TW 110138961A TW 110138961 A TW110138961 A TW 110138961A TW 202227441 A TW202227441 A TW 202227441A
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alkylene
compound
alkyl
substituted
esi
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TW110138961A
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吳顥
路淵
陳小平
李波燕
周曉
傅水標
何將旗
王維
湛波
朱小慣
宏 蘭
家炳 王
丁列明
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大陸商貝達藥業股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Abstract

A novel compound with cancer therapeutic activity. The present invention also relates to a method for preparing these compounds and a pharmaceutical composition containing same.

Description

喹唑啉化合物、包含其的藥物組合物及其應用Quinazoline compound, pharmaceutical composition containing same and use thereof

本發明關於一種新型化合物，其具有癌症治療活性。本發明還關於這些化合物的製備方法以及包含其的藥物組合物。The present invention relates to a novel compound having cancer therapeutic activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.

臨床資料顯示，RAS是人類腫瘤中發生突變率最高的基因，所有腫瘤中，約20-30%有RAS突變，大約98%的胰腺癌，52%的結腸癌，43%的多發性骨髓瘤，及32%的肺腺癌中存在RAS基因突變。RAS最常見的突變方式是點突變，經常發生在12、13、61 密碼子，其中又以第12 位密碼子突變最常見。KRAS-G12C突變占KRAS突變的約10-20%，在非小細胞肺癌中占14%。Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which the 12th codon mutation is the most common. KRAS-G12C mutations account for approximately 10-20% of KRAS mutations and 14% in non-small cell lung cancer.

40多年來，科學家一直在嘗試開發靶向KRAS藥物。AMGEN公司開發的AMG510是首個進入臨床的KRAS G12C抑制劑。2020年12月，AMGEN公司向美國FDA遞交AMG510的新藥上市申請，用於治療KRAS G12C突變的晚期轉移性非小細胞肺癌。此前，FDA已經授予其突破性療法認證資格。2021年5月，FDA批准全球首個KRAS靶向藥AMG510上市。For more than 40 years, scientists have been trying to develop drugs that target KRAS. AMG510 developed by AMGEN is the first KRAS G12C inhibitor to enter the clinic. In December 2020, AMGEN submitted a New Drug Application for AMG510 to the US FDA for the treatment of KRAS G12C-mutated advanced metastatic non-small cell lung cancer. The FDA has previously granted it Breakthrough Therapy designation. In May 2021, the FDA approved the world's first KRAS-targeted drug, AMG510.

ARAXES公司專利WO2015054572A1記載一種具有特定軸手性片段的KRAS抑制劑，為外消旋體形式。該分子理論上具有R/S兩種手性，但是專利未記載何種為優勢活性構型。

Figure 02_image003
ARAXES company patent WO2015054572A1 describes a KRAS inhibitor with a specific axial chiral fragment in the form of a racemate. The molecule theoretically has both R/S chirality, but the patent does not describe which is the dominant active configuration.
Figure 02_image003

勁方公司專利WO2020177629A1公開了特定手性分子的活性資料（表1）。根據說明書記載，具有相同軸手性片段的兩對手性分子Z2-1/Z2-2和Z25-1/Z25-2，其活性較優的分子Z2-1和Z25-2的構型完全相反。

Figure 02_image005
The patent WO2020177629A1 of Jinfang Company discloses the activity data of specific chiral molecules (Table 1). According to the description, the two chiral molecules Z2-1/Z2-2 and Z25-1/Z25-2 with the same axial chiral fragment, the more active molecules Z2-1 and Z25-2 have completely opposite configurations.
Figure 02_image005

[表1]

Figure 02_image007
[Table 1]
Figure 02_image007

本發明提供一種新型結構的手性KRAS抑制劑。預料不到的是，該手性分子活性優於其對應軸手性異構體，活性差異大於100倍。使用活性更優的手性分子，能夠有效降低藥物用量和避免藥物不良反應，具有重要臨床意義。The present invention provides a chiral KRAS inhibitor with a novel structure. Unexpectedly, this chiral molecule is more active than its corresponding axial chiral isomer, with a greater than 100-fold difference in activity. The use of chiral molecules with better activity can effectively reduce the dosage of drugs and avoid adverse drug reactions, which has important clinical significance.

本發明提供一種通式(I)所示的手性化合物、氘代物或藥用鹽，

Figure 02_image009
(I) 其中X選自C 3-14環烷基、3-14員雜環基、3-14員雜環基氨基；X任選地進一步被 1-4 個取代基取代，其中每個取代基獨立地選自 C 1-6烷基、氨基、C 1-6氨基烷基、氨基甲醯基、C 1-6氨基甲醯基烷基、羧基、C 1-6羧基烷基、氰基、C 1-6氰基烷基、鹵素、C 1-6鹵代烷基、羥基、C 1-6羥烷基，所述C 1-6烷基可任選地被一個或多個選自氨基、氨基甲醯基、羧基、氰基、鹵素、羥基、氧代基所取代； R 1為丙烯醯基、取代的丙烯醯基或
Figure 02_image011
； R 2選自H、C 2-6烯基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 1-6烷基、4-10員雜環基取代的 C 1-6烷基、C 1-6烷基磺醯基、C 1-6烷基亞磺醯基、C 1-6烷硫基、C 2-6炔基、C 1-6烷基氨基、氨基、C 1-6氨基烷基、氨基甲醯基、C 1-6氨基甲醯基烷基、C 1-6羧基烷基、氰基、C 1-6氰基烷基、鹵素、C 1-6鹵代烷基、取代或未取代的芳基、取代或未取代的5-10員雜芳基、取代或未取代的C 3-7環烷基、取代或未取代的4-10員雜環基、羥基或氧代基，所述C 1-6烷基可任選地被一個或多個選自氨基、氨基甲醯基、羧基、氰基、鹵素、羥基、氧代基所取代； R 3選自H、鹵素、C 1-6烷基、取代的C 1-6烷基、C 2-6烯基、取代的C 2-6烯基、C 3-6環烷基或取代的C 3-6環烷基； R 4或R 5獨立地選自H、鹵素、C 1-6烷基、取代的C 1-6烷基、C 3-6環烷基、取代的C 3-6環烷基； R 6選自羥基、氧代基、C 1-6烷氧基、C 3-10環烷基氧基、氰基取代的環丙基C 1-6亞烷基氧基，所述C 1-6烷氧基任選地進一步被一個或多個選自鹵素、羥基、C 1-6烷氧基、C 3-8環烷基的取代基所取代； m或n獨立地選自0、1、2、3、4； Y選自3-14員雜環基，所述雜環基通過環上C原子與喹唑啉環直連相連，所述雜環基任選地進一步被1-4個選自R 7或R 8的取代基所取代；R 7或R 8獨立地選自H、=O、=S、氰基、鹵素、硝基、C 1-6烷基、-C 0-6亞烷基-OR a、 -C 0-6亞烷基-OC(O)N（R a） 2、-C 0-6亞烷基-N（R a） 2、-C 0-6亞烷基-NR aC(O)R a、-C 0-6亞烷基-NR aC(O)N（R a） 2、-C 0-6亞烷基-NR aS(O)R a、-C 0-6亞烷基-NR aS(O) 2R a、-C 0-6亞烷基-S(=O)R a、-C 0-6亞烷基-S(=O) 2R a、-C 0-6亞烷基-SR a、-C 0-6亞烷基-S(R a) 5、-C 0-6亞烷基-C(=O)R a、-C 0-6亞烷基-C(=O)OR a、-C 0-3亞烷基-C(=O)N（R a） 2、C 2-6烯基、C 2-6炔基、丙烯醯基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)任選地還可被1個或多個R a所取代；每個R a各自獨立地選自H、鹵素、羥基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羥基烷基、C 1-6氨基烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 1-6雜烷基、C 3-8環烷基、3-8員雜環基、C 6-14芳基、5-14員雜芳基、C 1-6醯基或
Figure 02_image013
。 The present invention provides a chiral compound, a deuterated compound or a pharmaceutically acceptable salt represented by the general formula (I),
Figure 02_image009
(I) wherein X is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 3-14 membered heterocyclylamino; X is optionally further substituted by 1-4 substituents, wherein each substituted The radicals are independently selected from C 1-6 alkyl, amino, C 1-6 aminoalkyl, carbamoyl, C 1-6 carbamoyl alkyl, carboxy, C 1-6 carboxyalkyl, cyano , C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, hydroxy, C 1-6 hydroxyalkyl, the C 1-6 alkyl may be optionally selected from one or more amino groups, substituted with carbamoyl, carboxyl, cyano, halogen, hydroxyl, oxo; R 1 is acryl, substituted acryl or
Figure 02_image011
; R 2 is selected from H, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 substituted by 4-10-membered heterocyclyl Alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, amino, C 1-6 aminoalkyl, aminocarbamoyl, C 1-6 aminocarbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkane base, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo, the C 1-6 alkyl can be optionally substituted by one or more selected from amino, carboxyl, carboxyl, cyano, halogen, hydroxyl, oxo; R is selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 Cycloalkyl; R 4 or R 5 is independently selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl ; R 6 is selected from hydroxyl, oxo, C 1-6 alkoxy, C 3-10 cycloalkyloxy, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, the C 1 -6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkoxy, C 3-8 cycloalkyl; m or n are independently selected from 0, 1, 2, 3, 4; Y is selected from a 3-14 membered heterocyclic group, the heterocyclic group is directly connected to the quinazoline ring through the C atom on the ring, and the heterocyclic group is optionally further 1- 4 substituents selected from R 7 or R 8 are substituted; R 7 or R 8 are independently selected from H, =O, =S, cyano, halogen, nitro, C 1-6 alkyl, -C 0 -6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 Alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O) R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S( =O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-3 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2- 6 alkynyl, acryloyl, -C 0-6 sub Alkyl-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0- 6 -alkylene-(5-14-membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3- 14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-( 5-14 membered heteroaryl) optionally can also be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano , carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 membered aryl, 5-14 membered heteroaryl, C 1-6 membered acyl or
Figure 02_image013
.

一些實施方式中，式（I）中的 X選自4-10員雜環基，所述4-10員雜環基任選地進一步被1-4個選自C 1-6烷基、氰基、C 1-6氰基烷基、C 1-6羥基烷基的取代基所取代；較佳為

Figure 02_image015
、
Figure 02_image017
、
Figure 02_image019
、
Figure 02_image021
、
Figure 02_image023
、
Figure 02_image025
、
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
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image061
、
Figure 02_image063
或
Figure 02_image065
；更佳為
Figure 02_image047
。 In some embodiments, X in formula (I) is selected from a 4-10 membered heterocyclyl group optionally further selected from 1-4 members selected from C 1-6 alkyl, cyano substituted by substituents of C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl; preferably
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
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
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
,
Figure 02_image057
,
Figure 02_image059
,
Figure 02_image061
,
Figure 02_image063
or
Figure 02_image065
; preferably
Figure 02_image047
.

一些實施方式中，式（I）中的 R 1選自

Figure 02_image067
、
Figure 02_image069
、
Figure 02_image071
、
Figure 02_image073
、
Figure 02_image075
、
Figure 02_image077
、
Figure 02_image079
、
Figure 02_image081
、
Figure 02_image083
、
Figure 02_image085
、
Figure 02_image087
或
Figure 02_image089
；較佳為
Figure 02_image067
。 In some embodiments, R in formula ( I ) is selected from
Figure 02_image067
,
Figure 02_image069
,
Figure 02_image071
,
Figure 02_image073
,
Figure 02_image075
,
Figure 02_image077
,
Figure 02_image079
,
Figure 02_image081
,
Figure 02_image083
,
Figure 02_image085
,
Figure 02_image087
or
Figure 02_image089
; preferably
Figure 02_image067
.

一些實施方式中，式（I）中的 R 2選自H、鹵素或C 1-3烷基；較佳為H。 In some embodiments, R 2 in formula (I) is selected from H, halogen or C 1-3 alkyl; preferably H.

一些實施方式中，式（I）中的 R 3選自H、C 1-6烷基、取代的C 1-6烷基、C 2-6烯基、取代的C 2-6烯基、C 3-6環烷基或取代的C 3-6環烷基；較佳C 1-3烷基、C 3-6環烷基或C 2-4烯基；更佳為乙基、乙烯基或環丙基。 In some embodiments, R in formula (I) is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl; preferably C 1-3 alkyl, C 3-6 cycloalkyl or C 2-4 alkenyl; more preferably ethyl, vinyl or Cyclopropyl.

一些實施方式中，式（I）中的 R 4或R 5選自H、鹵素或C 1-6烷基；較佳R 4為H且R 5為甲基。 In some embodiments, R 4 or R 5 in formula (I) is selected from H, halogen or C 1-6 alkyl; preferably R 4 is H and R 5 is methyl.

一些實施方式中，式（I）中的 R 6選自C 1-6烷氧基、C 3-8環烷基氧基、氰基取代的環丙基C 1-6亞烷基氧基，所述C 1-6烷氧基任選地進一步被一個或多個選自鹵素、羥基、甲氧基、C 3-8環烷基的取代基所取代；較佳R 6選自

Figure 02_image091
、
Figure 02_image093
、
Figure 02_image095
、
Figure 02_image097
、
Figure 02_image099
、
Figure 02_image101
、
Figure 02_image103
、
Figure 02_image105
、
Figure 02_image107
、
Figure 02_image109
或
Figure 02_image111
。 In some embodiments, R 6 in formula (I) is selected from C 1-6 alkoxy, C 3-8 cycloalkyloxy, cyano-substituted cyclopropyl C 1-6 alkyleneoxy, The C 1-6 alkoxy group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, methoxy, C 3-8 cycloalkyl; preferably R 6 is selected from
Figure 02_image091
,
Figure 02_image093
,
Figure 02_image095
,
Figure 02_image097
,
Figure 02_image099
,
Figure 02_image101
,
Figure 02_image103
,
Figure 02_image105
,
Figure 02_image107
,
Figure 02_image109
or
Figure 02_image111
.

一些實施方式中，式（I）中的 Y選自

Figure 02_image113
、
Figure 02_image115
、
Figure 02_image117
、
Figure 02_image119
或
Figure 02_image121
；較佳為
Figure 02_image119
或
Figure 02_image121
；更佳為
Figure 02_image119
。 In some embodiments, Y in formula (I) is selected from
Figure 02_image113
,
Figure 02_image115
,
Figure 02_image117
,
Figure 02_image119
or
Figure 02_image121
; preferably
Figure 02_image119
or
Figure 02_image121
; preferably
Figure 02_image119
.

一些實施方式中，式（I）中的 R 7選自H、氰基、鹵素、C 1-6烷基、-C 0-6亞烷基-OR a、 -C 0-6亞烷基-OC(O)N（R a） 2、-C 0-6亞烷基-N（R a） 2、-C 0-6亞烷基-NR aC(O)R a、-C 0-6亞烷基-NR aC(O)N（R a） 2、-C 0-6亞烷基-NR aS(O)R a、-C 0-6亞烷基-NR aS(O) 2R a、-C 0-6亞烷基-S(=O)R a、-C 0-6亞烷基-S(=O) 2R a、-C 0-6亞烷基-SR a、-C 0-6亞烷基-S(R a) 5、-C 0-6亞烷基-C(=O)R a、-C 0-6亞烷基-C(=O)OR a、-C 0-3亞烷基-C(=O)N（R a） 2、丙烯醯基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)，所述C 1-6烷基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)任選地還可被1個或多個R a所取代；每個R a各自獨立地選自H、鹵素、羥基、氨基、氧代基、氰基、羧基、C 1-6烷基、C 3-8環烷基、3-8員雜環基、C 6-14芳基、5-14員雜芳基、C 1-6醯基或

Figure 02_image013
；較佳R 7選自H、丙烯醯基、C 1-6烷基、C 1-6鹵代烷基、C 1-6醯基、 -C 0-3亞烷基-C 1-6烷氧基、C 1-6羥基烷基、C 1-6氰基烷基、-C 0-3亞烷基-S(=O) 2-C 1-6烷基、C 3-6酮基、
Figure 02_image123
、 、
Figure 02_image125
、
Figure 02_image127
、-C 0-3亞烷基-C 3-6環烷基、-C 0-3亞烷基-C 3-8雜環基、-C 0-3亞烷基-苯基、-C 0-3亞烷基-吡唑基，所述-C 0-3亞烷基-C 3-6環烷基、-C 0-3亞烷基-C 3-8雜環基、-C 0-3亞烷基-苯基、-C 0-3亞烷基-吡唑基任選地進一步被一個或多個選自C 1-6醯基、羥基、C 1-6烷基、C 3-6環烷基、鹵素、
Figure 02_image013
或氰基地取代基所取代，所述C 3-8雜環基含有一個選自O或N的雜原子；更佳R 7選自H、C 1-6烷基、乙醯基、
Figure 02_image129
、
Figure 02_image131
、
Figure 02_image133
、
Figure 02_image135
、
Figure 02_image137
、
Figure 02_image139
、
Figure 02_image141
、
Figure 02_image143
、
Figure 02_image123
、
Figure 02_image145
、
Figure 02_image147
、
Figure 02_image149
、
Figure 02_image151
、
Figure 02_image153
、
Figure 02_image155
、
Figure 02_image157
、
Figure 02_image159
、
Figure 02_image161
、
Figure 02_image163
、
Figure 02_image165
、
Figure 02_image167
、
Figure 02_image169
、
Figure 02_image171
、
Figure 02_image127
、
Figure 02_image173
、
Figure 02_image175
、
Figure 02_image177
或
Figure 02_image179
。 In some embodiments, R 7 in formula (I) is selected from H, cyano, halogen, C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene- OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 Alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-3 alkylene-C(=O)N(R a ) 2 , acryloyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene base-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclic group), -C 0-6 alkylene -C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) optionally can also be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, cyano, carboxyl, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, C 1-6 aryl or
Figure 02_image013
; preferably R 7 is selected from H, acrylyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aryl, -C 0-3 alkylene-C 1-6 alkoxy , C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, -C 0-3 alkylene-S(=O) 2 -C 1-6 alkyl, C 3-6 keto,
Figure 02_image123
, ,
Figure 02_image125
,
Figure 02_image127
, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0-3 alkylene-phenyl, -C 0 -3 alkylene-pyrazolyl, the -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0- 3 alkylene-phenyl, -C 0-3 alkylene-pyrazolyl is optionally further selected from one or more C 1-6 aryl groups, hydroxy, C 1-6 alkyl, C 3- 6 cycloalkyl, halogen,
Figure 02_image013
or cyano substituent, the C 3-8 heterocyclic group contains a heteroatom selected from O or N; more preferably R 7 is selected from H, C 1-6 alkyl, acetyl,
Figure 02_image129
,
Figure 02_image131
,
Figure 02_image133
,
Figure 02_image135
,
Figure 02_image137
,
Figure 02_image139
,
Figure 02_image141
,
Figure 02_image143
,
Figure 02_image123
,
Figure 02_image145
,
Figure 02_image147
,
Figure 02_image149
,
Figure 02_image151
,
Figure 02_image153
,
Figure 02_image155
,
Figure 02_image157
,
Figure 02_image159
,
Figure 02_image161
,
Figure 02_image163
,
Figure 02_image165
,
Figure 02_image167
,
Figure 02_image169
,
Figure 02_image171
,
Figure 02_image127
,
Figure 02_image173
,
Figure 02_image175
,
Figure 02_image177
or
Figure 02_image179
.

一些實施方式中，式（I）中的 R 8選自H或C 1-6烷基；較佳為H。 In some embodiments, R 8 in formula (I) is selected from H or C 1-6 alkyl; preferably H.

一些實施方式中，通式（I）所示的手性化合物選自式(IA)-(ID)化合物，

Figure 02_image181
Figure 02_image183
(IA)                                       (IB)
Figure 02_image185
Figure 02_image187
(IC)                                          (ID) ；較佳為
Figure 02_image181
(IA) 其中，取代基如通式（I）所定義。 In some embodiments, the chiral compound represented by general formula (I) is selected from the compounds of formula (IA)-(ID),
Figure 02_image181
Figure 02_image183
(IA) (IB)
Figure 02_image185
Figure 02_image187
(IC) (ID); preferably
Figure 02_image181
(IA) wherein the substituents are as defined in general formula (I).

本發明還提供一種手性化合物、氘代物或藥用鹽，其選自：

Figure 02_image189
Figure 02_image191
Figure 02_image193
；較佳為
Figure 02_image195
、
Figure 02_image197
或
Figure 02_image199
。 The present invention also provides a chiral compound, a deuterated substance or a pharmaceutically acceptable salt, which is selected from:
Figure 02_image189
Figure 02_image191
Figure 02_image193
; preferably
Figure 02_image195
,
Figure 02_image197
or
Figure 02_image199
.

本發明提供一種藥物組合物，所述藥物組合物含有式（I）中的任一項所述的手性化合物、氘代物或藥用鹽和至少一種藥學上可接受的輔料，藥物組合物中所述手性化合物含量比其對應軸手性異構體含量更高。The present invention provides a pharmaceutical composition, the pharmaceutical composition contains the chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of formula (I) and at least one pharmaceutically acceptable excipient, in the pharmaceutical composition The chiral compound is present in a higher content than its corresponding axial chiral isomer.

本發明還提供一種藥物組合物，藥物組合物中所述通式(I)所示的手性化合物、氘代物、藥用鹽在活性成分中的含量高於51%、61%、71%、81%、91%、99%或更高。The present invention also provides a pharmaceutical composition, in which the content of the chiral compound, deuterated compound and pharmaceutically acceptable salt represented by the general formula (I) in the active ingredient is higher than 51%, 61%, 71%, 81%, 91%, 99% or higher.

本發明還提供一種藥物組合物，藥物組合物中治療有效量的至少一種式（I）所示的化合物、氘代物、藥用鹽和藥學上可接受的輔料的質量百分比為0.0001:1-10。The present invention also provides a pharmaceutical composition, in which the therapeutically effective amount of at least one compound represented by formula (I), deuterated substance, pharmaceutically acceptable salt and pharmaceutically acceptable adjuvant is 0.0001:1-10 .

本發明還提供通式(I)中手性化合物、氘代物、藥用鹽或含有結構式（I）所示化合物的藥物組合物在製備藥物中的應用；較佳所述藥物為抗癌藥物。The present invention also provides the application of the chiral compound, deuterated compound, pharmaceutically acceptable salt or pharmaceutical composition containing the compound represented by structural formula (I) in the preparation of medicine; preferably, the medicine is an anticancer medicine .

作為較佳，所述應用為製備用於治療由KRAS G12C介導的疾病的藥物的應用。作為較佳，所述疾病是癌症。Preferably, the application is the application of a medicine for the treatment of a disease mediated by KRAS G12C. Preferably, the disease is cancer.

作為較佳，所述癌症選自乳腺癌、多發性骨髓瘤、膀胱癌、子宮內膜癌、胃癌、宮頸癌、橫紋肌肉瘤、非小細胞肺癌、小細胞肺癌、多形性肺癌、卵巢癌、食道癌、黑色素瘤、結腸直腸癌、肝細胞瘤、頭頸部腫瘤、肝膽管細胞癌、骨髓增生異常症候群、惡性膠質瘤、***癌、甲狀腺癌、許旺氏細胞瘤、肺鱗狀細胞癌、苔蘚樣角化病、滑膜肉瘤、皮膚癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, Esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, Lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

本發明還提供一種治療和/或預防癌症的方法，包括向治療物件施用治療有效量的通式(I)中手性化合物、氘代物、藥用鹽或含有結構式（I）所示化合物的藥物組合物；較佳所述癌症是由KRAS G12C，HRAS G12C或NRAS G12C突變介導的。The present invention also provides a method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of a chiral compound, a deuterated compound, a pharmaceutically acceptable salt or a compound of formula (I) to a therapeutic object. Pharmaceutical composition; preferably the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.

作為較佳，在上述方法中，所述的癌症選自乳腺癌、多發性骨髓瘤、膀胱癌、子宮內膜癌、胃癌、宮頸癌、橫紋肌肉瘤、非小細胞肺癌、小細胞肺癌、多形性肺癌、卵巢癌、食道癌、黑色素瘤、結腸直腸癌、肝細胞瘤、頭頸部腫瘤、肝膽管細胞癌、骨髓增生異常症候群、惡性膠質瘤、***癌、甲狀腺癌、許旺氏細胞瘤、肺鱗狀細胞癌、苔蘚樣角化病、滑膜肉瘤、皮膚癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular tumor, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, Lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

除非另有說明，所述結構通式中使用的一般化學術語具有通常的含義。Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.

例如，除非另有說明，本發明所用的術語“鹵素”是指氟、氯、溴或碘。For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

在本發明中，除非另有說明，“烷基”包括直鏈或支鏈的一價飽和烴基。 例如，烷基包括甲基、乙基、丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。類似的，“C 1-8烷基”中的“ 1-8”是指包含有1、2、3、4、5、6、7或8個碳原子的直鏈或支鏈形式排列的基團。 In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " 1-8 " in "C 1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.

“C 1-3亞烷基”是指包括直鏈或支鏈的二價飽和烴基。例如亞甲基、1,2-亞乙基、1,3-亞丙基或1,2-亞異丙基。類似的，“C 1-6亞烷基”中的“ 1-6”是指包含有1、2、3、4、5或6個碳原子的直鏈或支鏈形式排列的基團。 "C 1-3 alkylene" means a divalent saturated hydrocarbon group including straight or branched chains. For example methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene. Similarly, " 1-6 " in " C1-6 alkylene" refers to groups containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in straight or branched chain form.

在本發明中，“一”、“一個”、“該”、“至少一個”和“一個或多個”可互換使用。因此，例如，包含“一種”藥學上可接受的賦形劑的組合物可以被解釋為表示該組合物包括“一種或多種”藥學上可接受的賦形劑。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

術語“芳基”，在本發明中，除非另有說明，是指未取代或取代的包括碳環的原子的單環或稠環芳香基團，具有完全共軛的π電子體系。較佳芳基為6-14員的單環或多環的芳香環基團。較佳為苯基、萘基。最佳為苯基。所述芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環。The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring, having a fully conjugated pi-electron system. The preferred aryl group is a 6-14 membered monocyclic or polycyclic aromatic ring group. Preferred are phenyl and naphthyl. The best is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

術語“雜環基”，在本發明中，除非另有說明，是指由碳原子和1-3個選自N、O或S的雜原子組成的未取代或取代的3-14員穩定環系統，其為飽和或部分不飽和單環或多環環狀烴取代基，如螺環或橋環。雜環基中氮或硫雜原子可以選擇性地被氧化，並且氮雜原子可以選擇性地被季銨化。該雜環基可以被連接到任何的雜原子或碳原子上以形成穩定的結構。這些雜環基的實例包括但不限於氮雜環丁烷基、吡咯烷基、呱啶基、呱嗪基、氧代呱嗪基、氧代呱啶基、四氫呋喃基、二氧戊環基、四氫咪唑基、四氫噻唑基、四氫噁唑基、四氫吡喃基、嗎啉基、硫代嗎啉基、硫代嗎啉基亞碸、硫代嗎啉基碸基和四氫噁二唑基。所述雜環基可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基。The term "heterocyclyl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. system, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, such as a spiro or bridged ring. Nitrogen or sulfur heteroatoms in heterocyclyl groups can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxidyl, oxazinyl, oxoxazinyl, oxoxaziridinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylidene, thiomorpholinyl and tetrahydro oxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.

術語“螺環基”，在本發明中，除非另有說明，是指兩個單環共用一個碳原子的多環化合物，這些螺環基的實例包括但不限於

Figure 02_image201
、
Figure 02_image203
、
Figure 02_image205
、
Figure 02_image207
、
Figure 02_image209
、
Figure 02_image211
、
Figure 02_image213
、
Figure 02_image215
、
Figure 02_image217
、
Figure 02_image219
、
Figure 02_image221
、
Figure 02_image223
、
Figure 02_image225
、
Figure 02_image227
、
Figure 02_image229
Figure 02_image231
、
Figure 02_image233
或
Figure 02_image235
。 The term "spirocyclyl", in the present invention, unless otherwise specified, refers to a polycyclic compound in which two monocyclic rings share one carbon atom, and examples of these spirocyclyls include but are not limited to
Figure 02_image201
,
Figure 02_image203
,
Figure 02_image205
,
Figure 02_image207
,
Figure 02_image209
,
Figure 02_image211
,
Figure 02_image213
,
Figure 02_image215
,
Figure 02_image217
,
Figure 02_image219
,
Figure 02_image221
,
Figure 02_image223
,
Figure 02_image225
,
Figure 02_image227
,
Figure 02_image229
Figure 02_image231
,
Figure 02_image233
or
Figure 02_image235
.

術語“橋環基”，在本發明中，除非另有說明，是指兩個單環共用兩個或兩個以上碳原子的多環化合物，這些橋環基的實例包括但不限於

Figure 02_image063
或
Figure 02_image065
。 The term "bridged ring group", in the present invention, unless otherwise specified, refers to a polycyclic compound in which two monocyclic rings share two or more carbon atoms, and examples of these bridged ring groups include but are not limited to
Figure 02_image063
or
Figure 02_image065
.

術語“雜芳基”，在本發明中，除非另有說明，是指未取代或取代的穩定的5員或6員單環芳族環系統或未取代或取代的9-14員苯并稠合雜芳族環系統或多環雜芳族環系統，其由碳原子和1-4個選自N、O或S的雜原子組成，並且其中所述氮或硫雜原子可以選擇性地被氧化，所述氮雜原子可以選擇性地被季銨化。雜芳基可以連接在任何雜原子或碳原子上以形成穩定的結構。雜芳基的實例包括但不限於噻吩基、呋喃基、咪唑基、異噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、噠嗪基、吲哚基、氮雜吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并異噁唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或異喹啉基。所述雜芳基可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環。The term "heteroaryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- to 14-membered benzo-fused A heteroaromatic ring system or a polycyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally replaced by oxidation, the nitrogen heteroatom can be selectively quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

術語“環烷基”是指具有3-14個碳原子的環狀飽和或部分不飽和單環或多環環狀烴取代基，例如，環丙基、環丁基、環戊基或環己基。所述環烷基可以稠合於芳基、雜環基或雜芳基環上，其中與母體結構連接在一起的環為環烷基。The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl . The cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.

術語“取代的”是指基團中的一個或多個氫原子分別被相同的或者不同的取代基所取代。典型的取代基包括但不限於H、=O、=S、氰基、鹵素、硝基、C 1-6烷基、-C 0-6亞烷基-OR a、 -C 0-6亞烷基-OC(O)N（R a） 2、-C 0-6亞烷基-N（R a） 2、-C 0-6亞烷基-NR aC(O)R a、-C 0-6亞烷基-NR aC(O)N（R a） 2、-C 0-6亞烷基-NR aS(O)R a、-C 0-6亞烷基-NR aS(O) 2R a、-C 0-6亞烷基-S(=O)R a、-C 0-6亞烷基-S(=O) 2R a、-C 0-6亞烷基-SR a、-C 0-6亞烷基-S(R a) 5、-C 0-6亞烷基-C(=O)R a、-C 0-6亞烷基-C(=O)OR a、-C 0-3亞烷基-C(=O)N（R a） 2、C 2-6烯基、C 2-6炔基、丙烯醯基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)任選地還可被1個或多個R a所取代；每個R a各自獨立地選自H、鹵素、羥基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羥基烷基、C 1-6氨基烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 1-6雜烷基、C 3-8環烷基、3-8員雜環基、C 6-14芳基、5-14員雜芳基、C 1-6醯基或

Figure 02_image013
。在一些實施例中，取代基獨立地選自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺醯基和乙醯基的基團。 The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, H, =O, =S, cyano, halogen, nitro, C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene Base-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0 -6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S( O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene- SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O) OR a , -C 0-3 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, acrylidene, -C 0-6 alkylene -C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene Alkyl-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3-14 ring Alkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5- 14-membered heteroaryl) optionally can also be substituted by one or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl , C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 membered aryl, 5-14 membered heteroaryl, C 1-6 membered heteroaryl or
Figure 02_image013
. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.

取代烷基的實例包括但不限於2,3-二羥基丙基、2-氨基乙基、2-羥乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二噁茂基甲基和呱嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and oxazinylmethyl.

取代烷氧基的實例包括但不限於2-羥基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羥基丙氧基、環丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羥基丙氧基。Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.

術語“羥基烷基”是指一個或多個羥基取代的烷基，例如-(亞烷基)-OH。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, eg, -(alkylene)-OH.

術語“鹵代烷基”是指一個或多個鹵素取代的烷基，例如-(亞烷基)-鹵素。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, eg, -(alkylene)-halogen.

術語“烷氧基”是指-O-(烷基)。The term "alkoxy" refers to -O-(alkyl).

術語“藥學上可接受的鹽”是指從藥學上可接受的無毒的鹼或酸製備的鹽。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

由於式（I）所示化合物將作為藥物應用，較佳地，使用一定純度，例如，至少為60%純度，比較合適的純度為至少75%，特別合適地純度為至少98%（%是重量比）。Since the compound represented by the formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).

本發明化合物的藥物前體包含在本發明的保護範圍內。通常，所述藥物前體是指很容易在體內轉化成所需化合物的功能性衍生物。例如，本發明化合物的任何藥學上可接受的鹽、酯、酯的鹽或其它衍生物，其在向受體施用後能夠直接或間接地提供本發明的化合物或其具有藥學活性的代謝物或殘基。特別較佳的衍生物或前藥是在施用於患者時可以提高本發明化合物生物利用度的那些化合物(例如，可以使口服的化合物更易於被吸收到血液中)，或者促進母體化合物向生物器官或作用位點(例如腦部或淋巴系統)遞送的那些化合物。因此，本發明提供的治療方法中的術語“給藥”是指施用能治療不同疾病的本發明公開的化合物，或雖未明確公開但對受試者給藥後能夠在體內轉化為本發明公開的化合物的化合物。Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a pharmaceutically active metabolite thereof or Residues. Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the present invention when administered to a patient (eg, make orally administered compounds more readily absorbed into the bloodstream), or promote the delivery of the parent compound to a biological organ or those compounds delivered to the site of action (eg, the brain or lymphatic system). Therefore, the term "administration" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or, although not explicitly disclosed, can be transformed into the disclosed compounds in vivo after administration to a subject compounds of compounds.

顯然的，一個分子中任何取代基或特定位置的變數的定義是獨立於分子中其他位置的。很容易理解，本領域技術人員可以通過現有技術手段及本發明中所述的方法來選擇本發明中的化合物的取代基或取代形式，以獲得化學上穩定且易於合成的化合物。Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substituted forms of the compounds of the present invention by means of the prior art and the methods described in the present invention, so as to obtain chemically stable and easy-to-synthesize compounds.

本發明所述化合物可能含有一個或多個不對稱中心，並可能由此產生非對映異構體和光學異構體。本發明包括所有可能的非對映異構體及其外消旋混合物、其基本上純的拆分對映異構體、所有可能的幾何異構體及其藥學上可接受的鹽。The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

當式（I）所示化合物存在互變異構體時，除非特別聲明，本發明包括任何可能的互變異構體和其藥學上可接受的鹽，及它們的混合物。When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

當式（I）所示化合物用較重的同位素（例如氘）替代可能提供某些治療優勢，這是由於更大的代謝穩定性，例如增加體內半衰期或減少劑量要求。Substitution of compounds of formula (I) with heavier isotopes such as deuterium may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

當式（I）所示化合物及其藥學上可接受的鹽存在溶劑化物或多晶型時，本發明包括任何可能的溶劑化物和多晶型。形成溶劑化物的溶劑類型沒有特別的限定，只要該溶劑是藥學上可以接受的。例如，水、乙醇、丙醇、丙酮等類似的溶劑都可以採用。When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

術語“組合物”，在本發明中，是指包括包含指定量的各指定成分的產品，以及直接或間接地由指定量的各指定成分的組合生產的任何產品。因此，含有本發明的化合物作為活性成分的藥物組合物以及製備本發明化合物的方法也是本發明的一部分。此外，化合物的一些結晶形式可以多晶型存在，並且此多晶型包括在本發明中。另外，一些化合物可以與水（即水合物）或常見的有機溶劑形成溶劑化物，並且此類溶劑化物也落入本發明的範圍內。The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.

本發明提供的藥物組合物包括作為活性組分的式（I）所示化合物（或其藥學上可接受的鹽）、一種藥學上可接受的賦形劑及其他可選的治療組分或輔料。儘管任何給定的情況下，最適合的活性組分給藥方式取決於接受給藥的特定的主體、主體性質和病情嚴重程度。本發明的藥物組合物可以方便地以本領域公知的單位劑型存在和藥學領域公知的任何製備方法製備。The pharmaceutical composition provided by the present invention includes the compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or excipients . Although in any given situation, the most appropriate mode of administration of the active ingredient will depend on the particular subject to be administered, the nature of the subject and the severity of the condition. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.

本發明的藥物組合物包括藥學上可接受的載體和式（I）所示化合物或其立體異構體、互變異構體，多晶型物、溶劑化物、其藥學上可接受的鹽、其藥物前體。式（I）所示化合物或其藥學上可接受的鹽，與其他一種或多種具有治療活性的化合物的聯合用藥也包括在本發明的藥物組合物中。The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or its stereoisomer, tautomer, polymorph, solvate, its pharmaceutically acceptable salt, its prodrugs. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, combined with one or more other compounds with therapeutic activity are also included in the pharmaceutical composition of the present invention.

本發明的藥物組合物包括適於口腔、直腸、局部和不經腸道（包括皮下給藥、肌肉注射、靜脈給藥）給藥的藥物組合物。含有本發明化合物或藥物組合物的片劑或膠囊可含有一種或多種輔助組分。較佳地，每個片劑或膠囊含有大約0.05mg到5g的活性組分。本發明還提供適用於注射的藥物組合物，包括無菌水溶液或分散體系。進一步地，上述藥物組合物可以製備成無菌粉末形式以用於即時配製無菌注射液或分散液。本發明提供的藥物組合物可以是適於局部用藥的形式，例如，氣溶膠、乳劑、軟膏、洗液、撒粉或其他類似的劑型。進一步地，本發明提供的藥物組合物可以採用適於經皮給藥設備使用的形式。本發明提供的藥物組合物，可以以固體為載體，適用於直腸給藥的形式。單位劑量的栓劑是最典型的劑型。栓劑可以方便地製備，首先藥物組合物與軟化或熔化的輔料混合，然後冷卻和模具成型而制得。The pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. Tablets or capsules containing a compound or pharmaceutical composition of the present invention may contain one or more accessory ingredients. Preferably, each tablet or capsule contains about 0.05 mg to 5 g of active ingredient. The present invention also provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared in sterile powder form for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical compositions provided by the present invention may be in a form suitable for topical administration, eg, an aerosol, cream, ointment, lotion, dusting powder, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. The pharmaceutical composition provided by the present invention can be in the form of rectal administration by using a solid as a carrier. Unit-dose suppositories are the most typical dosage form. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and moulding.

上述製劑配方還可以包括，適當的，一種或多種附加的輔料組分，如稀釋劑、緩衝劑、調味劑、黏合劑、表面活性劑、增稠劑、潤滑劑和防腐劑（包括抗氧化劑）等。進一步地，其他的輔藥還可以包括調節藥物與血液等滲壓的促滲劑。包含式（I）所示化合物，或其藥學上可接受的鹽的藥物組合物，可以製備成粉劑或濃縮液的形式。The above formulation formulations may also include, where appropriate, one or more additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants and preservatives (including antioxidants) Wait. Further, other adjuvants may also include osmotic enhancers that adjust the isotonic pressure of the drug and blood. The pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of powder or concentrated solution.

一般情況下，治療上述所示的狀況或不適，藥物的劑量水平約為每天0.01mg/kg體重到150mg/kg體重，或者每個病人每天0.5mg到7g。但是，可以理解，可能需要比上述那些更低或更高的劑量。任何特定病人的具體劑量水平和治療方案將取決於多種因素，包括所用具體化合物的活性、年齡、體重、綜合健康狀況、性別、飲食、給藥時間、給藥途徑、***率、藥物聯用的情況和接受治療的特定疾病的嚴重程度。In general, to treat the conditions or disorders indicated above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. It will be appreciated, however, that lower or higher doses than those described above may be required. The specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination used. condition and the severity of the specific disease being treated.

為使上述內容更清楚、明確，本發明將用以下實施例來進一步闡述本發明的技術方案。以下實施例僅用於說明本發明的具體實施方式，以使本領域的技術人員能夠理解本發明，但不用於限制本發明的保護範圍。本發明的具體實施方式中，未作特別說明的技術手段或方法等為本領域的常規技術手段或方法等。In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.

除非另有說明，本發明所有的一部分和百分比均按重量計算，所有溫度均指攝氏度。All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

實施例中使用了下列縮略語： BOP：卡特縮合劑； CDI：羰基二咪唑； DBU:   1,8-二氮雜雙環[5.4.0]十一碳-7-烯； DIEA：N，N-二異丙基乙胺； DMF：N，N-二甲基甲醯胺； DCM: 二氯甲烷； Dioxane：二氧六環； ESI-MS：電噴霧電離質譜； EtOH：乙醇； HOAc：冰醋酸； MeOH：甲醇； NIS：N-碘代丁二醯亞胺； NCS：N-氯代丁二醯亞胺； PE:EA：石油醚和乙酸乙酯的比值； POCl 3：三氯氧磷； SOCl 2：二氯亞碸； THF ：四氫呋喃； TFA：三氟乙酸； TEA：三乙胺； Toluene：甲苯； Sphos Pd G2：氯(2-二環己基膦基-2,6-二甲氧基-1,1-聯苯基)(2-氨基-1,1-聯苯-2-基)鈀(II)； Pd(dppf)Cl 2.CH 2Cl 2：[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物； Pd(PPh 3) 4：四（三苯基膦）鈀； Pre-TLC: 薄層層析矽膠板。 The following abbreviations are used in the examples: BOP: Carter condensing agent; CDI: carbonyldiimidazole; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DIEA: N,N- Diisopropylethylamine; DMF: N,N-Dimethylformamide; DCM: Dichloromethane; Dioxane: Dioxane; ESI-MS: Electrospray Ionization Mass Spectrometry; EtOH: Ethanol; HOAc: Glacial Acetic Acid ; MeOH: methanol; NIS: N-iodosuccinimide; NCS: N-chlorosuccinimide; PE:EA: ratio of petroleum ether and ethyl acetate; POCl 3 : phosphorus oxychloride; SOCl 2 : dichlorosulfite; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TEA: triethylamine; Toluene: toluene; Sphos Pd G2: chloro(2-dicyclohexylphosphino-2,6-dimethoxy -1,1-biphenyl)(2-amino-1,1-biphenyl- 2 -yl)palladium( II ); Pd(dppf) Cl2.CH2Cl2 : [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex; Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium; Pre-TLC: thin layer chromatography on silica gel plate.

中間體化合物M1合成

Figure 02_image237
Synthesis of intermediate compound M1
Figure 02_image237

步驟1：化合物M1-2的合成Step 1: Synthesis of Compound M1-2

在室溫下，向化合物M1-1(40g)，HOAc (76.8g)，EtOH (400mL)與H 2O(160mL)的混合物中逐份添加鐵粉(26.52g)。所得混合物在室溫下攪拌2小時，隨後用NaOH (5N)溶液中和。隨後用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮得褐色油狀的所要粗品產物(34g，98%產率)，即化合物M1-2。 To a mixture of compound M1-1 (40 g), HOAc (76.8 g), EtOH (400 mL) and H2O (160 mL) was added iron powder (26.52 g) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then neutralized with NaOH (5N) solution. The mixture was then extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired crude product as a brown oil (34 g, 98% yield), compound M1-2.

ESI-MS m/z: 190.02 [M+H] +。 ESI-MS m/z: 190.02 [M+H] + .

步驟2：化合物M1-3的合成Step 2: Synthesis of Compound M1-3

將2,2,2-三氯乙烷-1,1-二醇(66.4g)與Na 2SO 4(503.4g)溶於水（560mL）中，然後升溫熱至55℃。添加含有化合物M1-2(34g)的水（240mL）和35% HC1（72mL），再添加鹽酸羥胺(81.4g)的水溶液（100mL）。所得混合物在90℃攪拌3小時且形成黃色沉澱物。將混合物冷卻至室溫。通過過濾收集固體,用水沖洗,且風乾,得到黃褐色固體產物(47g，99%產率) ，即化合物M1-3。 2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na 2 SO 4 (503.4 g) were dissolved in water (560 mL) and heated to 55°C. Water (240 mL) containing compound M1-2 (34 g) and 35% HCl (72 mL) were added, followed by an aqueous solution (100 mL) of hydroxylamine hydrochloride (81.4 g). The resulting mixture was stirred at 90°C for 3 hours and a yellow precipitate formed. The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with water, and air-dried to give the product as a tan solid (47 g, 99% yield), compound M1-3.

ESI-MS m/z: 261.03 [M+H] +。 ESI-MS m/z: 261.03 [M+H] + .

步驟3：化合物M1-4的合成Step 3: Synthesis of Compounds M1-4

在60℃，向濃硫酸(300mL)中添加化合物M1-3(47g),將溫度升高至90℃且維持3小時，反應完全，將反應混合物冷卻至室溫且傾注入冰水中。通過過濾收集黃色沉澱物且乾燥，得到黑色固體產物(43g，99%產率) ，即化合物M1-4。Compound M1-3 (47 g) was added to concentrated sulfuric acid (300 mL) at 60 °C, the temperature was raised to 90 °C and maintained for 3 hours, the reaction was complete, the reaction mixture was cooled to room temperature and poured into ice water. The yellow precipitate was collected by filtration and dried to give the product as a black solid (43 g, 99% yield), compound M1-4.

步驟4：化合物M1-5的合成Step 4: Synthesis of Compounds M1-5

在0℃，將化合物M1-4(43g)於NaOH (2N, 500mL)中的溶液中添加H 2O 2溶液(30%，80mL)且所得混合物在0℃攪拌30分鐘。再移至室溫下攪拌2小時，反應完全，將混合物傾注入冰水中再用濃HCI溶液酸化，通過過濾收集沉澱物且風乾，得到呈白色固體狀產物(20g，48.9%產率)，即化合物M1-5。 To a solution of compound M1-4 (43 g) in NaOH (2N, 500 mL) was added H2O2 solution (30%, 80 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. Then moved to room temperature and stirred for 2 hours, the reaction was complete, the mixture was poured into ice water and acidified with concentrated HCl solution, the precipitate was collected by filtration and air-dried to obtain a white solid product (20 g, 48.9% yield), namely Compounds M1-5.

ESI-MS m/z: 233.97 [M+H] +。 ESI-MS m/z: 233.97 [M+H] + .

步驟5：化合物M1-6的合成Step 5: Synthesis of Compounds M1-6

在室溫下，向化合物M1-5(20g)於DMF (200mL)中的溶液中添加NIS (29g)且所得混合物在70℃攪拌過夜。反應完全，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮得褐色固體狀的所要粗品產物(30g，98%產率) ，即化合物M1-6。 To a solution of compound M1-5 (20 g) in DMF (200 mL) was added NIS (29 g) at room temperature and the resulting mixture was stirred at 70 °C overnight. The reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired crude product (30 g, 98% yield) as a brown solid, i.e. Compounds M1-6.

ESI-MS m/z: 359.87[M+H] +。 ESI-MS m/z: 359.87 [M+H] + .

1H NMR (500 MHz, DMSO) δ 13.34 (s, 1H), 7.99 (s, 1H), 6.87 (s, 2H)。1H NMR (500 MHz, DMSO) δ 13.34 (s, 1H), 7.99 (s, 1H), 6.87 (s, 2H).

步驟6：化合物M1的合成Step 6: Synthesis of Compound M1

在室溫下，將二（咪唑-1-基）甲酮(2.70g)加入到粗品化合物M1-6(4.0g)的THF(20mL)中，再將N-乙基-N-異丙基丙-2-胺(1.44g，1.94mL)加入其中，混合物移至50℃反應，約反應2小時化合物M1-6基本完全轉化為中間產物，接著將混合物逐滴加入到冰的氨水(35mL)中，攪拌5min即反應完全。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（石油醚/乙酸乙酯=70:30）純化，得到褐色固體狀的所要目標產物化合物M1(1.64g)。 At room temperature, bis(imidazol-1-yl)methanone (2.70 g) was added to crude compound M1-6 (4.0 g) in THF (20 mL), followed by N-ethyl-N-isopropyl Propan-2-amine (1.44g, 1.94mL) was added, the mixture was moved to 50°C for reaction, and the reaction was about 2 hours. Compound M1-6 was almost completely converted into an intermediate product, and then the mixture was added dropwise to ice-water ammonia (35mL) , the reaction was completed after stirring for 5 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=70:30) , the desired target product compound M1 (1.64 g) was obtained as a brown solid.

中間體化合物M2合成

Figure 02_image239
Synthesis of intermediate compound M2
Figure 02_image239

步驟1：化合物M2-1的合成Step 1: Synthesis of Compound M2-1

在室溫條件下，將化合物M1-5(3.6g)溶於DMF(20mL)中，加入NCS (2.05g)，在70℃反應1.5 h。反應完全，降到室溫，加水稀釋，用EA萃取三次，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾得棕色固體M2-1 (3.86 g，粗品)。 At room temperature, compound M1-5 (3.6 g) was dissolved in DMF (20 mL), NCS (2.05 g) was added, and the reaction was carried out at 70° C. for 1.5 h. The reaction was completed, cooled to room temperature, diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, and spin-dried to obtain a brown solid M2-1 (3.86 g, crude product).

ESI-MS m/z: 267.91 [M+H] +。 ESI-MS m/z: 267.91 [M+H] + .

步驟2：化合物M2-2的合成Step 2: Synthesis of Compound M2-2

在室溫條件下，將化合物M2-1(3.7g)溶於THF（20mL）中，依次加入CDI(2.98g，)，DIEA (5.34g)，在50℃反應1.5h後，在冰浴條件下將反應液逐滴到氨水(40mL)中，攪拌5min即反應完全。加水稀釋，用EA萃取三次，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾。矽膠柱分離純化（PE:EA=2:1）得黃色固體M2-2 (2.32 g，62.93%產率)。 At room temperature, compound M2-1 (3.7 g) was dissolved in THF (20 mL), CDI (2.98 g, ) and DIEA (5.34 g) were added successively, and the reaction was carried out at 50 °C for 1.5 h. The reaction solution was added dropwise to ammonia water (40 mL) and stirred for 5 min to complete the reaction. Diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na2SO4 , filtered, and spin-dried. Silica gel column separation and purification (PE:EA=2:1) gave yellow solid M2-2 (2.32 g, 62.93% yield).

ESI-MS m/z: 266.93 [M+H] +。 ESI-MS m/z: 266.93 [M+H] + .

步驟3：化合物M2-3的合成Step 3: Synthesis of Compound M2-3

在室溫條件下，將化合物1-1 (4.17g)溶於THF(10mL)中，加入M2-2(2.3g)，40℃反應4h。降到室溫，加水淬滅，用EA萃取三次，合併有機相並用無水硫酸鈉乾燥，過濾，旋乾。得棕色固體M2-3（3.4 g，粗品）。At room temperature, compound 1-1 (4.17 g) was dissolved in THF (10 mL), M2-2 (2.3 g) was added, and the reaction was performed at 40° C. for 4 h. It was cooled to room temperature, quenched by adding water, extracted three times with EA, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and spin-dried. M2-3 was obtained as a brown solid (3.4 g, crude).

ESI-MS m/z: 392.01 [M+H] +。 ESI-MS m/z: 392.01 [M+H] + .

步驟4：化合物M2-4的合成Step 4: Synthesis of Compound M2-4

在室溫條件下，將甲醇鈉(2.34g)加入到化合物M2-3(3.4g)的甲苯(50mL)中，移至110℃回流攪拌5小時。降到室溫，加水稀釋，用3N HCl調節pH至6，用EA萃取三次，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，得到棕色固體M2-4（2.63g，粗品）。 At room temperature, sodium methoxide (2.34 g) was added to a solution of compound M2-3 (3.4 g) in toluene (50 mL), and the mixture was moved to 110° C. and stirred under reflux for 5 hours. Cooled to room temperature, diluted with water, adjusted pH to 6 with 3N HCl, extracted three times with EA, combined organic phases and dried over anhydrous Na 2 SO 4 , filtered, and spin-dried to give brown solid M2-4 (2.63 g, crude).

ESI-MS m/z: 374.01 [M+H] +。 ESI-MS m/z: 374.01 [M+H] + .

步驟5：化合物M2-5的合成Step 5: Synthesis of Compound M2-5

在室溫條件下，氮氣保護下，將DIEA(5mL)加入到化合物M2-4(2.6g)的POCl 3(50mL)中，移至110℃攪拌2小時。待反應完全後，直接濃縮除去POCl 3，得到棕褐色固體M2-5（2.8 g，粗品）。 Under nitrogen protection, DIEA (5 mL) was added to POCl 3 (50 mL) of compound M2-4 (2.6 g) at room temperature, moved to 110° C. and stirred for 2 hours. After the reaction was completed, the POCl 3 was directly concentrated to remove the tan solid M2-5 (2.8 g, crude product).

ESI-MS m/z: 391.97 [M+H] +。 ESI-MS m/z: 391.97 [M+H] + .

步驟6：化合物M2的合成Step 6: Synthesis of Compound M2

在室溫條件下，將DIEA(4.60g)加入到化合物M2-5(2.8g)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(1.93g)的二氧六環(30mL)中，室溫反應5min。加水淬滅，用EA萃取三次，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，矽膠柱分離純化（DCM:MeOH=10:1），得到棕色固體M2(3.4g，81.9%產率)。 DIEA (4.60 g) was added to compound M2-5 (2.8 g), a diazepine solution of 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (1.93 g) at room temperature In oxane (30 mL), the reaction was carried out at room temperature for 5 min. It was quenched by adding water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spin-dried, and purified by silica gel column separation (DCM:MeOH=10:1) to obtain a brown solid M2 (3.4 g, 81.9% yield). Rate).

ESI-MS m/z: 582.16 [M+H] +。 ESI-MS m/z: 582.16 [M+H] + .

實施例1：化合物1（1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image241
Example 1: Compound 1 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1methylpyridin-4-yl)-8-(2, 2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one )Synthesis
Figure 02_image241

步驟1：化合物1-1的合成Step 1: Synthesis of Compound 1-1

在室溫下，氮氣保護下，將1-甲基呱啶-4-羧酸(500mg)溶於SOCl 2(2mL)中，移至70℃下，攪拌反應1h。真空濃縮，除去氯化亞碸，得到白色固體狀目標產物，即化合物1-1(520mg，粗品)。 At room temperature, under nitrogen protection, 1-methylpyridine-4-carboxylic acid (500 mg) was dissolved in SOCl 2 (2 mL), moved to 70° C., and the reaction was stirred for 1 h. Concentration in vacuo to remove the thionous chloride gave the desired product as a white solid, namely compound 1-1 (520 mg, crude).

步驟2：化合物1-2的合成Step 2: Synthesis of Compounds 1-2

在室溫下，將化合物1-1(405.27mg)加入到化合物M1(450mg)的THF(10mL)中，移至40℃攪拌4小時。待反應完全後，直接濃縮出去THF，得到白色固體狀粗品目標產物，即化合物1-2（600mg，粗品）。Compound 1-1 (405.27 mg) was added to compound M1 (450 mg) in THF (10 mL) at room temperature, and the mixture was moved to 40°C and stirred for 4 hours. After the reaction was complete, the THF was directly concentrated to obtain the crude target product as a white solid, namely compound 1-2 (600 mg, crude).

ESI-MS m/z: 483.94 [M+H] +。 ESI-MS m/z: 483.94 [M+H] + .

步驟3：化合物1-3的合成Step 3: Synthesis of Compounds 1-3

在室溫下，將甲醇鈉(200.87mg)加入到化合物1-2(600mg)的甲苯(15mL)中，移至110℃回流攪拌5小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到白色固體狀粗品目標產物，即化合物1-3（600mg，粗品）。 At room temperature, sodium methoxide (200.87 mg) was added to compound 1-2 (600 mg) in toluene (15 mL), and the mixture was moved to 110° C. and stirred under reflux for 5 hours. After the reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude target product as a white solid, namely compound 1-3 (600 mg, crude).

ESI-MS m/z: 465.96 [M+H] +。 ESI-MS m/z: 465.96 [M+H] + .

步驟4：化合物1-4的合成Step 4: Synthesis of Compounds 1-4

在室溫下，氮氣保護下，將DIEA(0.5mL)加入到化合物1-3(600mg)的POCl 3(5mL)中，移至110℃攪拌3小時。待反應完全後，直接濃縮除去POCl 3，得到棕褐色固體狀粗品目標產物，即化合物1-4（600mg，粗品）。 DIEA (0.5 mL) was added to compound 1-3 (600 mg) in POCl 3 (5 mL) at room temperature under nitrogen protection, moved to 110° C. and stirred for 3 hours. After the reaction was completed, the POCl 3 was directly concentrated to remove the target product as a tan solid crude product, namely compound 1-4 (600 mg, crude product).

ESI-MS m/z: 483.96 [M+H] +。 ESI-MS m/z: 483.96 [M+H] + .

步驟5：化合物1-5的合成Step 5: Synthesis of Compounds 1-5

在室溫下，將DIEA(480.12mg)加入到化合物1-4(600mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(280.25mg)的1,4-二氧六環(10mL)中，室溫攪拌3小時。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（DCM:MeOH=10:1）純化，得到黃色固體狀的所要目標產物，即化合物1-5(750mg，89.81%產率)。 DIEA (480.12 mg) was added to compound 1-4 (600 mg), 1,4 of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (280.25 mg) at room temperature - in dioxane (10 mL), stirred at room temperature for 3 hours. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (DCM:MeOH=10:1) 1) Purification to obtain the desired target product, compound 1-5 (750 mg, 89.81% yield) as a yellow solid.

ESI-MS m/z: 674.10 [M+H] +。 ESI-MS m/z: 674.10 [M+H] + .

步驟6：化合物1-6的合成Step 6: Synthesis of Compounds 1-6

在氮氣保護下，將三氟乙醇(244.76mg)加入到化合物1-5(550mg)，Cs 2CO 3(531.45mg，)的1,4-二氧六環(5mL)中，移至100℃反應30min。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物，即化合物1-6(590mg，粗品)。 Under nitrogen protection, trifluoroethanol (244.76 mg) was added to compound 1-5 (550 mg), Cs 2 CO 3 (531.45 mg, ) in 1,4-dioxane (5 mL), and moved to 100° C. The reaction was carried out for 30 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol = 10:1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired target product, compound 1-6 as a yellow solid (590 mg, crude).

ESI-MS m/z: 755.30 [M+H] +。 ESI-MS m/z: 755.30 [M+H] + .

步驟7：化合物1-7的合成Step 7: Synthesis of Compounds 1-7

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(63.82mg)加入到化合物1-6(590mg)，K 2CO 3(216.17mg)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(120.45mg)的1,4-二氧六環(5.0mL)，H 2O(0.5mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物1-7(329mg，64.27%產率)。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (63.82 mg) was added to compound 1-6 (590 mg), K 2 CO 3 (216.17 mg), 4,4,5,5-tetramethyl In a mixed solution of yl-2-vinyl-1,3,2-dioxaborolane (120.45 mg) in 1,4-dioxane (5.0 mL) and H 2 O (0.5 mL), Stir at 70°C for 1 h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH=10:1) gave the desired product, compound 1-7 (329 mg, 64.27% yield) as a yellow solid.

ESI-MS m/z: 655.63 [M+H] +。 ESI-MS m/z: 655.63 [M+H] + .

步驟8：化合物1-8的合成Step 8: Synthesis of Compounds 1-8

在氮氣保護下，將Pd(PPh 3) 4(116.16mg)加入到化合物1-7(329mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(344.04mg)，K 3PO 4(213.38mg，)的1,4-二氧六環(3mL)，H 2O(0.75mL)溶液中，移至85℃反應反應約3小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物1-8(244mg，61.45%產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (116.16 mg) was added to compound 1-7 (329 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (344.04 mg), K 3 PO 4 (213.38 mg, ) in 1,4-dioxane (3 mL ), H 2 O (0.75 mL) solution, moved to 85° C. to react for about 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH=10:1) gave the desired product, compound 1-8 (244 mg, 61.45% yield) as a yellow solid.

ESI-MS m/z: 874.10 [M+H] +。 ESI-MS m/z: 874.10 [M+H] + .

步驟9：化合物1-9的合成Step 9: Synthesis of Compounds 1-9

在室溫下，將化合物1-8(244mg)溶於DCM(4mL)和TFA(2mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀粗品目標產物，即化合物1-9（190mg，粗品）。Compound 1-8 (244 mg) was dissolved in a mixed solvent of DCM (4 mL) and TFA (2 mL) at room temperature, moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated and removed to obtain the crude target product as a yellow solid, namely compound 1-9 (190 mg, crude product).

ESI-MS m/z: 606.38 [M+H] +。 ESI-MS m/z: 606.38 [M+H] + .

步驟10：化合物1的合成Step 10: Synthesis of Compound 1

在氮氣保護下，冰水浴中，將丙烯醯氯(17.03mg)的THF溶液加入到化合物1-9(95mg)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物，即化合物1(24.1mg，22.96%產率) 。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (17.03 mg) in THF was added to a solution of compound 1-9 (95 mg), THF (4 mL), and saturated Na 2 CO 3 (1 mL) solution, and the reaction was completed after the addition. . The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product, compound 1 (24.1 mg, 22.96% yield) as a yellow solid.

ESI-MS m/z: 660.37 [M+H]+。ESI-MS m/z: 660.37 [M+H]+.

1H NMR (500 MHz, Methanol- d 4) δ 8.08 (s, 1H), 7.52 (d, J= 8.6 Hz, 1H), 7.43 – 7.32 (m, 2H), 6.40 (d, J= 17.0, 10.3 Hz, 1H), 6.32 – 6.17 (m, 2H), 5.78 – 5.69 (m, 2H), 5.09 (d, J= 11.1 Hz, 1H), 4.86 – 4.75 (m, 1H), 4.51 (m, 1H), 4.15 (s, 2H), 3.90 (s, 2H), 3.72 (td, J= 6.4, 5.2, 3.0 Hz, 4H), 3.02 (d, J= 11.4 Hz, 2H), 2.85 (t, J= 11.5 Hz, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 2.13 (m, 5H), 2.06 (m, 3H), 1.90 – 1.83 (m, 4H). 1 H NMR (500 MHz, Methanol- d 4 ) δ 8.08 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.43 – 7.32 (m, 2H), 6.40 (d, J = 17.0, 10.3 Hz, 1H), 6.32 – 6.17 (m, 2H), 5.78 – 5.69 (m, 2H), 5.09 (d, J = 11.1 Hz, 1H), 4.86 – 4.75 (m, 1H), 4.51 (m, 1H) , 4.15 (s, 2H), 3.90 (s, 2H), 3.72 (td, J = 6.4, 5.2, 3.0 Hz, 4H), 3.02 (d, J = 11.4 Hz, 2H), 2.85 (t, J = 11.5 Hz, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 2.13 (m, 5H), 2.06 (m, 3H), 1.90 – 1.83 (m, 4H).

實施例1A：化合物1的拆分與異構體結構解析Example 1A: Resolution and Isomer Structure Analysis of Compound 1

使用色譜條件：CHIRALCEL OD（2.5 cm I.D. ×25 cm L, 10μm），UV 254 nm，流動相Hexane/IPA/DEA=70/30/0.1(V/V/V)，流速20 ml/min，拆分92mg化合物1，獲得異構體1a（56.3mg）和異構體1b（34.3mg）。

Figure 02_image243
Figure 02_image245
1a                            1b Chromatographic conditions used: CHIRALCEL OD (2.5 cm ID × 25 cm L, 10 μm), UV 254 nm, mobile phase Hexane/IPA/DEA=70/30/0.1 (V/V/V), flow rate 20 ml/min, removal 92 mg of compound 1 were divided to obtain isomer 1a (56.3 mg) and isomer 1b (34.3 mg).
Figure 02_image243
Figure 02_image245
1a 1b

異構體1a： 1H NMR (500 MHz, DMSO- d 6) δ 13.00 (s, 1H), 8.00 (s, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J= 8.6 Hz, 1H), 6.35 (dd, J= 17.0, 10.3 Hz, 1H), 6.18 – 6.06 (m, 2H), 5.79 – 5.66 (m, 2H), 5.11 (d, J= 11.1 Hz, 1H), 4.97 (dq, J= 12.3, 9.1 Hz, 1H), 4.68 (dq, J= 12.3, 9.1 Hz, 1H), 4.05 (s, 2H), 3.81 – 3.72 (m, 6H), 2.86 (dt, J= 11.5, 3.1 Hz, 2H), 2.68 (tt, J= 11.4, 3.6 Hz, 1H), 2.19 (s, 3H), 2.04 (s, 3H), 1.98 (dt, J= 6.7, 4.1 Hz, 8H), 1.85 (qd, J= 13.0, 3.9 Hz, 2H).ESI-MS m/z: 660.4 [M+H]+。色譜條件：CHIRALCEL OD（2.5 cm I.D. ×25 cm L, 10μm），UV 254 nm，流動相Hexane/IPA/DEA=70/30/0.1(V/V/V)，流速20 ml/min，保留時間6.39min（後出峰）。 Isomer 1a: 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.00 (s, 1H), 8.00 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H) , 7.32 (d, J = 8.6 Hz, 1H), 6.35 (dd, J = 17.0, 10.3 Hz, 1H), 6.18 – 6.06 (m, 2H), 5.79 – 5.66 (m, 2H), 5.11 (d, J = 11.1 Hz, 1H), 4.97 (dq, J = 12.3, 9.1 Hz, 1H), 4.68 (dq, J = 12.3, 9.1 Hz, 1H), 4.05 (s, 2H), 3.81 – 3.72 (m, 6H) , 2.86 (dt, J = 11.5, 3.1 Hz, 2H), 2.68 (tt, J = 11.4, 3.6 Hz, 1H), 2.19 (s, 3H), 2.04 (s, 3H), 1.98 (dt, J = 6.7 , 4.1 Hz, 8H), 1.85 (qd, J = 13.0, 3.9 Hz, 2H). ESI-MS m/z: 660.4 [M+H]+. Chromatographic conditions: CHIRALCEL OD (2.5 cm ID × 25 cm L, 10 μm), UV 254 nm, mobile phase Hexane/IPA/DEA=70/30/0.1 (V/V/V), flow rate 20 ml/min, retention time 6.39min (after peak).

異構體1b： 1H NMR (500 MHz, DMSO- d 6) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.50 (d, J= 8.5 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J= 8.6 Hz, 1H), 6.35 (dd, J= 17.0, 10.3 Hz, 1H), 6.19 – 6.06 (m, 2H), 5.80 – 5.60 (m, 2H), 5.11 (d, J= 11.2 Hz, 1H), 4.98 (dq, J= 12.2, 9.1 Hz, 1H), 4.69 (dq, J= 12.2, 9.2 Hz, 1H), 4.05 (s, 2H), 3.76 (d, J= 7.1 Hz, 6H), 2.85 (dd, J= 8.9, 5.8 Hz, 2H), 2.68 (tt, J= 11.6, 3.7 Hz, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 2.02 – 1.96 (m, 8H), 1.85 (qd, J= 13.2, 4.0 Hz, 2H).ESI-MS m/z: 660.4 [M+H]+。色譜條件：CHIRALCEL OD（2.5 cm I.D. ×25 cm L, 10μm），UV 254 nm，流動相Hexane/IPA/DEA=70/30/0.1(V/V/V)，流速20 ml/min，保留時間4.09min（先出峰）。 Isomer 1b: 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H) , 7.32 (d, J = 8.6 Hz, 1H), 6.35 (dd, J = 17.0, 10.3 Hz, 1H), 6.19 – 6.06 (m, 2H), 5.80 – 5.60 (m, 2H), 5.11 (d, J = 11.2 Hz, 1H), 4.98 (dq, J = 12.2, 9.1 Hz, 1H), 4.69 (dq, J = 12.2, 9.2 Hz, 1H), 4.05 (s, 2H), 3.76 (d, J = 7.1 Hz) , 6H), 2.85 (dd, J = 8.9, 5.8 Hz, 2H), 2.68 (tt, J = 11.6, 3.7 Hz, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 2.02 – 1.96 ( m, 8H), 1.85 (qd, J = 13.2, 4.0 Hz, 2H). ESI-MS m/z: 660.4 [M+H]+. Chromatographic conditions: CHIRALCEL OD (2.5 cm ID × 25 cm L, 10 μm), UV 254 nm, mobile phase Hexane/IPA/DEA=70/30/0.1 (V/V/V), flow rate 20 ml/min, retention time 4.09min (peak first).

通過在DMSO/H 2O體系液面擴散方法進行單晶培養，得到異構體1a的DMSO溶劑合物的單晶。晶體繞射實驗用晶體尺寸為0.03×0.19×0.23mm，採用Bruker D8 Venture Photon II 繞射儀進行單晶測試，光源為CuKα輻射，掃描方式為φ/ w掃描。採用直接法(Shelxs97)解析晶體結構，獲得全部100個非氫原子位置，晶體屬於單斜晶系，空間群為 P21，晶胞參數：a=18.4614(13)，b=11.8865(8)，c=18.9132(13)Å，α=γ=90°，β=110.112(3)°，晶胞體積V=3897.3(5)Å 3，晶胞內不對稱單位數Z=2。使用最小二乘法修正結構參數和判別原子種類，使用幾何計算法和差值Fourier法獲得全部氫原子位置。單晶結構解析結果表明：晶態下分子排列屬第一類空間群，化合物應具有旋光活性，Flack係數0.044(12)，可確定晶體中化合物的絕對構型為S構型。 A single crystal of the DMSO solvate of the isomer 1a was obtained by culturing the single crystal by the liquid surface diffusion method in the DMSO/H 2 O system. The crystal size of the crystal diffraction experiment was 0.03 × 0.19 × 0.23 mm, and the single crystal was tested by a Bruker D8 Venture Photon II diffractometer. The light source was CuKα radiation, and the scanning method was φ/ w scanning. The crystal structure was analyzed by the direct method (Shelxs97), and all 100 non-hydrogen atomic positions were obtained. The crystal belongs to the monoclinic system, the space group is P21, and the unit cell parameters are: a=18.4614(13), b=11.8865(8), c =18.9132(13)Å, α=γ=90°, β=110.112(3)°, the unit cell volume V=3897.3(5)Å 3 , and the number of asymmetric units in the unit cell Z=2. The least squares method was used to correct the structural parameters and identify the atomic species, and the geometric calculation method and the difference Fourier method were used to obtain all the hydrogen atom positions. The results of single crystal structure analysis show that the molecular arrangement in the crystalline state belongs to the first space group, the compound should have optical activity, and the Flack coefficient is 0.044(12), which can confirm that the absolute configuration of the compound in the crystal is the S configuration.

實施例2：化合物2（1-（7-（2-環己基-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬烷-2-基）丙-2-烯-1-酮）的合成

Figure 02_image247
Example 2: Compound 2 (1-(7-(2-cyclohexyl-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy) )-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one) synthesis
Figure 02_image247

步驟1：化合物2-1的合成Step 1: Synthesis of Compound 2-1

在室溫下，將環己甲醯氯(367.63mg)加入到化合物M1(300mg)的THF(10mL)中，移至40℃攪拌4小時。待反應完全後，直接濃縮出去THF，得到白色固體狀粗品目標產物，即化合物2-1（390mg，粗品）。At room temperature, cyclohexylformyl chloride (367.63 mg) was added to compound M1 (300 mg) in THF (10 mL), and the mixture was moved to 40°C and stirred for 4 hours. After the reaction was completed, the THF was directly concentrated to obtain the crude target product as a white solid, namely compound 2-1 (390 mg, crude).

ESI-MS m/z: 469.00 [M+H] +。 ESI-MS m/z: 469.00 [M+H] + .

步驟2：化合物2-2的合成Step 2: Synthesis of Compound 2-2

在室溫下，將甲醇鈉(224.56mg)加入到2-1(390mg)的甲苯 (15mL)中，移至110℃回流攪拌5小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到白色固體狀粗品目標產物，即化合物2-2（350mg，粗品）。 At room temperature, sodium methoxide (224.56 mg) was added to 2-1 (390 mg) in toluene (15 mL), and the mixture was moved to 110° C. and stirred under reflux for 5 hours. After the reaction was completed, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude target product as a white solid, namely compound 2-2 (350 mg, crude).

ESI-MS m/z: 450.94 [M+H] +。 ESI-MS m/z: 450.94 [M+H] + .

步驟3：化合物2-3的合成Step 3: Synthesis of Compounds 2-3

在室溫下，氮氣保護下，將DIEA(1.0mL)加入到化合物2-2(350mg)的POCl 3(10.0mL)中，移至110℃攪拌12小時。待反應完全後，直接濃縮除去POCl 3，得到棕褐色固體狀粗品目標產物，即化合物2-3（340mg，粗品）。 DIEA (1.0 mL) was added to compound 2-2 (350 mg) in POCl 3 (10.0 mL) at room temperature under nitrogen protection, moved to 110° C. and stirred for 12 hours. After the reaction was completed, the POCl 3 was directly concentrated to remove the target product as a tan solid crude product, namely compound 2-3 (340 mg, crude product).

ESI-MS m/z:468.87[M+H]+。ESI-MS m/z: 468.87 [M+H]+.

步驟4：化合物2-4的合成Step 4: Synthesis of Compounds 2-4

在室溫下，將DIEA(279mg)加入到化合物2-3(340mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(163mg)的1,4-二氧六環(10mL)中，室溫攪拌5分鐘。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=10:1-15:1）純化，得到黃色固體狀的所要目標產物，即化合物2-4(348mg，42.62%產率)。 DIEA (279 mg) was added to compound 2-3 (340 mg), 1,4-di-1,4-di-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (163 mg) at room temperature in oxane (10 mL) and stirred at room temperature for 5 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=10:1-15:1) Purification gave the desired target product, compound 2-4 (348 mg, 42.62% yield) as a yellow solid.

ESI-MS m/z: 659.06 [M+H] +。 ESI-MS m/z: 659.06 [M+H] + .

步驟5：化合物2-5的合成Step 5: Synthesis of Compounds 2-5

在氮氣保護下，將三氟乙醇(158.4mg)加入到化合物2-4(348mg)，Cs 2CO 3(343.92mg，)的1,4-二氧六環(5mL)中，移至100℃反應30min。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物，即化合物2-5(400mg，粗品)。 Under nitrogen protection, trifluoroethanol (158.4 mg) was added to compound 2-4 (348 mg), Cs 2 CO 3 (343.92 mg, ) in 1,4-dioxane (5 mL), and moved to 100° C. The reaction was carried out for 30 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired target product, compound 2-5 (400 mg, crude) as a yellow solid.

ESI-MS m/z: 739.01 [M+H] +。 ESI-MS m/z: 739.01 [M+H] + .

步驟6：化合物2-6的合成Step 6: Synthesis of Compounds 2-6

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(63.82mg)加入到化合物2-5(400mg)，K 2CO 3(149.53mg)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(83.32mg，)的1,4-二氧六環(4.0mL)，H 2O(0.4mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=10:1-15:1）純化，得到黃色固體狀的所要目標產物，即化合物2-6(213mg，61.56%產率)。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (63.82 mg) was added to compound 2-5 (400 mg), K 2 CO 3 (149.53 mg), 4,4,5,5-tetramethyl In a mixed solution of yl-2-vinyl-1,3,2-dioxaborolane (83.32 mg, ) in 1,4-dioxane (4.0 mL), H 2 O (0.4 mL) , and stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=10:1-15:1) was purified to obtain the desired target product, compound 2-6 (213 mg, 61.56% yield) as a yellow solid.

ESI-MS m/z: 639.01 [M+H] +。 ESI-MS m/z: 639.01 [M+H] + .

步驟7：化合物2-7的合成Step 7: Synthesis of Compounds 2-7

在氮氣保護下，將Pd(PPh 3) 4(116.16mg)加入到化合物2-6(213mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(227.96mg)，K 3PO 4(141.39mg，)的1,4-二氧六環(2mL), H 2O(0.5mL)溶液中，移至85℃反應反應約3小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(PE:EA=2:1)純化，得到呈黃色固體狀的所要產物，即化合物2-7(180mg，69.74%產率)。ESI-MS m/z: 775.42 [M+H] +。 Under nitrogen protection, Pd(PPh 3 ) 4 (116.16 mg) was added to compound 2-6 (213 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (227.96 mg), K 3 PO 4 (141.39 mg, ) in 1,4-dioxane (2 mL ), H 2 O (0.5 mL) solution, moved to 85°C and reacted for about 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC (PE:EA=2: 1) Purification gave the desired product, compound 2-7 (180 mg, 69.74% yield) as a yellow solid. ESI-MS m/z: 775.42 [M+H] + .

步驟8：化合物2-8的合成Step 8: Synthesis of Compounds 2-8

在室溫下，將化合物2-7(180mg)溶於DCM(6mL)和TFA(3mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀粗品目標產物，即化合物2-8（135mg，粗品）。Compound 2-7 (180 mg) was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL) at room temperature, moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated and removed to obtain the crude target product as a yellow solid, namely compound 2-8 (135 mg, crude product).

ESI-MS m/z: 591.40 [M+H] +。 ESI-MS m/z: 591.40 [M+H] + .

步驟9：化合物2-9的合成Step 9: Synthesis of Compounds 2-9

在氮氣保護下，冰水浴中，將丙烯醯氯(17.03mg)的THF溶液加入到化合物2-8(135mg，)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物2(66.71mg，44.36%產率) 。ESI-MS m/z: 645.44 [M+H] +。 1HNMR(500MHz, CDCl 3) δ：7.94 (s, 1H), 7.45-7.48 (m, 2H), 7.36-7.36 (m, 1H),  6.37-6.41 (m, 1H), 6.22-6.28 (m, 2H), 5.70-5.73 (m, 1H), 5.62-5.66 (m, 1H), 5.05-5.07 (m, 1H), 4.83-4.91 (m, 1H), 4.47-4.54 (m, 1H), 4.04 (s, 2H), 3.94 (s, 2H), 3.70-3.79 (m, 4H), 2.81-2.87 (m, 1H), 2.15 (s, 3H), 2.07-2.09 (m, 2H), 1.85-1.87 (m, 2H), 1.74-1.77 (m, 1H), 1.61-1.71 (m, 3H), 1.41-1.48 (m, 3H), 1.25-1.37 (m, 3H)。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (17.03 mg) in THF was added to a solution of compound 2-8 (135 mg, ), THF (4 mL), and saturated Na 2 CO 3 (1 mL) solution, and the reaction was performed after the addition. completely. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product, compound 2 (66.71 mg, 44.36% yield) as a yellow solid. ESI-MS m/z: 645.44 [M+H] + . 1 HNMR (500MHz, CDCl 3 ) δ: 7.94 (s, 1H), 7.45-7.48 (m, 2H), 7.36-7.36 (m, 1H), 6.37-6.41 (m, 1H), 6.22-6.28 (m, 2H), 5.70-5.73 (m, 1H), 5.62-5.66 (m, 1H), 5.05-5.07 (m, 1H), 4.83-4.91 (m, 1H), 4.47-4.54 (m, 1H), 4.04 ( s, 2H), 3.94 (s, 2H), 3.70-3.79 (m, 4H), 2.81-2.87 (m, 1H), 2.15 (s, 3H), 2.07-2.09 (m, 2H), 1.85-1.87 ( m, 2H), 1.74-1.77 (m, 1H), 1.61-1.71 (m, 3H), 1.41-1.48 (m, 3H), 1.25-1.37 (m, 3H).

實施例3：化合物3（1-（7-（2-四氫呋喃-3-基-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬烷-2-基）丙-2-烯-1-酮）的合成

Figure 02_image249
Example 3: Compound 3 (1-(7-(2-tetrahydrofuran-3-yl-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoro Synthesis of ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)prop-2-en-1-one)
Figure 02_image249

步驟1：化合物3-1的合成Step 1: Synthesis of Compound 3-1

在室溫下，將四氫呋喃-3-甲醯氯(402mg)加入到化合物M1(300mg)的THF(10mL)中，移至40℃攪拌4小時。待反應完全後，直接濃縮出去THF，得到黃色固體狀粗品目標產物，即化合物3-1（460mg，粗品）。At room temperature, tetrahydrofuran-3-carbamoyl chloride (402 mg) was added to compound M1 (300 mg) in THF (10 mL), and the mixture was moved to 40°C and stirred for 4 hours. After the reaction was completed, the THF was directly concentrated to obtain the crude target product as a yellow solid, namely compound 3-1 (460 mg, crude).

ESI-MS m/z: 456.94 [M+H] +。 ESI-MS m/z: 456.94 [M+H] + .

步驟2：化合物3-2的合成Step 2: Synthesis of Compound 3-2

在室溫下，將甲醇鈉(224.56mg)加入到化合物3-1(460mg，0.83mmol)的甲苯 (10mL)中，移至110℃回流攪拌8小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到白色固體狀粗品目標產物，即化合物3-2（200mg，粗品）。 At room temperature, sodium methoxide (224.56 mg) was added to compound 3-1 (460 mg, 0.83 mmol) in toluene (10 mL), and the mixture was moved to 110° C. and stirred under reflux for 8 hours. After the reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude target product as a white solid, namely compound 3-2 (200 mg, crude).

ESI-MS m/z: 438.96 [M+H]+。ESI-MS m/z: 438.96 [M+H]+.

步驟3：化合物3-3的合成Step 3: Synthesis of Compound 3-3

在室溫下，氮氣保護下，將DIEA(1.0mL)加入到化合物3-2(200mg)的POCl 3(10.0mL)中，移至110℃攪拌12小時。待反應完全後，直接濃縮除去POCl 3，得到棕褐色固體狀粗品目標產物，即化合物3-3（230 mg，粗品）。 DIEA (1.0 mL) was added to compound 3-2 (200 mg) in POCl 3 (10.0 mL) at room temperature under nitrogen protection, moved to 110° C. and stirred for 12 hours. After the reaction was completed, the POCl 3 was directly concentrated to remove the target product as a tan solid crude product, namely compound 3-3 (230 mg, crude product).

ESI-MS m/z:456.87[M+H] +。 ESI-MS m/z: 456.87 [M+H] + .

步驟4：化合物3-4的合成Step 4: Synthesis of Compounds 3-4

在室溫下，將DIEA(279mg)加入到化合物3-3(200mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(90mg)的1,4-二氧六環(2mL)中，室溫攪拌5分鐘。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過矽膠板分離純化，得到黃色固體狀的所要目標產物，即化合物3-4(88mg，34.1 %產率)。 DIEA (279 mg) was added to compound 3-3 (200 mg), 1,4-di-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (90 mg) at room temperature in oxane (2 mL) and stirred at room temperature for 5 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was separated and purified by silica gel plate to give the desired target product, compound 3, as a yellow solid -4 (88 mg, 34.1% yield).

ESI-MS m/z: 647.14 [M+H] +。 ESI-MS m/z: 647.14 [M+H] + .

步驟5：化合物3-5的合成Step 5: Synthesis of Compounds 3-5

在氮氣保護下，將三氟乙醇(68mg)加入到化合物3-4(88mg)，Cs 2CO 3(88mg)的1,4-二氧六環(2mL)中，移至100℃反應30min。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物，即化合物3-5(97mg，粗品)。 Under nitrogen protection, trifluoroethanol (68 mg) was added to compound 3-4 (88 mg), Cs 2 CO 3 (88 mg) in 1,4-dioxane (2 mL), moved to 100° C. to react for 30 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired target product, compound 3-5 (97 mg, crude) as a yellow solid.

ESI-MS m/z: 727.08 [M+H] +。 ESI-MS m/z: 727.08 [M+H] + .

步驟6：化合物3-6的合成Step 6: Synthesis of Compounds 3-6

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(10mg)加入到化合物3-5(90mg)，K 2CO 3(34mg，)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(19mg)的1,4-二氧六環(2.5mL)，H 2O(0.5mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=10:1-3:1）純化，得到黃色固體狀的所要目標產物，即化合物3-6(213mg，64.4 %產率)。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (10 mg) was added to compound 3-5 (90 mg), K 2 CO 3 (34 mg, ), 4,4,5,5-tetramethyl - A mixed solution of 2-vinyl-1,3,2-dioxaborolane (19 mg) in 1,4-dioxane (2.5 mL), H 2 O (0.5 mL) at 70 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=10:1-3:1) was purified to give the desired target product, compound 3-6 (213 mg, 64.4% yield) as a yellow solid.

ESI-MS m/z: 627.21 [M+H] +。 ESI-MS m/z: 627.21 [M+H] + .

步驟7：化合物3-7的合成Step 7: Synthesis of Compounds 3-7

在氮氣保護下，將Pd(PPh 3) 4(18.5mg)加入到化合物3-6(50mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(54.6mg)，K 3PO 4(34mg)的1,4-二氧六環(2mL), H 2O(0.5mL)溶液中，移至85℃反應反應約4小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(PE:EA=2:1)純化,得到呈黃色固體狀的所要產物，即化合物3-7(45 mg，73.8 %產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (18.5 mg) was added to compound 3-6 (50 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (54.6 mg), 1,4-dioxane (2 mL) in K3PO4 ( 34 mg), H 2 O (0.5 mL) solution, moved to 85° C. to react for about 4 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC (PE:EA=2: 1) Purification gave the desired product, compound 3-7 (45 mg, 73.8% yield) as a yellow solid.

ESI-MS m/z: 763.39 [M+H] +。 ESI-MS m/z: 763.39 [M+H] + .

步驟8：化合物3-8的合成Step 8: Synthesis of Compounds 3-8

在室溫下，將化合物3-7(45mg)溶於DCM(1mL)和TFA(0.5mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀粗品目標產物，即化合物3-8（56 mg，粗品）。ESI-MS m/z: 579.32 [M+H] +。 Compound 3-7 (45 mg) was dissolved in a mixed solvent of DCM (1 mL) and TFA (0.5 mL) at room temperature, moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the target product as a yellow solid crude product, namely compound 3-8 (56 mg, crude product). ESI-MS m/z: 579.32 [M+H] + .

步驟9：化合物3-9的合成Step 9: Synthesis of Compounds 3-9

在氮氣保護下，冰水浴中，將丙烯醯氯(5.85mg)的THF溶液加入到化合物3-8(56mg，)，THF(2mL)，飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物3(12.05mg，32.2 %產率) 。ESI-MS m/z: 633.41 [M+H]+。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (5.85 mg) in THF was added to a solution of compound 3-8 (56 mg, ), THF (2 mL), saturated Na 2 CO 3 (0.5 mL), and a solution of The reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product, compound 3 (12.05 mg, 32.2 % yield) as a yellow solid. ESI-MS m/z: 633.41 [M+H]+.

1H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.40 (d, J = 7.5 Hz, 2H), 7.19 (s, 1H), 6.32 (dd, J = 17.0, 1.9 Hz, 1H), 6.18 (m, J = 17.0, 10.6, 4.9 Hz, 2H), 5.65 (dd, J = 10.3, 1.9 Hz, 1H), 5.58 (dd, J = 17.4, 1.0 Hz, 1H), 5.01 (dd, J = 10.9, 1.0 Hz, 1H), 4.78 – 4.64 (m, 1H), 4.34 (m, 1H), 4.20 (td, J = 8.1, 3.7 Hz, 1H), 4.05 (dd, J = 8.3, 6.8 Hz, 1H), 4.02 – 3.95 (m, 3H), 3.94 – 3.89 (m, 1H), 3.87 (s, 2H), 3.75 (td, J = 10.0, 9.0, 5.5 Hz, 2H), 3.71 – 3.62 (m, 3H), 2.41 (m, 1H), 2.29 (m, 1H), 2.08 (s, 3H), 1.18 (d, J = 7.2 Hz, 4H)。 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.40 (d, J = 7.5 Hz, 2H), 7.19 (s, 1H), 6.32 (dd, J = 17.0, 1.9 Hz, 1H ), 6.18 (m, J = 17.0, 10.6, 4.9 Hz, 2H), 5.65 (dd, J = 10.3, 1.9 Hz, 1H), 5.58 (dd, J = 17.4, 1.0 Hz, 1H), 5.01 (dd, J = 10.9, 1.0 Hz, 1H), 4.78 – 4.64 (m, 1H), 4.34 (m, 1H), 4.20 (td, J = 8.1, 3.7 Hz, 1H), 4.05 (dd, J = 8.3, 6.8 Hz) , 1H), 4.02 – 3.95 (m, 3H), 3.94 – 3.89 (m, 1H), 3.87 (s, 2H), 3.75 (td, J = 10.0, 9.0, 5.5 Hz, 2H), 3.71 – 3.62 (m , 3H), 2.41 (m, 1H), 2.29 (m, 1H), 2.08 (s, 3H), 1.18 (d, J = 7.2 Hz, 4H).

實施例4：化合物4（1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image251
Example 4: Compound 4 (1-(7-(6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl) -8-(2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1- ketone) synthesis
Figure 02_image251

步驟1：化合物4-1的合成Step 1: Synthesis of Compound 4-1

在室溫下，在氫氣氛圍中，將Pd/C (80 mg)  加入到化合物1-9 (95mg)  的MeOH (10mL)  的溶液中，在室溫攪拌2小時。待反應完全後，過濾除去Pd/C，並用MeOH洗滌Pd/C，將濾液濃縮，即得黃色固體粗品，即化合物4-1（70mg，粗品）。Pd/C (80 mg) was added to a solution of compound 1-9 (95 mg) in MeOH (10 mL) at room temperature under a hydrogen atmosphere, and stirred at room temperature for 2 hours. After the reaction was completed, the Pd/C was removed by filtration, and the Pd/C was washed with MeOH, and the filtrate was concentrated to obtain a yellow solid crude product, namely compound 4-1 (70 mg, crude product).

ESI-MS m/z: 608.43 [M+H] +。 ESI-MS m/z: 608.43 [M+H] + .

步驟2：化合物4的合成Step 2: Synthesis of Compound 4

在氮氣保護下，冰水浴中，將丙烯醯氯(12.51mg)的THF溶液加入到化合物4-1(70mg)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物4(18.3mg，23.79%產率)。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (12.51 mg) in THF was added to a solution of compound 4-1 (70 mg), THF (4 mL), and saturated Na 2 CO 3 (1 mL) solution, and the reaction was completed after the addition. . The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product, compound 4 (18.3 mg, 23.79% yield) as a yellow solid.

ESI-MS m/z: 662.37 [M+H] +。 ESI-MS m/z: 662.37 [M+H] + .

實施例5：化合物5（1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（四氫-2H-吡喃-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image253
Example 5: Compound 5 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-8-( 2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1 -ketone) synthesis
Figure 02_image253

步驟1：化合物5-1的合成Step 1: Synthesis of Compound 5-1

在室溫下，將四氫吡喃-4-甲醯氯(248.38mg，1.67mmol)加入到化合物M1(300mg，)的THF(3mL)中，移至40℃攪拌4小時。待反應完全後，直接濃縮出去THF，得到白色固體狀粗品目標產物，即化合物5-1（390mg，粗品）。At room temperature, tetrahydropyran-4-carboxychloride (248.38 mg, 1.67 mmol) was added to compound M1 (300 mg, ) in THF (3 mL), moved to 40°C and stirred for 4 hours. After the reaction was completed, the THF was directly concentrated to obtain the crude target product as a white solid, namely compound 5-1 (390 mg, crude).

ESI-MS m/z: 470.92 [M+H] +。 ESI-MS m/z: 470.92 [M+H] + .

步驟2：化合物5-2的合成Step 2: Synthesis of Compound 5-2

在室溫下，將甲醇鈉(224.56mg)加入到化合物5-1(390mg)的甲苯 (4mL)中，移至110℃回流攪拌5小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到白色固體狀粗品目標產物，即化合物5-2（350mg，粗品）。 At room temperature, sodium methoxide (224.56 mg) was added to a solution of compound 5-1 (390 mg) in toluene (4 mL), and the mixture was moved to 110° C. and stirred under reflux for 5 hours. After the reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to obtain the crude target product as a white solid, namely compound 5-2 (350 mg, crude).

ESI-MS m/z: 452.96 [M+H] +。 ESI-MS m/z: 452.96 [M+H] + .

步驟3：化合物5-3的合成Step 3: Synthesis of Compound 5-3

在室溫下，氮氣保護下，將DIEA(0.4mL)加入到化合物5-2(350mg, 0.77mmol)的POCl 3(4mL)中，移至110℃攪拌12小時。待反應完全後，直接濃縮除去POCl 3，得到棕褐色固體狀粗品目標產物，即化合物5-3（210mg，粗品）。 At room temperature, under nitrogen protection, DIEA (0.4 mL) was added to compound 5-2 (350 mg, 0.77 mmol) in POCl 3 (4 mL), moved to 110° C. and stirred for 12 hours. After the reaction was completed, the POCl 3 was directly concentrated to remove the target product as a tan solid crude product, namely compound 5-3 (210 mg, crude product).

ESI-MS m/z:470.95 [M+H] +。 ESI-MS m/z: 470.95 [M+H] + .

步驟4：化合物5-4的合成Step 4: Synthesis of Compounds 5-4

在室溫下，將DIEA(115.13mg)加入到化合物5-3(210mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(120.96mg)的1,4-二氧六環(3mL)中，室溫攪拌30分鐘。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=10:1-15:1）純化，得到黃色固體狀的所要目標產物，即化合物5-4(110mg，37.34%產率)。 DIEA (115.13 mg) was added to compound 5-3 (210 mg), 1,4 of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (120.96 mg) at room temperature - in dioxane (3 mL), stirred at room temperature for 30 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=10:1-15:1) Purification gave the desired target product, compound 5-4 (110 mg, 37.34% yield) as a yellow solid.

ESI-MS m/z: 661.17 [M+H] +。 ESI-MS m/z: 661.17 [M+H] + .

步驟5：化合物5-5的合成Step 5: Synthesis of Compounds 5-5

在氮氣保護下，將三氟乙醇(49.92mg)加入到化合物5-4(110mg)，Cs 2CO 3(108.39mg，)的1,4-二氧六環(2mL)中，移至100℃反應30min。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物，即化合物5-5(105mg，粗品)。 Under nitrogen protection, trifluoroethanol (49.92 mg) was added to compound 5-4 (110 mg), Cs 2 CO 3 (108.39 mg, ) in 1,4-dioxane (2 mL), and moved to 100° C. The reaction was carried out for 30 minutes. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired target product, compound 5-5 (105 mg, crude) as a yellow solid.

ESI-MS m/z: 741.14 [M+H] +。 ESI-MS m/z: 741.14 [M+H] + .

步驟6：化合物5-6的合成Step 6: Synthesis of Compounds 5-6

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(11.56mg)加入到化合物5-5(105mg)，K 2CO 3(39.15mg)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(21.81mg)的1,4-二氧六環(2mL)，H 2O(0.4mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=10:1-15:1）純化，得到黃色固體狀的所要目標產物，即化合物5-6(60mg，66.04%產率)。ESI-MS m/z: 641.25 [M+H] +。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (11.56 mg) was added to compound 5-5 (105 mg), K 2 CO 3 (39.15 mg), 4,4,5,5-tetramethyl In a mixed solution of yl-2-vinyl-1,3,2-dioxaborolane (21.81 mg) in 1,4-dioxane (2 mL) and H 2 O (0.4 mL), Stir at 70°C for 1 h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=10:1-15:1) was purified to give the desired target product, compound 5-6 (60 mg, 66.04% yield) as a yellow solid. ESI-MS m/z: 641.25 [M+H] + .

步驟7：化合物5-7的合成Step 7: Synthesis of Compounds 5-7

在氮氣保護下，將Pd(PPh 3) 4(21.60mg)加入到化合物5-6(60mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(64.02mg)，K 3PO 4(39.71mg，)的1,4-二氧六環(2mL), H 2O(0.2mL)溶液中，移至85℃反應反應約3小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(PE:EA=2:1)純化，得到呈黃色固體狀的所要產物，即化合物5-7(25mg，34.41%產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (21.60 mg) was added to compound 5-6 (60 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (64.02 mg), K 3 PO 4 (39.71 mg, ) in 1,4-dioxane (2 mL ), H 2 O (0.2 mL) solution, moved to 85°C and reacted for about 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC (PE:EA=2: 1) Purification gave the desired product, compound 5-7 (25 mg, 34.41% yield) as a yellow solid.

ESI-MS m/z: 777.42 [M+H] +。 ESI-MS m/z: 777.42 [M+H] + .

步驟8：化合物5-8的合成Step 8: Synthesis of Compounds 5-8

在室溫下，將化合物5-7(25mg)溶於DCM(1mL)和TFA(0.5mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色油狀粗品目標產物，即化合物5-8（20mg，粗品）。Compound 5-7 (25 mg) was dissolved in a mixed solvent of DCM (1 mL) and TFA (0.5 mL) at room temperature, moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain the target product as a yellow oily crude product, namely compound 5-8 (20 mg, crude product).

ESI-MS m/z: 593.33 [M+H] +。 ESI-MS m/z: 593.33 [M+H] + .

步驟9：化合物5的合成Step 9: Synthesis of Compound 5

在氮氣保護下，冰水浴中，將丙烯醯氯(3.20mg)的THF溶液加入到化合物5-8(20mg，)，THF(2mL)，飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物，即化合物5 (5.2mg，33.48 %產率)。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (3.20 mg) in THF was added to a solution of compound 5-8 (20 mg, ), THF (2 mL), saturated Na 2 CO 3 (0.5 mL), and the solution was The reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product, compound 5 (5.2 mg, 33.48% yield) as a yellow solid.

ESI-MS m/z: 647.33 [M+H] +。 ESI-MS m/z: 647.33 [M+H] + .

實施例6：化合物6（1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（N-甲基吡咯-3-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image255
Example 6: Compound 6 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(N-methylpyrrol-3-yl)-8-(2, 2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one )Synthesis
Figure 02_image255

步驟1：化合物6-1的合成Step 1: Synthesis of Compound 6-1

在室溫、氮氣保護下，將N-甲基吡咯-3-羧酸(600mg)溶於SOCl 2(5.5mL)中，升溫至70℃，攪拌反應1h。真空濃縮，除去氯化亞碸，得到白色固體目標產物，即化合物6-1(68mg，粗品)。 At room temperature under nitrogen protection, N-methylpyrrole-3-carboxylic acid (600 mg) was dissolved in SOCl 2 (5.5 mL), the temperature was raised to 70° C., and the reaction was stirred for 1 h. It was concentrated in vacuo to remove the thionite chloride to obtain the target product as a white solid, namely compound 6-1 (68 mg, crude).

步驟2：化合物6-2的合成Step 2: Synthesis of Compound 6-2

在室溫下，將化合物6-1(369mg)加入到化合物M1(300mg)的THF(5mL)中，攪拌16小時。待反應完全後，旋蒸除去THF。使用二氯甲烷：甲醇=90:10作為展開劑，柱層析分離得到淡黃色固體目標產物，即化合物6-2（262mg）。Compound 6-1 (369 mg) was added to compound M1 (300 mg) in THF (5 mL) at room temperature and stirred for 16 hours. After the reaction was completed, the THF was removed by rotary evaporation. Using dichloromethane:methanol=90:10 as a developing solvent, column chromatography was used to obtain a pale yellow solid target product, namely compound 6-2 (262 mg).

ESI-MS m/z: 469.93, 471.94 [M+H] +。 ESI-MS m/z: 469.93, 471.94 [M+H] + .

步驟3：化合物6-3的合成Step 3: Synthesis of Compound 6-3

在室溫下，將甲醇鈉(151mg)加入到化合物6-2(262mg)的甲苯 (10mL)中，升溫至110℃回流攪拌16小時。待反應完全後，將混合物傾入40mL冰水中，用乙酸乙酯萃取該混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到淡黃色固體目標產物，即化合物6-3（240mg，粗品）。 At room temperature, sodium methoxide (151 mg) was added to a solution of compound 6-2 (262 mg) in toluene (10 mL), the temperature was raised to 110° C. and refluxed and stirred for 16 hours. After the reaction was completed, the mixture was poured into 40 mL of ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to obtain the target product as a pale yellow solid, namely compound 6-3 (240 mg, crude product) .

ESI-MS m/z: 451.96, 453.91 [M+H] +。 ESI-MS m/z: 451.96, 453.91 [M+H] + .

步驟4：化合物6-4的合成Step 4: Synthesis of Compounds 6-4

在室溫、氮氣保護下，將DIEA(0.5mL)加入到化合物6-3(226mg)的POCl 3(5mL)溶液中，升溫至110℃攪拌3小時。待反應完全後，旋蒸除去POCl 3，將混合物倒入冰水中，用乙酸乙酯萃取混合物，收集有機相，用飽和鹵水洗滌，經Na 2SO 4乾燥且真空濃縮，得到棕黃色固體目標產物，即化合物6-4（116mg，粗品）。 Under nitrogen protection, DIEA (0.5 mL) was added to a solution of compound 6-3 (226 mg) in POCl 3 (5 mL) at room temperature, and the temperature was raised to 110° C. and stirred for 3 hours. After the reaction was completed, the POCl 3 was removed by rotary evaporation, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over Na 2 SO 4 and concentrated in vacuo to obtain the target product as a brown solid , namely compound 6-4 (116 mg, crude).

ESI-MS m/z: 469.96 ,471.94 [M+H] +。 ESI-MS m/z: 469.96 , 471.94 [M+H] + .

步驟5：化合物6-5的合成Step 5: Synthesis of Compounds 6-5

在室溫下，將DIEA(96mg)加入到化合物6-4(116mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(56mg)的二氧六環(5mL)溶液中，室溫攪拌2小時。反應結束後，旋乾二氧六環，加入冰水，用乙酸乙酯/甲醇=10:1萃取混合物，收集有機相旋乾。剩餘物通過矽膠柱層析色譜（展開劑為DCM:MeOH=10:1）純化，得到黃色固體目標產物，即化合物6-5(58mg)。DIEA (96 mg) was added to compound 6-4 (116 mg), dioxane ( 5 mL) solution, stirred at room temperature for 2 hours. After the reaction, dioxane was spin-dried, ice water was added, the mixture was extracted with ethyl acetate/methanol=10:1, and the organic phase was collected and spin-dried. The residue was purified by silica gel column chromatography (developing solvent: DCM:MeOH=10:1) to obtain the yellow solid target product, namely compound 6-5 (58 mg).

ESI-MS m/z: 660.08, 662.07 [M+H] +。 ESI-MS m/z: 660.08, 662.07 [M+H] + .

步驟6：化合物6-6的合成Step 6: Synthesis of Compounds 6-6

向充分乾燥的反應瓶中加入化合物6-5(56mg)，用二氧六環(3mL)溶解，隨後加入三氟乙醇(42mg)及Cs 2CO 3(55mg)，升溫至100℃反應1h。反應結束後，用THF稀釋反應液，過濾除去Cs 2CO 3。濾液旋乾後，使用隔膜泵乾燥樣品，得到黃色固體目標產物，即化合物6-6 (60mg)。 Compound 6-5 (56 mg) was added to the well-dried reaction flask, dissolved in dioxane (3 mL), then trifluoroethanol (42 mg) and Cs 2 CO 3 (55 mg) were added, and the temperature was raised to 100° C. to react for 1 h. After completion of the reaction, the reaction solution was diluted with THF, and Cs 2 CO 3 was removed by filtration. After the filtrate was spin-dried, the sample was dried using a diaphragm pump to obtain the yellow solid target product, namely compound 6-6 (60 mg).

ESI-MS m/z: 740.03,742.07 [M+H] +。 ESI-MS m/z: 740.03, 742.07 [M+H] + .

步驟7：化合物6-7的合成Step 7: Synthesis of Compounds 6-7

N 2保護下，向乾燥反應瓶中加入化合物6-6(60mg)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷 (13mg)，用二氧六環(5mL)溶解，隨後加入K 2CO 3(22.40mg)、H 2O(0.5mL)，分散均勻後，加入1,1'-雙二苯基膦二茂鐵二氯化鈀 (5.93mg)，N 2置換體系三次。升溫至70℃攪拌1h。反應結束後，將反應液冷卻至室溫，加入水後用乙酸乙酯:甲醇=10:1萃取，飽和食鹽水反萃取，收集有機相，經Na 2SO 4乾燥、過濾、旋乾，濃縮物通過pre-TLC(展開劑為DCM/MeOH=10:1)純化,得到黃色固體產物，即化合物6-7(44mg)。 Under N2 protection, into a dry reaction flask was added compound 6-6 (60 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (13 mg), dissolved in dioxane (5 mL), then K 2 CO 3 (22.40 mg), H 2 O (0.5 mL) were added, and after the dispersion was uniform, 1,1'-bis-diphenylphosphinodioxin was added Iron palladium chloride (5.93 mg), N 2 displacement system three times. The temperature was raised to 70 °C and stirred for 1 h. After the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate: methanol = 10:1 after adding water, back-extracted with saturated brine, collected the organic phase, dried over Na 2 SO 4 , filtered, spin-dried, concentrated The product was purified by pre-TLC (developing solvent was DCM/MeOH=10:1) to give the product as a yellow solid, namely compound 6-7 (44 mg).

ESI-MS m/z: 640.11,642.13 [M+H] +。 ESI-MS m/z: 640.11, 642.13 [M+H] + .

步驟8：化合物6-8的合成Step 8: Synthesis of Compounds 6-8

向氮氣保護的反應瓶中加入化合物6-7(44mg)，用二氧六環(5mL) 溶解後，依次加入5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(47mg)、K 3PO 4(29mg)、去離子水(0.5mL)以及Pd(PPh 3) 4(8mg)。升溫至85℃反應3小時。將反應混合物冷卻至室溫，加入水後用乙酸乙酯:甲醇=10:1萃取，飽和食鹽水反萃取，收集有機相，經Na 2SO 4乾燥、過濾、旋乾，濃縮物通過pre-TLC(展開劑為DCM/MeOH=10:1)純化，得到黃色固體產物，即化合物6-8(18mg)。ESI-MS m/z: 776.87 [M+H] +。 Compound 6-7 (44 mg) was added to a nitrogen-protected reaction flask, dissolved in dioxane (5 mL), followed by 5-methyl-1-tetrahydropyran-2-yl-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (47 mg), K 3 PO 4 (29 mg), deionized water (0.5 mL) and Pd ( PPh3 ) 4 (8 mg). The temperature was raised to 85°C for 3 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate: methanol = 10: 1 after adding water, back-extracted with saturated brine, the organic phase was collected, dried over Na 2 SO 4 , filtered, and rotated to dryness, and the concentrate was passed through a pre- Purification by TLC (developing solvent: DCM/MeOH=10:1) gave the product as a yellow solid, namely compound 6-8 (18 mg). ESI-MS m/z: 776.87 [M+H] + .

步驟9：化合物6-9的合成Step 9: Synthesis of Compounds 6-9

在室溫下，將化合物6-8(18mg)溶於DCM(2mL)和TFA(1mL)的混合溶劑中，升溫至40℃反應1h。待反應完全後，濃縮除去溶劑，得到黃色固體粗品產物，即化合物6-9（21mg，粗品）直接用於下一步投料。ESI-MS m/z: 592.94 [M+H] +。 Compound 6-8 (18 mg) was dissolved in a mixed solvent of DCM (2 mL) and TFA (1 mL) at room temperature, and the temperature was raised to 40° C. to react for 1 h. After the reaction was completed, the solvent was concentrated and removed to obtain a yellow solid crude product, that is, compound 6-9 (21 mg, crude product) was directly used for the next feeding. ESI-MS m/z: 592.94 [M+H] + .

步驟10：化合物6的合成Step 10: Synthesis of Compound 6

在氮氣保護、冰水浴下，將丙烯醯氯(2.0mg)的THF(1mL)溶液滴加到化合物6-9(13mg，)的THF(4mL)與飽和NaHCO 3(1mL)混合溶液中，攪拌10分鐘。將反應液倒入水中，用乙酸乙酯:甲醇=10:1萃取，飽和食鹽水反萃取，收集有機相，經Na 2SO 4乾燥、過濾、旋乾，濃縮物通過pre-TLC(展開劑為DCM/MeOH=10:1)純化，得到淡黃色固體產物，即化合物6(7mg，LC-MS 純度96.2%) 。 Under nitrogen protection and an ice-water bath, a solution of acrylyl chloride (2.0 mg) in THF (1 mL) was added dropwise to a mixed solution of compound 6-9 (13 mg, ) in THF (4 mL) and saturated NaHCO 3 (1 mL), and stirred. 10 minutes. The reaction solution was poured into water, extracted with ethyl acetate: methanol = 10: 1, back-extracted with saturated brine, the organic phase was collected, dried over Na 2 SO 4 , filtered, and spin-dried, and the concentrate was passed through pre-TLC (developing solvent). Purification for DCM/MeOH=10:1) gave the product as a pale yellow solid, compound 6 (7 mg, LC-MS purity 96.2%).

ESI-MS m/z: 646.34 [M+H] +。 ESI-MS m/z: 646.34 [M+H] + .

實施例7：化合物7（1-（7-（2-（1-乙基呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image257
Example 7: Compound 7 (1-(7-(2-(1-ethylpyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1- ketone) synthesis
Figure 02_image257

步驟1：化合物7-1的合成Step 1: Synthesis of Compound 7-1

在室溫下，將碘乙烷(3.27g)，K 2CO 3(2.89g)加入到甲基呱啶-4-羧酸甲酯(1.5g, )的EtOH(15mL)溶液中，移至85°C回流反應1h。真空濃縮，除去EtOH，得到白色固體狀目標產物7-1(1.7g，粗品)。 At room temperature, iodoethane (3.27 g), K 2 CO 3 (2.89 g) was added to a solution of methyl oxidine-4-carboxylate (1.5 g, ) in EtOH (15 mL), transferred to 85 DEG C of reflux reaction 1h. Concentration in vacuo to remove EtOH afforded the desired product 7-1 as a white solid (1.7 g, crude).

ESI-MS m/z: 172.06 [M+H] +。 ESI-MS m/z: 172.06 [M+H] + .

步驟2：化合物7-2的合成Step 2: Synthesis of Compound 7-2

在室溫下，將LiOH(447.57mg)加入到化合物7-1(1.7g)的MeOH(10mL)溶液中，移至50°C反應1小時。向其中加入與LiOH等當量的稀鹽酸溶液，使目標產物游離，直接旋乾，剩餘物通過快速矽膠柱色譜（DCM:MeOH= 92:8-90:10）純化，得到黃色固體狀的所要目標產物7-2(700mg，44.85%產率)。LiOH (447.57 mg) was added to a solution of compound 7-1 (1.7 g) in MeOH (10 mL) at room temperature, moved to 50° C. to react for 1 hour. Dilute hydrochloric acid solution equivalent to LiOH was added thereto to free the target product, directly spin-dried, and the residue was purified by flash silica gel column chromatography (DCM:MeOH=92:8-90:10) to obtain the desired target as a yellow solid Product 7-2 (700 mg, 44.85% yield).

ESI-MS m/z: 158.15[M+H] +。 ESI-MS m/z: 158.15 [M+H] + .

步驟3：化合物7-3的合成Step 3: Synthesis of Compound 7-3

在室溫下，氮氣保護下，將化合物7-2(400mg)溶於SOCl 2(3mL)中，移至70°C下，攪拌反應1h。真空濃縮，除去氯化亞碸，得到白色固體狀目標產物7-3(450 mg，粗品)。 At room temperature, under nitrogen protection, compound 7-2 (400 mg) was dissolved in SOCl 2 (3 mL), moved to 70 °C, and the reaction was stirred for 1 h. Concentration in vacuo to remove the thionite chloride gave the desired product 7-3 as a white solid (450 mg, crude).

步驟4：化合物7-4的合成Step 4: Synthesis of Compounds 7-4

在室溫下，將化合物7-3(293.63mg)加入到化合物M1(300mg)的THF(10mL)中，移至45℃攪拌12小時。反應有大量固體析出，抽濾，固體即是目標產物7-4（150mg，粗品）。Compound 7-3 (293.63 mg) was added to compound M1 (300 mg) in THF (10 mL) at room temperature, and the mixture was moved to 45°C and stirred for 12 hours. A large amount of solid was precipitated in the reaction, which was filtered with suction, and the solid was the target product 7-4 (150 mg, crude product).

ESI-MS m/z: 498.00 [M+H] +。 ESI-MS m/z: 498.00 [M+H] + .

步驟5：化合物7-5的合成Step 5: Synthesis of Compounds 7-5

在室溫下，將甲醇鈉(81.34mg)加入到化合物7-4(150mg)的toluene (5mL)中，移至110℃回流攪拌4小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到棕色固體狀粗品目標產物7-5（150mg，粗品）。 At room temperature, sodium methoxide (81.34 mg) was added to toluene (5 mL) of compound 7-4 (150 mg), and the mixture was moved to 110° C. and stirred under reflux for 4 hours. After the reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give the crude target product 7-5 as a brown solid (150 mg, crude).

ESI-MS m/z: 480.00 [M+H] +。 ESI-MS m/z: 480.00 [M+H] + .

步驟6：化合物7-6的合成Step 6: Synthesis of Compounds 7-6

在室溫下，氮氣保護下，將DIEA(1.0mL)加入到化合物7-5(150mg)的POCl 3(5mL)中，移至110℃攪拌3小時。待反應完全後，直接濃縮除去POCl 3，加入EA稀釋，用水萃取三次，合併有機相，乾燥濃縮，得到白色固體狀目標產物7-6（150mg，粗品）。 DIEA (1.0 mL) was added to compound 7-5 (150 mg) in POCl 3 (5 mL) at room temperature under nitrogen protection, moved to 110° C. and stirred for 3 hours. After the reaction was completed, it was directly concentrated to remove POCl 3 , diluted with EA, extracted with water three times, combined with the organic phases, dried and concentrated to obtain the target product 7-6 (150 mg, crude product) as a white solid.

ESI-MS m/z: 497.99 [M+H] +。 ESI-MS m/z: 497.99 [M+H] + .

步驟7：化合物7-7的合成Step 7: Synthesis of Compounds 7-7

在室溫下，將DIEA(116.65mg)加入到化合物7-6(150mg)，2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(68.09mg)的二氧六環(5 mL)中，移至45℃攪拌1小時。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（DCM:MeOH=10:1）純化，得到黃色固體狀的所要目標產物7-7(50mg, 24.14%產率)。 DIEA (116.65 mg) was added to compound 7-6 (150 mg), 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (68.09 mg) in dioxane at room temperature into a ring (5 mL), moved to 45°C and stirred for 1 hour. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (DCM:MeOH=10:1) 1) Purification to obtain the desired target product 7-7 as a yellow solid (50 mg, 24.14% yield).

ESI-MS m/z: 688.14 [M+H] +。 ESI-MS m/z: 688.14 [M+H] + .

步驟8：化合物7-8的合成Step 8: Synthesis of Compounds 7-8

在氮氣保護下，將三氟乙醇(21.80mg)加入到化合物7-7(50mg)，Cs 2CO 3(47.33mg)的二氧六環(1mL)中，移至100℃反應3h。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物7-7(55mg，粗品)。 Under nitrogen protection, trifluoroethanol (21.80 mg) was added to compound 7-7 (50 mg), Cs 2 CO 3 (47.33 mg) in dioxane (1 mL), moved to 100° C. to react for 3 h. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol = 10:1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired target product 7-7 as a yellow solid (55 mg, Crude).

ESI-MS m/z: 768.18[M+H] +。 ESI-MS m/z: 768.18[M+H] + .

步驟9：化合物7-9的合成Step 9: Synthesis of Compounds 7-9

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(5.84mg)加入到化合物7-8(55mg)，K 2CO 3(19.78mg)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(11.02mg)的二氧六環(1.0mL)，H 2O(0.1mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物7-9(25mg, 37.39μmol, 52.24%產率)。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (5.84 mg) was added to compound 7-8 (55 mg), K 2 CO 3 (19.78 mg), 4,4,5,5-tetramethyl A mixed solution of yl-2-vinyl-1,3,2-dioxaborolane (11.02 mg) in dioxane (1.0 mL) and H 2 O (0.1 mL) was stirred at 70°C 1h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH=10:1 ) afforded the desired product 7-9 (25 mg, 37.39 μmol, 52.24% yield) as a yellow solid.

ESI-MS m/z: 668.18 [M+H] +。 ESI-MS m/z: 668.18 [M+H] + .

步驟10：化合物7-10的合成Step 10: Synthesis of Compounds 7-10

在氮氣保護下，將Pd(PPh 3) 4(8.64mg)加入到化合物7-9(25mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(25.59mg)，K 3PO 4(15.87mg, )的二氧六環(1mL)，H 2O(0.25mL)溶液中，移至85℃反應反應約3小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物7-10(20mg,66.53%產率)。ESI-MS Under nitrogen protection, Pd(PPh 3 ) 4 (8.64 mg) was added to compound 7-9 (25 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (25.59 mg), K 3 PO 4 (15.87 mg, ) in dioxane (1 mL), H 2 O (0.25 mL) solution, moved to 85°C to react for about 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH = 10:1 ) gave the desired product 7-10 as a yellow solid (20 mg, 66.53% yield). ESI-MS

m/z: 804.56 [M+H] +。 m/z: 804.56 [M+H] + .

步驟11：化合物7-11的合成Step 11: Synthesis of Compounds 7-11

在室溫下，將化合物7-10(20mg)溶於DCM(1mL)和TFA(0.5mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀目標產物7-11（18mg，粗品）。Compound 7-10 (20 mg) was dissolved in a mixed solvent of DCM (1 mL) and TFA (0.5 mL) at room temperature, and moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain the target product 7-11 (18 mg, crude product) as a yellow solid.

ESI-MS m/z: 620.28 [M+H] +。 ESI-MS m/z: 620.28 [M+H] + .

步驟12：化合物7的合成Step 12: Synthesis of Compound 7

在氮氣保護下，冰水浴中，將丙烯醯氯(3.15mg)的THF溶液加入到化合物9-11(18mg, )，THF(2mL)，飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物7(10.7mg，52.69%產率)。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (3.15 mg) in THF was added to a solution of compound 9-11 (18 mg, ), THF (2 mL), saturated Na 2 CO 3 (0.5 mL), and a solution of The reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product 7 as a yellow solid (10.7 mg, 52.69% yield).

ESI-MS m/z: 674.37 [M+H] +。 ESI-MS m/z: 674.37 [M+H] + .

1H NMR (500 MHz, DMSO- d 6) δ 13.05 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.50 (d, J= 8.5 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J= 8.5 Hz, 1H), 6.35 (m, 1H), 6.18 – 6.05 (m, 2H), 5.82 – 5.66 (m, 2H), 5.11 (d, J= 11.1 Hz, 1H), 4.97 (m, 1H), 4.68 (m, 1H), 3.23 – 3.05 (m, 4H), 2.80 (m, 1H), 2.25 (m, 2H), 2.05 (d, J= 6.7 Hz, 5H), 1.95 (m, 6H), 1.62 – 1.55 (m, 1H), 1.32 (m, 1H), 1.07 (t, J= 7.2 Hz, 3H), 0.94 (t, J= 7.3 Hz, 2H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 13.05 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.35 (m, 1H), 6.18 – 6.05 (m, 2H), 5.82 – 5.66 (m, 2H), 5.11 (d, J = 11.1 Hz, 1H) ), 4.97 (m, 1H), 4.68 (m, 1H), 3.23 – 3.05 (m, 4H), 2.80 (m, 1H), 2.25 (m, 2H), 2.05 (d, J = 6.7 Hz, 5H) , 1.95 (m, 6H), 1.62 – 1.55 (m, 1H), 1.32 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.3 Hz, 2H).

實施例8：化合物8（1-（7-（6-氯-8-乙氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image259
Example 8: Compound 8 (1-(7-(6-Chloro-8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine) Synthesis of -4-yl)-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one)
Figure 02_image259

步驟1：化合物8-1的合成Step 1: Synthesis of Compound 8-1

在氮氣保護下，將乙醇(395mg)加入到化合物M2(1.0g)，Cs 2CO 3(1.68g)的二氧六環(10mL)中，移至80℃反應1h。降到室溫，緩慢加入水，析出固體，過濾，烘乾得到黃色固體8-1 (0.96g，粗品)。 Under nitrogen protection, ethanol (395 mg) was added to compound M2 (1.0 g), Cs 2 CO 3 (1.68 g) in dioxane (10 mL), moved to 80° C. to react for 1 h. It was lowered to room temperature, water was slowly added, a solid was precipitated, filtered, and dried to obtain a yellow solid 8-1 (0.96 g, crude product).

ESI-MS m/z: 608.19 [M+H] +。 ESI-MS m/z: 608.19 [M+H] + .

步驟2：化合物8-2的合成Step 2: Synthesis of Compound 8-2

在氮氣保護下，將Pd(PPh 3) 4(341mg)加入到化合物8-1 (900mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(758.6mg)，K 3PO 4(941.1mg，)的二氧六環(20mL)，H 2O(5mL)溶液中，移至85℃反應4h。降到室溫，加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，矽膠柱分離純化(DCM:MeOH=10:1)，得黃色固體8-2 (665mg，49.9% 產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (341 mg) was added to compound 8-1 (900 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indazole ( 758.6 mg), K3PO4 (941.1 mg, ) in dioxane (20 mL), H2O (5mL) solution, moved to 85°C to react for 4h. It was cooled to room temperature, diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, separated and purified by silica gel column (DCM:MeOH=10:1) to obtain yellow solid 8-2 (665 mg, 49.9% yield).

ESI-MS m/z: 744.39 [M+H] +。 ESI-MS m/z: 744.39 [M+H] + .

步驟3：化合物8-3的合成Step 3: Synthesis of Compound 8-3

在室溫條件下，將化合物8-2 (120mg)溶於DCM(6mL)和TFA(3mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到棕色油粗品8-3（73mg，粗品）。At room temperature, compound 8-2 (120 mg) was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL), moved to 40° C. and reacted for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 8-3 (73 mg, crude product).

ESI-MS m/z: 560.28 [M+H] +。 ESI-MS m/z: 560.28 [M+H] + .

步驟4：化合物8的合成Step 4: Synthesis of Compound 8

在氮氣保護下，冰水浴中，將丙烯醯氯(12.1mg)的THF（1mL）溶液加入到化合物8-3 (73mg)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，保持溫度攪拌5min。加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾， pre-TLC分離純化(DCM:MeOH=10:1)，得白色固體8 (36.5mg，43.3%產率) 。 Under nitrogen protection, a solution of acrylonitrile chloride (12.1 mg) in THF (1 mL) was added to a solution of compound 8-3 (73 mg), THF (4 mL), saturated Na 2 CO 3 (1 mL) in an ice-water bath, keeping the The temperature was stirred for 5 min. It was diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, and separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain 8 (36.5 mg, 43.3%) as a white solid Yield) .

ESI-MS m/z: 614.40 [M+H] +。 ESI-MS m/z: 614.40 [M+H] + .

實施例9：化合物9（1-（7-（8-乙氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image261
Example 9: Compound 9 (1-(7-(8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl) )-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one) synthesis
Figure 02_image261

步驟1：化合物9-1的合成Step 1: Synthesis of Compound 9-1

在氮氣保護下，將Sphos Pd G2 (51.7mg)加入到化合物8-2 (300mg)，K 3PO 4(228.4mg，)，乙烯基硼酸酯 (110.49mg)的二氧六環(4mL)，H 2O(1mL)混合溶液中，在100 ℃攪拌4h。降至室溫，加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，pre-TLC分離純化(DCM:MeOH=10:1)，得白色固體9-1(185mg，70.08% 產率)。 Under nitrogen protection, Sphos Pd G2 (51.7 mg) was added to compound 8-2 ( 300 mg), K3PO4 (228.4 mg, ), vinylborate (110.49 mg) in dioxane (4 mL) , H 2 O (1 mL) mixed solution, stirred at 100 ℃ for 4 h. It was cooled to room temperature, diluted with water, extracted three times with EA, the organic phases were combined and dried with anhydrous Na 2 SO 4 , filtered, spun dry, separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain a white solid 9- 1 (185 mg, 70.08% yield).

ESI-MS m/z: 736.45 [M+H] +。 ESI-MS m/z: 736.45 [M+H] + .

步驟2：化合物9-2的合成Step 2: Synthesis of Compound 9-2

在室溫條件下，將化合物9-1 (185mg)溶於DCM(4mL)和TFA(2mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到棕色油粗品9-2（138mg，粗品）。At room temperature, compound 9-1 (185 mg) was dissolved in a mixed solvent of DCM (4 mL) and TFA (2 mL), moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 9-2 (138 mg, crude product).

ESI-MS m/z: 552.34 [M+H] +。 ESI-MS m/z: 552.34 [M+H] + .

步驟3：化合物9的合成Step 3: Synthesis of Compound 9

在氮氣保護下，冰水浴中，將丙烯醯氯(22.6mg)的THF（1mL）溶液加入到化合物9-2 (138mg)，THF(4 mL)，飽和Na 2CO 3(1mL)溶液中，保持溫度攪拌5min。加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，pre-TLC分離純化(DCM:MeOH=10:1)，得白色固體9 (62.5mg，38.2%產率) 。 Under nitrogen protection, a solution of acrylonitrile chloride (22.6 mg) in THF (1 mL) was added to a solution of compound 9-2 (138 mg), THF (4 mL), saturated Na 2 CO 3 (1 mL) in an ice-water bath, The temperature was maintained and stirred for 5 min. It was diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, and separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain 9 (62.5 mg, 38.2%) as a white solid Yield) .

ESI-MS m/z: 606.45 [M+H] +。 ESI-MS m/z: 606.45 [M+H] + .

1H NMR (500 MHz, Chloroform- d) δ 7.90 (s, 1H), 7.51 (s, 1H), 7.46 (d, J= 8.5 Hz, 1H), 7.37 – 7.34 (m, 1H), 6.39 (dd, J= 17.0, 1.9 Hz, 1H), 6.24 (m, 2H), 5.71 (dd, J= 10.2, 1.9 Hz, 1H), 5.62 (d, J= 17.4 Hz, 1H), 5.03 (d, J= 11.0 Hz, 1H), 4.22 (m, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.91 – 3.84 (m, 1H), 3.75 (m, 4H), 3.00 (t, J= 6.1 Hz, 2H), 2.87 (m, 1H), 2.35 (s, 3H), 2.16 (s, 3H), 2.12 – 2.08 (m, 5H), 2.03 (m, 4H), 1.33 (m, 4H). 1 H NMR (500 MHz, Chloroform- d ) δ 7.90 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.37 – 7.34 (m, 1H), 6.39 (dd , J = 17.0, 1.9 Hz, 1H), 6.24 (m, 2H), 5.71 (dd, J = 10.2, 1.9 Hz, 1H), 5.62 (d, J = 17.4 Hz, 1H), 5.03 (d, J = 11.0 Hz, 1H), 4.22 (m, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.91 – 3.84 (m, 1H), 3.75 (m, 4H), 3.00 (t, J = 6.1 Hz, 2H), 2.87 (m, 1H), 2.35 (s, 3H), 2.16 (s, 3H), 2.12 – 2.08 (m, 5H), 2.03 (m, 4H), 1.33 (m, 4H).

實施例10：化合物10（1-（7-（6-氯-8-甲氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image263
Example 10: Compound 10 (1-(7-(6-Chloro-8-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine) Synthesis of -4-yl)-quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one)
Figure 02_image263

步驟1：化合物10-1的合成Step 1: Synthesis of Compound 10-1

在氮氣保護下，將甲醇(275mg)加入到化合物M2 (1.0g)，Cs 2CO 3(1.68g)的二氧六環(10mL)中，移至70℃反應 5h。降到室溫，緩慢加入水，析出固體，過濾，烘乾得到黃色固體10-1 (0.91 g，粗品)。 Under nitrogen protection, methanol (275 mg) was added to compound M2 (1.0 g), Cs 2 CO 3 (1.68 g) in dioxane (10 mL), and moved to 70° C. to react for 5 h. It was lowered to room temperature, water was slowly added, a solid was precipitated, filtered, and dried to obtain a yellow solid 10-1 (0.91 g, crude product).

ESI-MS m/z: 594.18 [M+H] +。 ESI-MS m/z: 594.18 [M+H] + .

步驟2：化合物10-2的合成Step 2: Synthesis of Compound 10-2

在氮氣保護下，將Pd(PPh 3) 4(77.69mg)加入到化合物10-1 (200mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(172.5mg)，K 3PO 4(214.1mg，)的二氧六環(4mL)，H 2O(1mL)溶液中，移至85℃反應4h。降到室溫，加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，矽膠柱分離純化(DCM:MeOH=10:1)，得黃色固體10-2（202mg，79.8% 產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (77.69 mg) was added to compound 10-1 (200 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (172.5 mg), K 3 PO 4 (214.1 mg, ) in dioxane (4 mL), H 2 O (1 mL) solution, moved to 85°C and reacted for 4h. It was cooled to room temperature, diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, separated and purified on a silica gel column (DCM:MeOH=10:1) to obtain a yellow solid 10-2 (202 mg, 79.8% yield).

ESI-MS m/z: 730.38 [M+H] +。 ESI-MS m/z: 730.38 [M+H] + .

步驟3：化合物12-3的合成Step 3: Synthesis of Compound 12-3

在室溫條件下，將化合物10-2 (200mg)溶於DCM(6mL)和TFA(3mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到棕色油粗品10-3（149mg，粗品）。At room temperature, compound 10-2 (200 mg) was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL), moved to 40° C. and reacted for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 10-3 (149 mg, crude product).

ESI-MS m/z: 546.27 [M+H] +。 ESI-MS m/z: 546.27 [M+H] + .

步驟4：化合物10的合成Step 4: Synthesis of Compound 10

在氮氣保護下，冰水浴中，將丙烯醯氯(24.7mg)的THF（1mL）溶液加入到化合物12-3 (149mg)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，保持溫度攪拌5min。加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾， pre-TLC分離純化(DCM:MeOH=10:1)，得白色固體10 (80.3mg，47.27%產率，96.39%純度) 。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (24.7 mg) in THF (1 mL) was added to a solution of compound 12-3 (149 mg), THF (4 mL), saturated Na 2 CO 3 (1 mL), keeping The temperature was stirred for 5 min. Diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spin-dried, separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain a white solid 10 (80.3 mg, 47.27%) yield, 96.39% purity).

ESI-MS m/z: 600.35 [M+H] +。 ESI-MS m/z: 600.35 [M+H] + .

實施例11：化合物11（1-（7-（8-甲氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image265
Example 11: Compound 11 (1-(7-(8-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl) )-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one) synthesis
Figure 02_image265

步驟1：化合物11-1的合成Step 1: Synthesis of Compound 11-1

在氮氣保護下，將Sphos Pd G2 (59.2mg)加入到化合物10-2 (300mg)，K 3PO 4(261.5mg)，乙烯基硼酸酯 (126.53mg)的二氧六環(4mL)，H 2O(1mL)混合溶液中，在100℃攪拌4h。降至室溫，加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾，pre-TLC分離純化(DCM:MeOH=10:1)，得白色固體11-1(205mg，69.13% 產率)。 Under nitrogen protection, Sphos Pd G2 (59.2 mg) was added to compound 10-2 (300 mg), K 3 PO 4 (261.5 mg), vinyl boronate (126.53 mg) in dioxane (4 mL), H 2 O (1 mL) mixed solution was stirred at 100° C. for 4 h. It was cooled to room temperature, diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain a white solid 11- 1 (205 mg, 69.13% yield).

ESI-MS m/z: 722.43 [M+H] +。 ESI-MS m/z: 722.43 [M+H] + .

步驟2：化合物11-2的合成Step 2: Synthesis of Compound 11-2

在室溫條件下，將化合物11-1 (205mg)溶於DCM(6mL)和TFA(3mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到棕色油粗品11-2（152mg，粗品）。At room temperature, compound 11-1 (205 mg) was dissolved in a mixed solvent of DCM (6 mL) and TFA (3 mL), moved to 40° C. and reacted for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain a brown oil crude product 11-2 (152 mg, crude product).

ESI-MS m/z: 538.32 [M+H] +。 ESI-MS m/z: 538.32 [M+H] + .

步驟3：化合物11的合成Step 3: Synthesis of Compound 11

在氮氣保護下，冰水浴中，將丙烯醯氯(25.4mg)的THF（1mL）溶液加入到化合物11-2 (152mg)，THF(4mL)，飽和Na 2CO 3(1mL)溶液中，保持溫度攪拌5min。加水稀釋，用EA萃取三次萃取，合併有機相並用無水Na 2SO 4乾燥，過濾，旋乾， pre-TLC分離純化(DCM:MeOH=10:1)，得黃色固體11 (87.2mg，52.1%產率) 。 Under nitrogen protection, a solution of acrylonitrile chloride (25.4 mg) in THF (1 mL) was added to a solution of compound 11-2 (152 mg), THF (4 mL), saturated Na 2 CO 3 (1 mL) in an ice-water bath, keeping The temperature was stirred for 5 min. It was diluted with water, extracted three times with EA, the organic phases were combined and dried over anhydrous Na 2 SO 4 , filtered, spun dry, and separated and purified by pre-TLC (DCM:MeOH=10:1) to obtain yellow solid 11 (87.2 mg, 52.1%). Yield) .

ESI-MS m/z: 592.43 [M+H] +。 ESI-MS m/z: 592.43 [M+H] + .

1H NMR (500 MHz, Chloroform- d) δ 7.90 (s, 1H), 7.52 (s, 1H), 7.47 (d, J= 8.5 Hz, 1H), 7.36 (d, J= 8.5 Hz, 1H), 6.39 (dd, J= 17.0, 2.0 Hz, 1H), 6.22 (m, 2H), 5.72 (dd, J= 10.2, 2.0 Hz, 1H), 5.62 (d, J= 17.4 Hz, 1H), 5.03 (d, J= 11.0 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.75 (m, 8H), 3.00 (m, 3H), 2.35 (s, 3H), 2.14 (s, 3H), 2.11 (d, J= 7.1 Hz, 5H), 2.04 (m, 4H). 1 H NMR (500 MHz, Chloroform- d ) δ 7.90 (s, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.39 (dd, J = 17.0, 2.0 Hz, 1H), 6.22 (m, 2H), 5.72 (dd, J = 10.2, 2.0 Hz, 1H), 5.62 (d, J = 17.4 Hz, 1H), 5.03 (d , J = 11.0 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 3.75 (m, 8H), 3.00 (m, 3H), 2.35 (s, 3H), 2.14 (s, 3H) , 2.11 (d, J = 7.1 Hz, 5H), 2.04 (m, 4H).

實施例12：化合物12（1-（7-（2 -（1-乙醯呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮）的合成

Figure 02_image267
Example 12: Compound 12 (1-(7-(2-(1-acetaziridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1- ketone) synthesis
Figure 02_image267

步驟1：化合物12-1的合成Step 1: Synthesis of Compound 12-1

在室溫下，將1乙醯基呱啶-4-碳醯氯(567mg)加入到化合物M1(300mg)的THF(10mL)中，移至40℃攪拌4小時。待反應完全後，直接濃縮出去THF，得到黃色固體狀目標產物12-1（460mg，粗品）。At room temperature, 1-acetoxypyridine-4-carbohydrin (567 mg) was added to compound M1 (300 mg) in THF (10 mL), and the mixture was moved to 40°C and stirred for 4 hours. After the reaction was completed, the THF was directly concentrated to obtain the target product 12-1 (460 mg, crude product) as a yellow solid.

ESI-MS m/z: 512.14 [M+H] +。 ESI-MS m/z: 512.14 [M+H] + .

步驟2：化合物12-2的合成Step 2: Synthesis of Compound 12-2

在室溫下，將甲醇鈉(224.56mg)加入到化合物12-1(460mg)的toluene (10mL)中，移至110℃回流攪拌8小時。待反應完全後，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機相經Na 2SO 4乾燥且真空濃縮，得到白色固體狀目標產物12-2（210mg，粗品）。 At room temperature, sodium methoxide (224.56 mg) was added to toluene (10 mL) of compound 12-1 (460 mg), and the mixture was moved to 110° C. and stirred under reflux for 8 hours. After the reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give the desired product 12-2 (210 mg, crude) as a white solid.

ESI-MS m/z: 494.06 [M+H] +。 ESI-MS m/z: 494.06 [M+H] + .

步驟3：化合物12-3的合成Step 3: Synthesis of Compound 12-3

在室溫下，將化合物12-2（170mg）加到DMF(5mL)中，接著加入2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(92mg)、BOP(376mg)、DBU(258mg)，40度反應6h。反應到後期原料剩30%不再進行，向反應物中加入水，用乙酸乙酯萃取，有機相經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(展開劑為DCM/MeOH=15:1)純化,得到黃色固體產物12-3（150mg，62.2%收率）。 Compound 12-2 (170 mg) was added to DMF (5 mL) at room temperature, followed by tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (92 mg), BOP ( 376mg), DBU (258mg), 40 degrees reaction for 6h. The reaction was not carried out until the remaining 30% of the raw materials in the later stage, water was added to the reactant, extracted with ethyl acetate, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo, and the concentrate was passed through pre-TLC (developing solvent: DCM/MeOH= 15:1) was purified to yield product 12-3 as a yellow solid (150 mg, 62.2% yield).

ESI-MS m/z: 702.28 [M+H] +。 ESI-MS m/z: 702.28 [M+H] + .

步驟4：化合物12-4的合成Step 4: Synthesis of Compound 12-4

在氮氣保護下，將三氟乙醇(106mg)加入到化合物12-3(150mg)，Cs 2CO 3(139mg，)的二氧六環(3mL)中，移至100℃反應3 h。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(展開劑為DCM/MeOH=15:1)純化，得到黃色油狀的所要目標產物12-4(120mg，71.9%收率)。 Under nitrogen protection, trifluoroethanol (106 mg) was added to compound 12-3 (150 mg), Cs 2 CO 3 (139 mg, ) in dioxane (3 mL), moved to 100° C. to react for 3 h. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was purified by pre-TLC (developing solvent: DCM/MeOH=15:1), The desired target product 12-4 was obtained as a yellow oil (120 mg, 71.9% yield).

ESI-MS m/z: 782.48 [M+H] +。 ESI-MS m/z: 782.48 [M+H] + .

步驟5：化合物12-5的合成Step 5: Synthesis of Compound 12-5

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(12mg)加入到化合物12-4(115mg)，K 2CO 3(41mg，)，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(22.7mg)的二氧六環(2.5mL)，H 2O(0.5mL)混合溶液中，在70℃攪拌6h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，剩餘物通過快速矽膠柱色譜（PE:EA=1:2）純化，得到黃色固體狀的所要目標產物12-5(65mg，65.4 %產率)。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (12 mg) was added to compound 12-4 (115 mg), K 2 CO 3 (41 mg, ), 4,4,5,5-tetramethyl A mixed solution of -2-vinyl-1,3,2-dioxaborolane (22.7 mg) in dioxane (2.5 mL) and H 2 O (0.5 mL) was stirred at 70 °C for 6 h . The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the residue was subjected to flash silica gel column chromatography (PE:EA=1 : 2) Purification to obtain the desired target product 12-5 (65 mg, 65.4% yield) as a yellow solid.

ESI-MS m/z: 682.58 [M+H] +。 ESI-MS m/z: 682.58 [M+H] + .

步驟6：化合物12-6的合成Step 6: Synthesis of Compound 12-6

在氮氣保護下，將Pd(PPh 3) 4(22mg)加入到化合物12-5(65mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(65mg)，K 3PO 4(40mg)的二氧六環(2mL)，H 2O(0.5mL)溶液中，移至85℃反應反應約4小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(PE:EA=2:1)純化，得到呈黃色油狀的所要產物12-6(70mg，89.7 %產率)。 Under nitrogen protection, Pd(PPh 3 ) 4 (22 mg) was added to compound 12-5 (65 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (65 mg), K3PO4 (40 mg) in dioxane ( 2 mL), H2O (0.5 mL) ) solution, moved to 85°C and reacted for about 4 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC (PE:EA=2: 1) Purification gave the desired product 12-6 as a yellow oil (70 mg, 89.7% yield).

ESI-MS m/z: 818.94 [M+H] +。 ESI-MS m/z: 818.94 [M+H] + .

步驟7：化合物12-7的合成Step 7: Synthesis of Compound 12-7

在室溫下，將化合物14-6(70mg，85.7μmol)溶於DCM(1mL)和TFA(0.5mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀目標產物12-7（93mg，粗品）。Compound 14-6 (70 mg, 85.7 μmol) was dissolved in a mixed solvent of DCM (1 mL) and TFA (0.5 mL) at room temperature, moved to 40° C. to react for about 1 h. After the reaction was complete, the solvent was directly concentrated to remove the solvent to obtain the target product 12-7 (93 mg, crude product) as a yellow solid.

ESI-MS m/z: 634.32 [M+H] +。 ESI-MS m/z: 634.32 [M+H] + .

步驟8：化合物12的合成Step 8: Synthesis of Compound 12

在氮氣保護下，冰水浴中，將丙烯醯氯(8.4mg，94μmol)的THF溶液加入到化合物14-7(54mg)，THF(2mL)，飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物12(25.7mg，43.2 %產率) 。 Under nitrogen protection, in an ice-water bath, a solution of acrylyl chloride (8.4 mg, 94 μmol) in THF was added to a solution of compound 14-7 (54 mg), THF (2 mL), saturated Na 2 CO 3 (0.5 mL), and added That is, the reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product 12 as a yellow solid (25.7 mg, 43.2 % yield).

ESI-MS m/z: 688.49 [M+H] +。 編號 結構與命名 1

Figure 02_image269
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮；ESI-MS m/z: 660.37 [M+H] + 2
Figure 02_image271
1-（7 -（2 -環己基）- 7 -（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮；ESI-MS m/z: 645.44 [M+H] + 3
Figure 02_image273
1 -（7 -（7 -（5 -甲基-1H-吲唑-4-基）-2-（四氫呋喃-3-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮；ESI-MS m/z: 633.41 [M+H] + 4
Figure 02_image275
1 -（7 -（6 - 乙基-7-（5 -甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮；ESI-MS m/z: 662.37 [M+H] + 5
Figure 02_image277
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（四氫-2H-吡喃-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮；ESI-MS m/z: 647.33 [M+H] + 6
Figure 02_image279
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基吡咯烷-3-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 646.34 [M+H] + 7
Figure 02_image281
1-（7-（2-（1 -乙基呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮螺環[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 674.37 [M+H] + 8
Figure 02_image283
1-（7-（6-氯-8-乙氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 614.40 [M+H] + 9
Figure 02_image285
1-（7-（8-乙氧基-7-（5-甲基-1H-吲唑-4-基）-2 -（1-甲基呱啶-4-基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 606.45 [M+H] + 10
Figure 02_image287
1-（7-（6-氯-8-甲氧基-7-（5-甲基-1H-吲唑-4-基）-2 -（1-甲基呱啶-4-基）-喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 600.35 [M+H] + 11
Figure 02_image289
1-（7-（8-甲氧基-7-（5-甲基-1H-吲唑-4-基）-2 -（1-甲基呱啶-4-基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 592.43 [M+H] + 12
Figure 02_image291
1-（7-（2 -（1-乙醯呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬-2-基）丙-2-烯-1-酮;ESI-MS m/z: 688.49 [M+H] + ESI-MS m/z: 688.49 [M+H] + . Numbering structure and naming 1
Figure 02_image269
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2,2-trifluoro Ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/ z: 660.37 [M+H] + 2
Figure 02_image271
1-(7-(2-Cyclohexyl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinyl quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 645.44 [M+H] + 3
Figure 02_image273
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(tetrahydrofuran-3-yl)-8-(2,2,2-trifluoroethoxy)- 6-Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 633.41 [M +H] + 4
Figure 02_image275
1-(7-(6-Ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2 ,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/ z: 662.37 [M+H] + 5
Figure 02_image277
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-8-(2,2,2-tris Fluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m /z: 647.33 [M+H] + 6
Figure 02_image279
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-methylpyrrolidin-3-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/ z: 646.34 [M+H] + 7
Figure 02_image281
1-(7-(2-(1-Ethylpyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/ z: 674.37 [M+H] + 8
Figure 02_image283
1-(7-(6-Chloro-8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-quinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 614.40 [M+H] + 9
Figure 02_image285
1-(7-(8-Ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-6-vinylquinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 606.45 [M+H] + 10
Figure 02_image287
1-(7-(6-Chloro-8-methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-quinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 600.35 [M+H] + 11
Figure 02_image289
1-(7-(8-Methoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-6-vinylquinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/z: 592.43 [M+H] + 12
Figure 02_image291
1-(7-(2-(1-Acetidine-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one; ESI-MS m/ z: 688.49 [M+H] +

實施例13：化合物13（1-（7-（6-環丙基-8-（2-甲氧基乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image293
Example 13: Compound 13 (1-(7-(6-Cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)- 2-(1-Methylpyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one )Synthesis
Figure 02_image293

步驟1：化合物13-1的合成Step 1: Synthesis of Compound 13-1

在氮氣保護下，將Pd(dppf) 2Cl 2DCM(112 mg)加入到碳酸鉀(378 mg), 化合物1-6(1 g )和環丙基硼酸 (124 mg)的甲苯(10 mL)和水(1 mL)的溶液中，100度攪拌3小時，TLC和LCMS顯示反應完畢，冷卻至室溫，乙酸乙酯稀釋，飽和食鹽水洗滌兩次，乾燥，過濾，濃縮得粗產物，柱層析（DCM/MeOH=15:1）得目標產物(530 mg, 60% 產率)。ESI-MS m/z: 668.30 [M+H]+ Pd(dppf) 2Cl2DCM (112 mg ) was added to potassium carbonate (378 mg), compound 1-6 (1 g) and cyclopropylboronic acid (124 mg) in toluene (10 mL) under nitrogen protection and water (1 mL), stirred at 100 degrees for 3 hours, TLC and LCMS showed that the reaction was complete, cooled to room temperature, diluted with ethyl acetate, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product. Chromatography (DCM/MeOH=15:1) gave the title product (530 mg, 60% yield). ESI-MS m/z: 668.30 [M+H]+

步驟2：化合物13-2的合成Step 2: Synthesis of Compound 13-2

在氮氣保護下，將Pd 2(dba) 3(9.9 mg)和SPhos(8.8 mg)加入到13-1(72 mg), 5-甲基-1-（四氫-2H-吡喃-2-基）-4-（4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基）-1H-吲唑(37 mg)和磷酸鉀(46 mg)的二氧六環(3 mL)和水(0.4 mL)的溶液中，加熱至110度反應2小時，TLC和LCMS顯示反應完畢，冷卻至室溫，濃縮，柱層析(DCM/MeOH=15:1)得產物(38 mg, 45%收率)。ESI-MS m/z: 804.50 [M+H]+ Under nitrogen protection, Pd 2 (dba) 3 (9.9 mg) and SPhos (8.8 mg) were added to 13-1 (72 mg), 5-methyl-1-(tetrahydro-2H-pyran-2- yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indazole (37 mg) and potassium phosphate (46 mg) in a solution of dioxane (3 mL) and water (0.4 mL), heated to 110 degrees and reacted for 2 hours, TLC and LCMS showed that the reaction was complete, cooled to room temperature, concentrated, column chromatography (DCM/MeOH=15 : 1) to obtain the product (38 mg, 45% yield). ESI-MS m/z: 804.50 [M+H]+

步驟3：化合物13-3的合成Step 3: Synthesis of Compound 13-3

在室溫下，將13-2 (200 mg)溶於DCM(4mL)和TFA(2mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀粗品目標產物13-3(100 mg)。ESI-MS m/z: 620.38 [M+H]+。At room temperature, 13-2 (200 mg) was dissolved in a mixed solvent of DCM (4 mL) and TFA (2 mL), moved to 40° C. to react for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain the crude target product 13-3 (100 mg) as a yellow solid. ESI-MS m/z: 620.38 [M+H]+.

步驟4：化合物13的合成Step 4: Synthesis of Compound 13

在氮氣保護下，冰水浴中，將丙烯醯氯(22 mg)的THF溶液加入到13-3 (100mg)的THF(4mL)和飽和Na2CO3(1mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化，得到呈黃色固體狀的所要產物13(24.1mg，22%產率)。ESI-MS m/z: 674.40 [M+H]+。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (22 mg) in THF was added to a solution of 13-3 (100 mg) in THF (4 mL) and saturated Na2CO3 (1 mL), and the reaction was complete. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product 13 as a yellow solid (24.1 mg, 22% yield). ESI-MS m/z: 674.40 [M+H]+.

實施例14：化合物14（1-（7-（6-環丙基-8-（2-甲氧基乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image295
Example 14: Compound 14 (1-(7-(6-Cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)- 2-(1-Methylpyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one )Synthesis
Figure 02_image295

在氮氣保護下，將乙二醇甲醚(762 mg)加入到1-5(1.35 g)，Cs 2CO 3(1.96 g)的Dioxane(15mL)中，移至100℃反應30 min。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物14-1 (1.3 g，粗產物)。ESI-MS m/z: 730.15 [M+H]+ Under nitrogen protection, ethylene glycol methyl ether (762 mg) was added to 1-5 (1.35 g), Cs 2 CO 3 (1.96 g) in Dioxane (15 mL), and moved to 100 °C to react for 30 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol = 10:1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired target product 14-1 as a yellow solid (1.3 g , the crude product). ESI-MS m/z: 730.15 [M+H]+

之後按照化合物13的合成步驟合成14-2，14-3和14-4，最終得到目標產物14。 ESI-MS m/z: 650.4 [M+H]+Then, 14-2, 14-3 and 14-4 were synthesized according to the synthesis steps of compound 13, and the target product 14 was finally obtained. ESI-MS m/z: 650.4 [M+H]+

實施例15：化合物15（1-（7-（6-環丙基-8-（2,2-二氟乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4 –基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image297
Example 15: Compound 15 (1-(7-(6-cyclopropyl-8-(2,2-difluoroethoxy)-7-(5-methyl-1H-indazol-4-yl)) -2-(1-Methylpyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1- ketone) synthesis
Figure 02_image297

步驟1：化合物15-1的合成Step 1: Synthesis of Compound 15-1

在氮氣保護下，將二氟乙醇(201 mg)加入到1-5(550mg)，Cs 2CO 3(531.45mg)的Dioxane(5mL)中，移至100℃反應30 min。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物15-1 (550mg，crude)。ESI-MS m/z: 736.30 [M+H]+ Under nitrogen protection, difluoroethanol (201 mg) was added to 1-5 (550 mg), Cs 2 CO 3 (531.45 mg) in Dioxane (5 mL), and moved to 100° C. to react for 30 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol = 10:1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired target product 15-1 as a yellow solid (550 mg, crude). ESI-MS m/z: 736.30 [M+H]+

之後按照化合物13的合成步驟合成15-2，15-3和15-4，最終得到目標產物15。 ESI-MS m/z: 656.4 [M+H]+ 編號 結構與命名 13

Figure 02_image299
1-（7-（6-環丙基-8-（2-甲氧基乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 674.40 [M+H]+ 14
Figure 02_image301
1-（7-（6-環丙基-8-（2-甲氧基乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 650.45 [M+H]+ 15
Figure 02_image303
1-（7-（6-環丙基-8-（2,2-二氟乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4 –基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 656.35 [M+H]+ Then, 15-2, 15-3 and 15-4 were synthesized according to the synthesis steps of compound 13, and the target product 15 was finally obtained. ESI-MS m/z: 656.4 [M+H]+ Numbering structure and naming 13
Figure 02_image299
1-(7-(6-Cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methyl) Quaridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z : 674.40 [M+H]+ 14
Figure 02_image301
1-(7-(6-Cyclopropyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methyl) Quaridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z : 650.45 [M+H]+ 15
Figure 02_image303
1-(7-(6-Cyclopropyl-8-(2,2-difluoroethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methyl) (ylguaridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/ z: 656.35 [M+H]+

實施例16：化合物16（1-（7-（8-乙氧基-6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image305
Example 16: Compound 16 (1-(7-(8-Ethoxy-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylguanidine) Synthesis of pyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one)
Figure 02_image305

步驟1：化合物16-1的合成Step 1: Synthesis of Compound 16-1

在氮氣保護下，將乙醇(112 mg)加入到1-5(550mg), Cs 2CO 3(531 mg)的Dioxane(5mL)中，移至100℃反應30 min。將混合物傾注入冰水中，用乙酸乙酯/甲醇=10:1萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到黃色固體狀的所要目標產物16-1(590mg，crude)。ESI-MS m/z: 700.3 [M+H]+。 Under nitrogen protection, ethanol (112 mg) was added to 1-5 (550 mg), Cs 2 CO 3 (531 mg) in Dioxane (5 mL), and the reaction was moved to 100° C. for 30 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate/methanol = 10:1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give the desired target product 16-1 as a yellow solid (590 mg, crude). ESI-MS m/z: 700.3 [M+H]+.

步驟2：化合物16-2的合成Step 2: Synthesis of Compound 16-2

在氮氣保護下，將Pd(dppf)Cl 2.CH 2Cl 2(67 mg)加入到16-1 (粗品590mg)，K 2CO 3(226 mg )，4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧雜硼雜環戊烷(126 mg)的dioxane (5.0mL)，H 2O(0.5mL)混合溶液中，在70℃攪拌1h。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物16-2 (329mg，66%產率).ESI-MS m/z: 600.6 [M+H]+。 Under nitrogen protection, Pd(dppf)Cl 2 .CH 2 Cl 2 (67 mg) was added to 16-1 (crude 590 mg), K 2 CO 3 (226 mg ), 4,4,5,5-tetramethyl A mixed solution of dioxane (5.0 mL) and H 2 O (0.5 mL) of yl-2-vinyl-1,3,2-dioxaborolane (126 mg) was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH=10:1) gave the desired product 16-2 as a yellow solid (329 mg, 66% yield). ESI-MS m/z: 600.6 [M+H]+.

步驟3：化合物16-3的合成Step 3: Synthesis of Compound 16-3

在氮氣保護下，將Pd(PPh 3) 4(116.16mg)加入到16-3 (329mg)，5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(344.04mg)，K 3PO 4(213.38mg)的dioxane(3mL), H 2O(0.75 mL)溶液中，移至85℃反應約3小時。將反應混合物冷卻至室溫，向反應混合物中加入水，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物16-3(244mg，65%產率)。ESI-MS m/z: 736.60 [M+H]+。 Under nitrogen protection, Pd(PPh 3 ) 4 (116.16 mg) was added to 16-3 (329 mg), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (344.04 mg), dioxane (3 mL) in K 3 PO 4 (213.38 mg), H 2 O (0.75 mL) The solution was moved to 85°C and reacted for about 3 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, extracted with ethyl acetate: methanol = 10: 1, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was passed through pre-TLC ( Purification with DCM/MeOH = 10:1 ) gave the desired product 16-3 as a yellow solid (244 mg, 65% yield). ESI-MS m/z: 736.60 [M+H]+.

步驟4：化合物16-4的合成Step 4: Synthesis of Compound 16-4

在室溫下，將16-3 (100 mg)溶於甲醇，加入鈀碳300 mg，置換氫氣，移至40℃反應過夜。待反應完全後，矽藻土助濾，濾液濃縮除去溶劑，得到黃色固體狀粗品目標產物16-4（150 mg，crude）。ESI-MS m/z:738.60 [M+H]+。At room temperature, 16-3 (100 mg) was dissolved in methanol, 300 mg of palladium on carbon was added, hydrogen was replaced, and the reaction was moved to 40° C. overnight. After the reaction was completed, diatomaceous earth was used for filtration, and the filtrate was concentrated to remove the solvent to obtain the crude target product 16-4 (150 mg, crude) as a yellow solid. ESI-MS m/z: 738.60 [M+H]+.

步驟5：化合物16-5的合成Step 5: Synthesis of Compound 16-5

在室溫下，將16-4 (150 mg, crude)溶於DCM(4mL)和TFA(2mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得到黃色固體狀粗品目標產物16-5（100 mg，crude）。ESI-MS m/z: 554.60 [M+H]+。At room temperature, 16-4 (150 mg, crude) was dissolved in a mixed solvent of DCM (4 mL) and TFA (2 mL), moved to 40°C and reacted for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain the crude target product 16-5 (100 mg, crude) as a yellow solid. ESI-MS m/z: 554.60 [M+H]+.

步驟6：化合物16的合成Step 6: Synthesis of Compound 16

在氮氣保護下，冰水浴中，將丙烯醯氯(17.03mg)的THF溶液加入到16-5 (100 mg)，THF(4mL)，飽和Na2CO3(1mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯:甲醇=10:1萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到呈黃色固體狀的所要產物16 (21 mg，20%產率) 。ESI-MS m/z: 608.40 [M+H]+。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (17.03 mg) in THF was added to a solution of 16-5 (100 mg), THF (4 mL), and saturated Na2CO3 (1 mL) solution, and the reaction was completed after the addition. The reaction mixture was poured into water, extracted with ethyl acetate:methanol=10:1, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, the concentrate was passed through pre-TLC (DCM/MeOH=10:1) Purification gave the desired product 16 as a yellow solid (21 mg, 20% yield). ESI-MS m/z: 608.40 [M+H]+.

實施例17-22分別採用環丁醇，異丙醇，二氟乙醇，2-氟乙醇，乙二醇甲醚和環丙甲醇與化合物1-5反應得到相應的產物，然後按照16的合成步驟合成相應的最終產物化合物17-22。 編號 結構與命名 16

Figure 02_image307
1-（7-（8-乙氧基-6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 608.46 [M+H]+ 17
Figure 02_image309
1-（7-（8-環丁氧基-6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 634.51 [M+H]+ 18
Figure 02_image311
1-（7-（6-乙基-8-異丙氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 622.52 [M+H]+ 19
Figure 02_image313
1-（7-（8-（2,2-二氟乙氧基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4 -基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 644.45 [M+H]+ 20
Figure 02_image315
1-（7-（6-乙基-8-（2-氟乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 626.50 [M+H]+ 21
Figure 02_image317
1-（7-（6-乙基-8-（2-甲氧基乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基 ）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 638.53 [M+H]+ 22
Figure 02_image319
1-（7-（8-（環丙基甲氧基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）- 2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 633.38 [M+H]+ Embodiments 17-22 respectively adopt cyclobutanol, isopropanol, difluoroethanol, 2-fluoroethanol, ethylene glycol methyl ether and cyclopropyl methanol to react with compounds 1-5 to obtain corresponding products, and then follow the synthetic steps of 16 The corresponding final product compounds 17-22 were synthesized. Numbering structure and naming 16
Figure 02_image307
1-(7-(8-Ethoxy-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)quinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 608.46 [M+H]+ 17
Figure 02_image309
1-(7-(8-Cyclobutoxy-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl) quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 634.51 [M+H] + 18
Figure 02_image311
1-(7-(6-Ethyl-8-isopropoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl) quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 622.52 [M+H] + 19
Figure 02_image313
1-(7-(8-(2,2-Difluoroethoxy)-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methyl) Quaridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z : 644.45 [M+H]+ 20
Figure 02_image315
1-(7-(6-Ethyl-8-(2-fluoroethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine- 4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 626.50 [ M+H]+ twenty one
Figure 02_image317
1-(7-(6-Ethyl-8-(2-methoxyethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylguaiac) pyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 638.53 [M+H]+ twenty two
Figure 02_image319
1-(7-(8-(Cyclopropylmethoxy)-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine- 4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 633.38 [ M+H]+

實施例23：化合物23（1-（7-（6-氯-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉 -4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image321
Example 23: Compound 23 (1-(7-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)- 8-(2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1- ketone) synthesis
Figure 02_image321

步驟1：化合物23-1的合成Step 1: Synthesis of Compound 23-1

在室溫下,向2-氨基-4-溴-3-氟苯甲酸(20 g)於DMF (200 mL)中的溶液中添加NCS (13.8 g)且所得混合物在70℃攪拌過夜。反應完全，將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na2SO4乾燥且真空濃縮得褐色固體狀的所要粗品產物(22 g, 98%產率) 。ESI-MS m/z: 267.10 [M+H]+。To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (20 g) in DMF (200 mL) was added NCS (13.8 g) at room temperature and the resulting mixture was stirred at 70 °C overnight. The reaction was complete, the mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired crude product as a brown solid (22 g, 98% yield). ESI-MS m/z: 267.10 [M+H]+.

步驟2：化合物23-2的合成Step 2: Synthesis of Compound 23-2

在室溫下，將1-1(2.42 g)加入到M1-5 (2.33 g)的THF(20 mL)中，移至40℃攪拌過夜。待反應完全後，加入氨水30 mL，調節溶液PH至11，35度攪拌，檢測直至反應完全，有大量不溶物析出，過濾得不溶物，即粗品23-2（3.5 g，crude）。ESI-MS m/z: 374.2 [M+H]+。1-1 (2.42 g) was added to M1-5 (2.33 g) in THF (20 mL) at room temperature, moved to 40°C and stirred overnight. After the reaction is complete, add 30 mL of ammonia water, adjust the pH of the solution to 11, stir at 35 degrees, and detect until the reaction is complete, a large amount of insoluble matter is precipitated, and the insoluble matter is filtered to obtain the crude product 23-2 (3.5 g, crude). ESI-MS m/z: 374.2 [M+H]+.

步驟3：化合物23-3的合成Step 3: Synthesis of Compound 23-3

室溫氮氣保護下，在反應瓶中加入化合物23-2(1 g)和2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(725 mg)，加入DMF(10 mL)和DBU(2.44 g)，冰水浴降溫，加入BOP(2.95 g)，升溫至45度反應2小時,檢測反應完畢，冷卻至室溫，乙酸乙酯稀釋，水稀釋，水相乙酸乙酯萃取一次，有機相合併，0.5N鹽酸和Brine（1:1）洗滌3次，aq. NaHCO 3洗滌一次，食鹽水洗滌一次，硫酸鈉乾燥，濃縮得目標產物23-3（1.2 g，粗產物）。 Under nitrogen protection at room temperature, compound 23-2 (1 g) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (725 mg) were added to the reaction flask, and DMF (10 g) was added. mL) and DBU (2.44 g), cooled in an ice-water bath, added BOP (2.95 g), heated to 45 degrees and reacted for 2 hours, detected the completion of the reaction, cooled to room temperature, diluted with ethyl acetate, diluted with water, and the aqueous phase ethyl acetate Extract once, combine the organic phases, wash 3 times with 0.5N hydrochloric acid and Brine (1:1), once with aq. NaHCO 3 , once with brine, dry with sodium sulfate, and concentrate to obtain the target product 23-3 (1.2 g, crude product) ).

參照化合物13的合成步驟，用三氟乙醇鹼性條件下取代氟原子合成23-4, 23-4用Suzuki偶聯的方法合成23-5, 23-5在三氟乙酸作用下脫掉保護基得到化合物23-6, 23-6在鹼性條件下與丙烯醯氯反應合成目標產物23。Referring to the synthesis steps of compound 13, 23-4 was synthesized by substituting the fluorine atom with trifluoroethanol under basic conditions, and 23-4 was synthesized by the method of Suzuki coupling, and 23-5 was deprotected under the action of trifluoroacetic acid. Compound 23-6 was obtained, and 23-6 was reacted with acryl chloride under basic conditions to synthesize target product 23.

參照化合物23的合成方法完成化合物24和25的合成，24和25分別用環丁醇和二氟乙醇代替三氟乙醇取代氟原子得到相應的產物，之後按照23的步驟合成目標產物24和25。 編號 結構與命名 23

Figure 02_image323
1-（7-（6-氯-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉 -4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 668.26 [M+H]+ 24
Figure 02_image325
1-（7-（6-氯-8-環丁氧基-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 321.22 [M+2H/2]+ 25
Figure 02_image327
1-（7-（6-氯-8-（2,2-二氟乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）喹唑啉-4 -基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 650.67 [M+H]+ The synthesis of compounds 24 and 25 was completed with reference to the synthesis method of compound 23, 24 and 25 were respectively replaced by cyclobutanol and difluoroethanol instead of trifluoroethanol to replace the fluorine atom to obtain the corresponding products, and then the target products 24 and 25 were synthesized according to the steps of 23. Numbering structure and naming twenty three
Figure 02_image323
1-(7-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2, 2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/ z: 668.26 [M+H]+ twenty four
Figure 02_image325
1-(7-(6-Chloro-8-cyclobutoxy-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)quinoline oxazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 321.22 [M+2H/2 ]+ 25
Figure 02_image327
1-(7-(6-Chloro-8-(2,2-difluoroethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylguaiac) pyridin-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 650.67 [M+H]+

實施例26：化合物26（1-（7-（6-乙基-2-（1-（2-甲氧基乙基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2， 2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image329
Example 26: Compound 26 (1-(7-(6-ethyl-2-(1-(2-methoxyethyl)pyridin-4-yl)-7-(5-methyl-1H- indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Synthesis of prop-2-en-1-one)
Figure 02_image329

步驟1：化合物26-1的合成Step 1: Synthesis of Compound 26-1

室溫下，將呱啶-4-羧酸(7.000 g) 加入THF (200 mL)和水 (40 mL) 中，加入三乙胺 (16.45 g)，加入(2,5-二氧雜吡咯烷-1-基）2-三甲基甲矽烷基乙基碳酸酯(15.46 g)，室溫攪拌至反應完畢，濃縮掉THF，降溫，1N HCl酸化至PH2-3左右，DCM萃取三次，有機相鹽水洗兩次，乾燥，濃縮得目標產物26-1(16 g, 粗品)。At room temperature, pyridine-4-carboxylic acid (7.000 g) was added to THF (200 mL) and water (40 mL), triethylamine (16.45 g) was added, (2,5-dioxapyrrolidine) was added -1-yl) 2-trimethylsilylethyl carbonate (15.46 g), stirred at room temperature until the reaction was completed, concentrated THF, cooled, acidified with 1N HCl to about pH 2-3, extracted with DCM three times, the organic phase Washed with brine twice, dried and concentrated to obtain the target product 26-1 (16 g, crude product).

步驟2：化合物26-2的合成Step 2: Synthesis of Compound 26-2

室溫下，將化合物26-1 (2.73 g) 加入DCM (30 mL)  中，加入2滴DMF, 滴入草醯氯 (3.81 g) ，有氣泡冒出，反應完畢，濃縮得26-2(3 g, 粗產物) ，直接用於下一步。At room temperature, compound 26-1 (2.73 g) was added to DCM (30 mL), 2 drops of DMF were added, and oxalic chloride (3.81 g) was added dropwise, bubbles appeared, the reaction was completed, and concentrated to obtain 26-2 ( 3 g, crude product), used directly in the next step.

步驟3：化合物26-3和26-4的合成Step 3: Synthesis of Compounds 26-3 and 26-4

在室溫下，將26-2(3 g)加入到M1 (1.8 g)的THF(40 mL)中，移至40℃攪拌過夜，檢測直至反應完全後得26-3，加入氨水30 mL，調節溶液PH至11，40度攪拌，檢測直至反應完全，有大量不溶物析出，過濾得不溶物，即26-4（1.9 g，63%收率）。ESI-MS m/z: 374.2 [M+H]+。At room temperature, 26-2 (3 g) was added to M1 (1.8 g) in THF (40 mL), moved to 40°C and stirred overnight, and detected until the reaction was complete to obtain 26-3, added 30 mL of ammonia water, Adjust the pH of the solution to 11, stir at 40 degrees, and detect until the reaction is complete, a large amount of insoluble matter is precipitated, and the insoluble matter is filtered to obtain 26-4 (1.9 g, 63% yield). ESI-MS m/z: 374.2 [M+H]+.

步驟4：化合物26-5的合成Step 4: Synthesis of Compound 26-5

室溫氮氣保護下，在反應瓶中加入化合物26-4(1.22 g)和2,7-二氮雜螺[3.5]壬烷-2-羧酸叔丁酯(695 mg)，加入DMF(12 mL)和DBU(1.87 g)，冰水浴降溫，加入BOP(2.2 g)，升溫至45度反應2小時,檢測反應完畢，冷卻至室溫，乙酸乙酯稀釋，水稀釋，水相乙酸乙酯萃取一次，有機相合併，0.5N鹽酸和Brine（1:1）洗滌3次，aq. NaHCO 3洗滌一次，Brine洗滌一次，硫酸鈉乾燥，濃縮得目標產物26-5（1 g，粗產物）。 Under nitrogen protection at room temperature, compound 26-4 (1.22 g) and 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (695 mg) were added to the reaction flask, and DMF (12 g) was added. mL) and DBU (1.87 g), cooled in an ice-water bath, added BOP (2.2 g), heated to 45 degrees and reacted for 2 hours, detected the completion of the reaction, cooled to room temperature, diluted with ethyl acetate, diluted with water, and the aqueous phase ethyl acetate Extract once, combine the organic phases, wash three times with 0.5N hydrochloric acid and Brine (1:1), wash once with aq. NaHCO 3 , wash once with Brine, dry over sodium sulfate, and concentrate to obtain the target product 26-5 (1 g, crude product) .

步驟5：化合物26-6的合成Step 5: Synthesis of Compound 26-6

在氮氣保護下，將三氟乙醇(2.77 g)加入到26-5(2.23 g), Cs 2CO 3(2.7 g)的Dioxane(25 mL)中，移至100℃反應30 min。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，得到固體狀的所要目標產物26-6(4.6 g，crude)。ESI-MS m/z: 784.30 [M+H]+ Under nitrogen protection, trifluoroethanol (2.77 g) was added to 26-5 (2.23 g), Cs 2 CO 3 (2.7 g) in Dioxane (25 mL), and the reaction was moved to 100 °C for 30 min. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired desired product 26-6 as a solid (4.6 g, crude). ESI-MS m/z: 784.30 [M+H]+

步驟6：化合物26-7的合成Step 6: Synthesis of Compound 26-7

在氮氣保護下，將Pd(dppf) 2Cl 2DCM(1.82 g)加入到碳酸鉀( 6.16 g), 化合物26-6(19.7 g)和乙烯基硼酸酯(3.43 g)的二氧六環(200 mL)和水(20 mL)的溶液中,100度攪拌3小時，TLC和LCMS顯示反應完畢，冷卻至室溫，乙酸乙酯稀釋，飽和食鹽水洗滌兩次，乾燥，過濾，濃縮得粗產物，柱層析得(DCM/EA=20:1)目標產物(9.6 g, 55% 產率)。ESI-MS m/z: 895.33 [M+H]+ Pd(dppf) 2 Cl 2 DCM (1.82 g) was added to the dioxane of potassium carbonate (6.16 g), compound 26-6 (19.7 g) and vinyl boronate (3.43 g) under nitrogen protection (200 mL) and water (20 mL), stirred at 100 degrees for 3 hours, TLC and LCMS showed that the reaction was complete, cooled to room temperature, diluted with ethyl acetate, washed twice with saturated brine, dried, filtered, and concentrated to obtain The crude product was obtained by column chromatography (DCM/EA=20:1) as the desired product (9.6 g, 55% yield). ESI-MS m/z: 895.33 [M+H]+

步驟7：化合物26-8的合成Step 7: Synthesis of Compound 26-8

在氮氣保護下，將Pd(PPh 3) 4(2.94 g)加入到D1-7(10 g), 5-甲基-1-四氫吡喃-2-基-4-（4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基）吲唑(7.85 g)和磷酸鉀(5.41 g)的二氧六環(100 mL)和水(20 mL)的溶液中，加熱至85度反應4小時，TLC和LCMS顯示反應完畢，冷卻至室溫，乙酸乙酯稀釋，水洗，飽和食鹽水洗滌，乾燥濃縮得粗品，柱層析得黃色泡沫狀固體（10 g，85%收率） 。ESI-MS m/z: 920.40 [M+H]+ Under nitrogen protection, Pd(PPh 3 ) 4 (2.94 g) was added to D1-7 (10 g), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (7.85 g) and potassium phosphate (5.41 g) in dioxane (100 mL) and water (20 mL) ) solution, heated to 85 degrees and reacted for 4 hours, TLC and LCMS showed that the reaction was completed, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried and concentrated to obtain the crude product, and column chromatography gave a yellow foamy solid (10 g, 85% yield). ESI-MS m/z: 920.40 [M+H]+

步驟8：化合物26-9的合成 在室溫下，將26-8 ( 1 g)溶於甲醇，加入鈀碳（1 g），置換氫氣，移至40℃反應過夜。待反應完全後，矽藻土助濾，濾液濃縮除去溶劑，得到黃色固體狀粗品目標產物26-9（1 g，crude）。ESI-MS m/z: 922.50 [M+H]+。 Step 8: Synthesis of Compound 26-9 At room temperature, 26-8 (1 g) was dissolved in methanol, palladium carbon (1 g) was added, hydrogen was replaced, and the reaction was moved to 40 °C overnight. After the reaction was completed, diatomaceous earth was used for filtration, and the filtrate was concentrated to remove the solvent to obtain the crude target product 26-9 (1 g, crude) as a yellow solid. ESI-MS m/z: 922.50 [M+H]+.

步驟9：化合物26-10的合成Step 9: Synthesis of Compounds 26-10

室溫下，將化合物26-9（1.6 g）溶於THF（10 mL），加入TBAF（4 mL， 1 M in THF），35度攪拌4小時，濃縮，乙酸乙酯稀釋，水洗2次，飽和食鹽水洗滌兩次，硫酸鈉乾燥，濃縮得產品（912 mg， 67%收率）。At room temperature, compound 26-9 (1.6 g) was dissolved in THF (10 mL), TBAF (4 mL, 1 M in THF) was added, stirred at 35 degrees for 4 hours, concentrated, diluted with ethyl acetate, washed twice with water, Washed with saturated brine twice, dried over sodium sulfate, and concentrated to obtain the product (912 mg, 67% yield).

步驟10：化合物26-11的合成Step 10: Synthesis of Compounds 26-11

室溫下將化合物26-10（100 mg）溶於DMF（5 mL），加入碳酸銫（126  mg），加入2-溴乙基甲基醚（54 mg）室溫攪拌過夜，LCMS監控反應完畢，乙酸乙酯稀釋，水洗一次，飽和食鹽水洗滌兩次，乾燥，濃縮得粗品，製備板（DCM/MeOH=10:1）製備得26-11（37 mg，34%收率）ESI-MS m/z: 836.46 [M+H]+Compound 26-10 (100 mg) was dissolved in DMF (5 mL) at room temperature, cesium carbonate (126 mg) was added, 2-bromoethyl methyl ether (54 mg) was added, and the mixture was stirred at room temperature overnight, and the reaction was monitored by LCMS. , diluted with ethyl acetate, washed once with water, twice with saturated brine, dried and concentrated to obtain crude product, which was prepared by preparative plate (DCM/MeOH=10:1) to obtain 26-11 (37 mg, 34% yield) ESI-MS m/z: 836.46 [M+H]+

步驟11：化合物26-12的合成Step 11: Synthesis of Compounds 26-12

在室溫下，將26-11 (37 mg)溶於DCM(2 mL)和TFA(1 mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得粗品目標產物26-12。ESI-MS m/z: 652.40 [M+H]+。At room temperature, 26-11 (37 mg) was dissolved in a mixed solvent of DCM (2 mL) and TFA (1 mL), moved to 40 °C for reaction for about 1 h. After the reaction is complete, the solvent is directly concentrated to remove the solvent to obtain the crude target product 26-12. ESI-MS m/z: 652.40 [M+H]+.

步驟12：化合物26的合成Step 12: Synthesis of Compound 26

在氮氣保護下，冰水浴中，將丙烯醯氯(4 mg)的THF溶液加入到26-12 (29 mg， 粗品)的THF(2mL)和飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到所要產物26 (3.1 mg，6%產率)。ESI-MS m/z: 706.45 [M+H]+。 Under nitrogen protection, a solution of acrylonitrile chloride (4 mg) in THF was added to a solution of 26-12 (29 mg, crude) in THF (2 mL) and saturated Na 2 CO 3 (0.5 mL) in an ice-water bath. That is, the reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was purified by pre-TLC (DCM/MeOH=10:1) to give the desired product 26 (3.1 mg, 6% yield). ESI-MS m/z: 706.45 [M+H]+.

實施例27：化合物27（1-（7-（6-乙基-2-（1-（2-羥基-2-甲基丙基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（ 2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image331
Example 27: Compound 27 (1-(7-(6-ethyl-2-(1-(2-hydroxy-2-methylpropyl)pyridin-4-yl)-7-(5-methyl) -1H-Indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2 -Synthesis of prop-2-en-1-one)
Figure 02_image331

步驟1：化合物27-11的合成Step 1: Synthesis of Compounds 27-11

將化合物27-10（100 mg， 0.13 mmol）溶於乙醇（2 mL），加入甲基環氧丙烷（93 mg，）和三乙胺（40 mg），100度微波反應0.5小時，LCMS檢測反應完畢，直接濃縮得粗品27-11。Compound 27-10 (100 mg, 0.13 mmol) was dissolved in ethanol (2 mL), methyl propylene oxide (93 mg, ) and triethylamine (40 mg) were added, and the reaction was carried out in a microwave at 100 degrees for 0.5 hours, and the reaction was detected by LCMS. After completion, the crude product 27-11 was obtained by direct concentration.

參照實施例26的合成方法在三氟乙酸作用下脫去保護基，然後鹼性條件下與丙烯醯氯反應得目標產物27（8.8 mg）。ESI-MS m/z: 720.35 [M+H]+Referring to the synthetic method of Example 26, the protective group was removed under the action of trifluoroacetic acid, and then reacted with acryl chloride under alkaline conditions to obtain the target product 27 (8.8 mg). ESI-MS m/z: 720.35 [M+H]+

實施例28：化合物28（1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-（氧雜環丁-3-基）呱啶-4-基）-8-（2， 2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image333
Example 28: Compound 28 (1-(7-(6-ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(oxetan-3-yl) ) pyridin-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl ) synthesis of prop-2-en-1-one)
Figure 02_image333

步驟1：化合物28-11的合成Step 1: Synthesis of Compounds 28-11

將化合物26-10（165 mg）溶於1，2-二氯乙烷（10 mL），加入3-氧雜環丁酮（76.4 mg， ）和醋酸硼氫化鈉（225 mg），室溫35度攪拌過夜，反應完畢，乙酸乙酯稀釋，水洗，飽和食鹽水洗滌，乾燥濃縮得粗品。Compound 26-10 (165 mg) was dissolved in 1,2-dichloroethane (10 mL), 3-oxetanone (76.4 mg, ) and sodium borohydride acetate (225 mg) were added, and the room temperature was 35 Stir overnight at 100 degrees, the reaction is completed, diluted with ethyl acetate, washed with water, washed with saturated brine, dried and concentrated to obtain the crude product.

參照實施例26的合成步驟在三氟乙酸作用下脫去保護基，然後鹼性條件下與丙烯醯氯反應得目標產物28（13.5 mg）。ESI-MS m/z: 704.50 [M+H]+ 編號 結構與命名 26

Figure 02_image335
1-（7-（6-乙基-2-（1-（2-甲氧基乙基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2， 2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 706.87 [M+H]+ 27
Figure 02_image337
1-（7-（6-乙基-2-（1-（2-羥基-2-甲基丙基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（ 2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 720.41 [M+H]+ 28
Figure 02_image339
1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-（氧雜環丁-3-基）呱啶-4-基）-8-（2， 2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 704.38 [M+H]+ Referring to the synthesis steps of Example 26, the protective group was removed under the action of trifluoroacetic acid, and then reacted with acryl chloride under alkaline conditions to obtain the target product 28 (13.5 mg). ESI-MS m/z: 704.50 [M+H]+ Numbering structure and naming 26
Figure 02_image335
1-(7-(6-Ethyl-2-(1-(2-methoxyethyl)pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl) -8-(2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -ketone; ESI-MS m/z: 706.87 [M+H]+ 27
Figure 02_image337
1-(7-(6-Ethyl-2-(1-(2-hydroxy-2-methylpropyl)pyridin-4-yl)-7-(5-methyl-1H-indazole-4) -yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2- En-1-one; ESI-MS m/z: 720.41 [M+H]+ 28
Figure 02_image339
1-(7-(6-Ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(oxetan-3-yl)piperidin-4-yl) )-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene- 1-keto; ESI-MS m/z: 704.38 [M+H]+

實施例29：化合物29（1-（7-（6-乙基-2-（1-（2-羥基-2-甲基丙基）氮雜環丁烷-3-基）-7-（5-甲基-1H-吲唑-4-基）-8-（ 2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成。

Figure 02_image341
Example 29: Compound 29 (1-(7-(6-ethyl-2-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-7-(5 -Methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nona Synthesis of yl-2-yl)prop-2-en-1-one).
Figure 02_image341

參照實施例26和27的合成步驟。See Examples 26 and 27 for synthetic procedures.

化合物29-1操作參考化合物26-1的合成操作，將3-吖丁啶羧酸的氮原子進行保護。化合物29-2操作參考化合物26-2的合成操作，將化合物26-2的羧酸轉變成醯氯，然後與化合物M1反應得到化合物29-3，化合物29-3不經過處理直接加入氨水調節pH至11關環合成化合物29-4。化合物29-4在DBU和BOP作用下引入螺環合成化合物29-5，然後用三氟乙醇取代其氟原子得到化合物29-6，化合物29-6進行兩次Suzuki偶聯反應合成化合物29-8，之後雙鍵還原，脫掉氮原子的保護基得到共用中間體29-10。化合物29-10參考27-11的合成步驟，在三乙胺和乙醇體系中與甲基環氧丙烷微波反應即可得到化合物29-11,之後三氟乙酸脫保護得到化合物29-12，在鹼性條件下與丙烯醯氯反應得到化合物29。Operation of compound 29-1 Referring to the synthesis operation of compound 26-1, the nitrogen atom of 3-azetidinecarboxylic acid was protected. Operation of compound 29-2 Refer to the synthesis operation of compound 26-2, the carboxylic acid of compound 26-2 is converted into acyl chloride, and then reacted with compound M1 to obtain compound 29-3, compound 29-3 is directly added with ammonia water without treatment to adjust pH Compound 29-4 was synthesized through 11 ring closure. Compound 29-4 was introduced into compound 29-5 by spiro ring under the action of DBU and BOP, and then its fluorine atom was replaced with trifluoroethanol to obtain compound 29-6. Compound 29-6 was subjected to two Suzuki coupling reactions to synthesize compound 29-8 , and then the double bond is reduced, and the protecting group of the nitrogen atom is removed to obtain the shared intermediate 29-10. Compound 29-10 can be obtained by microwave reaction with methyl propylene oxide in triethylamine and ethanol system with reference to the synthesis steps of 27-11, followed by deprotection of trifluoroacetic acid to obtain compound 29-12. Compound 29 can be obtained by reaction with acryl chloride under neutral conditions.

實施例30：化合物30（3-（3-（4-（2-丙烯醯基-2,7-二氮雜螺并[3.5]壬南-7-基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-8- （2,2,2-三氟乙氧基）喹唑啉-2-基）氮雜環丁烷-1-基）丙腈）的合成

Figure 02_image343
Example 30: Compound 30 (3-(3-(4-(2-propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-ethyl-7-( 5-Methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-2-yl)azetidin-1-yl)propionitrile )Synthesis
Figure 02_image343

步驟1；化合物30-11合成Step 1; Synthesis of compounds 30-11

將化合物29-10（50 mg）溶於乙醇（3 mL），加入丙烯腈（34 mg）和三乙胺（7mg），室溫35度反應4小時，濃縮，乙酸乙酯稀釋，水洗，飽和3食鹽水洗滌，乾燥濃縮，製備板（DCM/MeOH=20:1）純化得產物（26 mg）。ESI-MS m/z: 830.20 [M+H]+Compound 29-10 (50 mg) was dissolved in ethanol (3 mL), acrylonitrile (34 mg) and triethylamine (7 mg) were added, the reaction was carried out at room temperature 35 degrees for 4 hours, concentrated, diluted with ethyl acetate, washed with water, saturated 3 Washed with brine, dried and concentrated, and purified by preparative plate (DCM/MeOH=20:1) to obtain the product (26 mg). ESI-MS m/z: 830.20 [M+H]+

之後參照實施例26的合成方法在三氟乙酸條件下脫掉保護基，鹼性條件下引入丙烯醯基，得到化合物30。Then, referring to the synthetic method of Example 26, the protecting group was removed under the condition of trifluoroacetic acid, and the acryl group was introduced under the basic condition to obtain compound 30.

實施例31，33，34,  35和37參考實施例28的方法合成，共用中間體29-10分別與氧雜環丁酮，四氫吡喃酮，環丁酮，環戊酮和乙醛在還原胺化的條件下反應製備相應的目標化合物，然後分別進行脫保護和引入丙烯醯基最終得到目標化合物31，33，34,  35和37。Examples 31, 33, 34, 35 and 37 were synthesized with reference to the method of Example 28, sharing intermediates 29-10 with oxetanone, tetrahydropyranone, cyclobutanone, cyclopentanone and acetaldehyde, respectively. The corresponding target compounds were prepared under the condition of reductive amination, and then deprotection and introduction of acryl group were carried out respectively to obtain target compounds 31, 33, 34, 35 and 37 respectively.

實施例32的合成操作參照實施例30的合成操作，採用1，4-加成的方法，甲基乙烯碸與共用中間體29-10反應得到相應產物，然後脫保護和引入丙烯醯基最終得到目標化合物實施例32。The synthetic operation of embodiment 32 refers to the synthetic operation of embodiment 30, adopts the method of 1,4-addition, and methyl vinyl group reacts with common intermediate 29-10 to obtain the corresponding product, and then deprotection and introduction of acryl group finally obtain Target Compound Example 32.

實施例36的合成步驟是：用共用中間體29-10與環丙基甲醯氯在二氯甲烷和碳酸氫鈉水溶液體系中反應得到相應化合物，然後脫保護和引入丙烯醯基最終得到目標化合物實施例36。 編號 結構與命名 29

Figure 02_image345
1-（7-（6-乙基-2-（1-（2-羥基-2-甲基丙基）氮雜環丁烷-3-基）-7-（5-甲基-1H-吲唑-4-基）-8-（ 2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 692.37 [M+H]+ 30
Figure 02_image347
3-（3-（4-（2-丙烯醯基-2,7-二氮雜螺并[3.5]壬南-7-基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-8- （2,2,2-三氟乙氧基）喹唑啉-2-基）氮雜環丁烷-1-基）丙腈;ESI-MS m/z: 673.35 [M+H]+ 31
Figure 02_image349
1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-（氧雜環丁-3-基）氮雜環丁烷-3-基）-8-（2， 2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 338.84 [M+2H/2]+ 32
Figure 02_image351
1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-（2-（甲基磺醯基）乙基）氮雜環丁烷-3-基）-8-（2 ，2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮; ESI-MS m/z: 726.78 [M+H]+ 33
Figure 02_image353
1-（7-（6-乙基-7-（5-甲基-1H-吲唑-4-基）-2-（1-（四氫-2H-吡喃-4-基）氮雜環丁烷-3-基）-8 -（2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 352.89 [M+2H/2]+ 34
Figure 02_image355
1-（7-（2-（1-環丁基氮雜環丁烷-3-基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 337.86 [M+2H/2]+ 35
Figure 02_image357
1-（7-（2-（1-環戊基氮雜環丁烷-3-基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉 -4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 344.89 [M+2H/2]+ 36
Figure 02_image359
1-（7-（2-（1-（環丙烷羰基）氮雜環丁烷-3-基）-6-乙基-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2- 三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 688.39 [M+H]+ 37
Figure 02_image361
1-（7-（6-乙基-2-（1-乙基氮雜環丁烷-3-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）喹唑啉 -4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 325.09 [M+2H/2]+ The synthetic steps of embodiment 36 are: use common intermediate 29-10 and cyclopropylformyl chloride to react in dichloromethane and sodium bicarbonate aqueous solution to obtain corresponding compound, then deprotect and introduce acryl group to finally obtain target compound Example 36. Numbering structure and naming 29
Figure 02_image345
1-(7-(6-Ethyl-2-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-7-(5-methyl-1H-indone) oxazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propane -2-En-1-one; ESI-MS m/z: 692.37 [M+H]+ 30
Figure 02_image347
3-(3-(4-(2-Propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-ethyl-7-(5-methyl-1H- Indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-2-yl)azetidin-1-yl)propionitrile; ESI-MS m/z : 673.35 [M+H]+ 31
Figure 02_image349
1-(7-(6-Ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(oxetan-3-yl)azetidine- 3-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one; ESI-MS m/z: 338.84 [M+2H/2]+ 32
Figure 02_image351
1-(7-(6-Ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(2-(methylsulfonyl)ethyl)azacycle butan-3-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Prop-2-en-1-one; ESI-MS m/z: 726.78 [M+H]+ 33
Figure 02_image353
1-(7-(6-Ethyl-7-(5-methyl-1H-indazol-4-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)azacycle butan-3-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Prop-2-en-1-one; ESI-MS m/z: 352.89 [M+2H/2]+ 34
Figure 02_image355
1-(7-(2-(1-Cyclobutylazetidin-3-yl)-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-8- (2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 337.86 [M+2H/2]+ 35
Figure 02_image357
1-(7-(2-(1-Cyclopentylazetidine-3-yl)-6-ethyl-7-(5-methyl-1H-indazol-4-yl)-8- (2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 344.89 [M+2H/2]+ 36
Figure 02_image359
1-(7-(2-(1-(Cyclopropanecarbonyl)azetidin-3-yl)-6-ethyl-7-(5-methyl-1H-indazol-4-yl)- 8-(2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1- Ketone; ESI-MS m/z: 688.39 [M+H]+ 37
Figure 02_image361
1-(7-(6-Ethyl-2-(1-ethylazetidine-3-yl)-7-(5-methyl-1H-indazol-4-yl)-8-( 2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI -MS m/z: 325.09 [M+2H/2]+

實施例38：化合物38（1-（7-（8-（2-羥基-2-甲基丙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image363
Example 38: Compound 38 (1-(7-(8-(2-hydroxy-2-methylpropoxy)-7-(5-methyl-1H-indazol-4-yl)-2-( 1-Methylpyridin-4-yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1 -ketone) synthesis
Figure 02_image363

實施例38的合成操作參考實施例16的操作，用2-甲基-1,2-丙二醇與共用中間體1-5反應得到化合物38-1，之後按照實施例16進行兩次偶聯反應，脫保護和上丙烯醯基步驟完成38的合成。Synthetic operation of Example 38 Referring to the operation of Example 16, 2-methyl-1,2-propanediol was used to react with the common intermediate 1-5 to obtain compound 38-1, and then two coupling reactions were carried out according to Example 16, Deprotection and acrylation steps complete the synthesis of 38.

實施例39和40分別用二氟乙醇和1-(羥基甲基)環丙烷甲腈與共用中間體1-5反應得到相應的目標化合物，之後按照實施例16的步驟進行最終產物39和40的合成 編號 結構與命名 38

Figure 02_image365
1-（7-（8-（2-羥基-2-甲基丙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 650.50 [M+H]+ 39
Figure 02_image367
1-（7-（8-（2,2-二氟乙氧基）-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-6-乙烯基喹唑啉-4- 基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 642.36 [M+H]+ 40
Figure 02_image369
1-（（（（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬南-7-基] -7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶- 4-基）-6-乙烯基喹唑啉-8-基）氧基）甲基）環丙烷-1-甲腈;ESI-MS m/z: 657.50 [M+H]+ Examples 39 and 40 were respectively reacted with difluoroethanol and 1-(hydroxymethyl)cyclopropanecarbonitrile with the common intermediates 1-5 to obtain the corresponding target compounds, and then the final products 39 and 40 were prepared according to the steps of Example 16. synthesis Numbering structure and naming 38
Figure 02_image365
1-(7-(8-(2-Hydroxy-2-methylpropoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine- 4-yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m /z: 650.50 [M+H]+ 39
Figure 02_image367
1-(7-(8-(2,2-Difluoroethoxy)-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine-4- yl)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z : 642.36 [M+H]+ 40
Figure 02_image369
1-((((4-(2-Propenyl-2,7-diazaspiro[3.5]nonan-7-yl]-7-(5-methyl-1H-indazol-4-yl )-2-(1-methylpyridin-4-yl)-6-vinylquinazolin-8-yl)oxy)methyl)cyclopropane-1-carbonitrile; ESI-MS m/z: 657.50 [M+H]+

實施例41：化合物41（1-（6-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,6-二氮雜螺[3.3]庚-2-基）丙-2-烯-1-酮）的合成

Figure 02_image371
Example 41: Compound 41 (1-(6-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-ene-1- ketone) synthesis
Figure 02_image371

步驟1：化合物41-1的合成Step 1: Synthesis of Compound 41-1

在室溫下，將DIEA(480 mg)加入到1-4(600mg)，2,6-二氮雜螺[3.3]庚烷-2-甲酸叔丁酯(245 mg)的二氧六環溶液（10 mL)中，室溫40度攪拌。將混合物傾注入冰水中，用乙酸乙酯萃取混合物，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，粗產物通過快速矽膠柱色譜（DCM:MeOH=10:1）純化，得到黃色固體狀的所要目標產物41-1 (680mg，85 %產率)。 DIEA (480 mg) was added to a solution of 1-4 (600 mg), 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (245 mg) in dioxane at room temperature (10 mL), stirring at room temperature at 40 degrees. The mixture was poured into ice water, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to give a yellow color The desired target product 41-1 as a solid (680 mg, 85% yield).

之後參照實施例16的合成步驟完成目標產物41的合成。After that, the synthesis of the target product 41 was completed with reference to the synthesis steps of Example 16.

實施例42、43和44的合成，參考41-1的合成分別用2,7-二氮雜螺[3.5]壬烷-7-甲酸叔丁酯、(S)-4-N-叔丁氧羰基-2-甲基呱嗪和叔丁基（S）-2-（氰基甲基）呱嗪-1-羧酸鹽與共用中間體1-4反應得到相應的化合物，之後參考25的合成步驟完成目標產物42、43和44的合成。 編號 結構與命名 41

Figure 02_image373
1-（6-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,6-二氮雜螺[3.3]庚-2-基）丙-2-烯-1-酮;ESI-MS m/z: 632.36 [M+H]+ 42
Figure 02_image375
1-（2-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 660.50 [M+H]+ 43
Figure 02_image377
1-（（3S）-3-甲基-4-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2 -三氟乙氧基）-6-乙烯基喹唑啉-4-基）呱嗪-1-基）丙-2-烯-1-酮;ESI-MS m/z: 634.45 [M+H]+ 44
Figure 02_image379
2-（（2S）-1-丙烯醯-4-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）呱嗪-2-基）乙腈；ESI-MS m/z: 659.20 [M+H]+ For the synthesis of Examples 42, 43 and 44, refer to the synthesis of 41-1 using 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, (S)-4-N-tert-butoxy Carbonyl-2-methyloxazine and tert-butyl(S)-2-(cyanomethyl)oxazine-1-carboxylate react with common intermediates 1-4 to obtain the corresponding compounds, and then refer to the synthesis of 25 The steps complete the synthesis of target products 42, 43 and 44. Numbering structure and naming 41
Figure 02_image373
1-(6-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)prop-2-en-1-one; ESI-MS m/ z: 632.36 [M+H]+ 42
Figure 02_image375
1-(2-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m /z: 660.50 [M+H]+ 43
Figure 02_image377
1-((3S)-3-methyl-4-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8- (2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)oxazin-1-yl)prop-2-en-1-one; ESI-MS m/z: 634.45 [M+H]+ 44
Figure 02_image379
2-((2S)-1-propenyl-4-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8- (2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)oxazin-2-yl)acetonitrile; ESI-MS m/z: 659.20 [M+H]+

實施例45：化合物45（1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（2-（甲基磺醯基）乙基）呱啶-4-基）-8-（2,2,2 -三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image381
Example 45: Compound 45 (1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(2-(methylsulfonyl)ethyl)quanl) pyridin-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl- Synthesis of 2-yl)prop-2-en-1-one)
Figure 02_image381

步驟1:化合物45-1的合成Step 1: Synthesis of Compound 45-1

室溫下，將化合物26-8（340 mg）溶於THF（5 mL），加入TBAF（2 mL， 1 M in THF），35度攪拌過夜，濃縮，乙酸乙酯稀釋，水洗2次，飽和食鹽水洗滌兩次，硫酸鈉乾燥，濃縮得產品（311 mg， 粗產品）。At room temperature, compound 26-8 (340 mg) was dissolved in THF (5 mL), TBAF (2 mL, 1 M in THF) was added, stirred at 35 degrees overnight, concentrated, diluted with ethyl acetate, washed twice with water, saturated Washed twice with brine, dried over sodium sulfate, and concentrated to give the product (311 mg, crude product).

步驟2：化合物45-2的合成Step 2: Synthesis of Compound 45-2

室溫下將化合物45-1（50 mg）溶於乙醇（3 mL），加入甲基乙烯碸（68 mg），室溫攪拌過夜，LCMS監控反應完畢，濃縮，乙酸乙酯稀釋，水洗一次，飽和食鹽水洗滌兩次，乾燥，濃縮得粗品，製備板（DCM/MeOH=20:1）製備得45-2（32 mg， 36% 收率）。ESI-MS m/z: 882.46 [M+H]+Compound 45-1 (50 mg) was dissolved in ethanol (3 mL) at room temperature, methylvinyl chloride (68 mg) was added, stirred overnight at room temperature, monitored by LCMS for completion of the reaction, concentrated, diluted with ethyl acetate, washed once with water, It was washed twice with saturated brine, dried, and concentrated to obtain crude product, which was prepared by plate preparation (DCM/MeOH=20:1) to obtain 45-2 (32 mg, 36% yield). ESI-MS m/z: 882.46 [M+H]+

步驟3：化合物45-3的合成Step 3: Synthesis of Compound 45-3

在室溫下，將45-2 (32 mg)溶於DCM(2 mL)和TFA(1 mL)的混合溶劑中，移至40℃反應約1h。待反應完全後，直接濃縮除去溶劑，得粗品目標產物45-3。ESI-MS m/z: 698.40 [M+H]+。At room temperature, 45-2 (32 mg) was dissolved in a mixed solvent of DCM (2 mL) and TFA (1 mL), and moved to 40°C for reaction for about 1 h. After the reaction was completed, the solvent was directly concentrated to remove the solvent to obtain the crude target product 45-3. ESI-MS m/z: 698.40 [M+H]+.

步驟4：化合物45的合成Step 4: Synthesis of Compound 45

在氮氣保護下，冰水浴中，將丙烯醯氯(4 mg)的THF溶液加入到45-3 (25 mg 粗品)的THF(2mL)和飽和Na 2CO 3(0.5mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮物通過pre-TLC(DCM/MeOH=10:1)純化,得到所要產物45 (6.6 mg，24%產率)。ESI-MS m/z: 752.45 [M+H]+。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (4 mg) in THF was added to a solution of 45-3 (25 mg crude) in THF (2 mL) and saturated Na 2 CO 3 (0.5 mL) The reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, the concentrate was purified by pre-TLC (DCM/MeOH=10:1) to give the desired product 45 (6.6 mg, 24% yield). ESI-MS m/z: 752.45 [M+H]+.

實施例51：化合物51（1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4- 基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image383
Example 51: Compound 51 (1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(piridin-4-yl)-8-(2,2,2 -Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one) synthesis
Figure 02_image383

步驟1: 化合物51-1的合成Step 1: Synthesis of Compound 51-1

將化合物26-8（100 mg）溶於二氯甲烷（2 mL），加入鹽酸二氧六環溶液（0.5 mL， 4 N in dioxane），反應液濃縮得粗品（50 mg），直接用於下一步。Compound 26-8 (100 mg) was dissolved in dichloromethane (2 mL), hydrochloric acid dioxane solution (0.5 mL, 4 N in dioxane) was added, and the reaction solution was concentrated to obtain crude product (50 mg), which was directly used in the next step step.

步驟2：化合物51-2的合成Step 2: Synthesis of Compound 51-2

在氮氣保護下，冰水浴中，將丙烯醯氯(6 mg)的THF溶液加入到51-1 (50 mg， 粗品)的THF(2mL)和飽和Na 2CO 3(1 mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮得粗品（30 mg）。 Under nitrogen protection, in an ice-water bath, a solution of acrylonitrile chloride (6 mg) in THF was added to a solution of 51-1 (50 mg, crude) in THF (2 mL) and saturated Na 2 CO 3 (1 mL), and added That is, the reaction is complete. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude product (30 mg).

步驟3：化合物51的合成Step 3: Synthesis of Compound 51

將化合物51-2（30 mg）溶於二氯甲烷（1 mL），加入TFA（1 mL），室溫攪拌2小時，反應完畢，濃縮，製備板製備（DCM/MeOH=10：1）得目標產物（2.6 mg，11%收率）。Compound 51-2 (30 mg) was dissolved in dichloromethane (1 mL), TFA (1 mL) was added, stirred at room temperature for 2 hours, the reaction was completed, concentrated, and prepared on a plate (DCM/MeOH=10:1) to obtain The desired product (2.6 mg, 11% yield).

實施例47參考實施例1的步驟進行合成，用丙烯腈與共用中間體45-1反應即可得相應的目標產物，然後進行脫保護和引入丙烯醯基最終得到目標化合物47。Example 47 is synthesized with reference to the steps of Example 1, and the corresponding target product can be obtained by reacting acrylonitrile with the common intermediate 45-1, followed by deprotection and introduction of an acryl group to finally obtain the target compound 47.

實施例46，53，54，55，56，57，59，60，61，62，65，66，67，68，70和71參考實施例28採用還原胺化的方法，用不同的酮或者醛與共用中間體45-1反應得到相應的產物，之後再脫保護和引入乙醯基合成最終目標產物；實施例48參考實施例27，用共用中間體45-1與甲基環氧丙烷反應生成對應的產物，然後脫保護和引入丙烯醯基最終得到目標化合物48；實施例49，58，63，64，69採用烷基化的策略與共用中間體45-1反應生成對應的產物，然後脫保護和引入丙烯醯基最終得到最終目標產物。對應的合成中間體如下表: 編號 中間體 45

Figure 02_image385
46
Figure 02_image387
 47
Figure 02_image389
 48
Figure 02_image391
 49
Figure 02_image393
 50
Figure 02_image395
 51 / 52
Figure 02_image397
 53
Figure 02_image399
 54
Figure 02_image401
 55
Figure 02_image403
 56
Figure 02_image405
 57
Figure 02_image407
 58
Figure 02_image409
 59
Figure 02_image411
 60
Figure 02_image413
 61
Figure 02_image415
 62
Figure 02_image417
 63
Figure 02_image419
 64
Figure 02_image421
 65
Figure 02_image423
 66
Figure 02_image425
 67
Figure 02_image427
 68
Figure 02_image429
 69
Figure 02_image431
 70
Figure 02_image433
 71
Figure 02_image435
 編號 結構與命名 45
Figure 02_image437
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（2-（甲基磺醯基）乙基）呱啶-4-基）-8-（2,2,2 -三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 752.79 [M+H]+ 46
Figure 02_image439
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（四氫-2H-吡喃-4-基）呱啶-4-基）-8-（2， 2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 730.82 [M+H]+ 47
Figure 02_image441
3-（4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬南-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-基）丙腈;ESI-MS m/z: 699.77 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 6.35 (m, 1H), 6.16 – 6.02 (m, 2H), 5.72 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.69 (m, 1H), 4.05 (s, 2H), 3.77 (s, 6H), 3.01 (m, 2H), 2.76 – 2.64 (m, 3H), 2.60 (m, 2H), 2.14 (m, 2H), 2.07 – 1.93 (m, 9H), 1.84 (m, 2H). 48
Figure 02_image443
1-（7-（2-（1-（2-（2-羥基-2-甲基丙基））呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2， 2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮; ESI-MS m/z: 718.40 [M+H]+ 49
Figure 02_image445
1-（7-（2-（1-（2-（羥乙基））呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基） -6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 690.36 [M+H]+ 50
Figure 02_image447
甲基4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬基-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2 -三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-甲酸;ESI-MS m/z: 704.73 [M+H]+ 51
Figure 02_image449
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（呱啶-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4- 基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 646.36 [M+H]+ 52
Figure 02_image451
1-（4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬南-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-基）丙-2-烯-1-酮;ESI-MS m/z: 700.80 [M+H]+ 53
Figure 02_image453
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（氧雜環丁-3-基）呱啶-4-基）-8-（2,2,2- 三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 702.47 [M+H]+ 54
Figure 02_image455
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1'-甲基-[1,4'-聯呱啶] -4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 743.89 [M+H]+ 55
Figure 02_image457
4-（4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬南-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-基）環己烷-1-甲腈;ESI-MS m/z: 753.90 [M+H]+ 56
Figure 02_image459
1-（7-（2-（1-（1-（1-羥基丙烷-2-基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2， 2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 704.34 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.02 (s, 1H), 8.01 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.33 (m, 1H), 6.35 (m, 1H), 6.17 – 6.03 (m, 2H), 5.73 (m, 2H), 5.12 (m, 1H), 4.96 (s, 1H), 4.67 (s, 1H), 4.05 (s, 2H), 3.77 (s, 8H), 2.89 (m, 2H), 2.26 – 1.81 (m, 15H), 1.07 (m, 3H). 57
Figure 02_image461
1-（7-（2-（1-環丁基呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 700.36 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.03 (s, 1H), 8.01 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.33 (m, 1H), 6.35 (m, 1H), 6.17 – 6.07 (m, 2H), 5.73 (m, 2H), 5.12 (m, 1H), 4.96 (s, 1H), 4.75 – 4.54 (m, 1H), 4.01 (m, 2H), 3.77 (s, 6H), 2.81 (m, 3H), 2.41 – 1.82 (m, 17H), 1.64 (m, 3H). 58
Figure 02_image463
1-（4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬基-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-基）-3,3-二甲基丁烷-2-酮;ESI-MS m/z: 744.43 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.55 – 7.48 (m, 1H), 7.39 (m, 1H), 7.32 (s, 1H), 6.35 (m, 1H), 6.17 – 6.05 (m, 2H), 5.81 – 5.65 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.68 (m, 1H), 4.02 (m, 2H), 3.77 (m, 6H), 2.89 (m, 2H), 2.73 (s, 1H), 2.08 – 1.78 (m, 13H), 1.16 – 1.04 (m, 11H). 59
Figure 02_image465
1-（7-（2-（1-異丙基呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 688.50 [M+H]+ 60
Figure 02_image467
1-（7-（2-（1'-乙醯基-[1,4'-雙呱啶] -4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 801.59 [M+H]+ 61
Figure 02_image469
1-（7-（2-（1-（4-（羥基羥己基））呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基） -6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 744.54 [M+H]+ 62
Figure 02_image471
1-（7-（2-（1'-環丙基-[1,4'-雙呱啶] -4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 769.62 [M+H]+ 63
Figure 02_image473
1-（7-（2-（1-（2-（氟乙基））呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基） -6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 692.48 [M+H]+ 64
Figure 02_image475
1-（7-（2-（1-（（（3,3-二氟環丁基）甲基）呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2 ，2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 750.77[M+H]+ 65
Figure 02_image477
1-（7-（2-（1-苄基呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉- 4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 736.48 [M+H]+ 66
Figure 02_image479
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（（（1-甲基-1H-吡唑-4-基）甲基）呱啶-4-基]- 8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮; ESI-MS m/z: 740.40 [M+H]+ 67
Figure 02_image481
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（四氫呋喃-3-基）呱啶-4-基）-8-（2,2,2- 三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 715.41 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.35 (m, 1H), 6.19 – 6.02 (m, 2H), 5.87 – 5.61 (m, 2H), 5.11 (m, 1H), 4.96 (m, 1H), 4.74 – 4.53 (m, 1H), 4.05 (s, 2H), 3.85 – 3.73 (m, 8H), 3.65 (m, 1H),3.15-2.70 (m, 4H) 2.20 – 1.72 (m, 16H). 68
Figure 02_image483
1-（7-（2-（1-（3-（羥基環丁基））呱啶-4-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2-三氟乙氧基） -6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 716.77 [M+H]+ 69
Figure 02_image485
1-    乙基2-（4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬南-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2， 2,2-三氟乙氧基）-6-乙烯基喹唑啉-2-基呱啶-1-基乙酸酯;ESI-MS m/z: 732.81 [M+H]+ 1H NMR (500 MHz, DMSO) δ 13.03 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.32 (m, 1H), 6.35 (m, 1H), 6.19 – 6.05 (m, 2H), 5.82 – 5.64 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.69 (m, 1H), 4.19 – 3.99 (m, 4H), 3.74 (m, 6H), 3.34 (s, 2H), 2.94 (m 2H), 2.71 (m, 1H), 2.32 (m, 2H), 2.08 –1.75 (m, 11H), 1.21 (m, 3H). 70
Figure 02_image487
乙基4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬基-7-基）-7-（5-甲基-1H-吲唑-4-基）-8-（2,2,2 -三氟乙氧基）-6-乙烯基喹唑啉-2-基）-[1,4'-聯呱啶] -1'-羧酸鹽;ESI-MS m/z: 801.59 [M+H]+ 71
Figure 02_image489
1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-（8-甲基-8-氮雜雙環[3.2.1]辛丹-3-基]呱啶-4- 基）-8-（2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮; ESI-MS m/z: 769.41 [M+H]+ Examples 46, 53, 54, 55, 56, 57, 59, 60, 61, 62, 65, 66, 67, 68, 70 and 71 refer to Example 28 by reductive amination using different ketones or aldehydes Reaction with the common intermediate 45-1 to obtain the corresponding product, and then deprotection and introduction of an acetyl group to synthesize the final target product; Example 48 refers to Example 27, and the common intermediate 45-1 is reacted with methyl propylene oxide to generate Corresponding product, then deprotection and introduction of acryl group to finally obtain the target compound 48; Examples 49, 58, 63, 64, 69 adopt an alkylation strategy to react with the common intermediate 45-1 to generate the corresponding product, and then remove The protection and introduction of the acryl group finally yields the final target product. The corresponding synthetic intermediates are as follows: Numbering Intermediate 45
Figure 02_image385
 46
Figure 02_image387
 47
Figure 02_image389
 48
Figure 02_image391
 49
Figure 02_image393
 50
Figure 02_image395
 51 / 52
Figure 02_image397
 53
Figure 02_image399
 54
Figure 02_image401
 55
Figure 02_image403
 56
Figure 02_image405
 57
Figure 02_image407
 58
Figure 02_image409
 59
Figure 02_image411
 60
Figure 02_image413
 61
Figure 02_image415
 62
Figure 02_image417
 63
Figure 02_image419
 64
Figure 02_image421
 65
Figure 02_image423
 66
Figure 02_image425
 67
Figure 02_image427
 68
Figure 02_image429
 69
Figure 02_image431
 70
Figure 02_image433
 71
Figure 02_image435
 Numbering structure and naming 45
Figure 02_image437
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(2-(methylsulfonyl)ethyl)pyridin-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one; ESI-MS m/z: 752.79 [M+H]+ 46
Figure 02_image439
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one; ESI-MS m/z: 730.82 [M+H]+ 47
Figure 02_image441
3-(4-(4-(2-Propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-7-(5-methyl-1H-indazol-4-yl) )-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridin-1-yl)propionitrile; ESI-MS m/z: 699.77 [M +H]+ 1 H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 6.35 (m, 1H), 6.16 – 6.02 (m, 2H), 5.72 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.69 (m, 1H), 4.05 (s, 2H), 3.77 (s, 6H), 3.01 (m, 2H), 2.76 – 2.64 (m, 3H), 2.60 (m, 2H), 2.14 (m, 2H), 2.07 – 1.93 (m, 9H), 1.84 (m, 2H). 48
Figure 02_image443
1-(7-(2-(1-(2-(2-hydroxy-2-methylpropyl))pyridin-4-yl)-7-(5-methyl-1H-indazole-4- yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Prop-2-en-1-one; ESI-MS m/z: 718.40 [M+H]+ 49
Figure 02_image445
1-(7-(2-(1-(2-(hydroxyethyl))pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -ketone; ESI-MS m/z: 690.36 [M+H]+ 50
Figure 02_image447
Methyl 4-(4-(2-propenyl-2,7-diazaspiro[3.5]nonyl-7-yl)-7-(5-methyl-1H-indazol-4-yl) -8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridine-1-carboxylic acid; ESI-MS m/z: 704.73 [M+H]+ 51
Figure 02_image449
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(pyridin-4-yl)-8-(2,2,2-trifluoroethoxy) -6-Vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 646.36 [M+H]+ 52
Figure 02_image451
1-(4-(4-(2-Propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-7-(5-methyl-1H-indazol-4-yl) )-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridin-1-yl)prop-2-en-1-one; ESI-MS m/z: 700.80 [M+H]+ 53
Figure 02_image453
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(oxetan-3-yl)piperidin-4-yl)-8-( 2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene- 1-keto; ESI-MS m/z: 702.47 [M+H]+ 54
Figure 02_image455
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1'-methyl-[1,4'-bipyridin]-4-yl)-8 -(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2- En-1-one; ESI-MS m/z: 743.89 [M+H]+ 55
Figure 02_image457
4-(4-(4-(2-Propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-7-(5-methyl-1H-indazol-4-yl) )-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridin-1-yl)cyclohexane-1-carbonitrile; ESI-MS m /z: 753.90 [M+H]+ 56
Figure 02_image459
1-(7-(2-(1-(1-(1-hydroxypropan-2-yl)pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -en-1-one; ESI-MS m/z: 704.34 [M+H]+ 1 H NMR (500 MHz, DMSO) δ 13.02 (s, 1H), 8.01 (s, 1H), 7.50 (m, 1H ), 7.39 (s, 1H), 7.33 (m, 1H), 6.35 (m, 1H), 6.17 – 6.03 (m, 2H), 5.73 (m, 2H), 5.12 (m, 1H), 4.96 (s, 1H), 4.67 (s, 1H), 4.05 (s, 2H), 3.77 (s, 8H), 2.89 (m, 2H), 2.26 – 1.81 (m, 15H), 1.07 (m, 3H). 57
Figure 02_image461
1-(7-(2-(1-Cyclobutylpyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-tris Fluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 700.36 [M+H]+ 1 H NMR (500 MHz, DMSO) δ 13.03 (s, 1H), 8.01 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.33 (m, 1H), 6.35 (m, 1H), 6.17 – 6.07 (m, 2H), 5.73 (m, 2H), 5.12 (m, 1H), 4.96 (s, 1H), 4.75 – 4.54 (m, 1H) ), 4.01 (m, 2H), 3.77 (s, 6H), 2.81 (m, 3H), 2.41 – 1.82 (m, 17H), 1.64 (m, 3H). 58
Figure 02_image463
1-(4-(4-(2-Propenyl-2,7-diazaspiro[3.5]nonyl-7-yl)-7-(5-methyl-1H-indazol-4-yl) )-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridin-1-yl)-3,3-dimethylbutane-2- Ketone; ESI-MS m/z: 744.43 [M+H]+ 1 H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.55 – 7.48 (m, 1H), 7.39 (m, 1H), 7.32 (s, 1H), 6.35 (m, 1H), 6.17 – 6.05 (m, 2H), 5.81 – 5.65 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H) ), 4.68 (m, 1H), 4.02 (m, 2H), 3.77 (m, 6H), 2.89 (m, 2H), 2.73 (s, 1H), 2.08 – 1.78 (m, 13H), 1.16 – 1.04 ( m, 11H). 59
Figure 02_image465
1-(7-(2-(1-Isopropylpyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-tris Fluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 688.50 [M+H]+ 60
Figure 02_image467
1-(7-(2-(1'-Acetyl-[1,4'-bispyridin]-4-yl)-7-(5-methyl-1H-indazol-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one; ESI-MS m/z: 801.59 [M+H]+ 61
Figure 02_image469
1-(7-(2-(1-(4-(hydroxyhexyl))pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -ketone; ESI-MS m/z: 744.54 [M+H]+ 62
Figure 02_image471
1-(7-(2-(1'-Cyclopropyl-[1,4'-bispyridin]-4-yl)-7-(5-methyl-1H-indazol-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -En-1-one; ESI-MS m/z: 769.62 [M+H]+ 63
Figure 02_image473
1-(7-(2-(1-(2-(Fluoroethyl))pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2 ,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene-1 -ketone; ESI-MS m/z: 692.48 [M+H]+ 64
Figure 02_image475
1-(7-(2-(1-(((3,3-difluorocyclobutyl)methyl)pyridin-4-yl)-7-(5-methyl-1H-indazole-4- yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl) Prop-2-en-1-one; ESI-MS m/z: 750.77[M+H]+ 65
Figure 02_image477
1-(7-(2-(1-benzylpyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoro ethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m /z: 736.48 [M+H]+ 66
Figure 02_image479
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(((1-methyl-1H-pyrazol-4-yl)methyl)quay Perid-4-yl]-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl- 2-yl)prop-2-en-1-one; ESI-MS m/z: 740.40 [M+H]+ 67
Figure 02_image481
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(tetrahydrofuran-3-yl)pyridin-4-yl)-8-(2,2 ,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one ; ESI-MS m/z: 715.41 [M+H]+ 1 H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.35 (m, 1H), 6.19 – 6.02 (m, 2H), 5.87 – 5.61 (m, 2H), 5.11 (m, 1H), 4.96 (m, 1H), 4.74 – 4.53 (m, 1H), 4.05 (s, 2H), 3.85 – 3.73 (m, 8H), 3.65 (m, 1H), 3.15-2.70 (m, 4H) 2.20 – 1.72 ( m, 16H). 68
Figure 02_image483
1-(7-(2-(1-(3-(Hydroxycyclobutyl))pyridin-4-yl)-7-(5-methyl-1H-indazol-4-yl)-8-( 2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-ene- 1-keto; ESI-MS m/z: 716.77 [M+H]+ 69
Figure 02_image485
1-Ethyl 2-(4-(4-(2-propenyl-2,7-diazaspiro[3.5]nonan-7-yl)-7-(5-methyl-1H-indazole) -4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-ylguaridin-1-yl acetate; ESI-MS m/z: 732.81 [M+H]+ 1 H NMR (500 MHz, DMSO) δ 13.03 (s, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.32 (m, 1H) ), 6.35 (m, 1H), 6.19 – 6.05 (m, 2H), 5.82 – 5.64 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.69 (m, 1H), 4.19 – 3.99 (m, 4H), 3.74 (m, 6H), 3.34 (s, 2H), 2.94 (m 2H), 2.71 (m, 1H), 2.32 (m, 2H), 2.08 –1.75 (m, 11H), 1.21 (m, 3H). 70
Figure 02_image487
Ethyl 4-(4-(2-propenyl-2,7-diazaspiro[3.5]nonyl-7-yl)-7-(5-methyl-1H-indazol-4-yl) -8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-2-yl)-[1,4'-bipyridine]-1'-carboxylate; ESI- MS m/z: 801.59 [M+H]+ 71
Figure 02_image489
1-(7-(7-(5-Methyl-1H-indazol-4-yl)-2-(1-(8-methyl-8-azabicyclo[3.2.1]xindan-3- [methyl]pyridin-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5] Nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 769.41 [M+H]+

實施例72：化合物72（2-氟-1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）- 6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮）的合成

Figure 02_image491
Example 72: Compound 72 (2-Fluoro-1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)- 8-(2,2,2-Trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)propan-2 -en-1-one) synthesis
Figure 02_image491

將化合物2-8（120 mg）溶於DMF（5 mL），加入2-氟丙烯酸（54 mg），HATU（226 mmol），DIEA（77 mg），攪拌2小時，反應完畢，乙酸乙酯稀釋，飽和食鹽水洗滌三次，乾燥濃縮得粗品，製備板製備（DCM/MeOH=10/1）得目標產物（3 mg）。Compound 2-8 (120 mg) was dissolved in DMF (5 mL), 2-fluoroacrylic acid (54 mg), HATU (226 mmol), DIEA (77 mg) were added, stirred for 2 hours, the reaction was completed, diluted with ethyl acetate , washed three times with saturated brine, dried and concentrated to obtain the crude product, and the target product (3 mg) was obtained by preparative plate preparation (DCM/MeOH=10/1).

實施例75: 化合物75（（E）-1-（7-（6-氯-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2 -三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）-4-（二甲基氨基）丁-2-烯-1-酮）的合成

Figure 02_image493
Example 75: Compound 75 ((E)-1-(7-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridine-4) -yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)-4-( Synthesis of Dimethylamino)but-2-en-1-one)
Figure 02_image493

在氮氣保護下，冰水浴中，將新鮮製備的反式-4-二甲基胺基巴豆醯氯鹽酸鹽（12 mg）的THF溶液加入到23-6 (100 mg， 粗品)的THF(2mL)和飽和Na 2CO 3(1 mL)溶液中，加入即反應完全。將反應混合物倒入水中，用乙酸乙酯萃取，有機層用鹽水洗滌，經Na 2SO 4乾燥且真空濃縮，濃縮得粗品，粗品製備板製備（DCM/MeOH=10：1）（6 mg， 5%收率）. Under nitrogen protection, a freshly prepared solution of trans-4-dimethylaminocrotonyl chloride hydrochloride (12 mg) in THF was added to 23-6 (100 mg, crude) in THF (crude) in an ice-water bath. 2 mL) and saturated Na 2 CO 3 (1 mL) solution, the reaction was complete after the addition. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give crude product, which was prepared as a plate (DCM/MeOH=10:1) (6 mg, 5% yield).

實施例73合成參考50的合成步驟，不同點是用二氟乙醇替代三氟乙醇。The synthesis of Example 73 refers to the synthesis procedure of 50, except that difluoroethanol is used instead of trifluoroethanol.

實施例74合成參考72的合成步驟。 編號 結構與命名 72

Figure 02_image495
2-氟-1-（7-（7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2-三氟乙氧基）- 6-乙烯基喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）丙-2-烯-1-酮;ESI-MS m/z: 678.43 [M+H]+ 73
Figure 02_image497
甲基4-（4-（2-丙烯醯基-2,7-二氮雜螺[3.5]壬基-7-基）-8-（2,2-二氟乙氧基）-7-（5-甲基-1H-吲唑-4-基 ）-6-乙烯基喹唑啉-2-基）呱啶-1-甲酸;ESI-MS m/z: 686.50 [M+H]+ 74
Figure 02_image499
3-（4-（4-（2-（2-氟丙烯醯基）-2,7-二氮雜螺[3.5]壬南-7-基）-7-（5-甲基-1H-吲唑-4-基）-8- （2,2,2-三氟乙氧基）-6-乙烯基喹唑啉-2-基）呱啶-1-基）丙腈;ESI-MS m/z: 717.75 [M+H]+ 75
Figure 02_image501
（E）-1-（7-（6-氯-7-（5-甲基-1H-吲唑-4-基）-2-（1-甲基呱啶-4-基）-8-（2,2,2 -三氟乙氧基）喹唑啉-4-基）-2,7-二氮雜螺[3.5]壬基-2-基）-4-（二甲基氨基）丁-2-烯-1-酮;ESI-MS m/z: 725.32 [M+H]+ The synthesis of Example 74 refers to the synthetic procedure of 72. Numbering structure and naming 72
Figure 02_image495
2-Fluoro-1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-(2,2, 2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)prop-2-en-1-one; ESI-MS m/z: 678.43 [M+H]+ 73
Figure 02_image497
Methyl 4-(4-(2-propenyl-2,7-diazaspiro[3.5]nonyl-7-yl)-8-(2,2-difluoroethoxy)-7-( 5-Methyl-1H-indazol-4-yl)-6-vinylquinazolin-2-yl)pyridine-1-carboxylic acid; ESI-MS m/z: 686.50 [M+H]+ 74
Figure 02_image499
3-(4-(4-(2-(2-Fluoropropenyl)-2,7-diazaspiro[3.5]nonan-7-yl)-7-(5-methyl-1H-indone) oxazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-2-yl)pyridin-1-yl)propionitrile; ESI-MS m/ z: 717.75 [M+H]+ 75
Figure 02_image501
(E)-1-(7-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)-2-(1-methylpyridin-4-yl)-8-( 2,2,2-Trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)-4-(dimethylamino)butane- 2-En-1-one; ESI-MS m/z: 725.32 [M+H]+

參照實施例1A，採用基本相同的方法對實施例2~75化合物進行了拆分，分別獲得了對應的手性異構體2a~75a。例如，化合物9a結構式為

Figure 02_image197
；化合物47a結構式為
Figure 02_image199
。 Referring to Example 1A, the compounds of Examples 2 to 75 were separated by substantially the same method, and the corresponding chiral isomers 2a to 75a were obtained respectively. For example, the structure of compound 9a is
Figure 02_image197
; The structural formula of compound 47a is
Figure 02_image199
.

對比化合物1（D1）的合成Synthesis of Comparative Compound 1 (D1)

AMG510（D1）合成參考WO2018217651A1。

Figure 02_image504
D1。 AMG510(D1) was synthesized with reference to WO2018217651A1.
Figure 02_image504
D1.

對比化合物2（D2）的合成Synthesis of Comparative Compound 2 (D2)

D2合成參考WO2018143315A1。

Figure 02_image506
D2。 D2 synthesis reference WO2018143315A1.
Figure 02_image506
D2.

藥理實驗Pharmacological experiments

實施例A：細胞增殖抑制實驗Example A: Cell Proliferation Inhibition Experiment

將CALU-1細胞按1000細胞、190μL/孔鋪96孔超低吸附板。培養隔夜後，配製梯度濃度的化合物溶液，分別向各孔細胞中加入10μL各濃度的待測化合物DMSO溶液，化合物終濃度為30000、10000、3333.3、1111.1、370.4、123.5、41.2、13.7、4.6、0nM（DMSO終濃度均為0.25%）。37℃，5% CO 2培養120小時。向各孔中加入60μL Cell-titer Glo工作液，震盪混勻後室溫培養10分鐘，多功能酶標儀讀取Luminescence發光值，將發光值讀數轉換為抑制百分數： 抑制百分數=（最大值-讀數）/（最大值-最小值）* 100。 “最大值”為DMSO對照；“最小值”表示無細胞對照組。 The CALU-1 cells were plated in a 96-well ultra-low adsorption plate at 1000 cells and 190 μL/well. After overnight incubation, compound solutions with gradient concentrations were prepared, and 10 μL of the DMSO solution of each concentration of the compound to be tested was added to the cells in each well. 0 nM (the final concentration of DMSO is 0.25%). Incubate for 120 hours at 37°C, 5% CO 2 . Add 60 μL of Cell-titer Glo working solution to each well, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into the inhibition percentage: Inhibition percentage = (maximum value - readings)/(max-min)*100. "Max" is the DMSO control; "Min" is the cell-free control.

用Graphpad Prism軟體進行曲線擬合併得到IC 50值。 Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.

實施例化合物對CALU-1細胞具有良好的抑制活性，特別是Y取代基選自

Figure 02_image508
或
Figure 02_image510
時，相對於其他通過環上C原子與喹唑啉環直連相連的環結構分子具有更優活性。實施例合物對CALU-1細胞抑制的IC 50資料參見表2。 Example compounds have good inhibitory activity on CALU-1 cells, especially the Y substituent is selected from
Figure 02_image508
or
Figure 02_image510
Compared with other ring structure molecules directly connected to the quinazoline ring through the C atom on the ring, it has better activity. See Table 2 for the IC50 data of the compounds of the examples for inhibition of CALU-1 cells.

[表2] 化合物名稱 IC 50（nM） 化合物1 2.7 化合物2 776.1 化合物3 277.6 化合物4 2.9 化合物5 45.7 化合物6 4.6 [Table 2] Compound name IC50 (nM) Compound 1 2.7 Compound 2 776.1 Compound 3 277.6 Compound 4 2.9 Compound 5 45.7 Compound 6 4.6

實施例B：細胞增殖抑制實驗Example B: Cell Proliferation Inhibition Experiment

將MIA-PACA-2細胞按600細胞、160μL/孔鋪96孔超低吸附板。培養隔夜後，配製梯度濃度的化合物溶液，分別向各孔細胞中加入40μL各濃度的待測化合物DMSO溶液，化合物終濃度為10000、2000、400、80、16、3.2、0.64、0.12、 0.025、0nM（DMSO終濃度均為0.25%）。37℃，5% CO 2培養96h。向各孔中加入50μL Cell-titer Glo工作液，震盪混勻後室溫培養10min，多功能酶標儀讀取Luminescence發光值，將發光值讀數轉換為抑制百分數： 抑制百分數=（最大值-讀數）/（最大值-最小值）* 100。 “最大值”為DMSO對照；“最小值”表示無細胞對照組。 MIA-PACA-2 cells were plated in a 96-well ultra-low adsorption plate at 600 cells and 160 μL/well. After culturing overnight, compound solutions with gradient concentrations were prepared, and 40 μL of DMSO solutions of the compounds to be tested were added to each well of cells respectively. 0 nM (the final concentration of DMSO is 0.25%). Incubate for 96h at 37°C, 5% CO 2 . Add 50 μL of Cell-titer Glo working solution to each well, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage: Inhibition percentage = (maximum value - reading )/(max-min)*100. "Max" is the DMSO control; "Min" is the cell-free control.

用Graphpad Prism軟體進行曲線擬合併得到IC 50值。 實施例部分化合物對MIA-PACA-2細胞抑制的IC 50資料參見表3。 Curve fitting was performed with Graphpad Prism software and IC50 values were obtained. See Table 3 for IC50 data of some compounds in the examples to inhibit MIA-PACA-2 cells.

實施例C：細胞增殖抑制實驗Example C: Cell Proliferation Inhibition Experiment

將H358細胞按2000細胞、190μL/孔鋪96孔超低吸附板。培養隔夜後，配製梯度濃度的化合物溶液，分別向各孔細胞中加入10μL各濃度的待測化合物DMSO溶液，化合物終濃度為10000、3333.3、1111.1、370.4、123.5、41.2、13.7、4.6、 1.5、0nM（DMSO終濃度均為0.25%）。37℃，5% CO 2培養96h。向各孔中加入50μL Cell-titer Glo工作液，震盪混勻後室溫培養10min，多功能酶標儀讀取Luminescence發光值，將發光值讀數轉換為抑制百分數： 抑制百分數=（最大值-讀數）/（最大值-最小值）* 100。 “最大值”為DMSO對照；“最小值”表示無細胞對照組。 H358 cells were plated in 96-well ultra-low adsorption plates at 2000 cells and 190 μL/well. After culturing overnight, compound solutions with gradient concentrations were prepared, and 10 μL of DMSO solutions of the compounds to be tested were added to each well of cells respectively. 0 nM (the final concentration of DMSO is 0.25%). Incubate for 96h at 37°C, 5% CO 2 . Add 50 μL of Cell-titer Glo working solution to each well, shake and mix well, incubate at room temperature for 10 min, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage: Inhibition percentage = (maximum value - reading )/(max-min)*100. "Max" is the DMSO control; "Min" is the cell-free control.

用Graphpad Prism軟體進行曲線擬合併得到IC 50值。 Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.

實施例部分化合物對H358細胞抑制的IC 50資料參見表3。 See Table 3 for the IC50 data of some compounds in the examples to inhibit H358 cells.

[表3] 化合物名稱 IC 50（nM） 化合物名稱 IC 50（nM） MIA-PACA-2 H358 MIA-PACA-2 H358 7 2.1 3.7 51 406 187 8 25 / 52 57.1 16.6 9 4.8 4.7 53 8.9 4.4 10 107.3 76.2 54 8.5 11.5 11 22 26.3 55 6.9 4.6 12 40.6 6.4 56 2.4 1.6 13 4.8 3.2 57 3.7 3.4 14 21.0 49.6 58 13.7 15.5 15 14.5 17.7 59 8.3 7.4 16 32.6 13.0 60 5.9 5.2 17 68.2 24.9 61 24.1 24.3 18 388 392 62 10.3 6.7 19 61.4 44.7 63 3.6 2.6 20 455 1083 6+4 21.4 19.3 21 170.9 60.5 65 33.7 37.6 22 91.9 20.4 66 62.8 27.2 23 16.7 17.9 67 3.5 2.7 24 42.9 69.7 68 46.1 14.9 25 36.9 39 69 88.0 89.7 26 10.9 9.6 70 12.5 7.6 27 10.1 10.6 71 136 159 28 23.4 18.4 72 60.3 16.5 29 74.2 59.3 73 91.7 124 30 78.0 97.8 74 208 85.8 31 47.7 39.0 75 2188 1939 32 988 881 1a ＜1 ＜1 33 29.6 19.6 1b 485 513 34 378 315          35 169 155          36 778 466          37 34 37          38 47.7 39.0          39 9.8 11.5          40 9.8 11.5          41 278 243          42 188 462          43 114 104          44 525 /          45 6.8 7.3          46 2.6 4.4          47 6.9 6.4          48 4.0 4.1          49 8.0 4.9          50 43.5 29.3          [table 3] Compound name IC50 (nM) Compound name IC50 (nM) MIA-PACA-2 H358 MIA-PACA-2 H358 7 2.1 3.7 51 406 187 8 25 / 52 57.1 16.6 9 4.8 4.7 53 8.9 4.4 10 107.3 76.2 54 8.5 11.5 11 twenty two 26.3 55 6.9 4.6 12 40.6 6.4 56 2.4 1.6 13 4.8 3.2 57 3.7 3.4 14 21.0 49.6 58 13.7 15.5 15 14.5 17.7 59 8.3 7.4 16 32.6 13.0 60 5.9 5.2 17 68.2 24.9 61 24.1 24.3 18 388 392 62 10.3 6.7 19 61.4 44.7 63 3.6 2.6 20 455 1083 6+4 21.4 19.3 twenty one 170.9 60.5 65 33.7 37.6 twenty two 91.9 20.4 66 62.8 27.2 twenty three 16.7 17.9 67 3.5 2.7 twenty four 42.9 69.7 68 46.1 14.9 25 36.9 39 69 88.0 89.7 26 10.9 9.6 70 12.5 7.6 27 10.1 10.6 71 136 159 28 23.4 18.4 72 60.3 16.5 29 74.2 59.3 73 91.7 124 30 78.0 97.8 74 208 85.8 31 47.7 39.0 75 2188 1939 32 988 881 1a <1 <1 33 29.6 19.6 1b 485 513 34 378 315 35 169 155 36 778 466 37 34 37 38 47.7 39.0 39 9.8 11.5 40 9.8 11.5 41 278 243 42 188 462 43 114 104 44 525 / 45 6.8 7.3 46 2.6 4.4 47 6.9 6.4 48 4.0 4.1 49 8.0 4.9 50 43.5 29.3

實施例D：異構體活性Example D: Isomer Activity

使用色譜條件：CHIRALCEL OD（2.5 cm I.D. ×25 cm L, 10μm），UV 254 nm，流動相Hexane/IPA/DEA=70/30/0.1(V/V/V)，流速20 ml/min，將化合物進行拆分，然後採用實施例B和實施例C方法測定異構體活性。Chromatographic conditions used: CHIRALCEL OD (2.5 cm I.D. × 25 cm L, 10 μm), UV 254 nm, mobile phase Hexane/IPA/DEA=70/30/0.1 (V/V/V), flow rate 20 ml/min, the The compounds were resolved, and then the isomer activity was determined using the methods of Example B and Example C.

結果表明，本發明通式(I)所示手性化合物的代表性異構體活性優於其對應軸手性異構體，活性差異大於100倍。The results show that the activity of the representative isomer of the chiral compound represented by the general formula (I) of the present invention is better than that of its corresponding axial chiral isomer, and the activity difference is more than 100 times.

[表4] 化合物 活性比值 MIA-PACA-2 H358 1a/1b ＞500倍 ＞500倍 9a/9b ＞100倍 ＞100倍 47a/47b ＞100倍 ＞100倍 [Table 4] compound activity ratio MIA-PACA-2 H358 1a/1b ＞500 times ＞500 times 9a/9b ＞100 times ＞100 times 47a/47b ＞100 times ＞100 times

[表5]

Figure 02_image243
1a
Figure 02_image245
1b
Figure 02_image197
9a
Figure 02_image513
9b
Figure 02_image199
47a
Figure 02_image515
47b [table 5]
Figure 02_image243
1a
Figure 02_image245
1b
Figure 02_image197
9a
Figure 02_image513
9b
Figure 02_image199
47a
Figure 02_image515
47b

實施例E：人胰腺癌MIA PaCa-2 CDX腫瘤模型上的體內藥效學研究Example E: In vivo pharmacodynamic studies on human pancreatic cancer MIA PaCa-2 CDX tumor model

用經典的小鼠腫瘤模型試驗，觀察灌胃給藥後，目標化合物抑瘤率TGI（%），以評價其抗腫瘤活性。The classical mouse tumor model test was used to observe the tumor inhibition rate TGI (%) of the target compound after intragastric administration to evaluate its anti-tumor activity.

實驗方法：人胰腺癌MIA PaCa-2細胞體外單層培養，培養條件為DMEM/F12培養基中加10％胎牛血清，1%雙抗，37℃ 5%CO 2孵箱培養。一周兩次進行常規處理傳代。當細胞飽和度為80%-90%，數量到達要求時，收取細胞，計數，接種。將 0.2 mL（5×10 6個）MIA PaCa-2細胞（加基質膠，體積比為1:1）皮下接種於每只小鼠的右後背，腫瘤平均體積達到約149 mm 3時開始分組給藥。 Experimental methods: Human pancreatic cancer MIA PaCa-2 cells were cultured in monolayer in vitro, cultured in DMEM/F12 medium with 10% fetal bovine serum, 1% double antibody, and cultured in a 37°C 5% CO 2 incubator. Routine treatment passaging was performed twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded. 0.2 mL (5×10 6 cells) of MIA PaCa-2 cells (plus Matrigel, 1:1 by volume) were subcutaneously inoculated into the right back of each mouse, and the grouping started when the average tumor volume reached about 149 mm 3 . medicine.

實驗結果：目標化合物1a和AMG510均可有效降低腫瘤TGI，與溶劑對照組有顯著差異（圖4）。目標化合物1a處理小鼠體重變化情況更優，顯示出更好安全性潛力（圖5）。Experimental results: Both target compound 1a and AMG510 can effectively reduce tumor TGI, which is significantly different from the solvent control group (Figure 4). The target compound 1a treated mice with better body weight changes and showed better safety potential (Figure 5).

實施例F：人非小細胞肺癌PDX腫瘤模型的體內藥效學研究Example F: In vivo pharmacodynamic study of human non-small cell lung cancer PDX tumor model

用經典的小鼠腫瘤模型試驗，觀察灌胃給藥後，目標化合物抑瘤率TGI（%），以評價其抗腫瘤活性。The classical mouse tumor model test was used to observe the tumor inhibition rate TGI (%) of the target compound after intragastric administration to evaluate its anti-tumor activity.

實驗方法：人源肺癌LU-01-0030 PDX模型的建立最初來源於外科手術切除的G12C突變陽性患者臨床樣本，在植入裸鼠體內後被定義為P0代。將P0代的腫瘤組織植入下一代被稱為P1代。以此類推持續在裸鼠體內植入。其中FP3的腫瘤是通過P2代重新復蘇得到的。由FP3代產生的下一代被定為FP4，以此類推。FP5代的腫瘤組織皮下接種於每只小鼠的右上肢，腫瘤平均體積達到約141 mm3時開始分組給藥。Experimental methods: The establishment of the human-derived lung cancer LU-01-0030 PDX model was originally derived from surgically resected clinical samples of G12C mutation-positive patients, which were defined as P0 generation after implantation in nude mice. The implantation of tumor tissue from the P0 generation into the next generation is called the P1 generation. And so on for continuous implantation in nude mice. The FP3 tumor was recovered from the P2 generation. The next generation from the FP3 generation is designated as FP4, and so on. The tumor tissue of the FP5 generation was subcutaneously inoculated into the right upper limb of each mouse, and the group administration started when the average tumor volume reached about 141 mm3.

實驗結果：人非小細胞肺癌LU-01-0030 PDX模型上，給予10 mg/kg AMG 510觀察到微弱抑瘤效果，TGI為3.3%； 給予3 mg/kg、10 mg/kg或30 mg/kg 的目標化合物1a, TGI%分別為32%、28%和52%，效果優於AMG 510（圖6）。化合物1a顯示出良好耐藥性。Experimental results: On the human non-small cell lung cancer LU-01-0030 PDX model, a weak tumor inhibitory effect was observed with 10 mg/kg AMG 510, with a TGI of 3.3%; 3 mg/kg, 10 mg/kg or 30 mg/kg kg of the target compound 1a, the TGI% was 32%, 28% and 52%, respectively, and the effect was better than that of AMG 510 (Fig. 6). Compound 1a showed good resistance.

實施例G：hERG測試Example G: hERG test

1穩轉細胞準備1 Steady Transduced Cell Preparation

細胞株來源於過表達hERG 鉀離子通道HEK293 細胞，細胞在37°C、5 % CO2 培養箱中培養。當細胞密度達培養皿80 %時，先用磷酸鹽緩衝液（PBS）預清洗，然後用胰蛋白酶/ EDTA 消化細胞2-3 分鐘，加入細胞培養基停止消化，輕輕用移液管吹打並轉移到離心管中，1000 轉/ 分鐘離心3 分鐘，上清液倒掉，加入細胞培養基，輕輕吹打將細胞混勻，隨後轉移到培養皿中進行傳代培養，或將細胞滴於圓形玻片上在細胞培養液中培養待細胞貼壁用於實驗。The cell line was derived from HEK293 cells overexpressing the hERG potassium channel, and the cells were cultured in a 37°C, 5 % CO2 incubator. When the cell density reaches 80% of the dish, pre-wash with phosphate buffered saline (PBS), then trypsin/EDTA to digest the cells for 2-3 minutes, add cell culture medium to stop the digestion, gently pipette and transfer In a centrifuge tube, centrifuge at 1000 rpm for 3 minutes, pour off the supernatant, add the cell culture medium, mix the cells by gently pipetting, and then transfer to a petri dish for subculture, or drop the cells on a circular glass. The cells were cultured in cell culture medium and used for experiments.

細胞培養基組成：DMEM、15 %胎牛血清和1 % 100x 青黴素-鏈黴素。Cell culture medium composition: DMEM, 15% fetal bovine serum and 1% 100x penicillin-streptomycin.

2溶液配製2 solution preparation

細胞內液和外液的組成成分見表4。The composition of intracellular fluid and extracellular fluid is shown in Table 4.

[表6]

Figure 02_image517
[Table 6]
Figure 02_image517

3電生理手動膜片鉗系統實驗方案3 Electrophysiological Manual Patch Clamp System Experimental Protocol

將穩轉的細胞滴於圓形玻片上並置於培養皿中，細胞密度低於50%，培養過夜。將實驗用細胞轉移到一個嵌於倒置顯微鏡平臺的細胞浴槽中，灌流細胞外液，灌流速度為2.7ml/分鐘。穩定5 分鐘後即可開始實驗。採用HEKA EPC-10 膜片鉗放大器和PATCHMASTER 採集系統記錄膜電流（HEKA Instruments Inc., D - 67466 Lambrecht， Pfalz，Germany）。所有實驗均在室溫（22 -24°C）下完成。實驗中使用P-97 微電極拉制儀（Sutter Instrument Company，One Digital Drive，Novato，CA 94949）拉直電極（BF150-110-10）。電極內徑為1-1.5 mm，充滿內液後的入水電阻為2-4 MΩ。The stably transfected cells were dropped on a round glass slide and placed in a petri dish, the cell density was less than 50%, and cultured overnight. The experimental cells were transferred to a cell bath embedded in an inverted microscope platform and perfused with extracellular fluid at a rate of 2.7 ml/min. After 5 minutes of stabilization, the experiment can be started. Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were done at room temperature (22-24°C). Electrodes (BF150-110-10) were straightened in the experiments using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949). The inner diameter of the electrode is 1-1.5 mm, and the water entry resistance after filling with internal liquid is 2-4 MΩ.

hERG 鉀通道的電生理刺激方案，是首先將膜電壓鉗制在-80 mV，給予細胞持續2 s, +20 mV 電壓刺激，啟動hERG 鉀通道，再複極化至-50 mV, 持續5 s，產生外向尾電流，刺激頻率每15 s 一次。電流值為尾電流的峰值。The electrophysiological stimulation protocol of hERG potassium channel is to first clamp the membrane voltage at -80 mV, give the cell a continuous 2 s, +20 mV voltage stimulation to activate hERG potassium channel, and then repolarize to -50 mV for 5 s, Outward tail currents were generated with stimulation frequency every 15 s. The current value is the peak value of the tail current.

實驗中採用全細胞記錄模式記錄通道電流。首先灌流細胞外液（大約每分鐘2 毫升）並持續記錄，並等待電流穩定(5 分鐘內電流衰減（Run-Down）小於5 %)，此時尾電流峰值即為對照電流值。接著灌流含待測藥物的細胞外液並持續記錄直到藥物對hERG 電流的抑制作用到達穩定狀態，此時尾電流峰值即為加藥後電流值。穩定狀態的標準以最近的連續3 個電流記錄線是否重合來判斷。達到穩定態勢以後如果以細胞外液灌流沖洗後hERG 電流回復或接近加藥物之前的大小，則可以繼續灌流測試其它濃度或藥物。30 μM Quinidine（奎尼丁）被用於實驗中作為陽性對照以保證所使用的細胞反應正常。The channel currents were recorded in the whole-cell recording mode. First perfuse extracellular fluid (about 2 ml per minute) and record continuously, and wait for the current to stabilize (the current decay (Run-Down) is less than 5% within 5 minutes), at which time the peak tail current is the control current value. Then, the extracellular fluid containing the drug to be tested was perfused and recorded continuously until the inhibitory effect of the drug on the hERG current reached a steady state, at which time the peak value of the tail current was the current value after the drug was added. The standard of steady state is judged by whether the last three consecutive current recording lines overlap. After reaching a steady state, if the hERG current after perfusion and flushing with extracellular fluid returns to or is close to the size before adding the drug, you can continue to test other concentrations or drugs by perfusion. 30 μM Quinidine was used in the experiments as a positive control to ensure that the cells used were responding properly.

4化合物準備4 Compound Preparation

用DMSO 稀釋母液至下列濃度（次級母液），分別為： 3.3、1.1、0.37、0.12 mM，取母液和次級母液各30 μl 稀釋至10 ml 細胞外液中，用於電生理檢測； 化合物的終濃度為30, 10, 3.3, 1.1, 0.37 μM； DMSO 的終濃度為3: 1000。 Dilute the stock solution with DMSO to the following concentrations (secondary stock solution), respectively: 3.3, 1.1, 0.37, 0.12 mM, take 30 μl of each of the stock solution and the secondary stock solution and dilute to 10 ml of extracellular fluid for electrophysiological detection; The final concentrations of compounds were 30, 10, 3.3, 1.1, 0.37 μM; The final concentration of DMSO is 3:1000.

5資料分析5 Data Analysis

實驗資料使用PATCHMASTER V2X60（HEKA Instruments Inc., D-67466 Lambrecht，Pfalz ，Germany ） 採集， 並採用Origin 8.5 （ OriginLab Corporation ， Northampton ， MA ） 軟體以及Microsoft Excel 進行分析和統計。Experimental data were collected using PATCHMASTER V2X60 (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany) and analyzed and statistically analyzed using Origin 8.5 (OriginLab Corporation, Northampton, MA) software and Microsoft Excel.

通過測量對照組與藥物處理組的電流最大值，計算處理組最大電流值所占對照組最大電流值的比率，評估待測化合物在測試濃度下對hERG鉀離子通道的作用效果（Mean ± SE）。By measuring the maximum current of the control group and the drug-treated group, calculating the ratio of the maximum current value of the treatment group to the maximum current value of the control group, and evaluating the effect of the test compound on the hERG potassium ion channel at the test concentration (Mean ± SE) .

6質量控制6Quality Control

本研究按照科瑞斯實驗室標準操作規程（近似GLP 規範）執行，同時所有實驗方法均參考同行評議期刊發表的文獻，並按照科瑞斯生物的標準實驗操作規程執行。This study was performed in accordance with the standard operating procedures of Keruis laboratory (approximately GLP specifications), and all experimental methods were referenced to literature published in peer-reviewed journals, and were performed in accordance with the standard experimental operating procedures of Keruis Biological.

報告中的試驗資料需要滿足以下標準： 電生理記錄參數 封接電阻＞ 500 MΩ 直聯電阻(Rs) ＜10 MΩ 初始尾電流幅度＞ 300 pA 電流rundown（自發性減小）＜ 2 %/每分鐘 漏電流＜ 200 pA 或者hERG電流峰值的10%（在90%的記錄時間之內） The test data in the report need to meet the following criteria: Electrophysiological recording parameters Sealing resistance > 500 MΩ Direct connection resistance (Rs) <10 MΩ Initial tail current amplitude > 300 pA Current rundown (spontaneous decrease) < 2 %/min Leakage current < 200 pA or 10% of peak hERG current (within 90% of recording time)

7實驗結果：7 Experimental results:

[表7] 化合物 hERG IC 50（uM） 1a ＞30 D2 8.12 [Table 7] compound hERG IC50 (uM) 1a >30 D2 8.12

8實驗結論：8 Experimental conclusions:

藥物對於心臟hERG鉀離子通道的抑制是藥物導致QT延長綜合症的主要原因。化合物1a在測試濃度範圍內對hERG 鉀通道幾乎無阻滯作用（ IC 50＞30 μM）；化合物D2在測試濃度範圍內對hERG 鉀通道有中度的阻滯作用（3 μM＜ 預測IC 50＜ 10 μM），化合物存在一定程度的因為對hERG 的作用而導致的心臟風險。 Inhibition of cardiac hERG potassium channel by drugs is the main reason for drug-induced QT prolongation syndrome. Compound 1a has almost no blocking effect on hERG potassium channel within the tested concentration range (IC 50 >30 μM); Compound D2 has moderate blocking effect on hERG potassium channel within the tested concentration range (3 μM < predicted IC 50 < 10 μM), the compound has some degree of cardiac risk due to its effect on hERG.

實施例H：體外CYP酶抑制測試Example H: In vitro CYP enzyme inhibition assay

採用人肝微粒體孵化體系，通過代謝物的生成量來反映各種酶的活性。The human liver microsome incubation system was used to reflect the activities of various enzymes by the amount of metabolites generated.

實驗方法：稱取適量的待測物標準品，用DMSO稀釋至2 mM，得到工作液；探針底物用純乙腈配製，陽性對照抑制劑用DMSO配製，濃度詳見表8。取待測化合物/陽性對照抑制劑1μL、探針底物1μL、人肝微粒體(20 mg/ mL)1 μL和PBS緩衝液177 μL製備反應混合物(孵化反應待測化合物/陽性對照抑制劑終濃度為10 μM)。上述混合物在37℃預培養5分鐘。向反應混合物加入20 μL NADPH溶液(10 mM，PBS配製)，在37℃條件下CYP2C8、CYP2C9酶孵化10分鐘，CYP2C19酶孵化30分鐘。所有培養樣品設雙樣本。加入200 μL冰冷含內標的乙腈終止反應。在3200 rpm離心15分鐘。上清液轉移至LC-MS/MS分析。通過代謝物的生產量來反映各種酶的活性。採用單點法計算，公式如下： Inhibiton%=100%*(1-Test compound Aear ratio/Control Aear ratio)，實驗結果見表9。 Experimental method: Weigh an appropriate amount of the analyte standard and dilute it to 2 mM with DMSO to obtain a working solution; the probe substrate is prepared with pure acetonitrile, and the positive control inhibitor is prepared with DMSO. The concentrations are shown in Table 8. Take 1 μL of the test compound/positive control inhibitor, 1 μL of the probe substrate, 1 μL of human liver microsomes (20 mg/mL) and 177 μL of PBS buffer to prepare a reaction mixture (incubate the test compound/positive control inhibitor at the end of the incubation reaction). concentration of 10 μM). The above mixture was preincubated at 37°C for 5 minutes. 20 μL of NADPH solution (10 mM, prepared in PBS) was added to the reaction mixture, and the CYP2C8 and CYP2C9 enzymes were incubated at 37°C for 10 minutes, and the CYP2C19 enzymes were incubated for 30 minutes. All culture samples were double-sampled. The reaction was terminated by adding 200 μL of ice-cold acetonitrile containing internal standard. Centrifuge at 3200 rpm for 15 minutes. The supernatant was transferred to LC-MS/MS analysis. The activity of various enzymes is reflected by the production of metabolites. The single-point method is used to calculate, and the formula is as follows: Inhibiton%=100%*(1-Test compound Aear ratio/Control Aear ratio), the experimental results are shown in Table 9.

表8 代謝酶 探針底物/濃度 陽性對照/濃度 CYP2C8 Paclitaxel/2 mM Quercertin/2 mM CYP2C9 Diclofenac/1 mM Sulfaphenazole /2 mM CYP2C19 S-Mephenytoin/10 mM (+)-N-3-Benzylnirvanol /2 mM Table 8 metabolic enzymes Probe Substrate/Concentration Positive Control/Concentration CYP2C8 Paclitaxel/2mM Quercertin/2mM CYP2C9 Diclofenac/1mM Sulfaphenazole/2mM CYP2C19 S-Mephenytoin/10mM (+)-N-3-Benzylnirvanol /2 mM

表9  %Inhibition on major CYP isoforms @10 µM 化合物 CYP2C8 Paclitaxel CYP2C9 Diclofenac CYP2C19 S-Mephenytoin 1a 29.05 35.60 34.64 D2 67.36 73.60 50.22 Table 9 %Inhibition on major CYP isoforms @10 µM compound CYP2C8 Paclitaxel CYP2C9 Diclofenac CYP2C19 S-Mephenytoin 1a 29.05 35.60 34.64 D2 67.36 73.60 50.22

實驗結果：本發明的較佳化合物對於CYP2C8、CYP2C9和CYP2C19酶具有較弱程度的抑制作用，因此在臨床給藥時，藥物代謝性相互作用可能性較低。Experimental results: the preferred compounds of the present invention have weak inhibitory effects on CYP2C8, CYP2C9 and CYP2C19 enzymes, so the possibility of drug-metabolic interactions is low in clinical administration.

雖然本發明已通過其實施方式進行了全面的描述，但是值得注意的是，各種變化和修改對於本領域技術人員都是顯而易見的。這樣的變化和修改都應該包括在本發明所附申請專利範圍的範圍內。Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

無。none.

圖1 為實施例1A制得化合物1a的X射線單晶繞射譜圖A。Fig. 1 is the X-ray single crystal diffraction spectrum A of compound 1a prepared in Example 1A.

圖2 為實施例1A制得化合物1a的X射線單晶繞射譜圖B。Figure 2 is the X-ray single crystal diffraction spectrum B of Compound 1a prepared in Example 1A.

圖3 為實施例1A制得化合物1a的絕對構型圖。Figure 3 is the absolute configuration diagram of compound 1a prepared in Example 1A.

圖4 為人胰腺癌MIA PaCa-2 CDX腫瘤模型上的體內藥效學研究A。Figure 4 is an in vivo pharmacodynamic study A on the human pancreatic cancer MIA PaCa-2 CDX tumor model.

圖5 為人胰腺癌MIA PaCa-2 CDX腫瘤模型上的體內藥效學研究B。Figure 5 is an in vivo pharmacodynamic study B on the human pancreatic cancer MIA PaCa-2 CDX tumor model.

圖6 為人肺癌PDX腫瘤模型的體內藥效學研究。Figure 6 is an in vivo pharmacodynamic study of a human lung cancer PDX tumor model.

Claims (14)

一種通式(I)所示之手性化合物、氘代物或藥用鹽，
Figure 03_image009
(I) 其中X選自C 3-14環烷基、3-14員雜環基、3-14員雜環基氨基；X任選地進一步被 1-4 個取代基取代，其中每個取代基獨立地選自 C 1-6烷基、氨基、C 1-6氨基烷基、氨基甲醯基、C 1-6氨基甲醯基烷基、羧基、C 1-6羧基烷基、氰基、C 1-6氰基烷基、鹵素、C 1-6鹵代烷基、羥基、C 1-6羥烷基； R 1為丙烯醯基、取代的丙烯醯基或
Figure 03_image011
； R 2選自H、C 2-6烯基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 1-6烷基、4-10員雜環基取代的 C 1-6烷基、C 1-6烷基磺醯基、C 1-6烷基亞磺醯基、C 1-6烷硫基、C 2-6炔基、C 1-6烷基氨基、氨基、C 1-6氨基烷基、氨基甲醯基、C 1-6氨基甲醯基烷基、C 1-6羧基烷基、氰基、C 1-6氰基烷基、鹵素、C 1-6鹵代烷基、取代或未取代的芳基、取代或未取代的5-10員雜芳基、取代或未取代的C 3-7環烷基、取代或未取代的4-10員雜環基、羥基或氧代基; R 3選自H、鹵素、C 1-6烷基、取代的C 1-6烷基、C 2-6烯基、取代的C 2-6烯基、C 3-6環烷基或取代的C 3-6環烷基； R 4或R 5獨立地選自H、鹵素、C 1-6烷基、取代的C 1-6烷基、C 3-6環烷基、取代的C 3-6環烷基； R 6選自羥基、氧代基、C 1-6烷氧基、C 3-10環烷基氧基、氰基取代的環丙基C 1-6亞烷基氧基，所述C 1-6烷氧基任選地進一步被一個或多個選自鹵素、羥基、C 1-6烷氧基、C 3-8環烷基的取代基所取代； m或n獨立地選自0、1、2、3、4； Y選自3-14員雜環基，所述雜環基通過環上C原子與喹唑啉環直連相連，所述雜環基任選地進一步被1-4個選自R 7或R 8的取代基所取代；R 7或R 8獨立地選自H、=O、=S、氰基、鹵素、硝基、C 1-6烷基、-C 0-6亞烷基-OR a、 -C 0-6亞烷基-OC(O)N（R a） 2、-C 0-6亞烷基-N（R a） 2、-C 0-6亞烷基-NR aC(O)R a、-C 0-6亞烷基-NR aC(O)N（R a） 2、-C 0-6亞烷基-NR aS(O)R a、-C 0-6亞烷基-NR aS(O) 2R a、-C 0-6亞烷基-S(=O)R a、-C 0-6亞烷基-S(=O) 2R a、-C 0-6亞烷基-SR a、-C 0-6亞烷基-S(R a) 5、-C 0-6亞烷基-C(=O)R a、-C 0-6亞烷基-C(=O)OR a、-C 0-3亞烷基-C(=O)N（R a） 2、C 2-6烯基、C 2-6炔基、丙烯醯基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)任選地還可被1個或多個R a所取代；每個R a各自獨立地選自H、鹵素、羥基、氨基、氧代基、硝基、氰基、羧基、C 1-6烷基、C 1-6羥基烷基、C 1-6氨基烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 1-6雜烷基、C 3-8環烷基、3-8員雜環基、C 6-14芳基、5-14員雜芳基、C 1-6醯基或
Figure 03_image013
。 A kind of chiral compound, deuterated substance or pharmaceutically acceptable salt shown in general formula (I),
Figure 03_image009
(I) wherein X is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, 3-14 membered heterocyclylamino; X is optionally further substituted by 1-4 substituents, wherein each substituted The radicals are independently selected from C 1-6 alkyl, amino, C 1-6 aminoalkyl, carbamoyl, C 1-6 carbamoyl alkyl, carboxy, C 1-6 carboxyalkyl, cyano , C 1-6 cyanoalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl; R 1 is acryl, substituted acryl or
Figure 03_image011
; R 2 is selected from H, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 substituted by 4-10-membered heterocyclyl Alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, C 2-6 alkynyl, C 1-6 alkylamino, amino, C 1-6 aminoalkyl, aminocarbamoyl, C 1-6 aminocarbamoylalkyl, C 1-6 carboxyalkyl, cyano, C 1-6 cyanoalkyl, halogen, C 1-6 haloalkane base, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, hydroxy or oxo; R is selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 ring Alkyl or substituted C 3-6 cycloalkyl; R 4 or R 5 is independently selected from H, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, Substituted C 3-6 cycloalkyl; R 6 is selected from hydroxyl, oxo, C 1-6 alkoxy, C 3-10 cycloalkyloxy, cyano-substituted cyclopropyl C 1-6 idene Alkyloxy, the C 1-6 alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkoxy, C 3-8 cycloalkyl; m or n is independently selected from 0, 1, 2, 3, and 4; Y is selected from a 3-14 membered heterocyclic group, and the heterocyclic group is directly connected to the quinazoline ring through a C atom on the ring, and the heterocyclic group is directly connected to the quinazoline ring. The cyclic group is optionally further substituted by 1-4 substituents selected from R 7 or R 8 ; R 7 or R 8 is independently selected from H, =O, =S, cyano, halogen, nitro, C 1-6 alkyl, -C 0-6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene Alkyl-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(=O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene Alkyl-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-3 alkylene-C(=O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, propenyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocycle base), -C 0-6 alkylene -C 6-1 4 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl), the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0- 6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14-membered heterocyclic group), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) optionally can also be substituted by 1 or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxygen Substitute, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, C 1-6 Acrylic or
Figure 03_image013
. 如請求項1所述之手性化合物、氘代物或藥用鹽，其中，所述X選自4-10員雜環基，所述4-10員雜環基任選地進一步被1-4個選自C 1-6烷基、氰基、C 1-6氰基烷基、C 1-6羥基烷基的取代基所取代；較佳為
Figure 03_image015
、
Figure 03_image017
、
Figure 03_image019
、
Figure 03_image021
、
Figure 03_image023
、
Figure 03_image025
、
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
、
Figure 03_image047
、
Figure 03_image049
、
Figure 03_image051
、
Figure 03_image053
、
Figure 03_image055
、
Figure 03_image057
、
Figure 03_image059
、
Figure 03_image061
、
Figure 03_image063
或
Figure 03_image065
；更佳為
Figure 03_image047
。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to claim 1, wherein the X is selected from a 4-10-membered heterocyclic group, and the 4-10-membered heterocyclic group is optionally further replaced by 1-4 substituted with a substituent selected from C 1-6 alkyl, cyano, C 1-6 cyanoalkyl, and C 1-6 hydroxyalkyl; preferably
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
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
,
Figure 03_image047
,
Figure 03_image049
,
Figure 03_image051
,
Figure 03_image053
,
Figure 03_image055
,
Figure 03_image057
,
Figure 03_image059
,
Figure 03_image061
,
Figure 03_image063
or
Figure 03_image065
; preferably
Figure 03_image047
. 如請求項1或2所述之手性化合物、氘代物或藥用鹽，其中，所述R 1選自
Figure 03_image067
、
Figure 03_image069
、
Figure 03_image071
、
Figure 03_image073
、
Figure 03_image075
、
Figure 03_image077
、
Figure 03_image079
、
Figure 03_image081
、
Figure 03_image083
、
Figure 03_image085
、
Figure 03_image087
或
Figure 03_image089
；較佳為
Figure 03_image067
。 The chiral compound, deuterated product or pharmaceutically acceptable salt according to claim 1 or 2, wherein the R 1 is selected from
Figure 03_image067
,
Figure 03_image069
,
Figure 03_image071
,
Figure 03_image073
,
Figure 03_image075
,
Figure 03_image077
,
Figure 03_image079
,
Figure 03_image081
,
Figure 03_image083
,
Figure 03_image085
,
Figure 03_image087
or
Figure 03_image089
; preferably
Figure 03_image067
. 如請求項1至3中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 2選自H、鹵素或C 1-3烷基；較佳為H。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein the R 2 is selected from H, halogen or C 1-3 alkyl; preferably H. 如請求項1至4中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 3選自H、C 1-6烷基、取代的C 1-6烷基、C 2-6烯基、取代的C 2-6烯基、C 3-6環烷基或取代的C 3-6環烷基；較佳C 1-3烷基、C 3-6環烷基或C 2-4烯基；更佳為乙基、乙烯基或環丙基。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein the R 3 is selected from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl; preferably C 1-3 alkyl, C 3-6 cycloalkyl or C 2-4 alkenyl; more preferably ethyl, vinyl or cyclopropyl. 如請求項1至5中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 4或所述R 5選自H、鹵素或C 1-6烷基；較佳所述R 4為H且所述R 5為甲基。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein the R 4 or the R 5 is selected from H, halogen or C 1-6 alkyl; preferably The R4 is H and the R5 is methyl. 如請求項1至6中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 6選自C 1-6烷氧基、C 3-8環烷基氧基、氰基取代的環丙基C 1-6亞烷基氧基，所述C 1-6烷氧基任選地進一步被一個或多個選自鹵素、羥基、甲氧基、C 3-8環烷基的取代基所取代；較佳所述R 6選自
Figure 03_image091
、
Figure 03_image093
、
Figure 03_image095
、
Figure 03_image097
、
Figure 03_image099
、
Figure 03_image101
、
Figure 03_image103
、
Figure 03_image105
、
Figure 03_image107
、
Figure 03_image109
或
Figure 03_image111
。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein the R 6 is selected from C 1-6 alkoxy, C 3-8 cycloalkyloxy, Cyano-substituted cyclopropyl C 1-6 alkyleneoxy, optionally further C 1-6 alkoxy by one or more selected from halogen, hydroxy, methoxy, C 3-8 ring Substituents of the alkyl group are substituted; preferably the R 6 is selected from
Figure 03_image091
,
Figure 03_image093
,
Figure 03_image095
,
Figure 03_image097
,
Figure 03_image099
,
Figure 03_image101
,
Figure 03_image103
,
Figure 03_image105
,
Figure 03_image107
,
Figure 03_image109
or
Figure 03_image111
. 如請求項1至7中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述Y選自
Figure 03_image113
、
Figure 03_image115
、
Figure 03_image117
、
Figure 03_image119
或
Figure 03_image121
；較佳為
Figure 03_image119
或
Figure 03_image121
；更佳為
Figure 03_image119
。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein the Y is selected from
Figure 03_image113
,
Figure 03_image115
,
Figure 03_image117
,
Figure 03_image119
or
Figure 03_image121
; preferably
Figure 03_image119
or
Figure 03_image121
; preferably
Figure 03_image119
. 如請求項1至8中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 7選自H、氰基、鹵素、C 1-6烷基、-C 0-6亞烷基-OR a、-C 0-6亞烷基-OC(O)N（R a） 2、-C 0-6亞烷基-N（R a） 2、-C 0-6亞烷基-NR aC(O)R a、-C 0-6亞烷基-NR aC(O)N（R a） 2、-C 0-6亞烷基-NR aS(O)R a、-C 0-6亞烷基-NR aS(O) 2R a、-C 0-6亞烷基-S(=O)R a、-C 0-6亞烷基-S(=O) 2R a、-C 0-6亞烷基-SR a、-C 0-6亞烷基-S(R a) 5、-C 0-6亞烷基-C(=O)R a、-C 0-6亞烷基-C(=O)OR a、-C 0-3亞烷基-C(=O)N（R a） 2、丙烯醯基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)，所述C 1-6烷基、-C 0-6亞烷基-C 3-14環烷基、-C 0-6亞烷基-(3-14員雜環基)、-C 0-6亞烷基-C 6-14芳基或-C 0-6亞烷基-(5-14員雜芳基)任選地還可被1個或多個R a所取代；每個R a各自獨立地選自H、鹵素、羥基、氨基、氧代基、氰基、羧基、C 1-6烷基、C 3-8環烷基、3-8員雜環基、C 6-14芳基、5-14員雜芳基、C 1-6醯基或
Figure 03_image013
；較佳所述R 7選自H、丙烯醯基、C 1-6烷基、C 1-6鹵代烷基、C 1-6醯基、 -C 0-3亞烷基-C 1-6烷氧基、C 1-6羥基烷基、C 1-6氰基烷基、-C 0-3亞烷基-S(=O) 2-C 1-6烷基、C 3-6酮基、
Figure 03_image123
、 、
Figure 03_image125
、
Figure 03_image127
、-C 0-3亞烷基-C 3-6環烷基、-C 0-3亞烷基-C 3-8雜環基、-C 0-3亞烷基-苯基、-C 0-3亞烷基-吡唑基，所述-C 0-3亞烷基-C 3-6環烷基、-C 0-3亞烷基-C 3-8雜環基、-C 0-3亞烷基-苯基、-C 0-3亞烷基-吡唑基任選地進一步被一個或多個選自C 1-6醯基、羥基、C 1-6烷基、C 3-6環烷基、鹵素、
Figure 03_image013
或氰基地取代基所取代，所述C 3-8雜環基含有一個選自O或N的雜原子；更佳所述R 7選自H、C 1-6烷基、乙醯基、
Figure 03_image129
、
Figure 03_image131
、
Figure 03_image133
、
Figure 03_image135
、
Figure 03_image137
、
Figure 03_image139
、
Figure 03_image141
、
Figure 03_image143
、
Figure 03_image123
、
Figure 03_image145
、
Figure 03_image147
、
Figure 03_image149
、
Figure 03_image151
、
Figure 03_image153
、
Figure 03_image155
、
Figure 03_image157
、
Figure 03_image159
、
Figure 03_image161
、
Figure 03_image163
、
Figure 03_image165
、
Figure 03_image167
、
Figure 03_image169
、
Figure 03_image171
、
Figure 03_image127
、
Figure 03_image173
、
Figure 03_image175
、
Figure 03_image177
或
Figure 03_image179
。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein the R 7 is selected from H, cyano, halogen, C 1-6 alkyl, -C 0- 6 alkylene-OR a , -C 0-6 alkylene-OC(O)N(R a ) 2 , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene Alkyl-NR a C(O)R a , -C 0-6 alkylene-NR a C(O)N(R a ) 2 , -C 0-6 alkylene-NR a S(O)R a , -C 0-6 alkylene-NR a S(O) 2 R a , -C 0-6 alkylene-S(=O)R a , -C 0-6 alkylene-S(= O) 2 R a , -C 0-6 alkylene-SR a , -C 0-6 alkylene-S(R a ) 5 , -C 0-6 alkylene-C(=O)R a , -C 0-6 alkylene-C(=O)OR a , -C 0-3 alkylene-C(=O)N(R a ) 2 , acryloyl, -C 0-6 alkylene base-C 3-14 cycloalkyl, -C 0-6 alkylene-(3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 Alkylene-(5-14-membered heteroaryl), the C 1-6 alkyl, -C 0-6 alkylene-C 3-14 cycloalkyl, -C 0-6 alkylene-( 3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 aryl or -C 0-6 alkylene-(5-14 membered heteroaryl) optionally can also be replaced by 1 substituted by one or more R a ; each R a is independently selected from H, halogen, hydroxyl, amino, oxo, cyano, carboxyl, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-14 membered aryl, 5-14 membered heteroaryl, C1-6 membered aryl or
Figure 03_image013
; Preferably the R 7 is selected from H, acrylyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aryl, -C 0-3 alkylene-C 1-6 alkane Oxy group, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, -C 0-3 alkylene-S(=O) 2 -C 1-6 alkyl, C 3-6 keto,
Figure 03_image123
, ,
Figure 03_image125
,
Figure 03_image127
, -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0-3 alkylene-phenyl, -C 0 -3 alkylene-pyrazolyl, the -C 0-3 alkylene-C 3-6 cycloalkyl, -C 0-3 alkylene-C 3-8 heterocyclyl, -C 0- 3 alkylene-phenyl, -C 0-3 alkylene-pyrazolyl is optionally further selected from one or more C 1-6 aryl groups, hydroxy, C 1-6 alkyl, C 3- 6 cycloalkyl, halogen,
Figure 03_image013
or cyano substituent, the C 3-8 heterocyclic group contains a heteroatom selected from O or N; more preferably, the R 7 is selected from H, C 1-6 alkyl, acetyl,
Figure 03_image129
,
Figure 03_image131
,
Figure 03_image133
,
Figure 03_image135
,
Figure 03_image137
,
Figure 03_image139
,
Figure 03_image141
,
Figure 03_image143
,
Figure 03_image123
,
Figure 03_image145
,
Figure 03_image147
,
Figure 03_image149
,
Figure 03_image151
,
Figure 03_image153
,
Figure 03_image155
,
Figure 03_image157
,
Figure 03_image159
,
Figure 03_image161
,
Figure 03_image163
,
Figure 03_image165
,
Figure 03_image167
,
Figure 03_image169
,
Figure 03_image171
,
Figure 03_image127
,
Figure 03_image173
,
Figure 03_image175
,
Figure 03_image177
or
Figure 03_image179
. 如請求項1至9中任一項所述之手性化合物、氘代物或藥用鹽，其中，所述R 8選自H或C 1-6烷基；較佳為H。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 9, wherein the R 8 is selected from H or C 1-6 alkyl; preferably H. 如請求項1至10中任一項所述之手性化合物、氘代物或藥用鹽，其中，通式(I)所示的所述手性化合物選自式(IA)-(ID)化合物，
Figure 03_image181
Figure 03_image183
(IA)                                      (IB)
Figure 03_image185
Figure 03_image187
(IC)                                         (ID) ；較佳為
Figure 03_image181
(IA) 其中，取代基如請求項1至10所定義。 The chiral compound, deuterated compound or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein the chiral compound represented by general formula (I) is selected from compounds of formula (IA)-(ID) ,
Figure 03_image181
Figure 03_image183
(IA) (IB)
Figure 03_image185
Figure 03_image187
(IC) (ID); preferably
Figure 03_image181
(IA) wherein the substituents are as defined in claims 1 to 10. 一種手性化合物、氘代物或藥用鹽，其選自：
Figure 03_image189
Figure 03_image191
Figure 03_image193
；較佳為
Figure 03_image195
、
Figure 03_image197
或
Figure 03_image199
。 A chiral compound, deuterated substance or pharmaceutically acceptable salt selected from:
Figure 03_image189
Figure 03_image191
Figure 03_image193
; preferably
Figure 03_image195
,
Figure 03_image197
or
Figure 03_image199
. 一種藥物組合物，所述藥物組合物含有如請求項1至12中任一項所述之手性化合物、氘代物或藥用鹽；和至少一種藥學上可接受的輔料，所述藥物組合物中之所述手性化合物含量比其對應軸手性異構體含量更高；較佳所述藥物組合物中之通式(I)所示的所述手性化合物在活性成分中的含量高於51%、61%、71%、81%、91%、99%或更高。A pharmaceutical composition containing the chiral compound, deuterated substance or pharmaceutically acceptable salt as described in any one of claims 1 to 12; and at least one pharmaceutically acceptable excipient, the pharmaceutical composition The content of the chiral compound is higher than that of the corresponding axial chiral isomer; preferably, the content of the chiral compound represented by the general formula (I) in the pharmaceutical composition is high in the active ingredient at 51%, 61%, 71%, 81%, 91%, 99% or higher. 一種如請求項1至12中任一項所述之手性化合物、氘代物、藥用鹽或如請求項13所述之藥物組合物在製備藥物中的應用，較佳所述藥物為抗癌症藥物，更佳所述癌症是由KRAS G12C，HRAS G12C或NRAS G12C突變介導的。A chiral compound, deuterated compound, pharmaceutically acceptable salt as claimed in any one of claims 1 to 12, or application of the pharmaceutical composition as claimed in claim 13 in the preparation of a medicine, preferably the medicine is anticancer drug, more preferably said cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.
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