TW202227412A

TW202227412A - Aromatic compound, and preparation method therefor and use thereof

Info

Publication number: TW202227412A
Application number: TW110143799A
Authority: TW
Inventors: 少雲向; 蘇月王; 志堅呂; 楊帥; 方琪; 黃燾; 楊瑞
Original assignee: 大陸商杭州多域生物技術有限公司
Priority date: 2020-11-24
Filing date: 2021-11-24
Publication date: 2022-07-16
Also published as: CN116390915A; WO2022111513A1

Abstract

Provided are an aromatic compound represented by formula A or a pharmaceutically acceptable salt thereof, and a preparation method therefor and the use thereof. The aromatic compound has a good inhibitory effect on KRAS, especially KRAS G12C.

Description

一種芳香化合物、其製備方法及應用A kind of aromatic compound, its preparation method and application

本申請要求申請日為2020年11月24日的中國專利申請2020113346910的優先權；要求申請日為2021年11月16日的中國專利申請2021113580344的優先權。本申請引用上述中國專利申請的全文。This application claims the priority of Chinese patent application 2020113346910 with an application date of November 24, 2020; and the priority of Chinese patent application 2021113580344 with an application date of November 16, 2021. This application cites the full text of the above Chinese patent application.

本發明涉及一種芳香化合物、其製備方法及應用。The present invention relates to an aromatic compound, its preparation method and application.

KRAS屬於RAS基因家族主要成員之一，在RAS家族成員中，致癌突變最常見於KRAS(85%)，其中KRAS G12C是最常見的KRAS突變類型，而HRAS與NRAS則較為少見。在人類所有轉移性癌症中，有七分之一存在KRAS基因突變，使其成為最常見的致癌突變基因：在肺腺癌中的突變率超過30%，大腸癌的突變率超過40%，胰腺癌的突變率超過90%。KRAS基因突變被稱為“最難對付的突變”，經過多年的努力，國外已有KRAS抑制劑進入臨床一期實驗。本發明著重在全新的KRAS抑制劑和KRAS降解劑的發明。希望由此給腫瘤患者提供一種新的治療手段，解決通常的耐藥性問題，增加藥物的有效使用週期。KRAS is one of the main members of the RAS gene family. Among the members of the RAS family, oncogenic mutations are most common in KRAS (85%), of which KRAS G12C is the most common type of KRAS mutation, while HRAS and NRAS are less common. KRAS is mutated in one in seven of all metastatic human cancers, making it the most common oncogenic mutation: more than 30% in lung adenocarcinoma, more than 40% in colorectal cancer, and more than 40% in pancreatic cancer. The mutation rate of cancer exceeds 90%. KRAS gene mutation is called "the most difficult mutation to deal with". After years of efforts, KRAS inhibitors have entered clinical phase I trials abroad. The present invention focuses on the invention of novel KRAS inhibitors and KRAS degraders. It is hoped that this will provide tumor patients with a new treatment method, solve the usual drug resistance problem, and increase the effective use cycle of drugs.

因此，本發明的目的，即在提供一種芳香化合物、其製備方法及應用。本發明的芳香化合物對KRAS尤其是KRAS G12C具有良好的抑制作用。Therefore, the object of the present invention is to provide an aromatic compound, its preparation method and application. The aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.

本發明提供一種如式A所示的化合物或其藥學上可接受的鹽：

式中， Z為O或NR ⁵； R ⁵為C ₁-C ₆烷基、

、

、

、被R ^5-5取代或未取代的C ₂-C ₆烯基、

或

； R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為氫、被R ^5-1a取代或未取代的C ₁-C ₆烷基、被R ^5-2a取代或未取代的C ₂-C ₆烯基、C ₂-C ₆炔基或C ₁-C ₆烷氧基； R ^5-5為氰基或鹵素； R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基； R ^5-1a-1為C ₁-C ₆烷氧基； R ^5-2a為C ₁-C ₆烷基、氰基或鹵素； R ¹為氫或C ₁-C ₆烷基； R ²為OR ^2-1、被R ^2-2取代或未取代的C ₆-C ₁₅芳基或被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基； R ^2-2、R ^2-3和R ^2-1a獨立地為羥基、鹵素、胺基、C ₁-C ₆烷基、C ₁-C ₆烷氧基、

或

； R ^2-2a和R ^2-2b獨立地為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基； R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基； R ^2-2a-1a為C ₁-C ₆烷氧基； R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基、或被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為羥基、氰基、胺基、鹵素、C ₁-C ₆烷基、C ₁-C ₆烷氧基或-L-R ^3-1a； -L-為

、

、

、

或

；a端與R ^3-1a相連接，b端與C ₆-C ₁₅芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基相連接； n1、n2、n3、n4、n5、n6和n7獨立地為0、1、2、3、4、5或6； m1和m2獨立地為0、1、2、3、4或5；環D為C ₃-C ₆環烷烴、“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環、C ₆-C ₁₀芳環或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環； R ^3-1a為E3連接酶的配體，其結構例如可為

； R ^3-1a-1和R ^3-1a-2獨立地可為氫、C ₁-C ₆烷基、

或

；環A可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環；環B可為C ₆-C ₁₀芳環；環C可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環； R ^a、R ^b、R ^c、R ^d和R ^e獨立地可為氫、羥基或C ₁-C ₆烷基； o1、o2和o3獨立地可為0、1、2、3或4； R ⁴為鹵素、OCH ₃、OH、CN、CONH ₂或COOH； R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2的個數獨立地為1、2、3、4或5個，當為2、3、4或5個時，R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2獨立地相同或不同。 The present invention provides a compound of formula A or a pharmaceutically acceptable salt thereof:

In the formula, Z is O or NR ⁵ ; R ⁵ is C ₁ -C ₆ alkyl,

,

, C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 ,

or

; R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently hydrogen, R ^5-1a substituted or unsubstituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-2a ; R ^5-5 is cyano or halogen; R ^{5 -1a} is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a-1 ; R ^5-1a-1 is C ₁ -C ₆ alkoxy; R ^5-2a is C ₁ -C ₆ Alkyl, cyano or halogen; R ¹ is hydrogen or C ₁ -C ₆ alkyl; R ² is OR ^2-1 , C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-2 or R ^{2 -3-} substituted or unsubstituted 5-15-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"; R ^2-1 is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-1a ; R ^2-2 , R ^2-3 and R ^2-1a are independently hydroxy, halogen, amino, C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy,

or

; R ^2-2a and R ^{2-2b are} independently C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 ; R ^2-2a-1 is substituted or unsubstituted by R ^2-2a-1a Substituted C ₁ -C ₆ alkoxy; R ^2-2a-1a is C ₁ -C ₆ alkoxy; R ³ is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , or R ^3-2 substituted or unsubstituted 5-15-membered heteroaryl group of "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"; R ^{3 -1} and R ^3-2 are independently hydroxyl, cyano, amino, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or -LR ^3-1a ; -L- is

,

or

; The a-end is connected with R ^3-1a , the b-end is connected with C ₆ -C ₁₅ aryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 n1, n2, n3, n4, n5, n6 and n7 are independently 0, 1, 2, 3, 4, 5 or 6; m1 and m2 are independently 0 , 1, 2, 3, 4 or 5; Ring D is C ₃ -C ₆ cycloalkane, "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1-3" 3 -10-membered heterocyclic ring, C ₆ -C ₁₀ aromatic ring or 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; R ^3-1a is the ligand of E3 ligase, and its structure can be, for example,

; R ^3-1a-1 and R ^3-1a-2 can independently be hydrogen, C ₁ -C ₆ alkyl,

or

; Ring A can be a 5-6 membered heterocycle with "hetero atoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2"; Ring B can be a C ₆ -C ₁₀ aromatic ring ; Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; R ^a , R ^b , R ^c , R ^d and ^Re can be independently hydrogen, hydroxyl or C ₁ -C ₆ alkyl; o1, o2 and o3 can be independently 0, 1, 2, 3 or 4; R ⁴ is halogen, OCH ₃ , OH, CN , CONH ₂ or COOH; R ^5-1a , R ^5-1a-1 , R ^2-2 , R ^2-1a , R ^2-2a-1 , R ^2-2a-1a , R ^3-1 and R ^3- The number of ² is independently 1, 2, 3, 4 or 5, and when it is 2, 3, 4 or 5, R ^5-1a , R ^5-1a-1 , R ^2-2 , R ^{2- 1a} , R ^2-2a-1 , R ^2-2a-1a , R ^3-1 and R ^3-2 are independently the same or different.

在本發明的某一方案中，所述的如式A所示的化合物為如式I或式I’所示的化合物：

式中，標“*”的碳原子為S構型碳原子、R構型碳原子或非掌性碳原子；R ¹、R ²、R ³、R ⁴和Z的定義如上所示。 In a certain scheme of the present invention, the compound shown in formula A is the compound shown in formula I or formula I':

In the formula, the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or non-chiral carbon atoms; the definitions of R ¹ , R ² , R ³ , R ⁴ and Z are as shown above.

在本發明某一方案中，某些基團的定義如下，未定義的基團同前所述（以下簡稱在某一方案中）：當R ⁵為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基。 In a certain scheme of the present invention, the definitions of certain groups are as follows, and the undefined groups are as described above (hereinafter referred to as in a certain scheme): when R ⁵ is a C ₁ -C ₆ alkyl group, the The C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

在本發明某一方案中：

為

或

，R ¹為C ₁-C ₆烷基；例如

或

。 In a certain scheme of the present invention:

for

or

, R ¹ is C ₁ -C ₆ alkyl; for example

or

.

在本發明某一方案中：當R ⁵為被R ^5-5取代或未取代的C ₂-C ₆烯基時，所述的R ^5-5的個數可為1、2或3個。 In a certain scheme of the present invention: when R ⁵ is a C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 , the number of the R ^5-5 can be 1, 2 or 3.

在本發明某一方案中：當R ⁵為被R ^5-5取代或未取代的C ₂-C ₆烯基時，所述的C ₂-C ₆烯基可為C ₂-C ₄烯基，優選

、

或

。 In a certain scheme of the present invention: when R ⁵ is a C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 , the C ₂ -C ₆ alkenyl may be a C ₂ -C ₄ alkenyl , preferably

,

or

.

在本發明某一方案中：當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為被R ^5-1a取代或未取代的C ₁-C ₆烷基時，R ^5-1a的個數可獨立地為1、2或3個。 In a certain scheme of the present invention: when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently substituted or unsubstituted by R ^5-1a In the case of the C ₁ -C ₆ alkyl group, the number of R ^5-1a can be independently 1, 2 or 3.

在某一方案中：當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為被R ^5-1a取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可獨立地為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基、乙基或第三丁基。 In a certain scheme: when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C substituted or unsubstituted by R ^5-1a When ₁ - _C6 alkyl, the _C1 - _C6 alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl or third Butyl, preferably methyl, ethyl or tert-butyl.

在某一方案中：當R ^5-1為被R ^5-2a取代或未取代的C ₂-C ₆烯基時，所述的R ^5-2a的個數可為1、2或3個。 In a certain scheme: when R ^5-1 is C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-2a , the number of said R ^5-2a can be 1, 2 or 3.

在某一方案中：當R ^5-1為被R ^5-2a取代或未取代的C ₂-C ₆烯基時，所述的烯基可為C ₂-C ₄烯基，優選乙烯基。 In a certain scheme: when R ^5-1 is C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-2a , the alkenyl can be C ₂ -C ₄ alkenyl, preferably vinyl.

在某一方案中：當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₂-C ₆炔基時，所述的C ₂-C ₆炔基可為C ₂-C ₄炔基，優選乙炔基。 In a certain scheme: when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C ₂ -C ₆ alkynyl, the The C ₂ -C ₆ alkynyl group may be a C ₂ -C ₄ alkynyl group, preferably an ethynyl group.

在某一方案中：當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可獨立地為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C ₁ -C ₆ alkoxy, all Said C ₁ -C ₆ alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third butoxy oxy, preferably methoxy.

在某一方案中：當R ^5-5為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟。 In a certain scheme: when R ^5-5 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.

在某一方案中：當R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基時，R ^4-1a-1的個數可為1、2或3個。 In a certain scheme: when R ^5-1a is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^{5-1a-1, the number of R 4-1a-1} ^can be 1, 2 or 3 indivual.

在某一方案中：當R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基或乙氧基。 In a certain scheme: when R ^5-1a is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a-1 , the C ₁ -C ₆ alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy or ethoxy.

在某一方案中：當R ^5-1a-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^5-1a-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當R ^5-2a為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可獨立地為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基。 In a certain scheme: when R ^5-2a is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be independently methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, preferably methyl.

在某一方案中：當R ^5-2a為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟。 In a certain scheme: when R ^5-2a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.

在某一方案中：當R ¹為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可獨立地為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基。 In a certain scheme: when R ¹ is C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl can be independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

在某一方案中：當R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基時，R ^2-2的個數可為1、2、3或4個。 In a certain scheme: when R ² is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-2 , the number of R ^2-2 can be 1, 2, 3 or 4.

在某一方案中：當R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基可為C ₆-C ₁₀芳基，優選苯基或萘基。 In a certain scheme: when R ² is a C ₆ -C ₁₅ aryl group substituted or unsubstituted by R ^2-2 , the C ₆ -C ₁₅ aryl group can be a C ₆ -C ₁₀ aryl group, preferably phenyl or naphthyl.

在某一方案中：當R ²為被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，R ^2-3的個數可為1、2、3或4個。 In a certain scheme: when R ² is substituted or unsubstituted by R ^2-3 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" In the case of the 5-15-membered heteroaryl group, the number of R ^2-3 can be 1, 2, 3 or 4.

在某一方案中：當R ²為被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基或雙環雜芳基。 In a certain scheme: when R ² is substituted or unsubstituted by R ^2-3 "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group The group can be a 5-15-membered monocyclic heteroaryl group or a bicyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4".

所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基優選“雜原子選自N，雜原子個數為1或2個”的5-6元單環雜芳基，更優選吡啶基（例如

），或“雜原子選自N，雜原子個數為1-2個”的8-10元雙環雜芳基，優選吲唑基，例如

。 The 5-15-membered monocyclic heteroaryl group of "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" is preferably "the heteroatom is selected from N. , 5-6 membered monocyclic heteroaryl with 1 or 2" heteroatoms, more preferably pyridyl (such as

), or an 8-10-membered bicyclic heteroaryl group with "heteroatoms selected from N, the number of heteroatoms is 1-2", preferably an indazolyl group, such as

.

在某一方案中：當R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基時，R ^2-1a的個數可為1、2、3或4個。 In a certain scheme: when R ^2-1 is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-1a , the number of R ^2-1a may be 1, 2, 3 or 4.

在某一方案中：當R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基可為C ₆-C ₁₀芳基，優選苯基或萘基。 In a certain scheme: when R ^2-1 is a C ₆ -C ₁₅ aryl group substituted or unsubstituted by R ^2-1a , the C ₆ -C ₁₅ aryl group may be a C ₆ -C ₁₀ aryl group , preferably phenyl or naphthyl.

在某一方案中：當R ^2-2為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟或氯。 In a certain scheme: when R ^2-2 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

在某一方案中：當R ^2-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 In a certain scheme: when R ^2-2 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

在某一方案中：當R ^2-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^2-2 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy can be methoxy, ethoxy, propoxy, isopropoxy group, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當R ^2-1a為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟或氯。 In a certain scheme: when R ^2-1a is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

在某一方案中：當R ^2-1a為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 In a certain scheme: when R ^2-1a is C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

在某一方案中：當R ^2-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^2-1a is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy can be methoxy, ethoxy, propoxy, isopropoxy group, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當R ^2-2a為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，R ^2-2a-1的個數可為1、2或3個。 In a certain scheme: when R ^2-2a is C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a ^-1 , the number of R 2-2a-1 can be 1, 2 or 3 .

在某一方案中：當R ^2-2a為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基或乙基。 In a certain scheme: when R ^2-2a is a C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 , the C ₁ -C ₆ alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

在某一方案中：當R ^2-2b為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，R ^2-2a-1的個數可為1、2或3個。 In a certain scheme: when R ^2-2b is C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a ^-1 , the number of R 2-2a-1 can be 1, 2 or 3 .

在某一方案中：當R ^2-2b為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基或乙基。 In a certain scheme: when R ^2-2b is a C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 , the C ₁ -C ₆ alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.

在某一方案中：當R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基時，R ^2-2a-1a的個數可為1、2或3個。 In a certain scheme: when R ^2-2a-1 is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^2-2a ^-1a , the number of R 2-2a-1a can be 1 or 2 or 3.

在某一方案中：當R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基或乙氧基。 In a certain scheme: when R ^2-2a-1 is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^2-2a-1a , the C ₁ -C ₆ alkoxy may be methyl Oxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy or ethoxy.

在某一方案中：當R ^2-2a-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^2-2a-1a is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy can be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基時，R ^3-1的個數可為1、2、3或4個。 In a certain scheme: when R ³ is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , the number of R ^3-1 can be 1, 2, 3 or 4.

在某一方案中：當R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基可為C ₆-C ₁₀芳基，優選苯基或萘基。 In a certain scheme: when R ³ is a C ₆ -C ₁₅ aryl group substituted or unsubstituted by R ^3-1 , the C ₆ -C ₁₅ aryl group can be a C ₆ -C ₁₀ aryl group, preferably phenyl or naphthyl.

在某一方案中：當R ³為被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，R ^3-2的個數可為1、2、3或4個。 In a certain scheme: when R ³ is substituted or unsubstituted by R ^3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" In the case of 5-15-membered heteroaryl group, the number of R ^3-2 can be 1, 2, 3 or 4.

在某一方案中：當R ³為被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基或雙環雜芳基。 In a certain scheme: when R ³ is substituted or unsubstituted by R ^3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" When the 5-15-membered heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group The group can be a 5-15-membered monocyclic heteroaryl group or a bicyclic heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4".

）。 The 5-15-membered monocyclic heteroaryl group of "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" is preferably "the heteroatom is selected from N. , 5-6 membered monocyclic heteroaryl with 1 or 2" heteroatoms, more preferably pyridyl (such as

).

在某一方案中：當R ^3-1為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基、乙基或異丙基。 In a certain scheme: when R ^3-1 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.

在某一方案中：當R ^3-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^3-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkyl can be methoxy, ethoxy, propoxy, isopropoxy , n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當R ^3-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基、乙基或異丙基。 In a certain scheme: when R ^3-2 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl or isopropyl.

在某一方案中：當R ^3-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基，優選甲氧基。 In a certain scheme: when R ^3-2 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy can be methoxy, ethoxy, propoxy, isopropoxy group, n-butoxy, isobutoxy, second or third butoxy, preferably methoxy.

在某一方案中：當環D為C ₃-C ₆環烷烴時，所述的C ₃-C ₆環烷基可為環丙烷、環丁烷、環戊烷或環己烷，優選環己烷（

例如為

）。 In a certain scheme: when ring D is C ₃ -C ₆ cycloalkane, the C ₃ -C ₆ cycloalkyl can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane alkyl(

for example

).

在某一方案中：當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-6元雜環，優選四氫呋喃（

例如為

）、哌啶（

例如為

或

）或哌嗪（

例如為

）。 In a certain scheme: when ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "hetero-atom is 1-3". Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3." The 3-10-membered heterocycle can be "the heteroatoms are selected from one or more of N, O and S, and the heteroatom is selected from one or more of N, O and S. The number of atoms is 1-3" 3-6 membered heterocycle, preferably tetrahydrofuran (

for example

), piperidine (

for example

or

) or piperazine (

for example

).

在某一方案中：當環D為C ₆-C ₁₀芳環時，所述的C ₆-C ₁₀芳環可為苯環或萘環，優選苯環（

例如為

）。 In a certain scheme: when ring D is a C ₆ -C ₁₀ aromatic ring, the C ₆ -C ₁₀ aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (

for example

).

在某一方案中：當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-6元雜芳環，優選吡啶環（

例如為

或

）或吡嗪環（

例如為

、

或

）。 In a certain scheme: when Ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the " The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3. The 5-10-membered heteroaromatic ring can be "the heteroatom is selected from one or more of N, O and S". , a 5-6 membered heteroaromatic ring with 1-3" heteroatoms, preferably a pyridine ring (

for example

or

) or the pyrazine ring (

for example

,

or

).

在某一方案中：當R ^3-1a-1為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 In a certain scheme: when R ^3-1a-1 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl, or tert-butyl.

在某一方案中：當R ^3-1a-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。 In a certain scheme: when R ^3-1a-2 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl, or tert-butyl.

在某一方案中：環A中，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環烷基可為“雜原子選自N，雜原子個數為1-2個”的5-6元雜環烷基，優選四氫吡咯基（

例如為

）。 In a certain scheme: in Ring A, the 5-6 membered heterocycloalkyl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2" may be "The heteroatom is selected from N, and the number of heteroatoms is 1-2" 5-6 membered heterocycloalkyl, preferably tetrahydropyrrolyl (

for example

).

在某一方案中：環B中，所述的C ₆-C ₁₀芳環可為苯環或萘環，優選苯環（

例如為

）。 In a certain scheme: in ring B, the C ₆ -C ₁₀ aromatic ring can be a benzene ring or a naphthalene ring, preferably a benzene ring (

for example

).

在某一方案中：環C中，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元單環雜芳環或雙環雜芳環。In a certain scheme: in Ring C, the 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3" can be " The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring.

所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元單環雜芳環優選“雜原子選自N和S中的一種或多種，雜原子個數為1-2個”的5-6元單環雜芳環，更優選噻唑環（

例如為

）。 The 5-10-membered monocyclic heteroaromatic ring of "heteroatoms is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" is preferably "heteroatoms are selected from N and S. One or more, the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, more preferably thiazole ring (

for example

).

在某一方案中：當R ^a、R ^b、R ^c、R ^d和R ^e獨立地為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基，優選甲基或第三丁基。 In a certain scheme: when R ^a , R ^b , R ^c , R ^d and R ^e are independently C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl may be methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or tert-butyl.

在某一方案中：當R ⁴為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟。 ^In a certain scheme: when R4 is halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine.

在某一方案中：R ⁵可為

、

、

、

、

、

、

、

、

、

、

或

。 In one scheme: R ⁵ may be

,

or

.

在某一方案中：R ¹可為氫或甲基。 In ^a certain scheme: R1 can be hydrogen or methyl.

在某一方案中：

可為

、

、

、

、

、

、

、

、

、

、

、

或

。 In a scheme:

can be

,

or

.

在某一方案中：

可為

或

。 In a scheme:

can be

or

.

在某一方案中：

可為

、

或

。 In a scheme:

can be

,

or

.

在某一方案中：R ^2-2和R ^2-1a獨立地可為-OH、-F、-Cl、-NH ₂或-OMe。 In a certain scheme: ^{R2-2 and R2-1a} ^can independently be -OH, -F, -Cl, _-NH2 or -OMe.

在某一方案中：R ^2-1可為

、

或

。 In one scheme: R ^2-1 can be

,

or

.

在某一方案中：R ²可為

、

、

、

、

、

、

或

。 In one scheme: R ² may be

,

or

.

在某一方案中：-L-可為

、

、

、

、

、

、

、

或

。 In a scheme: -L- can be

,

or

.

在某一方案中：R ^3-1a可為

。 In one scheme: R ^3-1a may be

.

在某一方案中：R ^3-1和R ^3-2獨立地可為OH、Me、Et、CN、

、

、

、

、

、

或

。 In a certain scheme: R ^3-1 and R ^3-2 independently can be OH, Me, Et, CN,

,

or

.

在某一方案中：R ³可為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In one scheme: R ³ can be

,

or

.

在某一方案中：所述的E3連接酶可為von Hippel-Lindau(VHL)、CRBN、MDM2、cIAP、Cereblon、XIAP、E3A、後期促進複合物(APC)、UBR5(EDD1)、SOCS/BC-box/eloBC/ CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box蛋白15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/ HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、Mind Bomb 1/MIB1、Mind Bomb 2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5或ZNRF3，優選VHL、CRBN、MDM2或cIAP。In a certain scheme: the E3 ligase can be von Hippel-Lindau (VHL), CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, anaphase promoting complex (APC), UBR5 (EDD1), SOCS/BC -box/eloBC/ CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 , PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54 , β-TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-box protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP -2/ HIAP-1, cIAP(pan), ITCH/AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, preferably VHL, CRBN, MDM2 or cIAP.

在某一方案中：當R ¹為C ₁-C ₆烷基時，與R ¹相連的C原子的構型為S構型。 In a certain scheme: when R ¹ is a C ₁ -C ₆ alkyl group, the configuration of the C atom to which R ¹ is attached is the S configuration.

在某一方案中：R ⁴為F。 ^In one aspect: R4 is F.

在一些實施態樣中：R ³為

、

、

、

、

、

、

、

或

。 In some embodiments: ^R is

,

or

.

在某一方案中：Z可為NR ⁵。 ^In one aspect: Z can be NR5.

在某一方案中：R ⁵可為

、

或

。 In one scheme: R ⁵ may be

,

or

.

在某一方案中：R ⁵可為

或

。 In one scheme: R ⁵ may be

or

.

在某一方案中：R ⁵可為

。 In one scheme: R ⁵ may be

.

在某一方案中：R ^5-1可為被R ^5-1a取代或未取代的C ₁-C ₆烷基、C ₂-C ₆烯基或C ₁-C ₆烷氧基。 In a certain scheme: R ^5-1 can be C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a .

在某一方案中：R ^5-1可為被R ^5-1a取代或未取代的C ₁-C ₆烷基或C ₂-C ₆烯基。 In a certain scheme: R ^5-1 can be C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-1a .

在某一方案中：R ^5-1可為C ₂-C ₆烯基。 In a certain scheme: R ^5-1 can be C ₂ -C ₆ alkenyl.

在某一方案中：R ^5-2可為C ₁-C ₆烷基。 In a certain scheme: R ^5-2 can be C ₁ -C ₆ alkyl.

在某一方案中：R ^5-3和R ^5-4獨立地可為氫、或被R ^5-1a取代或未取代的C ₁-C ₆烷基。 In a certain scheme: R ^5-3 and R ^5-4 can independently be hydrogen, or C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a .

在某一方案中：R ¹可為氫。 In ^one aspect: R1 can be hydrogen.

在某一方案中：R ²可為被R ^2-2取代或未取代的C ₆-C ₁₅芳基。 In a certain scheme: R ² can be C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-2 .

在某一方案中：R ²可為被R ^2-2取代的C ₆-C ₁₅芳基。 In a certain scheme: R ² can be C ₆ -C ₁₅ aryl substituted with R ^2-2 .

在某一方案中：R ^2-2可為羥基、鹵素、胺基或C ₁-C ₆烷氧基。 In a certain scheme: R ^2-2 can be hydroxyl, halogen, amino or C ₁ -C ₆ alkoxy.

在某一方案中：R ^2-2可為羥基、鹵素或胺基。 In a certain scheme: R ^2-2 can be hydroxyl, halogen or amine.

在某一方案中：R ^2-2可為羥基或鹵素。 In a certain scheme: R ^2-2 can be hydroxy or halo.

在某一方案中：R ^2-1a可為鹵素。 In one aspect: R ^2-1a can be halogen.

在某一方案中：R ³可為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基。 In a certain scheme: R ³ can be C ₆ -C ₁₅ aryl substituted by R ^3-1 , or "hetero atoms are selected from one or more of N, O and S, and hetero atoms substituted by R ^3-2 . 5-15 membered heteroaryl with 1, 2, 3 or 4" atoms.

在某一方案中：R ³可為被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基。 In a certain scheme: R ³ can be substituted by R ^3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5- 15-membered heteroaryl.

在某一方案中：R ^3-1和R ^3-2獨立地可為C ₁-C ₆烷基或-L-R ^3-1a。 In one embodiment: R ^3-1 and R ^3-2 independently can be C ₁ -C ₆ alkyl or -LR ^3-1a .

在某一方案中：R ^3-1和R ^3-2獨立地可為C ₁-C ₆烷基。 In a certain scheme: R ^3-1 and R ^3-2 independently can be C ₁ -C ₆ alkyl.

在某一方案中：R ^3-1和R ^3-2獨立地可為甲基或異丙基。 In a certain scheme: R ^3-1 and R ^3-2 independently can be methyl or isopropyl.

在某一方案中：-L-可為

；a端與R ^3-1a相連接，b端與C ₆-C ₁₅芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基相連接。 In a scheme: -L- can be

; The a-end is connected with R ^3-1a , the b-end is connected with C ₆ -C ₁₅ aryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 A" 5-15 membered heteroaryl is connected.

在某一方案中：n1可為0、1、2、3、4、5或6。In a certain scheme: n1 can be 0, 1, 2, 3, 4, 5 or 6.

在某一方案中：m1可為0、1、2或3。In a certain scheme: m1 may be 0, 1, 2 or 3.

在某一方案中：R ^3-1a可為

。 In one scheme: R ^3-1a may be

.

在某一方案中：R ^3-1a-1和R ^3-1a-2獨立地可為氫或

。 In a certain scheme: R ^3-1a-1 and R ^3-1a-2 can independently be hydrogen or

.

在某一方案中：R ^3-1和R ^3-2的個數可為2個，且R ^3-1和R ^3-2不同。 In a certain scheme: the number of R ^3-1 and R ^3-2 can be 2, and R ^3-1 and R ^3-2 are different.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

、

或

； R ^5-1為被R ^5-1a取代或未取代的C ₁-C ₆烷基、C ₂-C ₆烯基或C ₁-C ₆烷氧基； R ^5-2為C ₁-C ₆烷基； R ^5-3和R ^5-4獨立地為氫、或被R ^5-1a取代或未取代的C ₁-C ₆烷基； R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基； R ^5-1a-1為C ₁-C ₆烷氧基； R ¹為氫或C ₁-C ₆烷基； R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基； R ^2-2為羥基、鹵素、胺基或C ₁-C ₆烷氧基； R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基、或被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基或-L-R ^3-1a； -L-為

；a端與R ^3-1a相連接，b端與C ₆-C ₁₅芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基相連接； n1為0、1、2、3、4、5或6； m1為0、1、2或3； R ^3-1a為

； R ^3-1a-1和R ^3-1a-2獨立地為氫或

。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

,

or

; R ^5-1 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a ; R ^5-2 is C ₁ -C ₆ alkyl; R ^5-3 and R ^5-4 are independently hydrogen, or C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a ; R ^5-1a is substituted by R ^5-1a-1 or unsubstituted C ₁ -C ₆ alkoxy; R ^5-1a-1 is C ₁ -C ₆ alkoxy; R ¹ is hydrogen or C ₁ -C ₆ alkyl; R ² is R ^2-2 Substituted or unsubstituted C ₆ -C ₁₅ aryl; R ^2-2 is hydroxyl, halogen, amino or C ₁ -C ₆ alkoxy; R ³ is C ₆ - substituted or unsubstituted by R ^3-1 C ₁₅ aryl, or 5-15 substituted or unsubstituted by R ^3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" Member heteroaryl; R ^3-1 and R ^3-2 are independently C ₁ -C ₆ alkyl or -LR ^3-1a ; -L- is

; The a-end is connected with R ^3-1a , the b-end is connected with C ₆ -C ₁₅ aryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 5-15-membered heteroaryl groups of "" are connected; n1 is 0, 1, 2, 3, 4, 5 or 6; m1 is 0, 1, 2 or 3; R ^3-1a is

; R ^3-1a-1 and R ^3-1a-2 are independently hydrogen or

.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

或

； R ^5-1為被R ^5-1a取代或未取代的C ₁-C ₆烷基或C ₂-C ₆烯基； R ^5-2為C ₁-C ₆烷基； R ^5-3和R ^5-4獨立地為氫、或被R ^5-1a取代或未取代的C ₁-C ₆烷基； R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基； R ^5-1a-1為C ₁-C ₆烷氧基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基、鹵素、胺基或C ₁-C ₆烷氧基； R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基、或被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

or

; R ^5-1 is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-1a ; R ^5-2 is C ₁ -C ₆ alkyl; R ^5-3 and R ^5-4 is independently hydrogen, or C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a ; R ^5-1a is C ₁ -C ₆ substituted or unsubstituted by R ^5-1a-1 Alkoxy; R ^5-1a-1 is C ₁ -C ₆ alkoxy; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl, Halogen, amino or C ₁ -C ₆ alkoxy; R ³ is a C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , or a "heteroatom selected" substituted or unsubstituted by R ^3-2 A 5-15-membered heteroaryl group selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4"; R ^3-1 and R ^3-2 are independently C ₁ - C ₆ alkyl.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基、鹵素或胺基； R ³為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基； R ^3-1和R ^3-2的個數為2個，且R ^3-1和R ^3-2不同。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

; R ^5-1 is C ₂ -C ₆ alkenyl; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl, halogen or amino; R ³ is a C ₆ -C ₁₅ aryl group substituted by R ^3-1 , or a "hetero atom substituted by R ^3-2 is selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl; R ^3-1 and R ^3-2 are independently C ₁ -C ₆ alkyl; R ^3-1 and R ^3-2 are 2 in number, And R ^3-1 and R ^3-2 are different.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基或鹵素； R ³為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為甲基或異丙基； R ^3-1和R ^3-2的個數為2個，且R ^3-1和R ^3-2不同。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

; R ^5-1 is C ₂ -C ₆ alkenyl; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl or halogen; R ³ is by C ₆ -C ₁₅ aryl substituted by R ^3-1 , or "heteroatoms substituted by R ^3-2 are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 R ^3-1 and R ^3-2 are independently methyl or isopropyl; the number of R ^3-1 and R ^3-2 is 2, and R ^{3- 1} and R ^3-2 are different.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基或鹵素； R ³為被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-2為C ₁-C ₆烷基。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

; R ^5-1 is C ₂ -C ₆ alkenyl; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl or halogen; R ³ is by R ^3-2 is a 5-15-membered heteroaryl group substituted by "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"; R ^3-2 is C ₁ -C ₆ alkyl.

本發明中，上述的如式I所示的化合物可為如下任一結構：

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In the present invention, the above-mentioned compound shown in formula I can be any of the following structures:

,

or

.

本發明中，所述的如式I’所示的化合物可為如下任一結構：

、

。 In the present invention, the compound shown in the formula I' can be any of the following structures:

,

.

本發明提供一種上述的如式A所示化合物的製備方法，其為方法一、方法二、方法三或方法四，方法一包括以下步驟：溶劑中，在鹼的存在下，將如式II-1A所示化合物和如式II-2所示化合物進行如下所示的反應，得所述的如式A所示的化合物，

；例如，式A為式I時，方法一包括以下步驟：溶劑中，在鹼的存在下，將如式II-1所示化合物和如式II-2所示化合物進行如下所示的反應，得所述的如式I所示的化合物，

；方法二包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式III-1A所示化合物和如式III-2或III-3所示化合物進行如下所示的反應，得所述的如式A所示的化合物，

；例如，式A為式I時，方法二包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式III-1所示化合物和如式III-2或III-3所示化合物進行如下所示的反應，得所述的如式I所示的化合物，

；方法一或方法二中，Z為NR ⁵，R ⁵為

；方法三包括以下步驟：溶劑中，在鹼的存在下，將如式IV-1A所示化合物和IV-2所示化合物進行如下所示的反應，得所述的如式A所示的化合物，

；例如，式A為式I時，方法三包括以下步驟：溶劑中，在鹼的存在下，將如式IV-1所示化合物和IV-2所示化合物進行如下所示的反應，得所述的如式I所示化合物，

；方法三中，Z為NR ⁵，R ⁵為

；方法四包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式V-1A所示化合物和如式V-2或V-3所示化合物進行如下所示的反應，得所述的如式A所示的化合物，

；例如，式A為式I時，方法四包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式V-1所示化合物和如式V-2或V-3所示化合物進行如下所示的反應，得所述的如式I所示的化合物，

；方法四中，Z為O或NR ⁵，R ⁵為C ₁-C ₆烷基；其中，R ¹、R ²、R ³、R ⁴、R ^5-1、R ^5-3和R ^5-4的定義同上所述。 The present invention provides a method for preparing the above-mentioned compound represented by formula A, which is method 1, method 2, method 3 or method 4. Method 1 includes the following steps: in a solvent, in the presence of a base, prepare a method such as formula II- The compound shown in 1A and the compound shown in formula II-2 are subjected to the following reaction to obtain the compound shown in formula A,

For example, when formula A is formula I, method 1 includes the following steps: in a solvent, in the presence of a base, the compound shown in formula II-1 and the compound shown in formula II-2 are subjected to the reaction shown below, to obtain the compound shown in the formula I,

Method 2 comprises the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1A and the compound shown in formula III-2 or III-3 are subjected to the reaction shown below to obtain the described The compound of formula A,

For example, when formula A is formula I, method two includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1 and the compound shown in formula III-2 or III-3 are carried out. The reaction shown below can obtain the compound shown in the formula I,

; In method one or method two, Z is NR ⁵ , and R ⁵ is

The method three comprises the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1A and the compound shown in IV-2 are subjected to the reaction shown below to obtain the compound shown in formula A. ,

For example, when formula A is formula I, method three includes the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1 and the compound shown in IV-2 are subjected to the reaction shown below to obtain the result: The compound shown in the formula I,

; In method three, Z is NR ⁵ , and R ⁵ is

; Method four includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula V-1A and the compound shown in formula V-2 or V-3 are subjected to the reaction shown below to obtain the described The compound of formula A,

For example, when formula A is formula I, method four includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula V-1 and the compound shown in formula V-2 or V-3 are carried out. The reaction shown below can obtain the compound shown in the formula I,

; In method 4, Z is O or NR ⁵ , and R ⁵ is C ₁ -C ₆ alkyl; wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5-1 , R ^5-3 and R ^{5- 4} is defined as above.

在某一方案中，方法一、方法二、方法三或方法四中，所述的反應的條件和操作與本領域該類反應常規的條件和操作相同。In a certain scheme, in Method 1, Method 2, Method 3 or Method 4, the conditions and operations of the described reaction are the same as those conventionally used for such reactions in the art.

本發明提供一種藥物組合物，其包括上述的如式A所示的化合物或其藥學上可接受的鹽，和藥用輔料。所述的如式A所示的化合物或其藥學上可接受的鹽可為治療有效量。The present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant. The compound represented by Formula A or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.

在某一方案中，本發明提供一種藥物組合物，其包括上述的如式I所示的化合物或其藥學上可接受的鹽，和藥用輔料。所述的如式I所示的化合物或其藥學上可接受的鹽可為治療有效量。In a certain aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient. The compound represented by formula I or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.

所述藥物組合物中，所述藥用輔料可包括藥學上可接受的載體、稀釋劑和/或賦形劑。In the pharmaceutical composition, the pharmaceutical excipients may include pharmaceutically acceptable carriers, diluents and/or excipients.

根據治療目的，藥物組合物可以本領域常規的劑型形式存在，如片劑、丸劑、粉劑、液體、懸浮液、乳液、顆粒劑、膠囊、栓劑和針劑（溶液及懸浮液）等，優選液體、懸浮液、乳液、栓劑和針劑（溶液及懸浮液）等。According to the purpose of treatment, the pharmaceutical composition can exist in the form of conventional dosage forms in the art, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc., preferably liquid, Suspensions, emulsions, suppositories and injections (solutions and suspensions), etc.

為了使片劑形式的藥物組合物成形，可使用本領域任何已知並廣泛使用的賦形劑。例如，載體，如乳糖、白糖、氯化鈉、葡萄糖、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素和矽酸等；黏合劑，如水、乙醇、丙醇、普通糖漿、葡萄糖溶液、澱粉溶液、明膠溶液，羧甲基纖維素、紫膠、甲基纖維素和磷酸鉀、聚乙烯吡咯烷酮等；崩解劑，如乾澱粉、藻酸鈉、瓊脂粉和海帶粉，碳酸氫鈉、碳酸鈣、聚乙烯脫水山梨醇的脂肪酸酯、十二烷基硫酸鈉、硬脂酸單甘酯、澱粉和乳糖等；崩解抑制劑，如白糖、甘油三硬脂酸酯、椰子油和氫化油；吸附促進劑，如季胺鹼和十二烷基硫酸鈉等；潤濕劑，如甘油、澱粉等；吸附劑，如澱粉、乳糖、高嶺土、膨潤土和膠體矽酸等；以及潤滑劑，如純淨的滑石，硬脂酸鹽、硼酸粉和聚乙二醇等。還可以根據需要選用通常的塗漬材料製成糖衣片劑、塗明膠膜片劑、腸衣片劑、塗膜片劑、雙層膜片劑及多層片劑。In order to shape the pharmaceutical composition in tablet form, any of the excipients known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution , gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate , fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.; disintegration inhibitors, such as white sugar, glyceryl tristearate, coconut oil and hydrogenated oil ; Adsorption accelerators, such as quaternary amine bases and sodium lauryl sulfate, etc.; Wetting agents, such as glycerol, starch, etc.; Adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; And lubricants, such as Pure talc, stearate, boric acid powder and polyethylene glycol, etc. The usual coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered film tablets and multi-layered tablets as required.

為了使丸劑形式的藥物組合物成形，可使用本領域任何已知的並廣泛使用的賦形劑，例如，載體，如乳糖，澱粉，椰子油，硬化植物油，高嶺土和滑石粉等；粘合劑，如***樹膠粉，黃蓍膠粉，明膠和乙醇等；崩解劑，如瓊脂和海帶粉等。In order to shape the pharmaceutical composition in pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.

為了使栓劑形式的藥物組合物成形，可使用本領域任何已知並廣泛使用的賦性劑，例如，聚乙二醇，椰子油，高級醇，高級醇的酯，明膠和半合成的甘油酯等。To shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art may be used, for example, polyethylene glycols, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides Wait.

為了製備針劑形式的藥物組合物，可將溶液或懸浮液消毒後（最好加入適量的氯化鈉，葡萄糖或甘油等），製成與血液等滲壓的針劑。在製備針劑時，也可使用本領域內任何常用的載體。例如，水，乙醇，丙二醇，乙氧基化的異硬脂醇，聚氧基化的異硬脂醇和聚乙烯脫水山梨醇的脂肪酸酯等。此外，還可加入通常的溶解劑、緩衝劑和止痛劑等。In order to prepare the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection of isotonic pressure with blood. In the preparation of injections, any carrier commonly used in the art can also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, and the like. In addition, usual solubilizers, buffers, pain relievers and the like may be added.

本發明中，所述的化合物在藥物組合物中的含量無特殊限制，可在很寬的範圍內進行選擇，通常可為質量百分比的5~95%，較佳的為質量百分比30~80%。In the present invention, the content of the compound in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5-95% by mass, preferably 30-80% by mass .

本發明中，所述藥物組合物的給藥方法沒有特殊限制。可根據病人年齡、性別和其它條件及症狀，選擇各種劑型的製劑給藥。例如，片劑、丸劑、溶液、懸浮液、乳液、顆粒劑或膠囊口服給藥；針劑可以單獨給藥，或者和注射用輸送液（如葡萄糖溶液及胺基酸溶液）混合進行靜脈注射；栓劑為給藥到直腸。In the present invention, the administration method of the pharmaceutical composition is not particularly limited. Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections may be administered alone or in combination with injectable delivery solutions (such as glucose solutions and amino acid solutions) for intravenous injection; suppositories For administration to the rectum.

本發明提供一種上述的如式A所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備KRAS抑制劑的應用，所述的KRAS抑制劑優選KRAS G12C抑制劑。所述的KRAS抑制劑在體外使用。The present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a KRAS inhibitor, the KRAS inhibitor is preferably a KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro.

某一方案中，本發明提供一種上述的如式I所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備KRAS抑制劑的應用，所述的KRAS抑制劑優選KRAS G12C抑制劑。所述的KRAS抑制劑在體外使用。In a certain scheme, the present invention provides an application of the above-mentioned compound shown in formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a KRAS inhibitor, the KRAS inhibitor is preferably KRAS G12C inhibitor. Said KRAS inhibitor is used in vitro.

本發明提供一種上述的如式A所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備用於預防和/或治療KRAS相關疾病的藥物中的應用。所述的KRAS優選KRAS G12C。The present invention provides the use of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in preparing a medicine for preventing and/or treating KRAS-related diseases. Said KRAS is preferably KRAS G12C.

某一方案中，本發明提供一種上述如式I所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備用於預防和/或治療KRAS相關疾病的藥物中的應用。所述的KRAS優選KRAS G12C。所述的KRAS相關疾病可為以KRAS突變為特徵的癌症，例如胰腺癌、大腸癌或肺腺癌。In a certain scheme, the present invention provides the use of the above-mentioned compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating KRAS-related diseases. Said KRAS is preferably KRAS G12C. The KRAS-related disease may be a cancer characterized by KRAS mutation, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.

本發明提供一種上述的如式A所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備藥物中的應用，所述的藥物為用於預防和/或治療癌症的藥物。The present invention provides an application of the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is a medicament for preventing and/or treating cancer .

某一方案中，本發明提供一種上述如式I所示的化合物或其藥學上可接受的鹽、或上述的藥物組合物在製備藥物中的應用，所述的藥物為用於預防和/或治療癌症的藥物。所述的癌症可為以KRAS突變為特徵的癌症，例如胰腺癌、大腸癌或肺腺癌。In a certain scheme, the present invention provides a kind of above-mentioned compound shown in formula I or its pharmaceutically acceptable salt or the application of above-mentioned pharmaceutical composition in the preparation of medicine, and described medicine is used for prevention and/or Drugs to treat cancer. The cancer may be a cancer characterized by KRAS mutations, such as pancreatic cancer, colorectal cancer, or lung adenocarcinoma.

本發明提供一種如式A所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物：

式中， Z為O或NR ⁵； R ⁵為C ₁-C ₆烷基、

、

、被R ^5-5取代或未取代的C ₂-C ₆烯基、

或

、

或

； R ^3-1a-1和R ^3-1a-2獨立地可為氫、C ₁-C ₆烷基、

或

；環A可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環；環B可為C ₆-C ₁₀芳環；環C可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環； R ^a、R ^b、R ^c、R ^d和R ^e獨立地可為氫、羥基或C ₁-C ₆烷基； o1、o2和o3獨立地可為0、1、2、3或4； R ⁴為鹵素、OCH ₃、OH、CN、CONH ₂或COOH； R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2的個數獨立地為1、2、3、4或5個，當為2、3、4或5個時，R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2獨立地相同或不同。 The present invention provides a compound represented by formula A, its pharmaceutically acceptable salts, its stereoisomers, its tautomers, its isotopic compounds, its nitrogen oxides, its metabolites, its prodrugs, its Crystal form, or its solvate:

In the formula, Z is O or NR ⁵ ; R ⁵ is C ₁ -C ₆ alkyl,

,

, C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 ,

or

,

or

; R ^3-1a-1 and R ^3-1a-2 can independently be hydrogen, C ₁ -C ₆ alkyl,

or

式中，R ¹、R ²、R ³、R ⁴、Z和*的定義如上所示。 In a certain scheme of the present invention, the compound shown in formula A is the compound shown in formula I or formula I':

In the formula, R ¹ , R ² , R ³ , R ⁴ , Z and * are as defined above.

、

或

,

or

.

所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基優選“雜原子選自N，雜原子個數為1、2或個”的5-6元單環雜芳基，更優選吡啶基（例如

）。 The 5-15-membered monocyclic heteroaryl group of "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" is preferably "the heteroatom is selected from N. , a 5-6 membered monocyclic heteroaryl group with 1, 2 or "hetero atoms", more preferably a pyridyl group (such as

).

在某一方案中：當環D為C ₃-C ₆環烷烴時，所述的C ₃-C ₆環烷烴可為環丙烷、環丁烷、環戊烷或環己烷，優選環己烷（

例如為

）。 In a certain scheme: when ring D is C ₃ -C ₆ cycloalkane, the C ₃ -C ₆ cycloalkane can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclohexane (

for example

).

例如為

）、哌啶（

例如為

或

）或哌嗪（

例如為

for example

), piperidine (

for example

or

) or piperazine (

for example

).

例如為

for example

).

例如為

或

）或吡嗪環（

例如為例如

、

或

for example

or

) or the pyrazine ring (

for example

,

or

).

例如為

for example

).

例如為

for example

).

例如為

for example

).

在某一方案中：R ⁵可為

、

或

。 In one scheme: R ⁵ may be

,

or

.

在某一方案中：

可為

、

或

。 In a scheme:

can be

,

or

.

在某一方案中：

可為

、

。 In a scheme:

can be

,

.

在某一方案中：

可為

、

或

。 In a scheme:

can be

,

or

.

在某一方案中：R ^2-1可為

、

或

。 In one scheme: R ^2-1 can be

,

or

.

在某一方案中：R ²可為

、

或

。 In one scheme: R ² may be

,

or

.

在某一方案中：-L-可為

、

或

。 In a scheme: -L- can be

,

or

.

在某一方案中：R ^3-1a可為

。 In one scheme: R ^3-1a may be

.

在某一方案中：R ^3-1和R ^3-2獨立地可為OH、Me、Et、CN、

、

或

。 In a certain scheme: R ^3-1 and R ^3-2 independently can be OH, Me, Et, CN,

,

or

.

在某一方案中：R ³可為

、

或

。 In one scheme: R ³ can be

,

or

.

在某一方案中：R ⁴為F。 ^In one aspect: R4 is F.

在某一方案中：R ³為

、

或

。 In one scheme: R ³ is

,

or

.

在某一方案中：Z可為NR ⁵。 ^In one aspect: Z can be NR5.

在某一方案中：R ⁵可為

、

或

。 In one scheme: R ⁵ may be

,

or

.

在某一方案中：R ⁵可為

或

。 In one scheme: R ⁵ may be

or

.

在某一方案中：R ⁵可為

。 In one scheme: R ⁵ may be

.

在某一方案中：R ¹可為氫。 In ^one aspect: R1 can be hydrogen.

在某一方案中：-L-可為

在某一方案中：R ^3-1a可為

。 In one scheme: R ^3-1a may be

.

在某一方案中：R ^3-1a-1和R ^3-1a-2獨立地可為氫或

.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

、

或

； R ^3-1a-1和R ^3-1a-2獨立地為氫或

。 In a certain scheme: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

,

or

; R ^3-1a-1 and R ^3-1a-2 are independently hydrogen or

.

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

或

or

在某一方案中： R ⁴為F； Z為NR ⁵； R ⁵為

本發明提供一種藥物組合物，其包括上述的如式A所示的化合物或其藥學上可接受的鹽，和藥用輔料；所述的如式A所示的化合物或其藥學上可接受的鹽可為治療有效量。The present invention provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula A or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients; the compound represented by formula A or a pharmaceutically acceptable salt thereof; Salt can be a therapeutically effective amount.

某一方案中，本發明提供一種藥物組合物，其包括上述的如式I所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物，和藥用輔料。所述的如式I所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物可為治療有效量。In a certain scheme, the present invention provides a pharmaceutical composition, which includes the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its Nitrogen oxides, their metabolites, their prodrugs, their crystalline forms, or their solvates, and pharmaceutical excipients. The compound shown in the formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystal form, or a solvate thereof, may be a therapeutically effective amount.

本發明提供一種上述如式A所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物在製備激酶調節劑的應用。The present invention provides a compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, Use of its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator.

某一方案中，本發明提供一種上述的如式I所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物在製備激酶調節劑的應用。所述的激酶調節劑可為激酶抑制劑或激酶激動劑。所述的激酶可為KRAS，例如KRAS G12C。所述的KRAS抑制劑在體外使用。In a certain scheme, the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolism Use of the product, its prodrug, its crystal form, or its solvate, or the above-mentioned pharmaceutical composition in the preparation of a kinase modulator. The kinase modulator can be a kinase inhibitor or a kinase agonist. The kinase can be KRAS, eg KRAS G12C. Said KRAS inhibitor is used in vitro.

本發明提供一種上述的如式A所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物在製備藥物中的應用。The present invention provides the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug , its crystal form, or its solvate, or the application of the above-mentioned pharmaceutical composition in the preparation of medicine.

某一方案中，本發明提供了一種上述的如式I所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物在製備藥物中的應用。所述的藥物可為預防和/或治療KRAS相關疾病的藥物或用於預防和/或治療癌症的藥物。所述的KRAS優選KRAS G12C。所述的KRAS相關疾病可為癌症。所述的癌症可為肺癌、胰腺癌、胰腺導管癌、大腸癌、結腸癌、直腸癌、闌尾癌、食道鱗狀細胞癌、頭頸鱗狀細胞癌或乳腺癌。所述的癌症可為以KRAS突變為特徵的癌症。In a certain scheme, the present invention provides a kind of above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its Use of metabolites, their prodrugs, their crystal forms, or their solvates, or the above-mentioned pharmaceutical compositions in the preparation of medicines. The medicament may be a medicament for preventing and/or treating KRAS-related diseases or a medicament for preventing and/or treating cancer. Said KRAS is preferably KRAS G12C. The KRAS-related disease may be cancer. The cancer may be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer. The cancer may be a cancer characterized by KRAS mutations.

本發明還提供一種治療KRAS相關疾病的方法，其包括向患者施用治療有效量的上述的如式A所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物。The present invention also provides a method for treating KRAS-related diseases, comprising administering to a patient a therapeutically effective amount of the above-mentioned compound represented by formula A, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a tautomer thereof , its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition.

某一方案中，本發明還提供一種治療KRAS相關疾病的方法，其包括向患者施用治療有效量的上述的如式I所示的化合物、其藥學上可接受的鹽、其立體異構體、其互變異構體、其同位素化合物、其氮氧化物、其代謝產物、其前藥、其晶型、或其溶劑化物、或上述的藥物組合物。所述的KRAS優選KRAS G12C。所述的KRAS相關疾病可為癌症。該癌症可為肺癌、胰腺癌、胰腺導管癌、大腸癌、結腸癌、直腸癌、闌尾癌、食道鱗狀細胞癌、頭頸鱗狀細胞癌或乳腺癌。所述的癌症可為以KRAS突變為特徵的癌症。In a certain scheme, the present invention also provides a method for the treatment of KRAS-related diseases, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound shown in formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, Its tautomer, its isotopic compound, its nitrogen oxide, its metabolite, its prodrug, its crystalline form, or its solvate, or the above-mentioned pharmaceutical composition. Said KRAS is preferably KRAS G12C. The KRAS-related disease may be cancer. The cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, or breast cancer. The cancer may be a cancer characterized by KRAS mutations.

還已經在血液惡性腫瘤(例如，影響血液、骨髓和/或淋巴結的癌症)中鑒別出KRAS突變。因此，某些實施例涉及將所披露的化合物(例如，呈藥物組合物形式)施用需要治療血液惡性腫瘤的患者。此類惡性腫瘤包括但不限於白血病和淋巴瘤。例如，當前所披露的化合物可以用於治療諸如以下等疾病：急性淋巴細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴細胞白血病(CLL)、小淋巴細胞淋巴瘤(SLL)、慢性骨髓性白血病(CML)、急性單核細胞白血病(AMoL)和/或其他白血病。在其他實施例中，這些化合物可用於治療淋巴瘤，例如所有亞型的霍奇金淋巴瘤或非霍奇金淋巴瘤。在各個實施例中，這些化合物可用於治療漿細胞惡性腫瘤，例如多發性骨髓瘤、被套細胞淋巴瘤和華氏巨球蛋白血症。KRAS mutations have also been identified in hematological malignancies (eg, cancers affecting the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds (eg, in the form of pharmaceutical compositions) to patients in need of treatment of hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds can be used to treat diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and/or other leukemias. In other embodiments, the compounds are useful in the treatment of lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, these compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.

如無特別說明，本發明所用術語具有如下含義：Unless otherwise specified, the terms used in the present invention have the following meanings:

術語“藥學上可接受的”是指鹽、溶劑、輔料等一般無毒、安全，並且適合於患者使用。所述的“患者”優選哺乳動物，更優選為人類。The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.

本發明“化合物”、“藥學上可接受的鹽”、“互變異構體”、“同位素化合物”或“溶劑化物”中的取代基R ₁、R ₂、R ₃和R ₄中如存在立體異構體，則可以以單一的立體異構體或它們的混合物（例如外消旋體）的形式存在。術語“立體異構體”是指順反異構體或旋光異構體。這些立體異構體可以通過不對稱合成方法或掌性分離法（包括但不限於薄層色譜、旋轉色譜、柱色譜、氣相色譜、高壓液相色譜等）分離、純化及富集，還可以通過與其它掌性化合物成鍵（化學結合等）或成鹽（物理結合等）等方式進行掌性拆分獲得。術語“單一的立體異構體”是指本發明化合物的一種立體異構體相對於該化合物的所有立體異構體的質量含量不低於95%。 Substituents R ₁ , R ₂ , R ₃ and R ₄ in the "compounds", "pharmaceutically acceptable salts", "tautomers", "isotopic compounds" or "solvates" of the present invention, if present in stereo Isomers can exist as single stereoisomers or as mixtures thereof (eg racemates). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It is obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

本發明所述的“藥學上可接受的鹽”在Berge，et al.，“Pharmaceutically acceptable salts”，J. Pharm. Sci., 66, 1-19(1977)中有討論，並對藥物化學家來說是顯而易見，所述的鹽是基本上無毒性的，並能提供所需的藥代動力學性質、適口性、吸收、分佈、代謝或***等。本發明所述的化合物可以具有酸性基團、鹼性基團或兩性基團，典型的藥學上可接受的鹽包括通過本發明化合物和酸反應製備得到的鹽，例如：鹽酸鹽、氫溴酸鹽、硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸一氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、硝酸鹽、乙酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、甲酸鹽、丙烯酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、苯甲酸鹽、甲基苯甲酸鹽、鄰苯二甲酸鹽、馬來酸鹽、甲磺酸鹽、對甲苯磺酸鹽、(D,L)-酒石酸，檸檬酸，馬來酸，(D,L)-蘋果酸，富馬酸，丁二酸、琥珀酸鹽、乳酸鹽、三氟甲磺酸鹽、萘-1-磺酸鹽、扁桃酸鹽、丙酮酸鹽、硬脂酸鹽、抗壞血酸鹽、水楊酸鹽。當本發明化合物含有酸性基團時，其藥學上可接受的鹽還可以包括：鹼金屬鹽，例如鋰、鈉或鉀鹽；鹼土金屬鹽，例如鋅、鈣或鎂鹽；有機鹼鹽，例如和胺、烷基胺類（包括但不限於：甲胺、三乙胺）、羥基烷基胺類、胺基酸（包括但不限於：離胺酸、精胺酸）、N-甲基葡糖胺等形成的鹽。"Pharmaceutically acceptable salts" according to the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. It will be apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion and the like. The compounds of the present invention may have acidic groups, basic groups or amphoteric groups, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with acids, such as hydrochloride, hydrobromide acid salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, Caprate, Caprylate, Formate, Acrylate, Isobutyrate, Caproate, Heptanoate, Oxalate, Malonate, Succinate, Suberate, Benzene Formate, methylbenzoate, phthalate, maleate, mesylate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, ( D,L)-Malic acid, Fumaric acid, Succinic acid, Succinate, Lactate, Triflate, Naphthalene-1-sulfonate, Mandelate, Pyruvate, Stearate , Ascorbate, Salicylate. When the compound of the present invention contains an acidic group, its pharmaceutically acceptable salts may also include: alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as zinc, calcium or magnesium salts; organic base salts such as and amines, alkylamines (including but not limited to: methylamine, triethylamine), hydroxyalkylamines, amino acids (including but not limited to: lysine, arginine), N-methylglucose Salts formed from sugar amines, etc.

本發明所述的“互變異構體”是指分子中某一原子在兩個位置迅速移動而產生的官能團異構體，例如烯醇式和酮式互變異構體。The "tautomer" in the present invention refers to a functional group isomer produced by the rapid movement of a certain atom in two positions in a molecule, such as an enol tautomer and a keto tautomer.

本發明所述的“同位素化合物”是指化合物中的一個或多個原子以其非天然豐度的形式存在。以氫原子為例，其非天然豐度的形式是指其中約95%為氘。The term "isotopic compound" as used in the present invention means that one or more atoms in the compound exist in the form of their unnatural abundance. In the case of hydrogen atoms, in their unnaturally abundant form, about 95% of them are deuterium.

本發明所述的“溶劑化物”是指本發明化合物與化學計量或非化學計量的溶劑結合形成的物質。溶劑合物中的溶劑分子可以有序或非有序排列的形式存在。所述的溶劑包括但不限於：水、甲醇、乙醇等。The "solvate" in the present invention refers to the substance formed by combining the compound of the present invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

術語“代謝產物”是指通過微生物新陳代謝活動中所產生的物質。The term "metabolite" refers to a substance produced by the metabolic activity of microorganisms.

術語“前藥”表示作為本發明的化合物的化學衍生物，該衍生物在體內如果發生化學反應轉化成通式I所示的化合物。The term "prodrug" refers to a chemical derivative of a compound of the present invention which, if chemically reacted in vivo, converts to a compound of general formula I.

術語“晶型”是指其中的離子或分子是按照一種確定的方式在三維空間作嚴格週期性排列，並具有間隔一定距離週期重複出現規律；因上述週期性排列的不同，可存在多種晶型，也即多晶型現象。術語“無定型”是指其中的離子或分子呈現雜亂無章的分佈狀態，即離子、分子間不具有週期性排列規律。The term "crystal form" means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a certain manner, and there are periodic repetitions at certain distances. , that is, polymorphism. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.

術語“鹵素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“烷基”是指具有指定的碳原子數的直鏈或支鏈烷基。烷基的實例包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基、正戊基、正己基、正庚基、正辛基及其類似烷基。The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl group and its analogous alkyl groups.

術語“烷氧基”是指基團-O-RX，其中，RX為如上文所定義的烷基。The term "alkoxy" refers to the group -O-RX, wherein RX is an alkyl group as defined above.

術語“烯基”是指具有一個或多個碳碳雙鍵的直鏈或支鏈不飽和非芳香烴基或環烯基，優選C ₂-C ₆烯基。烯基的實例包括

、

、

、

、

、

、

、

、

、

、

、環丙烯、環丁烯、環戊烯、環己烯等。 The term "alkenyl" refers to a straight or branched chain unsaturated non-aromatic hydrocarbon or cycloalkenyl group having one or more carbon-carbon double bonds, preferably a C2 _- _C6 alkenyl group. Examples of alkenyl groups include

,

, cyclopropene, cyclobutene, cyclopentene, cyclohexene, etc.

術語“炔基”是指具有一個或多個碳碳三鍵的直鏈或支鏈不飽和非芳香烴基，優選C ₂-C ₆炔基，例如乙炔基、丙炔基等。 The term "alkynyl" refers to a straight or branched chain unsaturated non-aromatic hydrocarbon group having one or more carbon-carbon triple bonds, preferably a C ₂ -C ₆ alkynyl group, such as ethynyl, propynyl and the like.

術語“胺基”是指NH ₂。 The term "amine group" refers to _NH2 .

術語“羧基”是指COOH。The term "carboxy" refers to COOH.

術語“環烷基”是指具有指定的碳原子數的直鏈或支鏈飽和烷基。其可為單環、雙環或多環。環烷基的實例包括環丙基、環丁基、環戊基或環己基。The term "cycloalkyl" refers to a straight or branched chain saturated alkyl group having the indicated number of carbon atoms. It can be monocyclic, bicyclic or polycyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

術語“雜環烷基”是指具有雜原子的飽和的單環基團，優選含有1個、2個或3個獨立選自N、O和S的環雜原子的3-10元飽和的單環，優選3-7元飽和的單環，更優選5-6元飽和的單環。雜環烷基的示例為：吡咯烷基、四氫呋喃基、四氫吡喃基、四氫噻吩基、四氫吡啶基、四氫吡咯基、氮雜環丁烷基、噻唑烷基、唑烷基、哌啶基、嗎啉基、硫代嗎啉基、哌嗪基、氮雜環庚烷基、二氮雜環庚烷基、氧氮雜環庚烷基等。優選的雜環基為嗎啉-4-基、哌啶-1-基、吡咯烷-1-基、硫代嗎啉-4-基和1,1-二氧代-硫代嗎啉-4-基。The term "heterocycloalkyl" refers to a saturated monocyclic group having a heteroatom, preferably a 3-10 membered saturated monocyclic group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. ring, preferably a 3-7 membered saturated monocycle, more preferably a 5-6 membered saturated monocycle. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like. Preferred heterocyclyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4 -base.

本發明中的“雜環”失去一個氫原子後的基團即為雜環烷基。因此，本發明中的雜環烷基得到一個氫原子後得到的環即為本發明的雜環。同樣地，本發明中的芳基、雜芳基、環烷基得到一個氫原子後得到的環即為本發明的芳環、雜芳環、環烷烴。The "heterocycle" in the present invention loses one hydrogen atom, which is a heterocycloalkyl group. Therefore, the ring obtained after the heterocycloalkyl group in the present invention obtains one hydrogen atom is the heterocycle of the present invention. Similarly, the ring obtained after the aryl group, heteroaryl group and cycloalkyl group in the present invention obtains a hydrogen atom is the aromatic ring, heteroaromatic ring and cycloalkane of the present invention.

本發明中，C ₃-C ₆環烷基是指環丙基、環丁基、環戊基或環已基。 In the present invention, C ₃ -C ₆ cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

術語“芳基”是指苯基或萘基。The term "aryl" refers to phenyl or naphthyl.

術語“雜芳基”是指含有雜原子的芳香基團，優選含有1個、2個或3個獨立選自氮、氧和硫的芳族5-6元單環或9-10元雙環，例如呋喃基、吡啶基、噠嗪基、嘧啶基、吡嗪基、噻吩基、異唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、***基、四唑基、噻唑基、異噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并異噻唑基、苯并唑基、苯并異唑基、喹啉基、異喹啉基等。The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, For example furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl , thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, benzisoxazolyl, quinoline base, isoquinolyl, etc.

本發明中，E3連接酶的配體可以為如式A所示化合物失去一個原子或原子團後的基團：

式A化合物中，Q ¹、Q ³、M ¹、M ²和M ³獨立地為C(R ^q1)(R ^q2)、N(R ^q3)、O或S，Q ²為C(R ^q4)或N；R ^q1、R ^q2、R ^q3和R ^q4獨立地為H、氘、鹵素、CN、NO ₂、OH、氧代（=O）、NH ₂、羧基、C ₁-C ₆烷基、C ₁-C ₆烷氧基或C ₁-C ₆鹵代烷基； R ¹’和R ²’獨立地為H、D、鹵素（例如F、Cl、Br或I）、CN、OH、NO ₂、(CR ^m1R ^m2) _q1COOR ^m3、氧代（=O）、C ₁-C ₁₀烷基、R ^m4取代的C ₁-C ₁₀烷基、C ₁-C ₆烷氧基、R ^m6取代的C ₁-C ₆烷氧基、-OR ^m7、NH ₂、O(CH ₂) _q2(CH ₂) _q3NH ₂、(CH ₂) _q4(NR ^m5)(CH ₂) _q5NH ₂、

、(CR ^m8R ^m9) _q7NH ₂、-S-C ₁-C ₆烷基、-COR ^m10、C ₃-C ₆環烷基、C ₃-C ₆環烯基、“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基、C ₆-C ₁₅芳基、雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基、(CH ₂) _q9SO ₂R ^m11、(CH ₂) _q10NR ^m5SO ₂C ₁-C ₆烷基、-NR ^m5SO ₂C ₁-C ₆烷基、-NR ^m5COC ₁-C ₆烷基、-NR ^m5(CH ₂) _q11CONR ^m5C ₁-C ₆烷基、(CH ₂) _q12NR ^m5(CH ₂) _q13(NR ^m5) _q14SO ₂R ^m12、-(CR ^m5R ^m13) _q15COOR ^m14或(CH ₂) _q16CONR ^m15R ^m16； R ^m1、R ^m2、R ^m5、R ^m13和R ^m14獨立地為H、氘、C ₁-C ₆烷基、C ₂-C ₆烯基或C ₂-C ₆炔基； R ^m3為H或C ₁-C ₆烷基； R ^m4為鹵素、OH、CN、C ₁-C ₆烷基、C ₁-C ₆烷氧基、NH ₂、NR ^m5C ₁-C ₆烷基、C ₆-C ₁₅芳基、“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基、C ₃-C ₆環烷基、“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基； R ^m6為鹵素、OH、CN、C ₁-C ₆烷基、C ₁-C ₆烷氧基、NH ₂、C ₆-C ₁₅芳基、雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基； R ^m7為C ₆-C ₁₅芳基、雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基；環N為C ₃-C ₆環烷烴、“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環、C ₆-C ₁₀芳環或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環； R ^m8和R ^m9獨立地為H、OH或CN； R ^m10為C ₁-C ₆烷基、-NH ₂、-NR ^m5C ₁-C ₆烷基、-NR ^m5(CH ₂) _q8C ₆-C ₁₅芳基、-NR ^m5C ₆-C ₁₅芳基、雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基、“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基； R ^m11為-NH ₂、-NR ^m5-C ₁-C ₆烷基或-C ₁-C ₆烷基； R ^m15和R ^m16獨立地為H、氘、C ₁-C ₆烷基、氰基取代的C ₁-C ₆烷基、C ₁-C ₆鹵代烷基、C ₁-C ₆烷氧基C ₁-C ₆烷基、C ₃-C ₆環烷基、C ₆-C ₁₅芳基、雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基；或R ^m15和R ^m16與其相連的N原子一起形成雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環烷基； q1、q6、q9、q10獨立地為0、1、2、3、4、5或6； q2、q3、q4、q5、q7、q8、q11、q12、q13、q15、q16獨立地為1、2、3、4、5或6； q14為0或1。 In the present invention, the ligand of E3 ligase can be a group after the compound represented by formula A loses one atom or atomic group:

In the compound of formula A, Q ¹ , Q ³ , M ¹ , M ² and M ³ are independently C(R ^q1 )(R ^q2 ), N(R ^q3 ), O or S, and Q ² is C(R ^q4 ) or N; R ^q1 , R ^q2 , R ^q3 and R ^q4 are independently H, deuterium, halogen, CN, NO ₂ , OH, oxo (=O), NH ₂ , carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl; R ¹ ' and R ² ' are independently H, D, halogen (eg F, Cl, Br or I), CN, OH, NO ₂ , (CR ^m1 R ^m2 ) _q1 COOR ^m3 , oxo (=O), C ₁ -C ₁₀ alkyl, R ^m4 substituted C ₁ -C ₁₀ alkyl, C ₁ -C ₆ alkoxy, R ^m6 substituted C ₁ -C ₆ alkoxy, -OR ^m7 , NH ₂ , O(CH ₂ ) _q2 (CH ₂ ) _q3 NH ₂ , (CH ₂ ) _q4 (NR ^m5 )(CH ₂ ) _q5 NH ₂ ,

, (CR ^m8 R ^m9 ) _q7 NH ₂ , -SC ₁ -C ₆ alkyl, -COR ^m10 , C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, "heteroatom selected from N, O And one or more of S, the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl, C ₆ -C ₁₅ aryl, heteroatoms are selected from one or more of N, O and S , 5-15-membered heteroaryl with 1, 2, 3 or 4" heteroatoms, (CH ₂ ) _q9 SO ₂ R ^m11 , (CH ₂ ) _q10 NR ^m5 SO ₂ C ₁ -C ₆ alkyl , -NR ^m5 SO ₂ C ₁ -C ₆ alkyl, -NR ^m5 COC ₁ -C ₆ alkyl, -NR ^m5 (CH ₂ ) _q11 CONR ^m5 C ₁ -C ₆ alkyl, (CH ₂ ) _q12 NR ^m5 (CH ₂ ) _q13 (NR ^m5 ) _q14 SO ₂ R ^m12 , -(CR ^m5 R ^m13 ) _q15 COOR ^m14 or (CH ₂ ) _q16 CONR ^m15 R ^m16 ; R ^m1 , R ^m2 , R ^m5 , R ^m13 and R ^m14 independently H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; R ^m3 is H or C ₁ -C ₆ alkyl; R ^m4 is halogen, OH , CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NH ₂ , NR ^m5 C ₁ -C ₆ alkyl, C ₆ -C ₁₅ aryl, "heteroatom selected from N, O and One or more of S, 5-15-membered heteroaryl with 1, 2, 3 or 4 heteroatoms, C ₃ -C ₆ cycloalkyl, "heteroatom selected from N, O and S" One or more of the 3-10-membered heterocycloalkyl with the number of heteroatoms being 1-3"; R ^m6 is halogen, OH, CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , NH ₂ , C ₆ -C ₁₅ aryl, heteroatoms selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15 membered heteroaryl or A 3-10-membered heterocycloalkyl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; R ^m7 is a C ₆ -C ₁₅ aryl group, a heteroatom selected from From one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl or "heteroatoms are selected from one or more of N, O and S" , the number of heteroatoms is 1-3" 3-10 membered heterocycloalkyl; Ring N is C ₃ -C ₆ cycloalkane, "hetero atoms are selected from one or more of N, O and S, hetero atoms 3-10-membered heterocyclic ring, C ₆ -C ₁₀ aromatic ring or "heteroatom selected from N, O and S in the number of 1-3" One or more, 5-10-membered heteroaromatic rings with 1-3"heteroatoms; R ^m8 and R ^m9 are independently H, OH or CN; R ^m10 is C ₁ -C ₆ alkyl, -NH ₂ , -NR ^m5 C ₁ -C ₆ alkyl, -NR ^m5 (CH ₂ ) _q8 C ₆ -C ₁₅ aryl, -NR ^m5 C ₆ -C ₁₅ aryl, heteroatoms are selected from N, O and S One or more, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 -3" 3-10 membered heterocycloalkyl; R ^m11 is -NH ₂ , -NR ^m5 -C ₁ -C ₆ alkyl or -C ₁ -C ₆ alkyl; R ^m15 and R ^{m16 are} independently H, deuterium, C ₁ -C ₆ alkyl, cyano-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₅ aryl, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroatoms Aryl or 3-10-membered heterocycloalkyl with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; or the N atom to which R ^m15 and R ^m16 are attached Together to form a heteroatom selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15 membered heteroaryl or "heteroatom selected from N, O and S" One or more of the 3-10-membered heterocycloalkyl groups with 1-3"heteroatoms; q1, q6, q9, q10 are independently 0, 1, 2, 3, 4, 5 or 6; q2, q3, q4, q5, q7, q8, q11, q12, q13, q15, q16 are independently 1, 2, 3, 4, 5, or 6; q14 is 0 or 1.

本發明中，E3連接酶的配體例如可為如式A-1至式A-4所示化合物失去一個原子或原子團後的基團：

其中，Q ³、M ¹、M ²和M ³獨立地為C(R ^q1)(R ^q2)、N(R ^q3)、O或S，Q ²為C(R ^q4)或N；R ^q1、R ^q2、R ^q3和R ^q4獨立地為H、氘、鹵素、CN、NO ₂、OH、氧代（=O）、NH ₂、羧基、C ₁-C ₆烷基、C ₁-C ₆烷氧基或C ₁-C ₆鹵代烷基； R ¹’和R ²’獨立地為H、D、鹵素（例如F、Cl、Br或I）、CN、OH、NO ₂、NH ₂、COOH、氧代（=O）或C ₁-C ₄烷基。 In the present invention, the ligand of E3 ligase can be, for example, a group after the compound represented by formula A-1 to formula A-4 loses one atom or atomic group:

wherein, Q ³ , M ¹ , M ² and M ³ are independently C(R ^q1 )(R ^q2 ), N(R ^q3 ), O or S, and Q ² is C(R ^q4 ) or N; R ^q1 , R ^q2 , R ^q3 and R ^q4 are independently H, deuterium, halogen, CN, NO ₂ , OH, oxo (=O), NH ₂ , carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkane Oxy or _C1 ^- _C6 haloalkyl; R1 ^' and R2' are independently H, D, halogen (eg F, Cl, Br or I ₎ , CN, OH, NO2, _NH2 , COOH, oxygen Generation (=O) or C ₁ -C ₄ alkyl.

本發明中，E3連接酶的配體例如可為下列化合物失去一個原子或原子團後的基團：

。 In the present invention, the ligand of E3 ligase can be, for example, a group after the following compounds lose one atom or atomic group:

.

本發明中，E3連接酶的配體例如可為以下任意基團：

、

、

、

、

或

。 In the present invention, the ligand of E3 ligase can be, for example, any of the following groups:

,

or

.

術語“配體”是一個生物領域概念，指能與目標蛋白結合的分子或基團。The term "ligand" is a biological field concept that refers to a molecule or group capable of binding to a target protein.

術語“調節劑”是指相對於標準對照（例如像不存在調節劑），使靶標分子的位準或靶標分子的功能增加或降低的化合物。The term "modulator" refers to a compound that increases or decreases the level of a target molecule or the function of a target molecule relative to a standard control (eg, such as the absence of a modulator).

在符合本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。On the basis of conforming to common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本發明的積極進步效果在於：本發明的芳香化合物對KRAS尤其是KRAS G12C具有良好的抑制作用。The positive improvement effect of the present invention is that the aromatic compound of the present invention has a good inhibitory effect on KRAS, especially KRAS G12C.

下面通過實施例的方式進一步說明本發明，但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未註明具體條件的實驗方法，按照常規方法和條件，或按照商品說明書選擇。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

實施例1：合成4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)喹啉-2(1H)-酮

Example 1: Synthesis of 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methyl) phenyl)quinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將2-溴-1-氟-4-碘苯(8.4 g, 27.92 mmol)溶解在無水甲苯(100 mL)中，然後加入2-異丙基-6-甲基苯胺(5.0 g, 33.50 mmol)、Pd(OAC) ₂(醋酸鈀, 0.627 g, 2.792 mmol)、BINAP(1,1'-聯萘-2,2'-雙二苯膦, 1.738 g, 2.792 mmol)和碳酸銫(Cs ₂CO ₃)(13.64 g, 41.88 mmol)。反應液在氮氣保護下回流過夜。液相質譜顯示原料消失後，用乙酸乙酯洗滌反應溶液，減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=10/1)得到N-(3-溴-4-氟苯基)-2-異丙基-6-甲基苯胺(6.068 g，橙色固體，產率67.68%)。MS (ESI) M/Z：324.1[M+H+]。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (8.4 g, 27.92 mmol) in dry toluene (100 mL), then add 2-isopropyl-6-methylaniline (5.0 g, 33.50 mmol), Pd(OAC) ₂ (palladium acetate, 0.627 g, 2.792 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.738 g, 2.792 mmol) and cesium carbonate (Cs ₂ CO ₃ ) (13.64 g, 41.88 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methyl Aniline (6.068 g, orange solid, 67.68% yield). MS (ESI) M/Z: 324.1 [M+H+].

步驟B(Step B)：將N-(3-溴-4-氟苯基)-2-異丙基-6-甲基苯胺(6.068 g, 18.897 mmol)和3-氯-3-氧代丙酸甲酯(15.48 g, 113.38 mmol)溶解在二氯甲烷(200 mL)中，然後在室溫下2小時內緩慢的滴加三乙胺(11.47 g, 113.38 mmol)並攪拌10分鐘。液相質譜監測顯示原料消失後，加入二氯甲烷(100 mL)稀釋反應液並加入水(100 mL)，混合液用二氯甲烷(80 mL×3次)萃取，合併有機相，有機相先用飽和食鹽水(80 mL×3次)洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到3-((3-溴-4-氟苯基)(2-異丙基-6-甲基苯基)胺基)-3-羰基丙酸甲酯(5.3 g，淡黃色固體，產率66.6%)。MS (ESI) M/Z：424.1[M+H ⁺]。 Step B: Combine N-(3-bromo-4-fluorophenyl)-2-isopropyl-6-methylaniline (6.068 g, 18.897 mmol) and 3-chloro-3-oxopropane Methyl acid (15.48 g, 113.38 mmol) was dissolved in dichloromethane (200 mL), then triethylamine (11.47 g, 113.38 mmol) was slowly added dropwise over 2 hours at room temperature and stirred for 10 minutes. LC-MS monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added. The mixture was extracted with dichloromethane (80 mL × 3 times), and the organic phases were combined. Washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2-isopropyl-6-methyl) (5.3 g, pale yellow solid, 66.6% yield). MS (ESI) M/Z: 424.1 [M+H ⁺ ].

步驟C(Step C)：將溶解在30 mL水中的氫氧化鈉(5.034 g, 125.86 mmol)加入到溶解在甲醇(120 mL)中的3-((3-溴-4-氟苯基)(2-異丙基-6-甲基苯基)胺基)-3-羰基丙酸甲酯(5.3 g, 12.586 mmol)溶液中，室溫條件下攪拌1小時。液相質譜(LCMS)監測顯示原料消失後，混合溶液用水(100 mL)稀釋，然後用稀鹽酸調節水相pH為2。用乙酸乙酯(100 mL)萃取兩次，有機層用鹽水清洗，NaSO ₄乾燥，過濾，最後減壓濃縮，得到3-((3-溴-4-氟苯基)(2-異丙基-6-甲基苯基)胺基)-3-氧丙酸(4.846 g，淡黃色固體，產率94.57%)。MS (ESI) M/Z：408.0[M+H ⁺]。 Step C (Step C): Sodium hydroxide (5.034 g, 125.86 mmol) dissolved in 30 mL of water was added to 3-((3-bromo-4-fluorophenyl)( 2-isopropyl-6-methylphenyl)amino)-3-carbonylpropionic acid methyl ester (5.3 g, 12.586 mmol) solution was stirred at room temperature for 1 hour. After liquid chromatography mass spectrometry (LCMS) monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (100 mL), the organic layer was washed with brine, dried over _NaSO4 , filtered, and finally concentrated under reduced pressure to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl) -6-Methylphenyl)amino)-3-oxopropionic acid (4.846 g, pale yellow solid, 94.57% yield). MS (ESI) M/Z: 408.0 [M+H ⁺ ].

步驟D(Step D)：將3-((3-溴-4-氟苯基)(2-異丙基-6-甲基苯基)胺基)-3-氧丙酸(4.846 g, 11.90 mmol)溶解在Eaton's Reagent(伊頓試劑)(40 mL)中並在55℃下攪拌過夜。液相質譜監測顯示原料消失後，向飽和的碳酸氫鈉溶液中逐滴緩慢加入反應液並用飽和碳酸氫鈉溶液調節pH為7-8。用二氯甲烷(2×100 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮，得到7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(4.51 g，白色固體，產率97.42%)。MS (ESI) M/Z：392.1[M+H ⁺]。 Step D (Step D): 3-((3-Bromo-4-fluorophenyl)(2-isopropyl-6-methylphenyl)amino)-3-oxopropionic acid (4.846 g, 11.90 mmol) was dissolved in Eaton's Reagent (40 mL) and stirred at 55°C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2×100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 7-bromo-1-(2,6-dimethylphenyl) -6-Fluoroquinoline-2,4(1H,3H)-dione (4.51 g, white solid, 97.42% yield). MS (ESI) M/Z: 392.1 [M+H ⁺ ].

步驟E(Step E)：將7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(4.51 g, 11.5938 mmol)溶解在三氯氧磷(30 mL)中並在90℃下攪拌2小時。液相質譜顯示原料消失後，減壓蒸餾除去三氯氧磷，緩慢加入水(40 mL)並用飽和碳酸氫鈉溶液調節溶液pH為7-8。用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。得到固體用N,N-二甲基甲醯胺溶解並製備得到7-溴-4-氯-6-氟-1-(2-異丙基苯基)喹啉-2(1H)-酮(0.705 g，黃色固體，產率14.94%)。MS (ESI) M/Z：408.1[M+H ⁺]。 Step E (Step E): Combine 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (4.51 g, 11.5938 mmol) Dissolve in phosphorus oxychloride (30 mL) and stir at 90°C for 2 hours. After the disappearance of the starting material by liquid chromatography mass spectrometry, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained solid was dissolved with N,N-dimethylformamide and prepared to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one ( 0.705 g, yellow solid, 14.94% yield). MS (ESI) M/Z: 408.1 [M+H ⁺ ].

步驟F(Step F)：將7-溴-4-氯-6-氟-1-(2-異丙基苯基)喹啉-2(1H)-酮(0.705 g, 1.732 mmol)溶解在二氧六環(10 mL)中，然後加入哌嗪-1-甲酸第三丁酯(1.613 g, 8.661 mmol)和N,N-二異丙基乙胺(2.239 g, 17.32 mmol)並在110℃下攪拌2天。液相質譜顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=5/2)得到4-(7-溴-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.832 g，白色固體，產率86.21%)。MS (ESI) M/Z：558.1[M+H ⁺]。 ¹H NMR (400 MHz, CDCl ₃) δ 7.58 – 7.51 (m, 1H), 7.46 – 7.35 (m, 2H), 7.25 (s, 1H), 6.74 – 6.53 (m, 1H), 6.32 (d, J= 4.7 Hz, 1H), 3.70 (s, 4H), 3.13 (s, 4H), 2.47 – 2.38 (m, 1H), 1.95 (s, 3H), 1.51 (s, 9H), 1.15 (d, J= 6.8 Hz, 3H), 1.03 (d, J= 6.9 Hz, 3H)。 Step F (Step F): Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (0.705 g, 1.732 mmol) in 2 oxane (10 mL), then 3-butyl piperazine-1-carboxylate (1.613 g, 8.661 mmol) and N,N-diisopropylethylamine (2.239 g, 17.32 mmol) were added and the mixture was heated at 110 °C under stirring for 2 days. After the disappearance of the starting material was shown by liquid phase mass spectrometry, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-6-fluoro). - tert-butyl 1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate (0.832 g, white solid, 86.21% yield). MS (ESI) M/Z: 558.1 [M+H ⁺ ]. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 – 7.51 (m, 1H), 7.46 – 7.35 (m, 2H), 7.25 (s, 1H), 6.74 – 6.53 (m, 1H), 6.32 (d, J = 4.7 Hz, 1H), 3.70 (s, 4H), 3.13 (s, 4H), 2.47 – 2.38 (m, 1H), 1.95 (s, 3H), 1.51 (s, 9H), 1.15 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).

步驟G(Step G)：將4-(7-溴-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.400 g, 0.7179 mmol)、2-氟-6-羥基苯硼酸(0.234 g, 1.4358 mmol)、正磷酸鉀(305 mg, 1.4358 mmol)、Pd ₂dba ₃(三(二亞苄基丙酮)二鈀, 0.099 g, 0.1077 mmol)及 PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷, 0.063 g, 0.2154 mmol)混合物溶解在用氬氣置換空氣15 分鐘的1,4-二氧六環和水混合溶液(8 mL/2 mL)中，再次用氬氣置換空氣，並在60℃下攪拌3天，液相質譜顯示原料消失後，用乙酸乙酯(2×40 mL次)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=10/1)得到4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.340 g，淡黃色固體，產率80.3%)。MS (ESI) M/Z：590.2[M+H ⁺]。 Step G (Step G): 4-(7-Bromo-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinoline-4 -yl)piperazine-1-carboxylate tert-butyl ester (0.400 g, 0.7179 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.234 g, 1.4358 mmol), potassium orthophosphate (305 mg, 1.4358 mmol), Pd ₂ dba ₃ (tris(dibenzylideneacetone)dipalladium, 0.099 g, 0.1077 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8- Trioxa-6-phosphoramadamantane, 0.063 g, 0.2154 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (8 mL/2 mL) with argon replacing air for 15 minutes, and again The air was replaced with argon and stirred at 60 °C for 3 days. After the disappearance of the raw material by liquid phase mass spectrometry, extraction was performed twice with ethyl acetate (2×40 mL times), and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. , and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-( 2-Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, pale yellow solid, yield 80.3%). MS (ESI) M/Z: 590.2 [M+H ⁺ ].

步驟H(Step H)：將4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.200 g, 0.339 mmol)溶解在二氯甲烷(6 mL)中並加入三氟乙酸(3 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.166 g，棕色固體，產率100%)。MS (ESI) M/Z：490.2[M+H ⁺]。 Step H (Step H): 4-(6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-2-carbonyl- 1,2-Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.200 g, 0.339 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added The mixture was stirred at room temperature for 1 hour. After monitoring by LC-MS showed that the raw materials disappeared, the mixture was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and added dichloromethane (10 mL) and concentrated again under reduced pressure until dichloromethane and trifluoroacetic acid were added. The acetic acid was completely removed to give 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-4-(piperazin-1-yl) ) quinolin-2(1H)-one (0.166 g, brown solid, 100% yield). MS (ESI) M/Z: 490.2 [M+H ⁺ ].

步驟I(Step I)：將6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.166 g, 0.339 mmol)溶解在二氯甲烷(13 mL)中並加入DIPEA(N,N-二異丙基乙胺)(0.219 g, 1.695 mmol)和丙烯醯氯(0.031 g, 0.339 mmol)並在室溫下攪拌2小時，液相質譜(LCMS)監測顯示原料消失後，減壓濃縮除去溶劑並將所得固體溶解在N,N-二甲基甲醯胺(5 mL)中製備得到4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)喹啉-2(1H)-酮(0.0329 g，白色固體，產率17.85%)。MS (ESI) M/Z：544.2[M+H ⁺]。 ¹H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 7.71 (d, J= 10.2 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.28 – 7.14 (m, 2H), 6.95 – 6.81 (m, 1H), 6.77 – 6.63 (m, 2H), 6.40 – 6.31 (m, 1H), 6.24 (s, 1H), 6.23 – 6.15 (m, 1H), 5.80 – 5.71 (m, 1H), 3.86 (s,4H), 3.20 (s, 4H), 2.47 – 2.32 (m, 1H), 1.84 (d, J= 20.9 Hz, 3H), 1.11 – 0.88 (m,6H)。 Step I (Step I): 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-4-(piperazine-1 -yl)quinolin-2(1H)-one (0.166 g, 0.339 mmol) was dissolved in dichloromethane (13 mL) and DIPEA (N,N-diisopropylethylamine) (0.219 g, 1.695 mmol) was added ) and acryl chloride (0.031 g, 0.339 mmol) and stirred at room temperature for 2 hours. After monitoring by liquid phase mass spectrometry (LCMS) showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformaldehyde. 4-(4-Propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-iso Propyl-6-methylphenyl)quinolin-2(1H)-one (0.0329 g, white solid, 17.85% yield). MS (ESI) M/Z: 544.2 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 7.71 (d, J = 10.2 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.28 – 7.14 (m, 2H), 6.95 – 6.81 (m, 1H), 6.77 – 6.63 (m, 2H), 6.40 – 6.31 (m, 1H), 6.24 (s, 1H), 6.23 – 6.15 (m, 1H), 5.80 – 5.71 (m, 1H), 3.86 (s, 4H), 3.20 (s, 4H), 2.47 – 2.32 (m, 1H), 1.84 (d, J = 20.9 Hz, 3H), 1.11 – 0.88 (m, 6H).

實施例2：合成4-(4-丙烯醯哌嗪-1-基)-1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)喹啉-2(1H)-酮

Example 2: Synthesis of 4-(4-propenylpiperazin-1-yl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyl) Phenyl)quinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將2-溴-1-氟-4-碘苯(5.0 g, 16.62 mmol)、2-乙基-6-甲基苯胺(2.25 g, 16.62 mmol)、醋酸鈀(0.373 g, 1.7 mmol)、BIANP (1,1'-聯萘-2,2'-雙二苯膦, 1.03 g, 1.7 mmol)及碳酸銫(8.12 g, 24.93 mmol)一起放進250 mL的單口瓶中，加入無水甲苯(100 mL)，再用氮氣置換3次，之後加熱100℃反應16小時。冷卻過濾，濾餅用乙酸乙酯洗滌。濾液濃縮，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=5/1)得到N-(3-溴-4-氟苯基)-2-乙基-6-甲基苯胺(4.2 g，棕黑色油狀物，產率82%)。MS (ESI) M/Z：308[M+H ⁺]。 Step A (Step A): Combine 2-bromo-1-fluoro-4-iodobenzene (5.0 g, 16.62 mmol), 2-ethyl-6-methylaniline (2.25 g, 16.62 mmol), palladium acetate (0.373 g, 1.7 mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1.03 g, 1.7 mmol) and cesium carbonate (8.12 g, 24.93 mmol) were put into a 250 mL single-necked flask In the solution, anhydrous toluene (100 mL) was added, and the mixture was replaced with nitrogen three times, and then heated at 100° C. for 16 hours. After cooling and filtering, the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain N-(3-bromo-4-fluorophenyl)-2-ethyl-6- Methylaniline (4.2 g, brown-black oil, 82% yield). MS (ESI) M/Z: 308 [M+H ⁺ ].

步驟B(Step B)：將N-(3-溴-4-氟苯基)-2-乙基-6-甲基苯胺(5.0 g, 16.22 mmol)和3-氯-3-氧代丙酸甲酯(13.29 g, 97.34 mmol)一起放進250 mL的單口瓶中，加入無水二氯甲烷 (150 mL)，冷卻到 0℃，緩慢加入三乙胺(16.77 g, 130 mmol)。之後再室溫攪拌一小時。反應液再加入二氯甲烷(200 mL)，用水，飽和氯化鈉各洗滌一次，有機相用無水硫酸鈉乾燥和濃縮，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=4/1)得到3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)胺基)-3-羰基丙酸甲酯(4.2g，棕色油狀物，產率63%)。MS (ESI) M/Z：409[M+H ⁺]。 Step B: Combine N-(3-bromo-4-fluorophenyl)-2-ethyl-6-methylaniline (5.0 g, 16.22 mmol) and 3-chloro-3-oxopropionic acid The methyl ester (13.29 g, 97.34 mmol) was put into a 250 mL single-necked flask, anhydrous dichloromethane (150 mL) was added, cooled to 0 °C, and triethylamine (16.77 g, 130 mmol) was slowly added. It was then stirred at room temperature for another hour. The reaction solution was then added with dichloromethane (200 mL), washed once with water and saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid). Ethyl ester=4/1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionate (4.2 g, brown oil, 63% yield). MS (ESI) M/Z: 409 [M+H ⁺ ].

步驟C(Step C)：將3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)胺基)-3-羰基丙酸甲酯(5.0 g, 12.25mmol)和氫氧化鈉 (2.45 g, 61.23 mmol)一起放進250 mL的單口瓶中，加入四氫呋喃(100 mL)和水(20 mL)，室溫攪拌16小時。將大部分的四氫呋喃蒸出，加入100 mL的水，用1莫耳的鹽酸調pH值到3。用乙酸乙酯(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥和濃縮，得到3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)胺基)-3-羰基丙酸(4.2 g，黃色固體，產率87%)。MS (ESI) M/Z：394[M+H ⁺]。 Step C (Step C): methyl 3-((3-bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionate (5.0 g, 12.25 mmol) and sodium hydroxide (2.45 g, 61.23 mmol) were put into a 250 mL single-neck flask, tetrahydrofuran (100 mL) and water (20 mL) were added, and the mixture was stirred at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, 100 mL of water was added, and the pH was adjusted to 3 with 1 molar hydrochloric acid. Extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 3-((3-bromo-4-fluorophenyl)(2-ethyl-6 -methylphenyl)amino)-3-carbonylpropionic acid (4.2 g, yellow solid, 87% yield). MS (ESI) M/Z: 394 [M+H ⁺ ].

步驟D(Step D)：將3-((3-溴-4-氟苯基)(2-乙基-6-甲基苯基)胺基)-3-羰基丙酸(4.2 g, 10.65 mmol)和伊頓試劑(15 mL)一起放進100 mL的單口瓶中，之後加熱到90℃反應16小時。降溫，用飽和碳酸鉀溶液調pH值到9，用乙酸乙酯(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥，濃縮得到7-溴-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(3.5 g，黃色固體，產率87%)。MS (ESI) M/Z：377[M+H ⁺]。 Step D: 3-((3-Bromo-4-fluorophenyl)(2-ethyl-6-methylphenyl)amino)-3-carbonylpropionic acid (4.2 g, 10.65 mmol) was added to the ) and Eaton's reagent (15 mL) into a 100 mL single-neck bottle, and then heated to 90 °C for 16 hours. The temperature was lowered, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 7-bromo-1-(2- Ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (3.5 g, yellow solid, 87% yield). MS (ESI) M/Z: 377 [M+H ⁺ ].

步驟E(Step E)：將7-溴-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮放進100 mL的單口瓶中，加入20 mL三氯氧磷，之後加熱到80℃反應3小時。降温蒸出大部分的三氯氧磷，用飽和碳酸鉀溶液調pH值到9，用乙酸乙酯(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥，濃縮所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=4/1)得到7-溴-4-氯-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(1.0 g，淡黃色固體，產率30%)。MS (ESI) M/Z：395[M+H ⁺]。 Step E (Step E): Put 7-bromo-1-(2-ethyl-6-methylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione into 100 mL of In a single-necked bottle, 20 mL of phosphorus oxychloride was added, and then heated to 80° C. to react for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4/1) to obtain 7-bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6 -Fluoroquinolin-2(1H)-one (1.0 g, pale yellow solid, 30% yield). MS (ESI) M/Z: 395 [M+H ⁺ ].

步驟F(Step F)：將7-溴-4-氯-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(1.0 g, 2.53 mmol)、哌嗪-1-甲酸第三丁酯 (2.36 g, 12.7 mmol)和DIPEA(N,N-二異丙基乙胺, 1.36 g, 12.7 mmol)一起放進50 mL的單口瓶中，加入5 mL 1,4-二氧六環，之後加熱到110℃反應3天。液相質譜檢測原料反應完，直接濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=1/5)得到4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.8 g，淡黃色固體，產率58%)。MS (ESI) M/Z：544[M+H ⁺]。 Step F (Step F): 7-Bromo-4-chloro-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (1.0 g, 2.53 mmol) ), tert-butyl piperazine-1-carboxylate (2.36 g, 12.7 mmol) and DIPEA (N,N-diisopropylethylamine, 1.36 g, 12.7 mmol) were put into a 50 mL single-necked bottle together, and added 5 mL of 1,4-dioxane, then heated to 110°C for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain 4-(7-bromo-1-(2-ethyl-6-methylphenyl)-6 - Fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (0.8 g, pale yellow solid, 58% yield). MS (ESI) M/Z: 544 [M+H ⁺ ].

步驟G(Step G)：將4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.4 g, 0.73 mmol)、2-氟-6-羥基苯硼酸(0.229 g, 1.47 mmol)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷(PA-PH, 44 mg, 0.14 mmol)、磷酸鉀(312 mg, 1.47 mmol)及Pd ₂dba ₃(三(二亞苄基丙酮)二鈀, 67 mg, 0.07 mmol)一起放進50 mL的單口瓶中，加入溶劑四氫呋喃(10 mL)和水(2.5 mL)，用氮氣置換三次，加熱到60℃反應16小時。降到室溫，加入乙酸乙酯(100 mL)用飽和氯化鈉(20 mL)洗滌，有機相用無水硫酸鈉乾燥，濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=1/5)得到4-(1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.2 g，淡黃色固體，產率38%)。MS (ESI) M/Z：576[M+H ⁺]。 Step G (Step G): 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.4 g, 0.73 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.229 g, 1.47 mmol), 1,3,5,7-tetramethyl- 6-Phenyl-2,4,8-trioxa-6-phosphoramadamantane (PA-PH, 44 mg, 0.14 mmol), potassium phosphate (312 mg, 1.47 mmol) and Pd ₂ dba ₃ (tri( Dibenzylidene acetone) and dipalladium, 67 mg, 0.07 mmol) were put into a 50 mL single-necked flask together, added solvent tetrahydrofuran (10 mL) and water (2.5 mL), replaced with nitrogen three times, heated to 60 ° C for reaction 16 Hour. After cooling to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7 -(2-Fluoro-6-hydroxyphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.2 g, pale yellow solid, yielded rate 38%). MS (ESI) M/Z: 576 [M+H ⁺ ].

步驟H(Step H)：將4-(1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.2 g, 0.28 mmol)溶在二氯甲烷(5 mL)中，加入三氟乙酸 (0.272 g, 2.8 mmol)，室溫反應2小時。液相質譜檢測原料反應完，直接濃縮，用二氯甲烷共沸2次，得到產物1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮 2,2,2-三氟乙酸鹽(0.2 g，淡黃色固體，產率92%)。MS (ESI) M/Z：476[M+H ⁺]。 Step H (Step H): 4-(1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1 , 3-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (0.2 g, 0.28 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.272 g, 2.8 mmol) at room temperature for 2 hours. Liquid chromatography mass spectrometry detected the reaction of the raw materials, concentrated directly, and azeotroped twice with dichloromethane to obtain the product 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6 -Hydroxyphenyl)-4-(piperazin-1-yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.2 g, pale yellow solid, 92% yield). MS (ESI) M/Z: 476 [M+H ⁺ ].

步驟I(Step I)：將1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮 2,2,2-三氟乙酸鹽(0.2 g, 0.255 mmol, 純度73%)和三乙胺(77 mg，0.75 mmol)溶在二氯甲烷(5 mL)中，冷卻到0℃，加入烯丙機醯氯(23 mg, 0.255 mmol)，室溫反應2小時。直接濃縮，反應物通過高效液相製備純化得到4-(4-丙烯醯哌嗪-1-基)-1-(2-乙基-6-甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)喹啉-2(1H)-酮(23mg，白色固體，產率23%)。MS (ESI) M/Z：530[M+H ⁺]。 ¹H NMR (400 MHz, DMSO) δ 10.10 (d, J= 12.8 Hz, 1H), 7.70 (d, J= 10.2 Hz, 1H), 7.41 – 7.14 (m, 4H), 6.93 – 6.81 (m, 1H), 6.78 – 6.63 (m, 2H), 6.37 (d, J=2.9 Hz, 1H), 6.27 – 6.09 (m, 2H), 5.82 – 5.69 (m, 1H), 3.86 (s, 4H), 3.19 (s, 4H), 2.25 – 2.10 (m, 2H), 1.86 (d, J= 17.4 Hz, 3H), 1.05 – 0.89 (m, 3H)。 Step I (Step I): 1-(2-ethyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one 2,2,2-trifluoroacetate (0.2 g, 0.255 mmol, 73% purity) and triethylamine (77 mg, 0.75 mmol) in dichloromethane (5 mL), cooled to 0 °C, added allylorganoyl chloride (23 mg, 0.255 mmol), and reacted at room temperature for 2 hours. Directly concentrated, the reactant was purified by high performance liquid phase preparation to obtain 4-(4-propenylpiperazin-1-yl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-7-( 2-Fluoro-6-hydroxyphenyl)quinolin-2(1H)-one (23 mg, white solid, 23% yield). MS (ESI) M/Z: 530 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO) δ 10.10 (d, J = 12.8 Hz, 1H), 7.70 (d, J = 10.2 Hz, 1H), 7.41 – 7.14 (m, 4H), 6.93 – 6.81 (m, 1H) ), 6.78 – 6.63 (m, 2H), 6.37 (d, J =2.9 Hz, 1H), 6.27 – 6.09 (m, 2H), 5.82 – 5.69 (m, 1H), 3.86 (s, 4H), 3.19 ( s, 4H), 2.25 – 2.10 (m, 2H), 1.86 (d, J = 17.4 Hz, 3H), 1.05 – 0.89 (m, 3H).

實施例3：合成4-(4-丙烯醯哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)喹啉-2(1H)-酮

Example 3: Synthesis of 4-(4-propenylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl) )quinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將2-溴-1-氟-4-碘苯(10 g, 33.23 mmol)溶解在無水甲苯(100 mL)中，然後加入2，6-二甲基苯胺(4.83 g, 39.88 mmol)、Pd(OAC) ₂(醋酸鈀, 0.746 g, 3.323 mmol)、BINAP(1,1'-聯萘-2,2'-雙二苯膦, 2.069 g, 3.323 mmol)及Cs ₂CO ₃(碳酸銫, 16.24 g, 49.8 mmol)。反應液在氮氣保護下回流過夜。液相質譜顯示原料消失後，用乙酸乙酯洗滌反應溶液，減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=10/1)，得到N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1 g，橙色油狀物，產率93.4%)。MS (ESI) M/Z：296.0[M+H ⁺]。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g) , 39.88 mmol), Pd(OAC) ₂ (palladium acetate, 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs ₂ _CO3 (cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline ( 9.1 g, orange oil, 93.4% yield). MS (ESI) M/Z: 296.0 [M+H ⁺ ].

步驟B(Step B)：將N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1 g, 31.06 mmol)和3-氯-3-氧代丙酸甲酯(25.44 g, 186.35 mmol)溶解在二氯甲烷(300 mL)中, 然後在室溫下3 小時內緩慢的滴加三乙胺(18.86 g, 186.35 mmol)並攪拌10 分鐘。液相質譜顯示原料消失後，加入二氯甲烷(200 mL)稀釋反應液並加入水(2×200 mL)，混合液用二氯甲烷(100 mL×3次)萃取，合併有機相，有機相先用飽和食鹽水(80 mL×3次)洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸甲酯(8.8 g，黃色油狀物，產率72%)。MS (ESI) M/Z：396.1[M+H ⁺]。 Step B: Combine N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise over 3 hours at room temperature and stirred for 10 minutes. After LC-MS showed the disappearance of the raw materials, dichloromethane (200 mL) was added to dilute the reaction solution and water (2×200 mL) was added. The mixture was extracted with dichloromethane (100 mL×3 times), and the organic phases were combined. First washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl) )amino)-3-carbonylpropionate methyl ester (8.8 g, yellow oil, 72% yield). MS (ESI) M/Z: 396.1 [M+H ⁺ ].

步驟C(Step C)：將溶解在60 mL水中的氫氧化鈉(8.957 g, 223.9 mmol)溶液加入到溶解在甲醇(240 mL)中的3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸甲酯(8.8 g, 22.39 mmol)溶液中，室溫條件下攪拌1 小時。液相質譜監測顯示原料消失後，混合溶液用水(200 mL)稀釋，然後用稀鹽酸調節水相pH為2。用乙酸乙酯(2×200 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸(7.7g，無色油狀物，產率90.7%)。MS (ESI) M/Z：380.0[M+H ⁺]。 Step C (Step C): A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in 60 mL of water was added to 3-((3-bromo-4-fluorophenyl) dissolved in methanol (240 mL) (2,6-dimethylphenyl)amino)-3-carbonylpropionate methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After LC-MS monitoring showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2×200 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (7.7 g, colorless oil, 90.7% yield) was obtained. MS (ESI) M/Z: 380.0 [M+H ⁺ ].

步驟D(Step D)：將3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸(6.7 g, 17.67 mmol)溶解在Eatons Reagent (伊頓試劑) (40 mL)中並在55℃下攪拌過夜。液相質譜監測顯示原料消失後，向飽和碳酸氫鈉溶液中逐滴加入反應液，並用飽和碳酸氫鈉溶液調節pH為7-8。用二氯甲烷(2×100 mL次)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。得到粗品7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮，(混合物, 6.25 g，白色固體，產率97%)。MS (ESI) M/Z：362.0[M+H ⁺]。 Step D: Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) Stir in Eatons Reagent (40 mL) at 55°C overnight. After monitoring by liquid chromatography mass spectrometry showed the disappearance of the starting material, the reaction solution was added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2×100 mL times), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. Obtained crude 7-bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, yield 97 %). MS (ESI) M/Z: 362.0 [M+H ⁺ ].

步驟E(Step E)：將7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮(6.25 g, 17.31 mmol)溶解在三氯氧磷(40 mL)中並在90℃下攪拌2小時。液相質譜監測顯示原料消失後，減壓蒸餾除去三氯氧磷，緩慢加入水(20 mL)並用飽和碳酸氫鈉溶液調節溶液pH為7-8。用乙酸乙酯(2×50 mL次)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。粗品經矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氫喹啉-2(1H)-二酮(1.02 g，白色固體，產率15.5%)。MS (ESI) M/Z：296.0[M+H ⁺]。 Step E (Step E): 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25 g, 17.31 mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After the liquid mass spectrometry monitoring showed that the raw materials disappeared, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2×50 mL times), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro- 3,4-Dihydroquinoline-2(1H)-dione (1.02 g, white solid, 15.5% yield). MS (ESI) M/Z: 296.0 [M+H ⁺ ].

步驟F(Step F)：將7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氫喹啉-2(1H)-二酮(0.65 g, 1.71 mmol)溶解在二氧六環(4.5 mL)中，然後加入哌嗪-1-甲酸第三丁酯(1.59 g, 8.55 mmol)和N,N-二異丙基乙胺(2.21 g, 17.1 mmol)並在110℃下攪拌2天。液相質譜(LCMS)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=5/2)得到4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.711 g，白色固體，產率78.6%)。MS (ESI) M/Z：530.2[M+H ⁺]。 Step F (Step F): 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (0.65 g, 1.71 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (1.59 g, 8.55 mmol) and N,N-diisopropylethylamine ( 2.21 g, 17.1 mmol) and stirred at 110 °C for 2 days. After the monitoring of liquid phase mass spectrometry (LCMS) showed that the raw materials disappeared, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo -1-(2,6-Dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.711 g , white solid, yield 78.6%). MS (ESI) M/Z: 530.2 [M+H ⁺ ].

步驟G(Step G)：將4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.711 g, 1.34 mmol)、2-氟-6-羥基苯硼酸(0.419 g, 2.688 mmol)、正磷酸鉀 (570 mg, 2.688 mmol)、Pd ₂dba ₃(三(二亞苄基丙酮)二鈀, 0.184 g, 0.21 mmol)及PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷, 0.177 g, 0.4 mmol)混合物溶解在用氬氣置換空氣15分鐘的1,4-二氧六環和水混合溶液(15mL, 4/1)中，再次用氬氣置換空氣，並在60℃下攪拌3天。液相質譜監測顯示原料消失後，用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。粗品經製備純化得到4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.251 g，淡黃色固體，產率33.2%)。MS (ESI) M/Z：562.2[M+H] ⁺。 Step G (Step G): 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) 3-butyl piperazine-1-carboxylate (0.711 g, 1.34 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.419 g, 2.688 mmol), potassium orthophosphate (570 mg, 2.688 mmol), Pd ₂ dba ₃ (Tris(dibenzylideneacetone)dipalladium, 0.184 g, 0.21 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa -6-phosphoramadamantane, 0.177 g, 0.4 mmol) mixture was dissolved in a mixed solution (15 mL, 4/1) of 1,4-dioxane and water (15 mL, 4/1) with argon replacing the air for 15 min, and the air was replaced with argon again. Air was replaced and stirred at 60°C for 3 days. After LC-MS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was preparatively purified to give 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1,2-dihydro Quinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.251 g, pale yellow solid, 33.2% yield). MS (ESI) M/Z: 562.2 [M+H] ⁺ .

步驟H(Step H)：將4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.251 g, 0.447 mmol)溶解在二氯甲烷(9 mL)中並加入三氟乙酸(4.2 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL) 再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.206 g，棕色固體，產率96.8%)。MS (ESI) M/Z：462.3[M+H ⁺]。 Step H (Step H): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-carbonyl-1,2 - Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.251 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (4.2 mL) was added and in room Stir at warm temperature for 1 hour, after liquid chromatography monitoring showed the disappearance of raw materials, concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and added dichloromethane (10 mL) and concentrated again under reduced pressure until dichloromethane and trifluoroacetic acid were completely Removal to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl)quinoline-2( 1H)-one (0.206 g, brown solid, 96.8% yield). MS (ESI) M/Z: 462.3 [M+H ⁺ ].

步驟I(Step I)：將1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.206 g, 0.447 mmol)溶解在二氯甲烷(9 mL)中並加入DIEA(N,N-二異丙基乙胺)(0.289 g, 2.235 mmol)和丙烯醯氯(0.041 g, 0.447 mmol)並在室溫下攪拌2小時，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑並將所得固體溶解在N,N-二甲基甲醯胺(5 mL)中製備純化得到4-(4-丙烯醯哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)喹啉-2(1H)-酮(0.1276 g，白色固體，產率55.4%)。MS (ESI) M/Z：516.2[M+H ⁺]。 ¹H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 7.71 (d, J= 10.3 Hz, 1H), 7.36 – 7.15 (m, 4H), 6.94 – 6.81 (m, 1H), 6.76 – 6.65 (m, 2H), 6.38 (d, J= 6.2 Hz, 1H),6.26 – 6.09 (m, 2H), 5.79 – 5.69 (m, 1H), 3.86 (s, 4H), 3.19 (s, 4H), 1.88 (d, J= 15.5 Hz, 6H)。 Step I (Step I): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.206 g, 0.447 mmol) was dissolved in dichloromethane (9 mL) and DIEA (N,N-diisopropylethylamine) (0.289 g, 2.235 mmol) and propylene were added Acrylic chloride (0.041 g, 0.447 mmol) was stirred at room temperature for 2 hours. After the disappearance of the starting material was monitored by liquid phase mass spectrometry, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide (5). mL) to obtain 4-(4-propenylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)quinolin-2(1H)-one (0.1276 g, white solid, 55.4% yield). MS (ESI) M/Z: 516.2 [M+H ⁺ ]. ¹ H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 7.71 (d, J = 10.3 Hz, 1H), 7.36 – 7.15 (m, 4H), 6.94 – 6.81 (m, 1H), 6.76 – 6.65 (m, 2H), 6.38 (d, J = 6.2 Hz, 1H), 6.26 – 6.09 (m, 2H), 5.79 – 5.69 (m, 1H), 3.86 (s, 4H), 3.19 (s, 4H), 1.88 (d, J = 15.5 Hz, 6H).

實施例4：合成4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮

Example 4: Synthesis of 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methyl) pyridin-3-yl)quinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將2-溴-1-氟-4-碘苯(10.0 g, 33.23 mmol)、2-異丙基-4-甲基-3-胺基吡啶(4.99 g, 33.23 mmol)、醋酸鈀(0.746 g, 3.32 mmol)、BIANP(1,1'-聯萘-2,2'-雙二苯膦, 2.07 g, 3.32 mmol)和碳酸銫(16.24 g， 49.85 mmol)一起放進500 mL的單口瓶中，加入無水甲苯(200 mL)，再用氮氣置換3次，之後加熱100℃反應16小時。冷卻過濾，濾餅用乙酸乙酯洗滌。濾液濃縮，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到N-(3-溴-4-氟苯基)-2-異丙基-4-甲基-3-胺基吡啶(7.9 g，棕色油狀物，產率74%)。MS (ESI) M/Z：323[M+H ⁺]。 Step A (Step A): Combine 2-bromo-1-fluoro-4-iodobenzene (10.0 g, 33.23 mmol), 2-isopropyl-4-methyl-3-aminopyridine (4.99 g, 33.23 mmol) ), palladium acetate (0.746 g, 3.32 mmol), BIANP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07 g, 3.32 mmol) and cesium carbonate (16.24 g, 49.85 mmol) were put together It was put into a 500 mL single-necked bottle, anhydrous toluene (200 mL) was added, and it was replaced with nitrogen three times, and then heated at 100° C. for 16 hours. After cooling and filtering, the filter cake was washed with ethyl acetate. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropyl-4 -Methyl-3-aminopyridine (7.9 g, brown oil, 74% yield). MS (ESI) M/Z: 323 [M+H ⁺ ].

步驟B(Step B)：將N-(3-溴-4-氟苯基)-2-異丙基-4-甲基-3-胺基吡啶(7.9 g, 24.44 mmol)和3-氯-3-氧代丙酸甲酯(10.01 g, 73.33 mmol)一起放進250 mL的單口瓶中，加入無水二氯甲烷(150 mL)，冷卻到0℃，緩慢加入三乙胺(12.3 g, 122 mmol)。之後在室溫攪拌一小時。反應液再加入二氯甲烷(200 mL)，用水、飽和氯化鈉各洗滌一次，有機相用無水硫酸鈉乾燥和濃縮，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-羰基丙酸甲酯(3.5g，棕色油狀物，產率34%)。MS (ESI) M/Z：423[M+H ⁺]。 Step B: Combine N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methyl-3-aminopyridine (7.9 g, 24.44 mmol) and 3-chloro- Methyl 3-oxopropionate (10.01 g, 73.33 mmol) was put into a 250 mL single-necked flask, anhydrous dichloromethane (150 mL) was added, cooled to 0°C, and triethylamine (12.3 g, 122 g) was slowly added. mmol). It was then stirred at room temperature for one hour. Dichloromethane (200 mL) was added to the reaction solution, washed once with water and saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ester=3/1) to give methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionate (3.5 g, brown oil, 34% yield). MS (ESI) M/Z: 423 [M+H ⁺ ].

步驟C(Step C)：將3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-羰基丙酸甲酯(3.5 g, 8.27mmol)和氫氧化鈉(1.65 g, 41.34 mmol)一起放進250 mL的單口瓶中，加入四氫呋喃(100 mL)和水(20 mL)，室溫攪拌16小時。將大部分的四氫呋喃蒸出，加入水(100 mL)，用1莫耳的鹽酸調pH值到7。用二氯甲烷(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥和濃縮，得到3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-羰基丙酸(3.2 g，黃色固體，產率95%)。MS (ESI) M/Z：409[M+H ⁺]。 Step C (Step C): methyl 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionate (3.5 g, 8.27 mmol) and sodium hydroxide (1.65 g, 41.34 mmol) were put into a 250 mL single-neck flask, tetrahydrofuran (100 mL) and water (20 mL) were added, and the mixture was stirred at room temperature for 16 hours. Most of the tetrahydrofuran was distilled off, water (100 mL) was added, and the pH was adjusted to 7 with 1 molar hydrochloric acid. Extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl- 4-Methylpyridin-3-yl)amino)-3-carbonylpropionic acid (3.2 g, yellow solid, 95% yield). MS (ESI) M/Z: 409 [M+H ⁺ ].

步驟D(Step D)：將3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-羰基丙酸(3.2 g, 7.82 mmol)和伊頓試劑(15 mL)一起放進100 mL的單口瓶中，之後加熱到90℃反應16小時。降溫，用飽和碳酸鉀溶液調pH值到9，用二氯甲烷(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥，濃縮得到7-溴-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2,4(1H,3H)-二酮(2.6 g，黃色固體，產率85%)。MS (ESI) M/Z：391[M+H ⁺]。 Step D (Step D): 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-carbonylpropionic acid (3.2 g, 7.82 mmol) and Eaton's reagent (15 mL) were put into a 100 mL single-neck flask, and then heated to 90 °C for 16 hours. Cool down, adjust the pH to 9 with saturated potassium carbonate solution, extract with dichloromethane (100 mL×3), wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, and concentrate to obtain 7-bromo-6-fluoro-1 -(2-Isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)-dione (2.6 g, yellow solid, 85% yield). MS (ESI) M/Z: 391 [M+H ⁺ ].

步驟E(Step E)：將7-溴-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2,4(1H,3H)-二酮(2.6 g, 6.65 mmol)放進100 mL的單口瓶中，加入20 mL三氯氧磷，之後加熱到80℃反應3小時。降溫蒸出大部分的三氯氧磷，用飽和碳酸鉀溶液調pH值到9，用二氯甲烷(100 mL×3)萃取，有機相用飽和氯化鈉洗滌，無水硫酸鈉乾燥，濃縮所得粗產品用高效液相製備純化得到7-溴-4-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(0.4 g，白色固體，產率15%)。MS (ESI) M/Z：409[M+H ⁺]。 Step E (Step E): 7-Bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinoline-2,4(1H,3H)-dione ( 2.6 g, 6.65 mmol) into a 100 mL single-neck flask, add 20 mL of phosphorus oxychloride, and then heat to 80 °C for 3 hours. The temperature was lowered and most of the phosphorus oxychloride was evaporated, the pH value was adjusted to 9 with saturated potassium carbonate solution, extracted with dichloromethane (100 mL×3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the result. The crude product was purified by HPLC to obtain 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one ( 0.4 g, white solid, 15% yield). MS (ESI) M/Z: 409 [M+H ⁺ ].

步驟F(Step F)：將7-溴-4-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(0.4 g, 0.98 mmol)、哌嗪-1-甲酸第三丁酯(909 mg, 4.88 mmol)及DIPEA(N,N-二異丙基乙胺, 631 mg, 4.88 mmol)一起放進50 mL的單口瓶中，加入3 mL 1,4-二氧六環，之後加熱到110℃反應3天。液相質譜檢測原料反應完，直接濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=1/9)得到4-(7-溴-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.35 g，淡黃色固體，產率64%)。MS (ESI) M/Z：559[M+H] ⁺。 Step F (Step F): 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one (0.4 g, 0.98 mmol), tert-butyl piperazine-1-carboxylate (909 mg, 4.88 mmol) and DIPEA (N,N-diisopropylethylamine, 631 mg, 4.88 mmol) were placed in a 50 mL single port Into the bottle, 3 mL of 1,4-dioxane was added, and then heated to 110°C for 3 days. Liquid chromatography mass spectrometry detected that the raw materials were reacted and concentrated directly. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/9) to obtain 4-(7-bromo-6-fluoro-1-(2-isopropyl-4-methyl) Pyridin-3-yl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.35 g, pale yellow solid, 64% yield). MS (ESI) M/Z: 559 [M+H] ⁺ .

步驟G(Step G)：將4-(7-溴-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.35g, 0.63 mmol)、2-氟-6-羥基苯硼酸(0.195 g, 1.26 mmol)、正磷酸鉀(267 mg, 1.26 mmol)、Pd ₂dba ₃(三(二亞苄基丙酮)二鈀, 0.027 g, 0.03 mmol)及PA-PH(1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷, 0.030 g, 0.06 mmol)混合物溶解在用氬氣置換空氣15分鐘的1,4-二氧六環和水混合溶液(10 mL, 4/1)中，再次用氬氣置換空氣，並在60℃下攪拌過夜。液相質譜監測顯示原料消失後，用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。粗品經製備純化得到4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.25g，淡黃色固體，產率68%)。MS (ESI) M/Z：591[M+H] ⁺。 Step G (Step G): 4-(7-Bromo-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinoline Lin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.35 g, 0.63 mmol), 2-fluoro-6-hydroxyphenylboronic acid (0.195 g, 1.26 mmol), potassium orthophosphate (267 mg, 1.26 mmol), Pd ₂ dba ₃ (tris(dibenzylideneacetone)dipalladium, 0.027 g, 0.03 mmol) and PA-PH (1,3,5,7-tetramethyl-6-phenyl-2,4 ,8-trioxa-6-phosphoramadamantane, 0.030 g, 0.06 mmol) mixture was dissolved in a mixed solution of 1,4-dioxane and water (10 mL, 4/1 ), the air was replaced with argon again and stirred at 60°C overnight. After LC-MS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was preparatively purified to give 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl- 1,2-Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.25 g, pale yellow solid, 68% yield). MS (ESI) M/Z: 591 [M+H] ⁺ .

步驟H(Step H)：將4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.25 g, 0.423 mmol)溶在5 mL的二氯甲烷中，加入三氟乙酸(0.482 g, 4.23 mmol)，室溫反應2小時。液相質譜檢測原料反應完，直接濃縮，用二氯甲烷共沸2次，得到產物6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-4-(哌嗪-1-基)喹啉-2(1H)-酮-2,2,2-三氟乙酸鹽(0.24 g，淡黃色固體，產率97%)。MS (ESI) M/Z：491[M+H] ⁺。 Step H (Step H): 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2 - Carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.25 g, 0.423 mmol) was dissolved in 5 mL of dichloromethane, trifluoroacetic acid (0.482 mmol) was added g, 4.23 mmol), reacted at room temperature for 2 hours. Liquid chromatography mass spectrometry detected the reaction of the raw materials, concentrated directly, and azeotroped twice with dichloromethane to obtain the product 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4) -Methylpyridin-3-yl)-4-(piperazin-1-yl)quinolin-2(1H)-one-2,2,2-trifluoroacetic acid salt (0.24 g, pale yellow solid, yield 97%). MS (ESI) M/Z: 491 [M+H] ⁺ .

步驟I(Step I)：將6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-4-(哌嗪-1-基)喹啉-2(1H)-酮-2,2,2-三氟乙酸鹽(0.25 g, 0.4 mmol)和三乙胺(80 mg, 0.8 mmol)溶在5 mL的二氯甲烷中，冷卻到0℃，加入丙烯醯氯(36 mg, 0.4 mmol)，室溫反應2小時。直接濃縮，反應物通過高效液相製備純化得到4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)喹啉-2(1H)-酮(60 mg，白色固體，產率68%)。MS (ESI) M/Z：545[M+H] ⁺。 ¹H NMR (400 MHz, CDCl ₃) δ 10.27 (s, 1H), 8.38 (s, 1H), 7.64 (d, J= 10.0 Hz, 1H), 7.23 – 7.08 (m, 2H), 6.80 – 6.58 (m, 4H), 6.43 – 6.34 (m, 1H), 6.31 (s, 1H), 5.86 – 5.73 (m, 1H), 3.95 (d, J= 44.9 Hz, 4H), 3.27 (d, J= 17.0 Hz, 4H), 2.71 (d, J= 6.8 Hz, 1H), 1.16 (d, J= 6.7 Hz, 3H), 0.99 (s, 3H)。 Step I (Step I): 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(piperidine) Azin-1-yl)quinolin-2(1H)-one-2,2,2-trifluoroacetate (0.25 g, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) were dissolved in 5 mL of bismuth In methyl chloride, cooled to 0 °C, acryl chloride (36 mg, 0.4 mmol) was added, and the reaction was carried out at room temperature for 2 hours. Concentrated directly, the reactant was purified by high performance liquid phase preparation to obtain 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Isopropyl-4-methylpyridin-3-yl)quinolin-2(1H)-one (60 mg, white solid, 68% yield). MS (ESI) M/Z: 545 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.27 (s, 1H), 8.38 (s, 1H), 7.64 (d, J = 10.0 Hz, 1H), 7.23 – 7.08 (m, 2H), 6.80 – 6.58 ( m, 4H), 6.43 – 6.34 (m, 1H), 6.31 (s, 1H), 5.86 – 5.73 (m, 1H), 3.95 (d, J = 44.9 Hz, 4H), 3.27 (d, J = 17.0 Hz , 4H), 2.71 (d, J = 6.8 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H), 0.99 (s, 3H).

實施例5：合成4-(4-丙烯醯哌嗪-1-基)-7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮

Example 5: Synthesis of 4-(4-propenylpiperazin-1-yl)-7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl) -6-Fluoroquinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將4-(7-溴-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.3 g, 0.55 mmol)、(2-胺基-6-氯苯基)硼酸(0.142 g, 0.83 mmol)、1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷醯金剛烷(32 mg, 0.11 mmol)、磷酸鉀(233 mg, 1.1 mmol)及Pd ₂dba ₃(三(二亞苄基丙酮)二鈀, 55 mg, 0.06 mmol)一起放進50 mL的單口瓶中，加入溶劑四氫呋喃(8 mL)和水(2 mL)，用氮氣置換三次，加熱到60℃反應16小時。降到室溫，加入乙酸乙酯(100 mL)用飽和氯化鈉(20 mL)洗滌，有機相用無水硫酸鈉乾燥，濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=1/5)，得到4-(7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(30 mg，淡黃色固體，產率9%)。MS (ESI) M/Z：591[M+H] ⁺。 Step A (Step A): 4-(7-Bromo-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinoline-4- yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.55 mmol), (2-amino-6-chlorophenyl)boronic acid (0.142 g, 0.83 mmol), 1,3,5,7- Tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoramadamantane (32 mg, 0.11 mmol), potassium phosphate (233 mg, 1.1 mmol) and Pd ₂ dba ₃ (tri( Dibenzylidene acetone) and dipalladium, 55 mg, 0.06 mmol) were put into a 50 mL single-necked bottle together, added solvent tetrahydrofuran (8 mL) and water (2 mL), replaced with nitrogen three times, heated to 60 ° C for reaction 16 Hour. After cooling to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated sodium chloride (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain 4-(7-(2-amino-6-chlorophenyl)-1-(2- Ethyl-6-methylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (30 mg, pale yellow solid , the yield is 9%). MS (ESI) M/Z: 591 [M+H] ⁺ .

步驟B(Step B)：將4-(7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(30 mg, 0.06 mmol)溶在2 mL的二氯甲烷中，加入三氟乙酸 (63 mg, 0.6 mmol)。室溫反應2小時，液相質譜(LCMS)檢測原料反應完，直接濃縮，用二氯甲烷帶2次，得到產物7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-4-(哌嗪-1-基)喹啉-2(1H)-酮-2,2,2-三氟乙酸鹽(33 mg，淡黃色固體，產率99%)。MS (ESI) M/Z：491[M+H] ⁺。 Step B (Step B): 4-(7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-2-carbonyl- 1,2-Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (30 mg, 0.06 mmol) was dissolved in 2 mL of dichloromethane, trifluoroacetic acid (63 mg, 0.6 mmol). The reaction was carried out at room temperature for 2 hours, and the liquid phase mass spectrometry (LCMS) detected the raw materials after the reaction was completed, and then concentrated directly and banded twice with dichloromethane to obtain the product 7-(2-amino-6-chlorophenyl)-1-(2- Ethyl-6-methylphenyl)-6-fluoro-4-(piperazin-1-yl)quinolin-2(1H)-one-2,2,2-trifluoroacetate (33 mg, pale yellow solid, 99% yield). MS (ESI) M/Z: 491 [M+H] ⁺ .

步驟C(Step C)：將7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟-4-(哌嗪-1-基)喹啉-2(1H)-酮-2,2,2-三氟乙酸鹽(33 mg, 0.061 mmol)和三乙胺(12 mg, 1.2 mmol)溶在2 mL的二氯甲烷中，冷卻到0℃，加入烯丙基醯氯(5.5 mg, 0.061 mmol)。室溫反應2小時，直接濃縮，反應物通過高效液相製備得到兩個產物4-(4-丙烯醯哌嗪-1-基)-7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(3.5 mg，白色固體，產率10.5%)和4-(4-丙烯醯哌嗪-1-基)-7-(2-胺基-6-氯苯基)-1-(2-乙基-6-甲基苯基)-6-氟喹啉-2(1H)-酮(2.5 mg，白色固體，產率7.5%)。MS (ESI) M/Z：545[M+H] ⁺。 Step C (Step C): 7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoro-4-(piperazine-1 -yl)quinolin-2(1H)-one-2,2,2-trifluoroacetate (33 mg, 0.061 mmol) and triethylamine (12 mg, 1.2 mmol) were dissolved in 2 mL of dichloromethane , cooled to 0 °C, and allyl chloride (5.5 mg, 0.061 mmol) was added. The reaction was carried out at room temperature for 2 hours, directly concentrated, and the reactants were prepared by high performance liquid phase to obtain two products 4-(4-propenylpiperazin-1-yl)-7-(2-amino-6-chlorophenyl)- 1-(2-Ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one (3.5 mg, white solid, 10.5% yield) and 4-(4-propenylpiperazine) -1-yl)-7-(2-amino-6-chlorophenyl)-1-(2-ethyl-6-methylphenyl)-6-fluoroquinolin-2(1H)-one ( 2.5 mg, white solid, 7.5% yield). MS (ESI) M/Z: 545 [M+H] ⁺ .

第一個產物1-a1核磁： ¹H NMR (400 MHz, CDCl ₃) δ 7.65 (d, J= 9.7 Hz, 1H), 7.33 (d, J= 7.6 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 7.08 (s, 1H), 6.83 (d, J= 7.9 Hz, 1H), 6.70 – 6.59 (m, 2H), 6.50 (d, J= 6.1 Hz, 1H), 6.41 – 6.32 (m, 2H), 5.84 – 5.73 (m, 1H), 3.96 (d, J= 56.0 Hz, 4H), 3.52 (s, 2H), 3.25 (s, 4H), 2.42 – 2.17 (m, 2H), 1.97 (s, 3H), 1.06 (t, J= 7.6 Hz, 3H)。 1-a1 NMR of the first product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 9.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.70 – 6.59 (m, 2H), 6.50 (d, J = 6.1 Hz, 1H), 6.41 – 6.32 ( m, 2H), 5.84 – 5.73 (m, 1H), 3.96 (d, J = 56.0 Hz, 4H), 3.52 (s, 2H), 3.25 (s, 4H), 2.42 – 2.17 (m, 2H), 1.97 (s, 3H), 1.06 (t, J = 7.6 Hz, 3H).

第二個產物1-a2核磁： ¹H NMR (400 MHz, CDCl ₃) δ 7.65 (d, J= 9.7 Hz, 1H), 7.34 (t, J= 7.5 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J= 7.4 Hz, 1H), 7.08 (t, J= 8.1 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.70 – 6.59 (m, 2H), 6.50 (d, J= 6.1 Hz, 1H), 6.43 – 6.34 (m, 2H), 5.83 – 5.76 (m, 1H), 3.96 (d, J= 63.1 Hz, 4H), 3.53 (s, 2H), 3.25 (s, 4H), 2.40 – 2.18 (m,2H), 1.98 (s, 3H), 1.07 (t, J= 7.6 Hz, 3H)。 1-a2 NMR of the second product: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 9.7 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H) , 7.21 (d, J = 7.4 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.70 – 6.59 (m, 2H), 6.50 (d, J = 6.1 Hz, 1H), 6.43 – 6.34 (m, 2H), 5.83 – 5.76 (m, 1H), 3.96 (d, J = 63.1 Hz, 4H), 3.53 (s, 2H), 3.25 (s, 4H) ), 2.40 – 2.18 (m, 2H), 1.98 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H).

實施例6：合成4-(4-丙烯醯基哌嗪-1-基)-1-(2,6-二乙基苯基)-6-氟-7-(2-氟苯基)喹啉-2(1H)-酮

Example 6: Synthesis of 4-(4-propenylpiperazin-1-yl)-1-(2,6-diethylphenyl)-6-fluoro-7-(2-fluorophenyl)quinoline -2(1H)-one

合成路線：

synthetic route:

其合成步驟與實施例4相同。MS (ESI) M/Z：528.3[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.59 (d, J= 10.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.36 (d, J= 6.4 Hz, 1H), 7.29 (d, J= 7.6 Hz, 2H), 7.18 (dt, J= 14.6, 7.4 Hz, 2H), 7.11 (t, J= 9.1 Hz, 1H), 6.65 (dd, J= 16.7, 10.6 Hz, 1H), 6.56 (d, J= 6.1 Hz, 1H), 6.39 (t, J= 8.0 Hz, 2H), 5.80 (d, J= 10.5 Hz, 1H), 3.94 (d, J= 62.8 Hz, 4H), 3.25 (s, 4H), 2.34 (dt, J= 14.9, 7.4 Hz, 2H), 2.23 (dd, J= 15.0, 7.5 Hz, 2H), 1.09 (t, J= 7.5 Hz, 6H)。 The synthesis steps are the same as those in Example 4. MS (ESI) M/Z: 528.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.59 (d, J = 10.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.18 (dt, J = 14.6, 7.4 Hz, 2H), 7.11 (t, J = 9.1 Hz, 1H), 6.65 (dd, J = 16.7, 10.6 Hz, 1H), 6.56 (d, J = 6.1 Hz, 1H), 6.39 (t, J = 8.0 Hz, 2H), 5.80 (d, J = 10.5 Hz, 1H), 3.94 (d, J = 62.8 Hz, 4H), 3.25 (s, 4H) , 2.34 (dt, J = 14.9, 7.4 Hz, 2H), 2.23 (dd, J = 15.0, 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 6H).

實施例7：4-(4-丙烯醯基哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)喹啉-2(1H)-酮

Example 7: 4-(4-Propenylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxy Phenyl)quinolin-2(1H)-one

合成路線：

synthetic route:

步驟A(Step A)：將2-溴-1-氟-4-碘苯(10 g, 33.23 mmol)溶解在無水甲苯(100 mL)中，然後加入2,6-二甲基苯胺(4.83 g, 39.88 mmol)、Pd(OAC) ₂(醋酸鈀, 0.746 g, 3.323 mmol)、BINAP(1,1'-聯萘-2,2'-雙二苯膦, 2.069 g, 3.323 mmol)及Cs ₂CO ₃(碳酸銫, 16.24 g, 49.8 mmol)。反應液在氮氣保護下回流過夜。液相質譜顯示原料消失後，用乙酸乙酯洗滌反應溶液，減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=10/1)，得到N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1 g，橙色油狀物，產率93.4%)。MS (ESI) M/Z：296.0[M+H] ⁺。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (100 mL), then add 2,6-dimethylaniline (4.83 g , 39.88 mmol), Pd(OAC) ₂ (palladium acetate, 0.746 g, 3.323 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.069 g, 3.323 mmol) and Cs ₂ _CO3 (cesium carbonate, 16.24 g, 49.8 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline ( 9.1 g, orange oil, 93.4% yield). MS (ESI) M/Z: 296.0 [M+H] ⁺ .

步驟B(Step B)：將N-(3-溴-4-氟苯基)-2,6-二甲基苯胺(9.1 g, 31.06 mmol)和3-氯-3-氧代丙酸甲酯(25.44 g, 186.35 mmol)溶解在二氯甲烷(300 mL)中，然後在室溫下3 小時內緩慢的滴加三乙胺(18.86 g, 186.35 mmol)並攪拌10 分鐘。液相質譜顯示原料消失後，加入二氯甲烷(200 mL)稀釋反應液並加入水(2×200 mL)，混合液用二氯甲烷(100 mL×3次)萃取，合併有機相，有機相先用飽和食鹽水(80 mL×3次)洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)，得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸甲酯(8.8 g，黃色油狀物，產率72%)。MS (ESI) M/Z：396.1[M+H] ⁺。 Step B: Combine N-(3-bromo-4-fluorophenyl)-2,6-dimethylaniline (9.1 g, 31.06 mmol) and methyl 3-chloro-3-oxopropionate (25.44 g, 186.35 mmol) was dissolved in dichloromethane (300 mL), then triethylamine (18.86 g, 186.35 mmol) was slowly added dropwise over 3 hours at room temperature and stirred for 10 minutes. After LC-MS showed the disappearance of the raw materials, dichloromethane (200 mL) was added to dilute the reaction solution and water (2×200 mL) was added. The mixture was extracted with dichloromethane (100 mL×3 times), and the organic phases were combined. First washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2,6-dimethylbenzene) (methyl)amino)-3-carbonylpropionate (8.8 g, yellow oil, 72% yield). MS (ESI) M/Z: 396.1 [M+H] ⁺ .

步驟C(Step C)：將溶解在水(60 mL)中的氫氧化鈉(8.957 g, 223.9 mmol)溶液加入到溶解在甲醇(240 mL)中的3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸甲酯(8.8 g, 22.39 mmol)溶液中，室溫條件下攪拌1 小時。液相質譜監測顯示原料消失後，混合溶液用水(200mL)稀釋，然後用稀鹽酸調節水相pH為2。用乙酸乙酯(2×200 mL次)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮，得到3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸(7.7 g，無色油狀物，產率90.7%)。MS (ESI) M/Z：380.0[M+H] ⁺。 Step C (Step C): A solution of sodium hydroxide (8.957 g, 223.9 mmol) dissolved in water (60 mL) was added to 3-((3-bromo-4-fluoro) dissolved in methanol (240 mL). phenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid methyl ester (8.8 g, 22.39 mmol) solution was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry showed the disappearance of the starting material, the mixed solution was diluted with water (200 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2×200 mL times), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 3-((3-bromo-4-fluorophenyl)(2 ,6-Dimethylphenyl)amino)-3-carbonylpropionic acid (7.7 g, colorless oil, 90.7% yield). MS (ESI) M/Z: 380.0 [M+H] ⁺ .

步驟D(Step D)：將3-((3-溴-4-氟苯基)(2,6-二甲基苯基)胺基)-3-羰基丙酸(6.7 g, 17.67 mmol)溶解在Eatons Reagent (伊頓試劑) (40 mL)中並在55℃下攪拌過夜。液相質譜監測顯示原料消失後，向飽和碳酸氫鈉溶液中逐滴加入反應液，並用飽和碳酸氫鈉溶液調節pH為7-8。用二氯甲烷(2×100 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮，得到粗品7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮，(混合物, 6.25 g，白色固體，產率97%)。MS (ESI) M/Z：362.0[M+H] ⁺。 Step D: Dissolve 3-((3-bromo-4-fluorophenyl)(2,6-dimethylphenyl)amino)-3-carbonylpropionic acid (6.7 g, 17.67 mmol) Stir in Eatons Reagent (40 mL) at 55°C overnight. After monitoring by liquid chromatography mass spectrometry showed the disappearance of the starting material, the reaction solution was added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2×100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain crude 7-bromo-1-(2,6-dimethylphenyl) )-6-fluoroquinoline-2,4(1H,3H)-dione, (mixture, 6.25 g, white solid, 97% yield). MS (ESI) M/Z: 362.0 [M+H] ⁺ .

步驟E(Step E)：將7-溴-1-(2,6-二甲基苯基)-6-氟喹啉-2,4(1H,3H)-二酮 (6.25 g, 17.31 mmol)溶解在三氯氧磷(40 mL)中並在90℃下攪拌2小時。液相質譜監測顯示原料消失後，減壓蒸餾除去三氯氧磷，緩慢加入水(20 mL)並用飽和碳酸氫鈉溶液調節溶液pH為7-8。用乙酸乙酯(2×50 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。粗品經矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=3/1)得到7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氫喹啉-2(1H)-二酮(1.02 g，白色固體，產率15.5%)。MS (ESI) M/Z：296.0[M+H] ⁺。 Step E: 7-Bromo-1-(2,6-dimethylphenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (6.25 g, 17.31 mmol) Dissolve in phosphorus oxychloride (40 mL) and stir at 90°C for 2 hours. After LC-MS monitoring showed the disappearance of the raw materials, phosphorus oxychloride was distilled off under reduced pressure, water (20 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 50 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 7-bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro- 3,4-Dihydroquinoline-2(1H)-dione (1.02 g, white solid, 15.5% yield). MS (ESI) M/Z: 296.0 [M+H] ⁺ .

步驟F(Step F)：將7-溴-4-氯-1-(2,6-二甲基苯基)-6-氟-3,4-二氫喹啉-2(1H)-二酮(300 mg, 0.78 mmol)溶解在二氧六環(4.5 mL)中，然後加入哌嗪-1-甲酸第三丁酯(725 mg, 3.9 mmol)和N,N-二異丙基乙胺(603.0 mg, 4.68 mmol)並在110℃下攪拌2天。液相質譜(LCMS)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=5/2)，得到4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(205 mg，白色固體，產率50%)。MS (ESI) M/Z：530.2[M+H] ⁺。 Step F (Step F): 7-Bromo-4-chloro-1-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydroquinoline-2(1H)-dione (300 mg, 0.78 mmol) was dissolved in dioxane (4.5 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (725 mg, 3.9 mmol) and N,N-diisopropylethylamine ( 603.0 mg, 4.68 mmol) and stirred at 110 °C for 2 days. After the monitoring of liquid phase mass spectrometry (LCMS) showed that the raw materials disappeared, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7- Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (205 mg, white solid, 50% yield). MS (ESI) M/Z: 530.2 [M+H] ⁺ .

步驟G(Step G)：將4-(7-溴-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(60 mg, 0.11 mmol)、2-氟-4-甲氧基苯硼酸(96 mg, 0.56 mmol)、醋酸鉀(89 mg, 0.91 mmol)及Pacl2(pddf)(8 mg, 0.01 mmol)溶解在用氬氣置換空氣15分鐘的1,4-二氧六環和水混合溶液(1mL, 4/1)中，再次用氬氣置換空氣，並在60℃下攪拌3天。液相質譜監測顯示原料消失後，用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。粗品經製備純化得到4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(60 mg，淡黃色固體，產率94.8%)。MS (ESI) M/Z：576.2[M+H] ⁺。 Step G (Step G): 4-(7-Bromo-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-dihydroquinolin-4-yl) 3-butyl piperazine-1-carboxylate (60 mg, 0.11 mmol), 2-fluoro-4-methoxyphenylboronic acid (96 mg, 0.56 mmol), potassium acetate (89 mg, 0.91 mmol) and Pacl2 ( pddf) (8 mg, 0.01 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (1 mL, 4/1) replaced with argon for 15 minutes, and the air was replaced with argon again at 60 Stir at °C for 3 days. After LC-MS monitoring showed the disappearance of the starting material, it was extracted twice with ethyl acetate (2×40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was preparatively purified to give 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-carbonyl-1,2- Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (60 mg, pale yellow solid, 94.8% yield). MS (ESI) M/Z: 576.2 [M+H] ⁺ .

步驟H(Step H)：將4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(60 mg, 0.11 mmol)溶解在二氯甲烷(1 mL)中，加入三氟乙酸(0.5 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40 mg，棕色固體，產率76.5%)。MS (ESI) 476.2M/Z：[M+H] ⁺。 Step H (Step H): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , 3-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added and the It was stirred at room temperature for 1 hour. After monitoring by LC-MS showed the disappearance of the raw materials, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until dichloromethane and trifluoroacetic acid were added. was completely removed to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline Lin-2(1H)-one (40 mg, brown solid, 76.5% yield). MS (ESI) 476.2M/Z: [M+H] ⁺ .

步驟I(Step I)：將1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40 mg, 0.084 mmol)溶解在二氯甲烷(1 mL)中，加入DIPEA(N,N-二異丙基乙胺)(21.67 g, 0.168 mmol)和丙烯醯氯(15 mg, 0.168 mmol)，並在室溫下攪拌2小時，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，並將所得固體溶解在N,N-二甲基甲醯胺(5 mL)中製備純化得到4-(4-丙烯醯哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-羥基苯基)喹啉-2(1H)-酮(30.4 mg，白色固體，產率68.4%)。MS (ESI) M/Z：530.2[M+H] ⁺。 ¹H NMR (500 MHz, DMSO) δ 7.74 (d, J= 10.5 Hz, 1H), 7.33 – 7.30 (m, 1H), 7.28 (d, J= 7.0 Hz, 2H), 7.21 (t, J= 8.5 Hz, 1H), 6.96 – 6.84 (m, 3H), 6.34 (d, J= 6.5 Hz, 1H), 6.23 (d, J= 8.5 Hz, 1H), 6.18 (dd, J= 16.5, 2.4 Hz, 1H), 5.75 (dd, J= 10.5, 2.5 Hz, 1H), 3.86 (d, J= 13.0 Hz, 4H), 3.77 (d, J= 10.0 Hz, 3H), 3.19 (s, 4H), 1.88 (d, J= 9.5 Hz, 6H)。 Step I (Step I): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.084 mmol) was dissolved in dichloromethane (1 mL) and DIPEA (N,N-diisopropylethylamine) (21.67 g, 0.168 mmol) was added and acrylyl chloride (15 mg, 0.168 mmol), and stirred at room temperature for 2 hours. After the disappearance of the starting material was detected by liquid phase mass spectrometry, the solvent was removed by concentration under reduced pressure, and the obtained solid was dissolved in N,N-dimethylmethane Preparation and purification in amide (5 mL) to give 4-(4-propenylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro- 6-Hydroxyphenyl)quinolin-2(1H)-one (30.4 mg, white solid, 68.4% yield). MS (ESI) M/Z: 530.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 7.74 (d, J = 10.5 Hz, 1H), 7.33 – 7.30 (m, 1H), 7.28 (d, J = 7.0 Hz, 2H), 7.21 (t, J = 8.5 Hz, 1H), 6.96 – 6.84 (m, 3H), 6.34 (d, J = 6.5 Hz, 1H), 6.23 (d, J = 8.5 Hz, 1H), 6.18 (dd, J = 16.5, 2.4 Hz, 1H ), 5.75 (dd, J = 10.5, 2.5 Hz, 1H), 3.86 (d, J = 13.0 Hz, 4H), 3.77 (d, J = 10.0 Hz, 3H), 3.19 (s, 4H), 1.88 (d , J = 9.5 Hz, 6H).

實施例8：合成 4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氫喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧醯胺

Example 8: Synthesis of 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2- Dihydroquinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide

合成路線：

synthetic route:

步驟A(Step A)：將2-甲氧基乙胺(100 mg, 1.33 mmol) 溶解於二氯甲烷(DCM)(1.5 mL)中，加入N,N-二異丙基乙胺(DIPEA)(344 mg, 2.67 mmol)並在室溫下攪拌0.5小時，加入對硝基苯基氯甲酸酯(320 mg, 1.60 mmol)，在室溫反應1小時，薄層色譜法(TLC)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化(沖提液：石油醚/乙酸乙酯=5/1)，得到4-硝基苯基(2-甲氧基乙基)胺基甲酸酯(200 mg，白色固體，產率62.6%)。MS (ESI) M/Z：241.22[M+H] ⁺。 Step A: 2-Methoxyethylamine (100 mg, 1.33 mmol) was dissolved in dichloromethane (DCM) (1.5 mL) and N,N-diisopropylethylamine (DIPEA) was added (344 mg, 2.67 mmol) and stirred at room temperature for 0.5 hours, added p-nitrophenyl chloroformate (320 mg, 1.60 mmol) and reacted at room temperature for 1 hour, monitoring by thin layer chromatography (TLC) showed After the raw materials disappeared, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 4-nitrophenyl (2-methoxyethyl acetate). (200 mg, white solid, 62.6% yield). MS (ESI) M/Z: 241.22 [M+H] ⁺ .

步驟B(Step B)：將4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(60 mg, 0.11 mmol)溶解在二氯甲烷(1 mL)中，加入三氟乙酸(0.5 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40 mg，淺黃色固體，產率76.5%)。MS (ESI) M/Z：476.2[M+H] ⁺。 Step B (Step B): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , 3-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added and the It was stirred at room temperature for 1 hour. After monitoring by liquid chromatography and mass spectrometry showed the disappearance of the raw materials, the mixture was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid. Dichloromethane (10 mL) was added and concentrated again under reduced pressure until the dichloromethane and trifluoroacetic acid were removed. Complete removal to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline -2(1H)-one (40 mg, pale yellow solid, 76.5% yield). MS (ESI) M/Z: 476.2 [M+H] ⁺ .

步驟C(Step C)：將1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40 mg, 0.11 mmol)溶解於四氫呋喃(THF)(1 mL)中，加入二(三甲基矽基)胺基鉀(KHMDS)(0.52 mL)並在室溫下攪拌0.5小時，加入4-硝基苯基(2-甲氧基乙基)胺基甲酸酯(62 mg, 0.261 mml)，在50℃反應2小時，液相質譜(LCMS)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化(沖提液：二氯甲烷/甲醇=20/1)，得到合成 4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氫喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧醯胺(45 mg，白色固體，產率92.9%)。MS (ESI) M/Z：577.2[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.57 (d, J= 10.5 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J= 7.5 Hz, 2H), 7.13 (t, J= 8.5 Hz, 1H), 6.72 (dd, J= 8.5, 2.5 Hz, 1H), 6.66 (dd, J= 12.0, 2.4 Hz, 1H), 6.54 (d, J= 6.5 Hz, 1H), 6.37 (s, 1H), 4.97 (s, 1H), 3.81 (s, 3H), 3.68 (s, 4H), 3.55 – 3.47 (m, 4H), 3.40 (s, 3H), 3.23 (s, 4H), 2.00 (s, 6H)。 Step C (Step C): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (THF) (1 mL), potassium bis(trimethylsilyl)amide (KHMDS) (0.52 mL) was added and the Stir at room temperature for 0.5 hours, add 4-nitrophenyl(2-methoxyethyl)carbamate (62 mg, 0.261 mml), react at 50 °C for 2 hours, liquid phase mass spectrometry (LCMS) After monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain the synthesis of 4-(1-(2,6-dichloromethane). Methylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-methyl) Oxyethyl)piperazine-1-carboxamide (45 mg, white solid, 92.9% yield). MS (ESI) M/Z: 577.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.57 (d, J = 10.5 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 7.5 Hz, 2H), 7.13 (t, J = 8.5 Hz , 1H), 6.72 (dd, J = 8.5, 2.5 Hz, 1H), 6.66 (dd, J = 12.0, 2.4 Hz, 1H), 6.54 (d, J = 6.5 Hz, 1H), 6.37 (s, 1H) , 4.97 (s, 1H), 3.81 (s, 3H), 3.68 (s, 4H), 3.55 – 3.47 (m, 4H), 3.40 (s, 3H), 3.23 (s, 4H), 2.00 (s, 6H) ).

實施例9：4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-2-氧-1,2-二氫喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧醯胺

Example 9: 4-(1-(2,6-Dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-di Hydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide

合成路線：

synthetic route:

步驟A(Step A)：將1-(2-胺基乙氧基)-2-甲氧基乙烷(130 mg, 1.1 mmol)溶解於二氯甲烷(DCM)(1.5 mL)中，加入N,N-二異丙基乙胺(DIPEA)(284 mg,2.2 mml)並在室溫下攪拌0.5小時，加入對硝基苯基氯甲酸酯（331 mg，1.65 mml），在室溫反應1h，液相質譜(LCMS)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化（沖提液：石油醚/乙酸乙酯=5/1）得到4-硝基苯基（2-（2-甲氧基乙氧基）乙基）胺基甲酸酯（250 mg，白色固體，產率80.0%）。MS (ESI) M/Z：285.1[M+H] ⁺。 Step A: Dissolve 1-(2-aminoethoxy)-2-methoxyethane (130 mg, 1.1 mmol) in dichloromethane (DCM) (1.5 mL), add N , N-diisopropylethylamine (DIPEA) (284 mg, 2.2 mml) and stirred at room temperature for 0.5 hours, added p-nitrophenyl chloroformate (331 mg, 1.65 mml), and reacted at room temperature After 1 h, liquid phase mass spectrometry (LCMS) monitoring showed that the raw materials disappeared, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 4-nitro Phenyl (2-(2-methoxyethoxy)ethyl)carbamate (250 mg, white solid, 80.0% yield). MS (ESI) M/Z: 285.1 [M+H] ⁺ .

步驟B（Step B）：將4-(1-(2,6-二甲基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(60 mg, 0.11 mmol)溶解在二氯甲烷(1 mL)中並加入三氟乙酸(0.5 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL) 再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮（40 mg，淺黃色固體，產率76.5%）。MS (ESI) M/Z：476.2[M+H] ⁺。 Step B (Step B): 4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-2-carbonyl-1 , 3-butyl 2-dihydroquinolin-4-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and the It was stirred at room temperature for 1 hour. After monitoring by LC-MS showed the disappearance of the raw materials, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added and concentrated again under reduced pressure until dichloromethane and trifluoroacetic acid were added. was completely removed to give 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazin-1-yl)quinoline Lin-2(1H)-one (40 mg, pale yellow solid, 76.5% yield). MS (ESI) M/Z: 476.2 [M+H] ⁺ .

步驟C（Step C）：將1-(2,6-二甲基苯基)-6-氟-7-(2-氟-4-甲氧基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(40 mg, 0.11 mmol) 溶解四氫呋喃(THF)(1 mL)中並加入二(三甲基矽基)胺基鉀(KHMDS)(0.52 mL) 並在室溫下攪拌0.5小時，加入4-硝基苯基（2-（2-甲氧基乙氧基）乙基）胺基甲酸酯（93.72 mg，0.33 mml），在50℃反應2h，液相質譜(LCMS)監測顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化（沖提液：二氯甲烷/甲醇=20/1）得到合成4-（1-（2,6-二甲基苯基）-6-氟-7-（2-氟-4-甲氧基苯基）-2-氧-1,2-二氫喹啉-4-基）-N-（2-（ 2-甲氧基乙氧基）乙基）哌嗪-1-羧醯胺（42 mg，白色固體，產率61.5%）。MS (ESI) M/Z：621.2[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.57 (d, J= 10.5 Hz, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.22 (d, J= 7.6 Hz, 2H), 7.13 (t, J= 8.3 Hz, 1H), 6.72 (dd, J= 8.6, 2.4 Hz, 1H), 6.66 (dd, J= 11.9, 2.4 Hz, 1H), 6.53 (d, J= 6.2 Hz, 1H), 6.34 (s, 1H), 5.21 (t, J= 5.3 Hz, 1H), 3.81 (s, 3H), 3.70 – 3.65 (m, 6H), 3.64 – 3.62 (m, 2H), 3.59 – 3.56 (m, 2H), 3.52 – 3.49 (m, 2H), 3.41 (s, 3H), 3.22 (d, J= 4.5 Hz, 4H), 2.00 (s, 6H)。 Step C (Step C): 1-(2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-4-(piperazine-1- yl)quinolin-2(1H)-one (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (THF) (1 mL) and potassium bis(trimethylsilyl)amide (KHMDS) (0.52 mL) was added and added to Stir at room temperature for 0.5 hours, add 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (93.72 mg, 0.33 mml), and react at 50 °C for 2 h, the liquid Phase mass spectrometry (LCMS) monitoring showed that the raw materials disappeared, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain the synthesis of 4-(1-(2 ,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)-N- (2-(2-Methoxyethoxy)ethyl)piperazine-1-carboxamide (42 mg, white solid, 61.5% yield). MS (ESI) M/Z: 621.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.57 (d, J = 10.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.13 (t , J = 8.3 Hz, 1H), 6.72 (dd, J = 8.6, 2.4 Hz, 1H), 6.66 (dd, J = 11.9, 2.4 Hz, 1H), 6.53 (d, J = 6.2 Hz, 1H), 6.34 (s, 1H), 5.21 (t, J = 5.3 Hz, 1H), 3.81 (s, 3H), 3.70 – 3.65 (m, 6H), 3.64 – 3.62 (m, 2H), 3.59 – 3.56 (m, 2H) ), 3.52 – 3.49 (m, 2H), 3.41 (s, 3H), 3.22 (d, J = 4.5 Hz, 4H), 2.00 (s, 6H).

實施例10：合成4-(4-丙烯醯基哌嗪-1-基)-6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基）喹啉-2(1H)-酮

Example 10: Synthesis of 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylbenzene yl)quinolin-2(1H)-one

步驟A（Step A）：將2-溴-1-氟-4-碘苯 (10 g, 33.23 mmol)溶解在無水甲苯(110 mL)中，然後加入2-異丙基苯胺 (5.39 g, 39.86 mmol)、Pd(OAC) ₂(醋酸鈀，0.75 g，3.34 mmol)、BINAP(1,1'-聯萘-2,2'-雙二苯膦, 2.07 g, 3.34mmol)和碳酸銫(16.24 g, 49.72mmol)。反應液在氮氣保護下回流過夜。液相質譜顯示原料消失後，用乙酸乙酯洗滌反應溶液，減壓濃縮。所得殘餘物用矽膠柱層析純化（沖提液：石油醚/乙酸乙酯=10/1）得到N-(3-溴-4-氟苯基)-2-異丙基苯胺（9.6g，黃色油狀物，產率93.75%）。MS (ESI) M/Z：308.2[M+H] ⁺。 Step A (Step A): Dissolve 2-bromo-1-fluoro-4-iodobenzene (10 g, 33.23 mmol) in dry toluene (110 mL), then add 2-isopropylaniline (5.39 g, 39.86 mmol), Pd(OAC) ₂ (palladium acetate, 0.75 g, 3.34 mmol), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2.07 g, 3.34 mmol) and cesium carbonate (16.24 mmol) g, 49.72 mmol). The reaction solution was refluxed overnight under nitrogen protection. After the disappearance of the starting material by liquid phase mass spectrometry, the reaction solution was washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6 g, Yellow oil, 93.75% yield). MS (ESI) M/Z: 308.2 [M+H] ⁺ .

步驟B（Step B）：將N-(3-溴-4-氟苯基)-2-異丙基苯胺 (9.6g,31.15mmol) 和3-氯-3-氧代丙酸甲酯 (8.5g,62.26mmol) 溶解在二氯甲烷 (100 mL)中, 然後在室溫下1 小時內緩慢的滴加三乙胺(6.3g, 62.26mmol) 並攪拌30 分鐘。液相質譜監測顯示原料消失後，加入二氯甲烷(100mL) 稀釋反應液並加入水（100 mL）, 混合液用二氯甲烷(80 mL×3次)萃取，合併有機相，有機相先用飽和食鹽水(80 mL×3次)洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（沖提液：石油醚/乙酸乙酯=3/1）得到3-((3-溴-4-氟苯基)(2-異丙基苯基)胺基)-3-羰基丙酸甲酯（11.2 g, 白色固體，產率88.2%）。MS (ESI) M/Z：408.3[M+H] ⁺。 Step B (Step B): N-(3-bromo-4-fluorophenyl)-2-isopropylaniline (9.6g, 31.15mmol) and methyl 3-chloro-3-oxopropionate (8.5 g, 62.26 mmol) was dissolved in dichloromethane (100 mL), then triethylamine (6.3 g, 62.26 mmol) was slowly added dropwise over 1 hour at room temperature and stirred for 30 minutes. LC-MS monitoring showed that the raw materials disappeared, dichloromethane (100 mL) was added to dilute the reaction solution and water (100 mL) was added. The mixture was extracted with dichloromethane (80 mL×3 times), and the organic phases were combined. Washed with saturated brine (80 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amine (11.2 g, white solid, 88.2% yield). MS (ESI) M/Z: 408.3 [M+H] ⁺ .

步驟C（Step C）：將56mL 2N氫氧化鈉加入到溶解在甲醇(110mL)中的3-((3-溴-4-氟苯基)(2-異丙基苯基)胺基)-3-羰基丙酸甲酯 (11.2 g, 27.47mmol) 溶液中，室溫條件下攪拌1 小時。液相質譜(LCMS)監測顯示原料消失後，混合溶液用水 (100mL)稀釋，然後用稀鹽酸調節水相pH為2。用乙酸乙酯(2×100 mL)萃取兩次，有機層用鹽水清洗，Na ₂SO ₄乾燥，過濾，最後減壓濃縮。得到3-((3-溴-4-氟苯基)(2-異丙基苯基)胺基)-3-氧丙酸 (9.8g，淡黃色固體，產率90.74%)。MS (ESI) M/Z：394.2[M+H] ⁺。 Step C: 56 mL of 2N sodium hydroxide was added to 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)- A solution of methyl 3-carbonylpropionate (11.2 g, 27.47 mmol) was stirred at room temperature for 1 hour. After monitoring by liquid phase mass spectrometry (LCMS) showed the disappearance of the starting material, the mixed solution was diluted with water (100 mL), and then the pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid. Extracted twice with ethyl acetate (2 x 100 mL), the organic layer was washed with brine, dried _over _Na2SO4 , filtered, and finally concentrated under reduced pressure. 3-((3-Bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionic acid (9.8 g, pale yellow solid, 90.74% yield) was obtained. MS (ESI) M/Z: 394.2 [M+H] ⁺ .

步驟D（Step D）：將3-((3-溴-4-氟苯基)(2-異丙基苯基)胺基)-3-氧丙酸(9.8g，24.86mmol) 溶解在 Eatons Reagent（伊頓試劑） (70 mL)中並在70 ^oC下攪拌過夜。液相質譜監測顯示原料消失後，向飽和的碳酸氫鈉溶液中逐滴緩慢加入反應液並用飽和碳酸氫鈉溶液調節pH為7-8。用二氯甲烷(2×100 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。得到7-溴-6-氟-1-(2-異丙基苯基)喹啉-2,4(1H,3H)-二酮（7.3g, 白色固體，產率78.07%）。MS (ESI) M/Z：376.2[M+H] ⁺。 Step D (Step D): Dissolve 3-((3-bromo-4-fluorophenyl)(2-isopropylphenyl)amino)-3-oxopropionic acid (9.8 g, 24.86 mmol) in Eatons Reagent (70 mL) and stirred at 70 ^° C overnight. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was slowly added dropwise to the saturated sodium bicarbonate solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with dichloromethane (2 x 100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 7-Bromo-6-fluoro-1-(2-isopropylphenyl)quinoline-2,4(1H,3H)-dione (7.3 g, white solid, 78.07% yield) was obtained. MS (ESI) M/Z: 376.2 [M+H] ⁺ .

步驟E（Step E）：將7-溴-6-氟-1-(2-異丙基苯基)喹啉-2,4(1H,3H)-二酮 (7.3g,19.40 mmol) 溶解在三氯氧磷（45 mL）中並在80 ^oC下攪拌6小時。液相質譜顯示原料消失後，減壓蒸餾除去三氯氧磷，緩慢加入水(40 mL)並用飽和碳酸氫鈉溶液調節溶液pH為7-8。用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。得到固體用N,N-二甲基甲醯胺溶解並製備得到7-溴-4-氯-6-氟-1-(2-異丙基苯基)喹啉-2(1H)-酮（2.4g,淡黃色固體，產率36.32%）。MS (ESI) M/Z：394.7[M+H] ⁺。 Step E (Step E): Dissolve 7-bromo-6-fluoro-1-(2-isopropylphenyl)quinoline-2,4(1H,3H)-dione (7.3 g, 19.40 mmol) in Phosphorus oxychloride (45 mL) and stirred at 80 ^o C for 6 hours. After the disappearance of the starting material by liquid chromatography mass spectrometry, phosphorus oxychloride was distilled off under reduced pressure, water (40 mL) was slowly added, and the pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. Extracted twice with ethyl acetate (2 x 40 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained solid was dissolved with N,N-dimethylformamide and prepared to obtain 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one ( 2.4 g, pale yellow solid, 36.32% yield). MS (ESI) M/Z: 394.7 [M+H] ⁺ .

步驟F（Step F）：將7-溴-4-氯-6-氟-1-(2-異丙基苯基)喹啉-2(1H)-酮 (2.4 g,6.08 mmol) 溶解在二氧六環（20 mL）中，然後加入哌嗪-1-甲酸第三丁酯 ( 5.65g, 30.38mmol) 和 N,N-二異丙基乙胺(4.72 g,36.52 mmol) 並在 110 ^oC下攪拌2天。液相質譜顯示原料消失後，減壓蒸餾除去溶劑，所得殘餘物用矽膠柱層析純化（沖提液：石油醚/乙酸乙酯=5/2）得到4-(7-溴-6-氟-1-(2-異丙基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯（ 2.9 g，白色固體，產率87.88%）。MS (ESI) M/Z：544.5[M+H] ⁺。 Step F (Step F): Dissolve 7-bromo-4-chloro-6-fluoro-1-(2-isopropylphenyl)quinolin-2(1H)-one (2.4 g, 6.08 mmol) in 2 oxane (20 mL), then 3-butyl piperazine-1-carboxylate (5.65 g, 30.38 mmol) and N,N-diisopropylethylamine (4.72 g, 36.52 mmol) were added and mixed at 110 ^o Stir at C for 2 days. After the disappearance of the starting material was shown by liquid phase mass spectrometry, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/2) to obtain 4-(7-bromo-6-fluoro). -1-(2-Isopropylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (2.9 g, white solid, yield 87.88%). MS (ESI) M/Z: 544.5 [M+H] ⁺ .

步驟G（Step G）：將4-(7-溴-6-氟-1-(2-異丙基苯基)-2-羰基-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.500 g, 0.918mmol)、（2-氟-4-甲氧基苯基）硼酸(0.624 g, 3.6717 mmol)、醋酸鉀 (0.54g, 3.923 mmol)和 PdCl ₂(dppf)1,1'-雙二苯基膦二茂鐵二氯化鈀(0.134 g, 0.183 mmol)混合物溶解在用氬氣置換空氣15 分鐘的1,4-二氧六環和水混合溶液(8 mL/2 mL)中，再次用氬氣置換空氣，並在90°C 下攪拌48h，液相質譜顯示原料消失後，用乙酸乙酯(2×40 mL)萃取兩次，有機層用鹽水清洗，無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（沖提液：石油醚/乙酸乙酯=10/1）得到4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-（2-異丙基苯基）-2-氧-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯（0.340 g,淡黃色固體，產率80.3%）。MS (ESI) M/Z：589.7[M+H] ⁺。 Step G (Step G): 4-(7-Bromo-6-fluoro-1-(2-isopropylphenyl)-2-carbonyl-1,2-dihydroquinolin-4-yl)piperazine - 3-butyl 1-carboxylate (0.500 g, 0.918 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (0.624 g, 3.6717 mmol), potassium acetate (0.54 g, 3.923 mmol) and PdCl A mixture of ₂ (dppf)1,1'-bisdiphenylphosphinoferrocene palladium dichloride (0.134 g, 0.183 mmol) was dissolved in 1,4-dioxane and water mixed with argon replacing the air for 15 minutes In the solution (8 mL/2 mL), the air was replaced with argon again, and stirred at 90 ° C for 48 h. After the liquid phase mass spectrometry showed that the raw material disappeared, it was extracted twice with ethyl acetate (2 × 40 mL), and the organic layer was Washed with brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1 -(2-Isopropylphenyl)-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, pale yellow solid, yield 80.3 %). MS (ESI) M/Z: 589.7 [M+H] ⁺ .

步驟H（Step H）：將4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-（2-異丙基苯基）-2-氧-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.340 g, 0.577 mmol) 溶解在二氯甲烷(6 mL)中並加入三氟乙酸(3 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮 (0.281 g，棕色固體，產率99.6%)。MS (ESI) M/Z：489.6[M+H] ⁺。 Step H (Step H): 4-(6-Fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2 - Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.340 g, 0.577 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and in room Stir at warm temperature for 1 hour, after liquid chromatography monitoring showed the disappearance of the raw materials, concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, and add dichloromethane (10 mL) and concentrate again under reduced pressure until dichloromethane and trifluoroacetic acid are completely Removal gave 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinoline-2( 1H)-one (0.281 g, brown solid, 99.6% yield). MS (ESI) M/Z: 489.6 [M+H] ⁺ .

步驟I（Step I）：將6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.281 g, 0.574 mmol) 溶解在二氯甲烷(10 mL) 中並加入DIPEA(N,N-二異丙基乙胺)(0.371 g,2.87 mmol)和丙烯醯氯(0.104g，1.15mmol)並在室溫下攪拌2小時，液相質譜(LCMS)監測顯示原料消失後，減壓濃縮除去溶劑並將所得固體溶解在N,N-二甲基甲醯胺（5 mL）中送製備得到4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)喹啉-2(1H)-酮（0.0562 g, 白色固體，產率17.95%）。MS (ESI) M/Z：543.6[M+H] ⁺。 ¹H NMR (500 MHz, DMSO) δ 7.74 (dd, J= 7.9, 1.3 Hz, 1H), 7.51 (dd, J= 7.7, 1.2 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.30 (dd, J= 16.7, 8.4 Hz, 2H), 7.19 (dd, J= 6.5, 2.3 Hz, 1H), 6.96 (dd, J= 12.2, 2.4 Hz, 1H), 6.87 (ddd, J= 20.9, 10.8, 6.5 Hz, 2H), 6.16 (dd, J= 16.7, 2.3 Hz, 1H), 6.03 (s, 1H), 5.76 – 5.71 (m, 1H), 3.82 (s, 2H), 3.81 (s, 3H), 3.11 (s, 5H), 2.62 – 2.53 (m, 1H), 1.25 (d, J= 11.9 Hz, 1H), 0.84 (d, J= 6.6 Hz, 6H)。 Step I (Step I): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.281 g, 0.574 mmol) was dissolved in dichloromethane (10 mL) and DIPEA (N,N-diisopropylethylamine) (0.371 g, 2.87 mmol) and propylene were added Chloride (0.104 g, 1.15 mmol) was stirred at room temperature for 2 hours. After monitoring by liquid phase mass spectrometry (LCMS) showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the resulting solid was dissolved in N,N-dimethylformamide The amine (5 mL) was sent to prepare 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-iso Propylphenyl)quinolin-2(1H)-one (0.0562 g, white solid, 17.95% yield). MS (ESI) M/Z: 543.6 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 7.74 (dd, J = 7.9, 1.3 Hz, 1H), 7.51 (dd, J = 7.7, 1.2 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.30 (dd , J = 16.7, 8.4 Hz, 2H), 7.19 (dd, J = 6.5, 2.3 Hz, 1H), 6.96 (dd, J = 12.2, 2.4 Hz, 1H), 6.87 (ddd, J = 20.9, 10.8, 6.5 Hz, 2H), 6.16 (dd, J = 16.7, 2.3 Hz, 1H), 6.03 (s, 1H), 5.76 – 5.71 (m, 1H), 3.82 (s, 2H), 3.81 (s, 3H), 3.11 (s, 5H), 2.62 – 2.53 (m, 1H), 1.25 (d, J = 11.9 Hz, 1H), 0.84 (d, J = 6.6 Hz, 6H).

實施例11：合成4-(6-氟-7-(2-氟-4-甲氧基苯基)-7-(2-異丙基苯基)-2-氧-1,2-二氫喹啉-4-基)-N-(2-甲氧基乙基)哌嗪-1-羧醯胺

Example 11: Synthesis of 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-7-(2-isopropylphenyl)-2-oxo-1,2-dihydro Quinolin-4-yl)-N-(2-methoxyethyl)piperazine-1-carboxamide

合成路線：

synthetic route:

步驟A（Step A）:將2-甲氧基乙胺（0.2g，2.66 mmol）溶解在四氫呋喃(THF)(3 mL)中並加入DIPEA(N,N-二異丙基乙胺)(0.688 g,5.32 mmol)在冰浴下攪拌10分鐘，緩慢加入4-硝基苯基碳醯氯(0.805 g,3.99 mmol)自然升至室溫攪拌2h，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，製備得到4-硝基苯基（2-甲氧基乙基）胺基甲酸酯(0.487 g，黃色油狀物，產率93.8%)。MS (ESI) M/Z：240.2[M+H] ⁺。 Step A: Dissolve 2-methoxyethylamine (0.2 g, 2.66 mmol) in tetrahydrofuran (THF) (3 mL) and add DIPEA (N,N-diisopropylethylamine) (0.688 g, 5.32 mmol) was stirred under an ice bath for 10 minutes, slowly added 4-nitrophenylcarbohydride chloride (0.805 g, 3.99 mmol), and the temperature was naturally raised to room temperature and stirred for 2 h. Concentration to remove the solvent gave 4-nitrophenyl(2-methoxyethyl)carbamate (0.487 g, yellow oil, 93.8% yield). MS (ESI) M/Z: 240.2 [M+H] ⁺ .

步驟B（Step B）:將4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-)2-異丙基苯基）-2-氧-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.3 g, 0.509mmol) 溶解在二氯甲烷(6 mL)中並加入三氟乙酸(3 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮 (0.248 g，棕色固體，產率99.6%)。MS (ESI) M/Z：489.6[M+H] ⁺。 Step B (Step B): 4-(6-Fluoro-7-(2-Fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 - Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and in room Stir at warm temperature for 1 hour, after liquid chromatography monitoring showed the disappearance of the raw materials, concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, and add dichloromethane (10 mL) and concentrate again under reduced pressure until dichloromethane and trifluoroacetic acid are completely Removal gave 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinoline-2( 1H)-one (0.248 g, brown solid, 99.6% yield). MS (ESI) M/Z: 489.6 [M+H] ⁺ .

步驟C（Step C）:將6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248g，0.506mmol) 溶解在二氯甲烷(4 mL)中並加入4-硝基苯基（2-甲氧基乙基）胺基甲酸酯(0.243g，1.01mmol)，在冰浴下緩慢加入1M的KHMDS(二(三甲基矽基)胺基鉀)(2 mL)，撤去冰浴在65°C下攪拌12h，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，製備得到4-(6-氟-7-(2-氟-4-甲氧基苯基)-7-(2-異丙基苯基)-2-氧-1,2-二氫喹啉-4-基)-N-(-甲氧基乙基)哌嗪-1-羧醯胺(0.0367 g，淡黃色固體，產率12.3%)。MS (ESI) M/Z：590.7[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.60 (d, J= 7.9 Hz, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.18 – 7.15 (m, 2H), 7.09 (d, J= 6.0 Hz, 1H), 6.67 (d, J= 8.6 Hz, 1H), 6.61 (d, J= 11.7 Hz, 1H), 6.08 (s, 1H), 4.88 (s, 1H), 3.75 (d, J= 1.8 Hz, 3H), 3.56 (s, 3H), 3.42 (d, J= 9.8 Hz, 5H), 3.31 (d, J= 1.7 Hz, 3H), 3.09 (s, 4H), 2.55 (d, J= 6.5 Hz, 1H), 0.82 (d, J= 6.4 Hz, 6H)。 Step C (Step C): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl(2-methoxyethyl)carbamate (0.243 g, 1.01 mmol), slowly added 1M KHMDS (potassium bis(trimethylsilyl)amide) (2 mL) under ice bath, removed ice bath and stirred at 65 ° C for 12 h, LC-MS monitoring showed the raw material After disappearing, the solvent was removed by concentration under reduced pressure to prepare 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-7-(2-isopropylphenyl)-2-oxo- 1,2-Dihydroquinolin-4-yl)-N-(-methoxyethyl)piperazine-1-carboxamide (0.0367 g, pale yellow solid, 12.3% yield). MS (ESI) M/Z: 590.7 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.18 – 7.15 (m, 2H), 7.09 (d, J = 6.0 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 11.7 Hz, 1H), 6.08 (s, 1H) , 4.88 (s, 1H), 3.75 (d, J = 1.8 Hz, 3H), 3.56 (s, 3H), 3.42 (d, J = 9.8 Hz, 5H), 3.31 (d, J = 1.7 Hz, 3H) , 3.09 (s, 4H), 2.55 (d, J = 6.5 Hz, 1H), 0.82 (d, J = 6.4 Hz, 6H).

實施例12：合成4-(6-氟-7-)2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-2-氧代-1,2-二氫喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧醯胺

Example 12: Synthesis of 4-(6-fluoro-7-)2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-di Hydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide

合成路線：

synthetic route:

步驟A（Step A）:將2-(2-甲氧基乙氧基）乙胺（0.2g，1.68mmol）溶解在THF(四氫呋喃)(3 mL)中並加入DIPEA(N,N-二異丙基乙胺)(434g, 3.36mmol)在冰浴下攪拌10分鐘，緩慢加入4-硝基苯基碳醯氯(0.507g,2.51 mmol)自然升至室溫攪拌2h，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，製備得到4-硝基苯基(2-(2-甲氧基乙氧基)乙基)胺基甲酸酯(0.419 g，黃色油狀物，產率88.2%)。MS (ESI) M/Z：284.3[M+H] ⁺。 Step A (Step A): 2-(2-Methoxyethoxy)ethanamine (0.2 g, 1.68 mmol) was dissolved in THF (tetrahydrofuran) (3 mL) and DIPEA (N,N-diiso) was added Propylethylamine) (434g, 3.36mmol) was stirred under ice bath for 10 minutes, and 4-nitrophenylcarbohydride chloride (0.507g, 2.51 mmol) was slowly added to the room temperature and stirred for 2h. Liquid phase mass spectrometry monitoring showed that After the raw materials disappeared, the solvent was removed by concentration under reduced pressure to prepare 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (0.419 g, yellow oil, yield) 88.2%). MS (ESI) M/Z: 284.3 [M+H] ⁺ .

步驟C（Step C）:將6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.248g，0.506mmol) 溶解在二氯甲烷(4 mL)中並加入4-硝基苯基(2-(2-甲氧基乙氧基)乙基)胺基甲酸酯(0.216g，0.76mmol)，在冰浴下緩慢加入1M的KHMDS(二(三甲基矽基)胺基鉀)(2 mL)，撤去冰浴在65°C下攪拌12h，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，製備得到4-(6-氟-7-)2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-2-氧代-1,2-二氫喹啉-4-基)-N-(2-(2-甲氧基乙氧基)乙基)哌嗪-1-羧醯胺(0. 0416 g，淡黃色固體，產率13.1%)。MS (ESI) M/Z：634.7[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.61 (d, J= 7.7 Hz, 1H), 7.36 (d, J= 7.5 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.21 (d, J= 8.9 Hz, 1H), 7.18 (s, 1H), 7.17 – 7.14 (m, 1H), 7.10 (d, J= 4.1 Hz, 1H), 6.67 (dd, J= 8.5, 2.1 Hz, 1H), 6.65 – 6.59 (m, 1H), 6.08 (s, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 3.56 (dt, J= 9.9, 4.6 Hz, 8H), 3.52 – 3.48 (m, 2H), 3.42 (s, 2H), 3.33 (s, 3H), 3.09 (s, 4H), 2.56 (dt, J= 13.0, 6.5 Hz, 1H), 0.82 (d, J= 6.5 Hz, 6H)。 Step C (Step C): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl) Quinolin-2(1H)-one (0.248 g, 0.506 mmol) was dissolved in dichloromethane (4 mL) and 4-nitrophenyl (2-(2-methoxyethoxy)ethyl) was added Carbamate (0.216g, 0.76mmol), slowly add 1M KHMDS (potassium bis(trimethylsilyl)amide) (2 mL) under ice bath, remove ice bath and stir at 65°C for 12h , LC-MS monitoring showed the disappearance of the raw materials, and then concentrated under reduced pressure to remove the solvent to prepare 4-(6-fluoro-7-)2-fluoro-4-methoxyphenyl)-1-(2-isopropylbenzene) yl)-2-oxo-1,2-dihydroquinolin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)piperazine-1-carboxamide (0 .0416 g, pale yellow solid, 13.1% yield). MS (ESI) M/Z: 634.7 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.17 – 7.14 (m, 1H), 7.10 (d, J = 4.1 Hz, 1H), 6.67 (dd, J = 8.5, 2.1 Hz, 1H), 6.65 – 6.59 (m, 1H), 6.08 (s, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 3.56 (dt, J = 9.9, 4.6 Hz, 8H), 3.52 – 3.48 (m, 2H) , 3.42 (s, 2H), 3.33 (s, 3H), 3.09 (s, 4H), 2.56 (dt, J = 13.0, 6.5 Hz, 1H), 0.82 (d, J = 6.5 Hz, 6H).

實施例13：合成6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(4-(3-(2-甲氧基乙氧基)丙醯基)哌嗪-1-基)喹啉-2(1H)-酮

Example 13: Synthesis of 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(4-(3-(2-methoxyphenyl) ethoxy)propionyl)piperazin-1-yl)quinolin-2(1H)-one

合成路線：

synthetic route:

步驟B（Step B）:將4-(6-氟-7-(2-氟-4-甲氧基苯基)-1-)2-異丙基苯基）-2-氧-1,2-二氫喹啉-4-基)哌嗪-1-羧酸第三丁酯(0.3 g, 0.509mmol) 溶解在二氯甲烷(6 mL)中並加入三氟乙酸(3 mL)並在室溫下攪拌1小時，液相質譜監測顯示原料消失後，減壓濃縮除去二氯甲烷和三氟乙酸，並加入二氯甲烷(10 mL)再次減壓濃縮直至二氯甲烷和三氟乙酸被完全除去，得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮 (0.228 g，棕色固體，產率91.6%)。MS (ESI) M/Z：489.6[M+H] ⁺。 Step B (Step B): 4-(6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-)2-isopropylphenyl)-2-oxo-1,2 - Dihydroquinolin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.3 g, 0.509 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added and in room Stir at warm temperature for 1 hour, after liquid chromatography monitoring showed the disappearance of the raw materials, concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, and add dichloromethane (10 mL) and concentrate again under reduced pressure until dichloromethane and trifluoroacetic acid are completely Removal to give 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinoline-2( 1H)-one (0.228 g, brown solid, 91.6% yield). MS (ESI) M/Z: 489.6 [M+H] ⁺ .

步驟C（StepC）:將6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(哌嗪-1-基)喹啉-2(1H)-酮(0.228 g，0.466 mmol) 溶解在二氯甲烷(4 mL)中並加入3-（2-甲氧基乙氧基）丙酸(0.103 g，0.695 mmol)和三乙胺(0.118 g，1.15 mmol），再加入BOP試劑(苯并三氮唑-1-基氧基三(二甲胺基)磷鎓六氟磷酸鹽)(0.226g，0.512mmol)在室溫下攪拌12h，液相質譜監測顯示原料消失後，減壓濃縮除去溶劑，製備得到6-氟-7-(2-氟-4-甲氧基苯基)-1-(2-異丙基苯基)-4-(4-(3-(2-甲氧基乙氧基)丙醯基)哌嗪-1-基)喹啉-2(1H)-酮(0. 0386 g，淡黃色固體，產率12.2%)。MS (ESI) M/Z：619.7[M+H] ⁺。 ¹H NMR (500 MHz, CDCl ₃) δ 7.60 (dd, J= 7.9, 1.4 Hz, 1H), 7.37 (dd, J= 7.7, 1.3 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 7.16 (d, J= 8.8 Hz, 1H), 7.10 (dd, J= 6.4, 2.3 Hz, 1H), 6.67 (dd, J= 8.5, 2.5 Hz, 1H), 6.62 (dd, J= 11.7, 2.4 Hz, 1H), 6.09 (s, 1H), 3.78 (d, J= 6.6 Hz, 2H), 3.76 – 3.74 (m, 3H), 3.73 – 3.66 (m, 3H), 3.61 – 3.55 (m, 3H), 3.48 (dt, J= 4.3, 3.1 Hz, 3H), 3.32 (d, J= 3.3 Hz, 3H), 3.09 (s, 4H), 2.66 (t, J= 6.6 Hz, 2H), 2.62 – 2.51 (m, 2H), 0.82 (d, J= 6.7 Hz, 6H)。 Step C (StepC): 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinoline Lin-2(1H)-one (0.228 g, 0.466 mmol) was dissolved in dichloromethane (4 mL) and 3-(2-methoxyethoxy)propionic acid (0.103 g, 0.695 mmol) and trichloromethane were added Ethylamine (0.118 g, 1.15 mmol) followed by BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) (0.226 g, 0.512 mmol) at room temperature The mixture was stirred for 12 h under low pressure. After monitoring by liquid phase mass spectrometry showed the disappearance of the raw materials, the solvent was removed by concentration under reduced pressure to prepare 6-fluoro-7-(2-fluoro-4-methoxyphenyl)-1-(2-isopropylbenzene) base)-4-(4-(3-(2-methoxyethoxy)propionyl)piperazin-1-yl)quinolin-2(1H)-one (0.0386 g, pale yellow solid , the yield is 12.2%). MS (ESI) M/Z: 619.7 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.20 ( s, 1H), 7.18 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 6.4, 2.3 Hz, 1H), 6.67 (dd, J = 8.5, 2.5 Hz, 1H) ), 6.62 (dd, J = 11.7, 2.4 Hz, 1H), 6.09 (s, 1H), 3.78 (d, J = 6.6 Hz, 2H), 3.76 – 3.74 (m, 3H), 3.73 – 3.66 (m, 3H), 3.61 – 3.55 (m, 3H), 3.48 (dt, J = 4.3, 3.1 Hz, 3H), 3.32 (d, J = 3.3 Hz, 3H), 3.09 (s, 4H), 2.66 (t, J = 6.6 Hz, 2H), 2.62 – 2.51 (m, 2H), 0.82 (d, J = 6.7 Hz, 6H).

實施例14：合成6-氟-7-(2-氟-6-羥基-苯基)-1-(2-異丙基-4-甲基-3-吡啶基)-4-[(3S)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮

Example 14: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)-4-[(3S) -3-Methyl-4-prop-2-enyl-piperazin-1-yl]quinolin-2-one

步驟A（Step A）:將2-異丙基-4-甲基-吡啶-3-胺（2g，13.3mmol）、醋酸鈀(147.8 mg, 0.66 mmol)、BINAP(808 mg, 1.3 mmol)和碳酸銫(8.6 g, 26.6 mmol)加入到甲苯中（30ml）置換氮氣三次在110℃下攪拌過夜，質譜監測反應完全後旋乾溶劑，柱層析純化得到N-(3-溴-4-氟苯基)-2-異丙基-4-甲基吡啶-3-胺(2.8g，8.7mmol，產率65%) 。MS (ESI) M/Z：323.3[M+H] ⁺。 Step A (Step A): Combine 2-isopropyl-4-methyl-pyridin-3-amine (2 g, 13.3 mmol), palladium acetate (147.8 mg, 0.66 mmol), BINAP (808 mg, 1.3 mmol) and Cesium carbonate (8.6 g, 26.6 mmol) was added to toluene (30 ml) to replace nitrogen three times and stirred overnight at 110 °C. After the reaction was completed by mass spectrometry, the solvent was spin-dried and purified by column chromatography to obtain N-(3-bromo-4-fluoro. Phenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8 g, 8.7 mmol, 65% yield). MS (ESI) M/Z: 323.3 [M+H] ⁺ .

步驟B（Step B）將N-(3-溴-4-氟苯基)-2-異丙基-4-甲基吡啶-3-胺(2.8g，8.7mmol)用二氯乙烷（30ml）溶解，向溶液中滴入3-氯-3-氧代丙酸甲酯（2.4g，17.4）在70攝氏度下攪拌過夜，冷卻至室溫，用碳酸鈉飽和溶液洗滌，乙酸乙酯萃取，乾燥旋乾有機相得到3-(3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-氧代丙酸甲酯（4g粗品）。MS (ESI) M/Z：423.4[M+H] ⁺。 Step B (Step B) N-(3-bromo-4-fluorophenyl)-2-isopropyl-4-methylpyridin-3-amine (2.8g, 8.7mmol) was dissolved in dichloroethane (30ml) ) was dissolved, and methyl 3-chloro-3-oxopropionate (2.4g, 17.4) was added dropwise to the solution, stirred at 70 degrees Celsius overnight, cooled to room temperature, washed with saturated sodium carbonate solution, extracted with ethyl acetate, The organic phase was dried and spin-dried to obtain methyl 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionate (4 g Crude). MS (ESI) M/Z: 423.4 [M+H] ⁺ .

步驟C（Step C）：將3-(3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-氧代丙酸甲酯（3g，7mmol）用甲醇（5ml）溶解向溶液中滴加2M氫氧化鈉溶液（10ml）攪拌1小時薄層色譜(TLC)監測，反應完全後用2M鹽酸溶液將pH調至中性，旋乾溶劑，用flash(反相色譜柱)（乙腈/水）純化得到3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-氧代丙酸（2g，5mmol）。MS (ESI) M/Z：409.5[M+H] ⁺。 Step C (Step C): methyl 3-(3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionate (3g, 7mmol) was dissolved in methanol (5ml), 2M sodium hydroxide solution (10ml) was added dropwise to the solution, stirred for 1 hour and monitored by thin layer chromatography (TLC). Dry solvent, flash (reverse phase column) (acetonitrile/water) to give 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amine yl)-3-oxopropionic acid (2 g, 5 mmol). MS (ESI) M/Z: 409.5 [M+H] ⁺ .

步驟D（Step D）：將3-((3-溴-4-氟苯基)(2-異丙基-4-甲基吡啶-3-基)胺基)-3-氧代丙酸（2g，5mmol）溶于5ml伊頓試劑在80℃下攪拌1小時，冷卻至室溫，加入冰水中用2M氫氧化鈉溶液將體系調至中性，用乙酸乙酯萃取，旋乾溶劑得到7-溴-6-氟-1-(2-異丙基-6-甲基-吡啶基)喹啉-2,4-二酮（2g粗品）。MS (ESI) M/Z：391.2[M+H]。Step D (Step D): 3-((3-bromo-4-fluorophenyl)(2-isopropyl-4-methylpyridin-3-yl)amino)-3-oxopropionic acid ( 2g, 5mmol) was dissolved in 5ml of Eaton's reagent, stirred at 80°C for 1 hour, cooled to room temperature, added to ice water and adjusted to neutrality with 2M sodium hydroxide solution, extracted with ethyl acetate, and the solvent was spin-dried to obtain 7- Bromo-6-fluoro-1-(2-isopropyl-6-methyl-pyridyl)quinoline-2,4-dione (2 g crude). MS (ESI) M/Z: 391.2 [M+H].

步驟E（Step E）：7-溴-6-氟-1-(2-異丙基-4-甲基-3-吡啶基)喹啉-2,4-二酮（1g粗品）用三氯氧磷（8ml）溶解，在80℃下攪拌2小時，旋乾溶劑，用2M氫氧化鈉溶液將pH調至中性用二氯甲烷萃取，旋乾有機相，柱層析純化（PE/EA 0~100%）得到7-溴-4-氯-6-氟-1-(2-異丙基-4-甲基-3-吡啶基)喹啉-2-酮（360mg，0.88mmol）。MS (ESI) M/Z：408.1[M+H]。Step E (Step E): 7-Bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinoline-2,4-dione (1 g crude) was treated with trichloromethane Phosphorus oxide (8ml) was dissolved, stirred at 80°C for 2 hours, the solvent was spin-dried, the pH was adjusted to neutral with 2M sodium hydroxide solution, extracted with dichloromethane, the organic phase was spin-dried, and purified by column chromatography (PE/EA 0~100%) to give 7-bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol). MS (ESI) M/Z: 408.1 [M+H].

步驟F（Step F）：將7-溴-4-氯-6-氟-1-(2-異丙基-4-甲基-3-吡啶基)喹啉-2-酮（360mg，0.88mmol）用DMF溶解，加入N,N-二異丙基乙胺（260mg，2mmol）和(S)-1-N-Boc-2-甲基哌嗪（200mg，1mmol）在60℃下攪拌兩小時，質譜確認反應完全後用flash(反相色譜柱)（乙腈/水0~100%）純化，得到第三丁基(2S)-4-[7-溴-6-氟-1-(2-異丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯（404mg，0.7mmol，產率80%）。MS (ESI) M/Z：573.1[M+H]。Step F (Step F): 7-Bromo-4-chloro-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)quinolin-2-one (360 mg, 0.88 mmol ) was dissolved in DMF, N,N-diisopropylethylamine (260 mg, 2 mmol) and (S)-1-N-Boc-2-methylpiperazine (200 mg, 1 mmol) were added and stirred at 60 °C for two hours , after confirming that the reaction was complete by mass spectrometry, it was purified by flash (reverse phase chromatography column) (acetonitrile/water 0~100%) to obtain tert-butyl(2S)-4-[7-bromo-6-fluoro-1-(2- Isopropyl-4-methyl-3-pyridyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-1-carboxylate (404 mg, 0.7 mmol, 80% yield ). MS (ESI) M/Z: 573.1 [M+H].

步驟G（Step G）：第三丁基(2S)-4-[7-溴-6-氟-1-(2-異丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯(200mg0.348mmol)溶於1,4-二氧六環中，向體系中加入1,3,5,7-四甲基-6-苯基-2,4,8-三氧雜-6-磷金剛烷（10.16mg，0.0348），磷酸鉀（148mg，0.7 mmol）、2-氟-6-羥基苯硼酸（108mg，0.7）和三(二亞芐基丙酮)二鈀（31mg，0.0348 mmol）置換氮氣三次之後在60℃下攪拌過夜，旋乾溶劑，用flash(反相色譜柱)（乙腈/水 0~100%）純化，得到第三丁基(2S)-4-[6-氟-7-(2-氟-6-羥基-苯基)-1-(2-異丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯（110mg）0.18mmol，產率52%）。MS (ESI) M/Z：605.3[M+H]。Step G (Step G): tert-butyl (2S)-4-[7-bromo-6-fluoro-1-(2-isopropyl-4-methyl-3-pyridyl)-2-oxo -4-Quinolinyl]-2-methyl-piperazine-1-carboxylate (200 mg 0.348 mmol) was dissolved in 1,4-dioxane, and 1,3,5,7- Tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoadamantane (10.16 mg, 0.0348), potassium phosphate (148 mg, 0.7 mmol), 2-fluoro-6-hydroxyphenylboronic acid ( 108 mg, 0.7) and tris(dibenzylideneacetone)dipalladium (31 mg, 0.0348 mmol) were replaced with nitrogen three times, and then stirred at 60 °C overnight, the solvent was spin-dried, and flash (reverse-phase column) (acetonitrile/water 0~ 100%) purification to give tert-butyl(2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl- 3-Pyridinyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-1-carboxylate (110 mg, 0.18 mmol, 52% yield). MS (ESI) M/Z: 605.3 [M+H].

步驟H（StepH）：第三丁基(2S)-4-[6-氟-7-(2-氟-6-羥基-苯基)-1-(2-異丙基-4-甲基-3-吡啶基)-2-氧代-4-喹啉基]-2-甲基-哌嗪-1-羧酸酯（55mg）0.09mmol）用二氯甲烷溶解（1ml）加入三氟乙酸（0.5ml）室溫攪拌1小時，旋乾，再加入二氯甲烷（2ml）和N,N-二異丙基乙胺（64mg，0.5mmol）攪拌過程中加入烯丙醯氯（8 Fmg，0.09mmol）反應半小時後質譜確認反應完全，旋乾溶劑，用flash(反相色譜柱)（乙腈/水）純化得到6-氟-7-(2-氟-6-羥基-苯基)-1-(2-異丙基-4-甲基-3-吡啶基)-4-[(3S)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮（22.3mg，0.04mmo l，產率44%）。MS (ESI) M/Z：559.3[M+H]。 ¹H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.54 (d, J= 4.7 Hz, 1H), 7.77 (dd, J= 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.26 – 7.18 (m, 1H), 6.86 (dd, J= 15.9, 10.6 Hz, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.69 (t, J= 8.9 Hz, 1H), 6.41 – 6.30 (m, 1H), 6.25 (s, 1H), 6.18 (d, J= 16.6 Hz, 1H), 5.75 (d, J= 12.0 Hz, 1H), 4.67 (d, J= 156.6 Hz, 1H), 4.24 (d, J= 161.2 Hz, 1H), 3.77 – 3.54 (m, 2H), 3.03 (s, 2H), 2.79 (s, 1H), 2.59 (dd, J= 12.8, 6.5 Hz, 1H), 1.92 (t, J= 19.3 Hz, 3H), 1.46 (s, 3H), 1.01 (dd, J= 51.7, 6.3 Hz, 6H)。 Step H (StepH): tert-butyl(2S)-4-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl- 3-Pyridinyl)-2-oxo-4-quinolinyl]-2-methyl-piperazine-1-carboxylate (55mg, 0.09mmol) was dissolved in dichloromethane (1ml) and trifluoroacetic acid ( 0.5ml) was stirred at room temperature for 1 hour, spin-dried, and then dichloromethane (2ml) and N,N-diisopropylethylamine (64mg, 0.5mmol) were added during stirring and allyl chloride (8 Fmg, 0.09 mmol) After half an hour of reaction, mass spectrometry confirmed that the reaction was complete, the solvent was spin-dried, and purified with flash (reverse phase chromatography column) (acetonitrile/water) to obtain 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1 -(2-Isopropyl-4-methyl-3-pyridyl)-4-[(3S)-3-methyl-4-prop-2-enyl-piperazin-1-yl]quinoline- 2-keto (22.3 mg, 0.04 mmol, 44% yield). MS (ESI) M/Z: 559.3 [M+H]. ¹ H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.54 (d, J = 4.7 Hz, 1H), 7.77 (dd, J = 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.26 – 7.18 (m, 1H), 6.86 (dd, J = 15.9, 10.6 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (t, J = 8.9 Hz, 1H), 6.41 – 6.30 (m, 1H), 6.25 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 156.6 Hz, 1H), 4.24 (d, J = 161.2 Hz, 1H), 3.77 – 3.54 (m, 2H), 3.03 (s, 2H), 2.79 (s, 1H), 2.59 (dd, J = 12.8, 6.5 Hz, 1H), 1.92 ( t, J = 19.3 Hz, 3H), 1.46 (s, 3H), 1.01 (dd, J = 51.7, 6.3 Hz, 6H).

實施例15：合成6-氟-7-(2-氟-6-羥基-苯基)-1-(2-異丙基-4-甲基-3-吡啶基)-4-[(3R)-3-甲基-4-丙-2-烯基-哌嗪-1-基]喹啉-2-酮

Example 15: Synthesis of 6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-1-(2-isopropyl-4-methyl-3-pyridyl)-4-[(3R) -3-Methyl-4-prop-2-enyl-piperazin-1-yl]quinolin-2-one

合成路線同實施例14。MS (ESI) M/Z：559.3[M+H]。 ¹H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.54 (d, J= 4.7 Hz, 1H), 7.77 (dd, J= 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J= 15.4, 8.1 Hz, 1H), 6.86 (dd, J= 16.0, 10.6 Hz, 1H), 6.73 (t, J= 7.8 Hz, 1H), 6.69 (t, J= 8.9 Hz, 1H), 6.40 – 6.30 (m, 1H), 6.25 (s, 1H), 6.19 (t, J= 13.6 Hz, 1H), 5.79 – 5.72 (m, 1H), 4.67 (d, J= 155.9 Hz, 1H), 4.24 (d, J= 160.8 Hz, 1H), 3.69 (d, J= 66.1 Hz, 2H), 3.50 – 3.41 (m, 1H), 3.05 (s, 1H), 2.79 (s, 1H), 2.66 – 2.54 (m, 1H), 1.90 (d, J= 19.8 Hz, 3H), 1.46 (s, 3H), 1.09 – 0.94 (m, 6H)。 The synthetic route is the same as that of Example 14. MS (ESI) M/Z: 559.3 [M+H]. ¹ H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 8.54 (d, J = 4.7 Hz, 1H), 7.77 (dd, J = 10.3, 4.4 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J = 15.4, 8.1 Hz, 1H), 6.86 (dd, J = 16.0, 10.6 Hz, 1H), 6.73 (t, J = 7.8 Hz, 1H), 6.69 (t, J = 8.9 Hz, 1H) ), 6.40 – 6.30 (m, 1H), 6.25 (s, 1H), 6.19 (t, J = 13.6 Hz, 1H), 5.79 – 5.72 (m, 1H), 4.67 (d, J = 155.9 Hz, 1H) , 4.24 (d, J = 160.8 Hz, 1H), 3.69 (d, J = 66.1 Hz, 2H), 3.50 – 3.41 (m, 1H), 3.05 (s, 1H), 2.79 (s, 1H), 2.66 – 2.54 (m, 1H), 1.90 (d, J = 19.8 Hz, 3H), 1.46 (s, 3H), 1.09 – 0.94 (m, 6H).

生物活性biological activity

測試方法testing method (1)(1)

實驗材料：KRAS G12C (SignalChem, Cat. No. R06-32DH-BULK) SOS1 exchange domain(564-1049) protein(Cytoskeleton, Inc., Cat. No.GE02-XL) Transcreener GDP FI Assay (BellBrook, Cat. No. 3014-1K) 384-well plate (Perkin Elmer, Cat. No. 6007279) BAY-293(MCE, Cat. No. HY-114398) AMG-510(MCE, Cat. HY-114277) Experimental materials: KRAS G12C (SignalChem, Cat. No. R06-32DH-BULK) SOS1 exchange domain(564-1049) protein (Cytoskeleton, Inc., Cat. No.GE02-XL) Transcreener GDP FI Assay (BellBrook, Cat. No. 3014-1K) 384-well plate (Perkin Elmer, Cat. No. 6007279) BAY-293(MCE, Cat. No. HY-114398) AMG-510(MCE, Cat. HY-114277)

實驗步驟：Experimental steps:

1.1. 化合物的處理Handling of Compounds

配製400倍終濃度的化合物，如檢測終濃度為25μM，配製成400倍濃度，即10mM。用自動微孔移液器將化合物梯度稀釋成設置的濃度點個數。Compounds with a 400-fold final concentration, such as the final detection concentration of 25 μM, are prepared to a 400-fold concentration, that is, 10 mM. The compound was serially diluted to the set number of concentration points using an automatic micropipette.

2.2. 轉移化合物到transfer compound to 384384 孔反應盤Well reaction plate

用超聲波納升液體處理系統將上述稀釋好的化合物從Echo 384孔盤中轉移75nL到384孔反應盤中，陰性對照和陽性對照均轉移75nL的100%DMSO。Transfer 75nL of the above diluted compounds from the Echo 384-well plate to the 384-well reaction plate using an ultrasonic nanoliter liquid processing system, and transfer 75nL of 100% DMSO for both the negative and positive controls.

3.3. 配製formulate 11 倍反應緩衝液fold reaction buffer

1倍反應緩衝液中含50mM Tris (pH7.5)，50mM NaCl，1mM EDTA，0.1% BSA，14mM MgCl ₂，0.01% Tween-20，1 mM DTT。 1x reaction buffer containing 50 mM Tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.1% BSA, 14 mM _MgCl2 , 0.01% Tween-20, 1 mM DTT.

4. 配製 3 倍 KRAS G12C 酶溶液， 6 倍 SOS1 酶溶液， 6 倍 GTP(BellBrook, Cat. No. 3014-1K) 溶液， 3 倍檢測溶液 4. Prepare 3 times KRAS G12C enzyme solution, 6 times SOS1 enzyme solution , 6 times GTP (BellBrook, Cat. No. 3014-1K) solution, 3 times detection solution

用1倍反應緩衝液分別配製3倍KRAS G12C酶溶液，6倍SOS1酶溶液，6倍GTP溶液，3倍檢測溶液（Antibody-IRDye和GDP-Tracer）。Prepare 3x KRAS G12C enzyme solution, 6x SOS1 enzyme solution, 6x GTP solution, and 3x detection solution (Antibody-IRDye and GDP-Tracer) with 1x reaction buffer.

5.5. 轉移transfer 33 倍times KRAS G12CKRAS G12C 酶溶液enzyme solution

轉移10μL 3倍KRAS G12C酶溶液到反應盤中，對於陰性對照孔，用10 μL的1倍反應緩衝液替代酶溶液。1000 rpm離心1 分鐘，室溫下培育15分鐘。Transfer 10 μL of 3x KRAS G12C enzyme solution to the reaction plate, and replace the enzyme solution with 10 μL of 1x reaction buffer for negative control wells. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

6.6. 轉移transfer 66 倍times SOS1SOS1 酶溶液enzyme solution

轉移5μL 6倍SOS1酶溶液到反應盤中。Transfer 5 μL of 6x SOS1 enzyme solution to the reaction dish.

7.7. 轉移transfer 66 倍times GTPGTP 溶液solution

轉移5μL 6倍GTP溶液到反應盤中。Transfer 5 μL of 6x GTP solution to the reaction dish.

8.8. 轉移transfer 33 倍檢測溶液double detection solution

轉移10μL 3倍檢測溶液到反應板中。1000 rpm離心1 分鐘。Transfer 10 μL of 3x detection solution to the reaction plate. Centrifuge at 1000 rpm for 1 minute.

9.9. 讀數reading

用酶素標示讀取儀SpectraMax Paradigm連續讀取2小時內（每5分鐘讀取一次）螢光訊號數值（Ex580/Em620）。The fluorescence signal value (Ex580/Em620) was continuously read within 2 hours (read every 5 minutes) with the enzyme label reader SpectraMax Paradigm.

10.10. 抑制率計算與Inhibition rate calculation with IC ₅₀ _IC50 擬合fit

從孔盤讀取儀上複製數值並計算斜率值，其中最大值是指陽性對照的讀值，最小值是指陰性對照的讀值。抑制率(%) = (最大值-樣本值)/(最大值-最小值)×100%。將數據導入MS Excel並用XLFit excel add-in version5.4.0.8擬合IC ₅₀值；擬合公式：Y=Bottom+(Top-Bottom)/(1+(IC ₅₀/X)^HillSlope)。 The values were replicated from the plate reader and the slope values were calculated, where the maximum value is the reading of the positive control and the minimum value is the reading of the negative control. Inhibition rate (%) = (maximum value - sample value)/(maximum value - minimum value) × 100%. Data were imported into MS Excel and _IC50 values were fitted with XLFit excel add-in version 5.4.0.8; fitting formula: Y=Bottom+(Top-Bottom)/(1+( _IC50 /X)^HillSlope).

本發明化合物在1μM和10μM時對KRAS G12C的抑制率、抑制KRAS G12C的IC ₅₀如表1所示。 Table 1 shows the inhibition rate and _IC50 of the compounds of the present invention on KRAS G12C at 1 μM and 10 μM.

測試方法testing method (2)(2)

檢測方法：Detection method: CTGCTG 方法method

實驗方法：experimental method:

1. 將處於對數生長期的細胞重新懸浮於生長培養基並稀釋至目標密度。將上述細胞懸浮液按照每孔100μL接種至96孔盤中，在37 ℃，5 % CO ₂培養箱中培育過夜。 1. Resuspend cells in log phase in growth medium and dilute to target density. The above cell suspension was seeded into a 96-well plate at 100 μL per well, and incubated overnight at 37 °C in a 5 % CO ₂ incubator.

2. 將待測化合物溶解在DMSO中，配製成濃度為10 mM的儲備液。首先用DMSO將儲備液稀釋至2mM，10個濃度，3倍梯度稀釋。然後用生長培養基稀釋至30μM。按50μL/孔加入接種細胞的96孔盤中。2. Dissolve the test compound in DMSO to make a 10 mM stock solution. The stock solution was first diluted with DMSO to 2 mM, 10 concentrations, 3-fold serial dilution. Then dilute to 30 μM with growth medium. Add 50 μL/well to the 96-well plate seeded with cells.

3. 將加入待測化合物的細胞置於37℃，5% CO ₂培養箱中培育72小時。室溫下平衡96孔盤，每孔中加入40μL CellTiter-Glo ^®試劑（Promega G7573），混合2分鐘，室溫培育60分鐘，EnVision RMultilabel Reader讀取發光值，用GraphPad Prism 5.0 software軟體計算化合物的IC ₅₀。 3. Incubate the cells to be tested in a 37°C, 5% CO ₂ incubator for 72 hours. The 96-well plate was equilibrated at room temperature, 40 μL of CellTiter-Glo ^® reagent (Promega G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 60 minutes, the luminescence value was read by EnVision RMultilabel Reader, and the compound was calculated by GraphPad Prism 5.0 software. _IC50 .

測試方法testing method (3)(3) ：:

Western Blot protocolWestern Blot protocol

細胞平盤培養：Cell plate culture:

1. 將處於對數生長期的細胞重新懸浮於生長培養基並稀釋至目標密度。將上述細胞懸浮液按照每孔2ml接種至6孔盤中，在37℃，5% CO ₂培養箱中培育過夜。 1. Resuspend cells in log phase in growth medium and dilute to target density. The above cell suspension was seeded into 6-well dishes at 2 ml per well, and incubated overnight at 37°C in a 5% CO ₂ incubator.

2. 將待測化合物溶解在DMSO中，配製成濃度為10 mM的儲備液。首先用DMSO將儲備液分別稀釋至3mM，2mM，1mM，然後用生長培養基分別稀釋至150μM，100μM，50μM。棄去6孔盤培養基，加入200μl稀釋化合物使6孔盤體積為2ml。37℃，5% CO ₂培養箱中分別培育8小時，24小時，48小時。 2. Dissolve the test compound in DMSO to make a 10 mM stock solution. The stock solutions were first diluted to 3 mM, 2 mM, and 1 mM with DMSO, and then to 150 μM, 100 μM, and 50 μM with growth medium. The 6-well plate medium was discarded and 200 μl of diluted compound was added to bring the 6-well plate volume to 2 ml. Incubate in a 37°C, 5% CO ₂ incubator for 8 hours, 24 hours, and 48 hours, respectively.

樣品製備(8小時、24小時、48小時) 1.將6孔盤平衡到室溫。 2.用150 μL含蛋白酶/磷酸酶抑制劑的RIPA裂解緩衝液重新懸浮細胞，將樣品置於冰中培育30分鐘以完成細胞裂解。 3.樣品13000 rpm, 4℃，離心10分鐘, 去沉澱。BCA定量，用4X樣品加載緩衝液製備蛋白樣品，95℃水浴煮沸15分鐘。 Sample preparation (8 hours, 24 hours, 48 hours) 1. Equilibrate the 6-well plate to room temperature. 2. Resuspend cells in 150 μL of RIPA lysis buffer containing protease/phosphatase inhibitors and incubate samples on ice for 30 minutes to complete cell lysis. 3. The sample was centrifuged at 13,000 rpm, 4°C for 10 minutes, to remove the pellet. For BCA quantification, protein samples were prepared with 4X sample loading buffer and boiled in a 95°C water bath for 15 minutes.

WB實驗步驟 1.將15 μL細胞裂解液加入SDS-PAGE凝膠中，200v電泳40分鐘，直到藍色條帶脫離凝膠。 2.使用電轉印將凝膠轉至PVDF膜(2.5A, 3分鐘)。 3.用5% BSA緩衝液將PVDF膜室溫下培育1小時。 4.一抗培育:稀釋抗體KRAS(1:1000)和a-tubulin(1:1000)，4℃過夜。 5.二抗培育:以1:3000的比例稀釋抗體，室溫培育1小時。 6.使用Westem ECL顯影液顯影。 WB experimental procedure 1. Add 15 μL of cell lysate to the SDS-PAGE gel and run electrophoresis at 200v for 40 minutes until the blue band breaks off the gel. 2. Transfer the gel to PVDF membrane using electroblotting (2.5A, 3 minutes). 3. Incubate the PVDF membrane with 5% BSA buffer for 1 hour at room temperature. 4. Primary antibody incubation: Dilute antibodies KRAS (1:1000) and a-tubulin (1:1000) at 4°C overnight. 5. Secondary antibody incubation: Dilute the antibody at a ratio of 1:3000 and incubate at room temperature for 1 hour. 6. Use Western ECL developer to develop.

蛋白降解的結果如表1所示。The results of protein degradation are shown in Table 1.

表1 實施例化合物結構酶活性（IC ₅₀nM) 抑制率（10μM）抑制率（1μM）細胞活性(NCI-H358，IC ₅₀nM 1

959 86.2 50.6 2

1984 53 42 3

20 4

240 5 1-a1 1-a2 1786 3278 6

2515 74 34 7

9.4 8

12 9

12 2.4 10

0.9 11

2.4 0.3 12

1.8 13

6.0 14

1380 15

194 Table 1

Example Compound structure Enzyme activity (IC ₅₀ nM) Inhibition rate (10 μM) Inhibition rate (1 μM) Cell viability (NCI-H358, IC ₅₀ nM 1

959 86.2 50.6 2

1984 53 42 3

20 4

240 5 1-a1 1-a2 1786 3278 6

2515 74 34 7

9.4 8

12 9

12 2.4 10

0.9 11

2.4 0.3 12

1.8 13

6.0 14

1380 15

194

惟以上所述者，僅為本發明的實施例而已，當不能以此限定本發明實施的範圍，凡是依本發明申請專利範圍及專利說明書內容所作的簡單的等效變化與修飾，皆仍屬本發明專利涵蓋的範圍內。However, the above are only examples of the present invention, and should not limit the scope of implementation of the present invention. Any simple equivalent changes and modifications made according to the scope of the patent application of the present invention and the contents of the patent specification are still included in the scope of the present invention. within the scope of the invention patent.

無。none.

Claims

一種如式A所示化合物或其藥學上可接受的鹽，

其中， Z為O或NR ⁵； R ⁵為C ₁-C ₆烷基、

、

、

、被R ^5-5取代或未取代的C ₂-C ₆烯基、

或

或

； R ^2-2a和R ^2-2b獨立地為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基； R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基； R ^2-2a-1a為C ₁-C ₆烷氧基； R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基、或被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為羥基、氰基、胺基、鹵素、C ₁-C ₆烷基、C ₁-C ₆烷氧基、-L-R ^3-1a； -L-為

、

、

、

或

； R ^3-1a-1和R ^3-1a-2獨立地可為氫、C ₁-C ₆烷基、

或

；環A可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環；環B可為C ₆-C ₁₀芳環；環C可為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環； R ^a、R ^b、R ^c、R ^d和R ^e獨立地為氫、羥基或C ₁-C ₆烷基； o1、o2和o3獨立地為0、1、2、3或4； R ⁴為鹵素、OCH ₃、OH、CN、CONH ₂或COOH； R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2的個數獨立地為1、2、3、4或5個，當為2、3、4或5個時，R ^5-1a、R ^5-1a-1、R ^2-2、R ^2-1a、R ^2-2a-1、R ^2-2a-1a、R ^3-1和R ^3-2獨立地相同或不同。 A compound of formula A or a pharmaceutically acceptable salt thereof,

Wherein, Z is O or NR ⁵ ; R ⁵ is C ₁ -C ₆ alkyl,

,

, C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 ,

or

; R ^2-2a and R ^{2-2b are} independently C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 ; R ^2-2a-1 is substituted or unsubstituted by R ^2-2a-1a Substituted C ₁ -C ₆ alkoxy; R ^2-2a-1a is C ₁ -C ₆ alkoxy; R ³ is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , or R ^3-2 substituted or unsubstituted 5-15-membered heteroaryl group of "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4"; R ^{3 -1} and R ^3-2 are independently hydroxyl, cyano, amino, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -LR ^3-1a ; -L- is

,

or

; R ^3-1a-1 and R ^3-1a-2 can independently be hydrogen, C ₁ -C ₆ alkyl,

or

; Ring A can be a 5-6 membered heterocycle with "hetero atoms selected from one or more of N, O and S, and the number of heteroatoms is 1-2"; Ring B can be a C ₆ -C ₁₀ aromatic ring ; Ring C can be a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3"; R ^a , R ^b , R ^c , R ^d and ^Re are independently hydrogen, hydroxyl or C ₁ -C ₆ alkyl; o1, o2 and o3 are independently 0, 1, 2, 3 or 4; R ⁴ is halogen, OCH ₃ , OH, CN, CONH ₂ or COOH; of R ^5-1a , R ^5-1a-1 , R ^2-2 , R ^2-1a , R ^2-2a-1 , R ^2-2a-1a , R ^3-1 and R ^3-2 The number is independently 1, 2, 3, 4 or 5, and when it is 2, 3, 4 or 5, R ^5-1a , R ^5-1a-1 , R ^2-2 , R ^2-1a , R ^2-2a-1 , R ^2-2a-1a , R ^3-1 and R ^3-2 are independently the same or different.

如請求項1所述的如式A所示化合物或其藥學上可接受的鹽，其中，所述的如式A所示化合物為如式I或式I’所示的化合物，

，

其中，標“*”的碳原子為S構型碳原子、R構型碳原子或非掌性碳原子；R ¹、R ²、R ³、R ⁴和Z的定義如請求項1所示。 The compound represented by formula A or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula A is a compound represented by formula I or formula I',

,

Wherein, the carbon atoms marked with "*" are S-configuration carbon atoms, R-configuration carbon atoms or non-chiral carbon atoms; the definitions of R ¹ , R ² , R ³ , R ⁴ and Z are as shown in claim 1.

如請求項1所述的如式A所示化合物或其藥學上可接受的鹽，其中，

為

或

；R ¹為C ₁-C ₆烷基；和/或，當R ⁵為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ⁵為被R ^5-5取代或未取代的C ₂-C ₆烯基時，所述的R ^5-5的個數為1、2或3個；和/或，當R ⁵為被R ^5-5取代或未取代的C ₂-C ₆烯基時，所述的C ₂-C ₆烯基為C ₂-C ₄烯基；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為被R ^5-1a取代或未取代的C ₁-C ₆烷基時，R ^5-1a的個數獨立地為1、2或3個；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為被R ^5-1a取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基獨立地為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^5-1為被R ^5-2a取代或未取代的C ₂-C ₆烯基時，所述的R ^5-2a的個數為1、2或3個；和/或，當R ^5-1為被R ^5-2a取代或未取代的C ₂-C ₆烯基時，所述的烯基為C ₂-C ₄烯基；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₂-C ₆炔基時，所述的C ₂-C ₆炔基為C ₂-C ₄炔基；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基獨立地為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^5-5為鹵素時，所述的鹵素為氟、氯、溴或碘；和/或，當R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基時，R ^4-1a-1的個數為1、2或3個；和/或，當R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^5-1a-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^5-2a為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^5-2a為鹵素時，所述的鹵素為氟、氯、溴或碘；和/或，當R ¹為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基獨立地為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基時，R ^2-2的個數為1、2、3或4個；和/或，當R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為C ₆-C ₁₀芳基；和/或，當R ²為被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，R ^2-3的個數為1、2、3或4個；和/或，當R ²為被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基或雙環雜芳基；和/或，當R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基時，R ^2-1a的個數為1、2、3或4個；和/或，當R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為C ₆-C ₁₀芳基；和/或，當R ^2-2為鹵素時，所述的鹵素為氟、氯、溴或碘；和/或，當R ^2-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^2-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^2-1a為鹵素時，所述的鹵素為氟、氯、溴或碘；和/或，當R ^2-1a為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^2-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^2-2a為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，R ^2-2a-1的個數為1、2或3個；和/或，當R ^2-2a為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^2-2b為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，R ^2-2a-1的個數為1、2或3個；和/或，當R ^2-2b為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基時，R ^2-2a-1a的個數為1、2或3個；和/或，當R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^2-2a-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基時，R ^3-1的個數為1、2、3或4個；和/或，當R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為C ₆-C ₁₀芳基；和/或，當R ³為被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，R ^3-2的個數為1、2、3或4個；和/或，當R ³為被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基或雙環雜芳基；和/或，當R ^3-1為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^3-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當R ^3-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^3-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷基為甲氧基、乙氧基、丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基；和/或，當環D為C ₃-C ₆環烷烴時，所述的C ₃-C ₆環烷烴為環丙烷、環丁烷、環戊烷或環己烷；和/或，當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-6元雜環；和/或，當環D為C ₆-C ₁₀芳環時，所述的C ₆-C ₁₀芳環為苯環或萘環；和/或，當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-6元雜芳環；和/或，當R ^3-1a-1為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ^3-1a-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，環A中，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環烷基為“雜原子選自N，雜原子個數為1-2個”的5-6元雜環烷基；和/或，環B中，所述的C ₆-C ₁₀芳環為苯環或萘環；和/或，環C中，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元單環雜芳環或雙環雜芳環；和/或，當R ^a、R ^b、R ^c、R ^d和R ^e獨立地為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基；和/或，當R ⁴為鹵素時，所述的鹵素為氟、氯、溴或碘。 The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 1, wherein,

for

or

; R ¹ is C ₁ -C ₆ alkyl; and/or, when R ⁵ is C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is methyl, ethyl, propyl, iso- propyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ⁵ is a C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 , the The number of R ^5-5 is 1, 2 or 3; and/or, when R ⁵ is a C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 , the C ₂ -C ₆ alkenyl is C ₂ -C ₄ alkenyl; and/or, when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently When R ^{5-1a is a} substituted or unsubstituted C ₁ -C ₆ alkyl group, the number of R ^5-1a is independently 1, 2 or 3; and/or, when R ^5-1 , R ^5-2 , When R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a , the C ₁ -C ₆ alkane and/or, when R ^5-1 is R ^5-2a independently When substituted or unsubstituted C ₂ -C ₆ alkenyl, the number of said R ^5-2a is 1, 2 or 3; and/or, when R ^5-1 is substituted or unsubstituted by R ^5-2a When substituted C ₂ -C ₆ alkenyl, the alkenyl is C ₂ -C ₄ alkenyl; and/or, when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , When R ^5-6 and R ^5-7 are independently C ₂ -C ₆ alkynyl, the C ₂ -C ₆ alkynyl is C ₂ -C ₄ alkynyl; and/or, when R ^5-1 , When R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is independently is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third butoxy; and/or, when R ^5-5 is When halogen, the halogen is fluorine, chlorine, bromine or iodine; and/or, when R ^5-1a is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a-1 , R ⁴ The number of -1a- ¹ is 1, 2 or 3; and/or, when R ^5-1a is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a-1 , the C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third butoxy; and/ Or, when R ^5-1a-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-propoxy Butoxy, isobutoxy, second or third butoxy and/or, when R ^5-2a is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isopropyl butyl, 2-butyl or 3-butyl; and/or, when R ^5-2a is halogen, the halogen is fluorine, chlorine, bromine or iodine; and/or, when R ¹ is C ₁ - When C ₆ alkyl group, the C ₁ -C ₆ alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R ² is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-2 , the number of R ^2-2 is 1, 2, 3 or 4; and/or, when R When ² is a C ₆ -C ₁₅ aryl group substituted or unsubstituted by R ^2-2 , the C ₆ -C ₁₅ aryl group is a C ₆ -C ₁₀ aryl group; and/or, when R ² is a C 6 -C 15 aryl group; ^{When 2-3} substituted or unsubstituted "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, R ² The number of ^-3 is 1, 2, 3 or 4; and/or, when R ² is substituted or unsubstituted by R ^2-3 "heteroatom is selected from one or more of N, O and S, the heteroatom is When the number of atoms is 1, 2, 3 or 4" 5-15 membered heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 , 3 or 4" 5-15-membered heteroaryl group is a 5-15-membered heteroaryl group with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" Monocyclic heteroaryl or bicyclic heteroaryl; and/or, when R ^2-1 is a C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-1a , the number of R ^2-1a is 1, 2, 3 or 4; and/or, when R ^2-1 is a C ₆ -C 15 aryl group substituted or unsubstituted by R ^2-1a , the C ₆ -C ₁₅ aryl group is a C ₆ -C ₁₅ aryl group C ₁₀ aryl; and/or, when R ^2-2 is halogen, the halogen is fluorine, chlorine, bromine or iodine; and/or, when R ^2-2 is C ₁ -C ₆ alkyl, The C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^2- When ² is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , the second butoxy group or the third butoxy group; and/or, when R ^2-1a is halogen, the halogen is fluorine, chlorine, bromine or iodine; and/or, when R ^2-1a is C In the case of ₁ - _C6 alkyl group, the _C1 - _C6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; And/or, when R ^2-1a is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, second butoxy or third butoxy; and/or, when R ^2-2a is C 1 substituted or unsubstituted by R ^2-2a- ₁ When -C ₆ alkyl, the number of R ^2-2a-1 is 1, 2 or 3; and/or, when R ^2-2a is C ₁ -C substituted or unsubstituted by R ^2-2a-1 When ₆ alkyl groups, the C ₁ -C ₆ alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl or tertiary butyl; and/or , when R ^2-2b is a C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a ^-1 , the number of R 2-2a-1 is 1, 2 or 3; and/or, when When R ^2-2b is a C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 , the C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^2-2a-1 is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^2-2a-1a , the number of R ^2-2a-1a is 1, 2 or 3; and/or, when R ^2-2a-1 is a C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^2-2a-1a In the case of base, the C ₁ -C ₆ alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third Butoxy; and/or, when R ^2-2a-1a is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, Isopropoxy, n-butoxy, isobutoxy, second butoxy or third butoxy; and/or, when R ³ is C ₆ -C ₁₅ substituted or unsubstituted by R ^3-1 In the case of an aryl group, the number of R ^3-1 is 1, 2, 3 or 4; and/or, when R ³ is a C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , the The C ₆ -C ₁₅ aryl group is a C ₆ -C ₁₀ aryl group; and/or, when R ³ is substituted or unsubstituted by R ^3-2 "heteroatom is selected from one or more of N, O and S , when the number of heteroatoms is 1, 2, 3 or 4" of a 5-15-membered heteroaryl group, the number of R ^3-2 is 1, 2, 3 or 4; and/or, when R ³ is When R ^3-2 is substituted or unsubstituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl, The 5-15-membered heteroaryl group of the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" is "the heteroatom is selected from N, O And one or more of S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl or bicyclic heteroaryl; and/or, when R ^3-1 is C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or th tributyl; and/or, when R ^3-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkyl is methoxy, ethoxy, propoxy, isopropoxy and/or, when R ^3-2 is C ₁ -C ₆ alkyl, the C ₁ -C ₆ Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^3-2 is C ₁ -C ₆ In the case of alkoxy, the C ₁ -C ₆ alkyl group is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy or third tributoxy; and/or, when ring D is C ₃ -C ₆ cycloalkane, the C ₃ -C ₆ cycloalkane is cyclopropane, cyclobutane, cyclopentane or cyclohexane; and/ Or, when Ring D is a 3-10-membered heterocycle with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "heteroatoms are selected from N" , one or more of O and S, the number of heteroatoms is 1-3" 3-10-membered heterocycle is "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 -3" 3-6 membered heterocycles; and/or, when ring D is a _C6 - _C10 aromatic ring, the _C6 - _C10 aromatic ring is a benzene ring or a naphthalene ring; and/or, When Ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "heteroatoms are selected from N, One or more of O and S, the number of heteroatoms is 1-3" and the 5-10-membered heteroaromatic ring is "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 -3" 5-6 membered heteroaromatic rings; and/or, when R ^3-1a-1 is C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, when R ^3-1a-2 is C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and/or, in ring A, the "The heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-2". 2" 5-6 membered heterocycloalkyl; and/or, in ring B, the C ₆ -C ₁₀ aromatic ring is a benzene ring or a naphthalene ring; and/or, in ring C, the " The heteroatom is selected from one or more of N, O and S, and the 5-10-membered heteroaromatic ring with the number of heteroatoms is 1-3" is "the heteroatom is selected from one or more of N, O and S, 5-10-membered monocyclic heteroaromatic ring or bicyclic heteroaromatic ring with 1-3"heteroatoms; and/or, when R ^a , R ^b , R ^c , R ^d and R ^e are independently C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is methyl and/or, when R ⁴ is halogen, the halogen is fluorine, chlorine, Bromine or iodine.

如請求項3所述的如式A所示化合物或其藥學上可接受的鹽，其中，當R ⁵為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基；和/或，當R ⁵為被R ^5-5取代或未取代的C ₂-C ₆烯基時，所述的C ₂-C ₆烯基為

、

或

；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為被R ^5-1a取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基獨立地為甲基、乙基或第三丁基；和/或，當R ^5-1為被R ^5-2a取代或未取代的C ₂-C ₆烯基時，所述的烯基為乙烯基；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₂-C ₆炔基時，所述的C ₂-C ₆炔基為乙炔基；和/或，當R ^5-1、R ^5-2、R ^5-3、R ^5-4、R ^5-6和R ^5-7獨立地為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基獨立地為甲氧基；和/或，當R ^5-5為鹵素時，所述的鹵素為氟；和/或，當R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基或乙氧基；和/或，當R ^5-1a-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基；和/或，當R ^5-2a為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基；和/或，當R ^5-2a為鹵素時，所述的鹵素為氟；和/或，當R ¹為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基可獨立地為甲基；和/或，當R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為苯基或萘基；和/或，當R ²為被R ^2-3取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基為“雜原子選自N，雜原子個數為1-2個”的5-6元單環雜芳基，優選吡啶基，例如

，或“雜原子選自N，雜原子個數為1-2個”的8-10元雙環雜芳基，優選吲唑基，例如

；和/或，當R ^2-1為被R ^2-1a取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為苯基或萘基；和/或，當R ^2-2為鹵素時，所述的鹵素為氟或氯；和/或，當R ^2-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基；和/或，當R ^2-1a為鹵素時，所述的鹵素為氟或氯；和/或，當R ^2-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基；和/或，當R ^2-2a為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基或乙基；和/或，當R ^2-2b為被R ^2-2a-1取代或未取代的C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基或乙基；和/或，當R ^2-2a-1為被R ^2-2a-1a取代或未取代的C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基或乙氧基；和/或，當R ^2-2a-1a為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基為甲氧基；和/或，當R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基時，所述的C ₆-C ₁₅芳基為苯基或萘基；和/或，當R ³為被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基為“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元單環雜芳基為“雜原子選自N，雜原子個數為1-2個”的5-6元單環雜芳基，優選吡啶基，例如

；和/或，當R ^3-1為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基或異丙基；和/或，當R ^3-1為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷基為甲氧基；和/或，當R ^3-2為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基、乙基或異丙基；和/或，當R ^3-2為C ₁-C ₆烷氧基時，所述的C ₁-C ₆烷氧基可為甲氧基；和/或，當環D為C ₃-C ₆環烷基時，所述的C ₃-C ₆環烷基為環己烷，

例如為

；和/或，當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環為四氫呋喃、哌啶或哌嗪，

例如為

、

、

或

；和/或，當環D為C ₆-C ₁₀芳環時，所述的C ₆-C ₁₀芳環為苯環，

例如為

；和/或，當環D為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環為吡啶環或吡嗪環，

例如為

、

、

、

或

；和/或，環A中，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-2個”的5-6元雜環為四氫吡咯，

例如為

；和/或，環B中，所述的C ₆-C ₁₀芳環可為苯環，

例如為

；和/或，環C中，當所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元雜芳環為“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元單環雜芳環時，所述的“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的5-10元單環雜芳環為“雜原子選自N和S中的一種或多種，雜原子個數為1-2個”的5-6元單環雜芳環，優選噻唑環，

例如為

；和/或，當R ^a、R ^b、R ^c、R ^d和R ^e獨立地為C ₁-C ₆烷基時，所述的C ₁-C ₆烷基為甲基或第三丁基；和/或，當R ⁴為鹵素時，所述的鹵素為氟。 The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 3, wherein when R ⁵ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a methyl group and/or, when R ⁵ is a C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-5 , the C ₂ -C ₆ alkenyl is

,

or

and/or, when R ^5-1 , R ^5-2 , R ^5-3 , R ^5-4 , R ^5-6 and R ^5-7 are independently C ₁ substituted or unsubstituted by R ^5-1a -C ₆ alkyl, the C ₁ -C ₆ alkyl is independently methyl, ethyl or tert-butyl; and/or, when R ^5-1 is substituted or unsubstituted by R ^5-2a and/or, when R ^5-1 , R _5-2 , R ^5-3 , ^{R 5-4} ^, ^{R 5-6} _and R When ^5-7 is independently C ₂ -C ₆ alkynyl, the C ₂ -C ₆ alkynyl is ethynyl; and/or, when R ^5-1 , R ^5-2 , R ^5-3 , R When ^5-4 , R ^5-6 and R ^5-7 are independently C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is independently methoxy; and/or, when R When ^5-5 is halogen, the halogen is fluorine; and/or, when R ^5-1a is C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a-1 , the C ₁ -C ₆ alkoxy is methoxy or ethoxy; and/or, when R ^5-1a-1 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is Methoxy; and/or, when R ^5-2a is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a methyl group; and/or, when R ^5-2a is a halogen, The halogen is fluorine; and/or, when R ¹ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group can be independently methyl; and/or, when R ² is a When R ^2-2 is a substituted or unsubstituted C ₆ -C ₁₅ aryl group, the C ₆ -C ₁₅ aryl group is phenyl or naphthyl; and/or, when R ² is substituted by R ^2-3 or Unsubstituted "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4". One or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group is "the heteroatom is selected from one or more of N, O and S, When the number of heteroatoms is 1, 2, 3 or 4" of a 5-15-membered monocyclic heteroaryl group, the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered monocyclic heteroaryl is a 5-6-membered monocyclic heteroaryl with "heteroatoms selected from N, and the number of heteroatoms is 1-2", preferably pyridine base, e.g.

, or "the heteroatom is selected from N, the number of heteroatoms is 1-2" 8-10-membered bicyclic heteroaryl, preferably indazolyl, such as

and/or, when R ^2-1 is a C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-1a , the C ₆ -C ₁₅ aryl group is phenyl or naphthyl; and/or , when R ^2-2 is halogen, the halogen is fluorine or chlorine; and/or, when R ^2-2 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy and/or, when R ^2-1a is halogen, the halogen is fluorine or chlorine; and/or, when R ^2-1a is C ₁ -C ₆ alkoxy, the halogen C ₁ -C ₆ alkoxy may be methoxy; and/or, when R ^2-2a is C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 , the C ₁ -C ₆ alkyl is methyl or ethyl; and/or, when R ^2-2b is C ₁ -C ₆ alkyl substituted or unsubstituted by R ^2-2a-1 , the C ₁ -C ₆ alkyl is methyl or ethyl; and/or, when R ^2-2a-1 is C ₁ -C 6 alkoxy substituted or unsubstituted by R ^2-2a-1a , the C ₁ -C ₆ alkoxy group C ₆ alkoxy is methoxy or ethoxy; and/or, when R ^2-2a-1a is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy is methoxy and/or, when R ³ is a C ₆ -C ₁₅ aryl group substituted or unsubstituted by R ^3-1 , the C ₆ -C ₁₅ aryl group is phenyl or naphthyl; and/or, When R ³ is a 5-15-membered heteroatom substituted or unsubstituted by R ^3-2 "hetero atoms are selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" Aryl, the 5-15-membered heteroaryl group in which the "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4" is "the heteroatom is selected from One or more of N, O and S, when the number of heteroatoms is 1, 2, 3 or 4" 5-15 membered monocyclic heteroaryl group, the "heteroatom is selected from N, O and S" One or more of, the 5-15-membered monocyclic heteroaryl group with the number of heteroatoms is 1, 2, 3 or 4" is the 5-membered monocyclic heteroaryl group with "the number of heteroatoms is selected from N, and the number of heteroatoms is 1-2". -6-membered monocyclic heteroaryl, preferably pyridyl, eg

; and/or, when R ^3-1 is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is methyl, ethyl or isopropyl; and/or, when R ^3-1 When it is C ₁ -C ₆ alkoxy, said C ₁ -C ₆ alkyl is methoxy; and/or, when R ^3-2 is C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl is methyl, ethyl or isopropyl; and/or, when R ^3-2 is C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkoxy may be methyl and/or, when ring D is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is cyclohexane,

for example

and/or, when ring D is a 3-10-membered heterocyclic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "heteroatoms" One or more selected from N, O and S, the number of heteroatoms is 1-3" 3-10-membered heterocycle is tetrahydrofuran, piperidine or piperazine,

for example

,

or

and/or, when ring D is a C ₆ -C ₁₀ aromatic ring, the C ₆ -C ₁₀ aromatic ring is a benzene ring,

for example

and/or, when ring D is a 5-10-membered heteroaromatic ring with "heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the "heteroaromatic" The atom is selected from one or more of N, O and S, and the 5-10-membered heteroaromatic ring with 1-3" heteroatoms is a pyridine ring or a pyrazine ring,

for example

,

or

and/or, in Ring A, the 5-6-membered heterocyclic ring of "heteroatoms is selected from N, O and S, and the number of heteroatoms is 1-2" is tetrahydropyrrole,

for example

and/or, in ring B, the C ₆ -C ₁₀ aromatic ring can be a benzene ring,

for example

and/or, in ring C, when the "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3", the 5-10-membered heteroaromatic ring is "heteroaromatic". The atom is selected from one or more of N, O and S, and when the number of heteroatoms is 1-3" of a 5-10-membered monocyclic heteroaromatic ring, the "heteroatom is selected from N, O and S" One or more of the 5-10-membered monocyclic heteroaromatic rings with the number of heteroatoms being 1-3" is "the heteroatom is selected from one or more of N and S, and the number of heteroatoms is 1-2" 5-6 membered monocyclic heteroaromatic ring, preferably thiazole ring,

for example

and/or, when R ^a , R ^b , R ^c , R ^d and R ^e are independently C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl is methyl or tert-butyl ^; and/or, when R4 is halogen, the halogen is fluorine.

如請求項4所述的如式A所示化合物或其藥學上可接受的鹽，其中， R ⁵為甲基、

、

、

、

、

、

、

、

、

、

、

或

；和/或，R ¹為氫或甲基；和/或，R ^2-2和R ^2-1a獨立地可為-OH、-F、-Cl、-NH ₂或-OMe；和/或，R ^2-1為

、

或

；和/或，-L-為

、

、

、

、

、

、

、

或

，a端與R ^3-1a相連接，b端與C ₆-C ₁₅芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基相連接；和/或，R ^3-1a為

。 The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ⁵ is methyl,

,

or

and/or, R ¹ is hydrogen or methyl; and/or, R ^2-2 and R ^2-1a can be independently -OH, -F, -Cl, -NH ₂ or -OMe; and/or, R ^2-1 is

,

or

; and/or, -L- is

,

or

, the a-end is connected with R ^3-1a , the b-end is connected with C ₆ -C ₁₅ aryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 and/or, R ^3-1a is

.

如請求項5所述的如式A所示化合物或其藥學上可接受的鹽，其中，

為

、

、

、

、

、

、

、

、

、

、

、

或

；和/或，R ²為

、

、

、

、

、

、

或

；和/或，R ³為

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

；和/或，所述的E3連接酶為VHL、CRBN、MDM2、cIAP、Cereblon、XIAP、E3A、APC、UBR5(EDD1)、SOCS/BC-box/eloBC/CUL5/RING、LNXp80、CBX4、CBLL1、HACE1、HECTD1、HECTD2、HECTD3、HECW1、HECW2、HERC1、HERC2、HERC3、HERC4、HUWE1、ITCH、NEDD4、NEDD4L、PPIL2、PRPF19、PIAS1、PIAS2、PIAS3、PIAS4、RANBP2、RNF4、RBX1、SMURF1、SMURF2、STUB1、TOPORS、TRIP12、UBE3A、UBE3B、UBE3C、UBE4A、UBE4B、UBOX5、UBR5、WWP1、WWP2、Parkin、A20/TNFAIP3、AMFR/gp78、ARA54、β-TrCP1/BTRC、BRCA1、CBL、CHIP/STUB1、E6、E6AP/UBE3A、F-box蛋白15/FBXO15、FBXW7/Cdc4、GRAIL/RNF128、HOIP/RNF31、cIAP-1/HIAP-2、cIAP-2/HIAP-1、cIAP(pan)、ITCH/AIP4、KAP1、MARCH8、Mind Bomb 1/MIB1、Mind Bomb 2/MIB2、MuRF1/TRIM63、NDFIP1、NEDD4、NleL、Parkin、RNF2、RNF4、RNF8、RNF168、RNF43、SART1、Skp2、SMURF2、TRAF-1、TRAF-2、TRAF-3、TRAF-4、TRAF-5、TRAF-6、TRIM5、TRIM21、TRIM32、UBR5或ZNRF3，優選VHL、CRBN、MDM2或cIAP。 The compound of formula A or a pharmaceutically acceptable salt thereof according to claim 5, wherein,

for

,

or

; and/or, R ² is

,

or

; and/or, R ³ is

,

or

and/or, the E3 ligase is VHL, CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, APC, UBR5(EDD1), SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1 , HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2 , STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54, β-TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1 , E6, E6AP/UBE3A, F-box protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP-2/HIAP-1, cIAP(pan), ITCH/ AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, preferably VHL, CRBN, MDM2 or cIAP.

如請求項1所述的如式A所示化合物或其藥學上可接受的鹽，其中，當R ¹為C ₁-C ₆烷基時，與R ¹相連的C原子的構型為S構型；和/或，R ⁴為F；和/或，R ³為

、

、

、

、

、

、

、

或

；和/或，Z為NR ⁵和/或，R ⁵為

、

或

，優選R ⁵為

或

，更優選R ⁵為

；和/或，R ^5-1為被R ^5-1a取代或未取代的C ₁-C ₆烷基、C ₂-C ₆烯基或C ₁-C ₆烷氧基，優選R ^5-1為被R ^5-1a取代或未取代的C ₁-C ₆烷基或C ₂-C ₆烯基，更優選R ^5-1為C ₂-C ₆烯基；和/或，R ^5-2為C ₁-C ₆烷基；和/或，R ^5-3和R ^5-4獨立地為氫、或被R ^5-1a取代或未取代的C ₁-C ₆烷基；和/或，R ¹為氫；和/或，R ²為被R ^2-2取代或未取代的C ₆-C ₁₅芳基，優選R ²為被R ^2-2取代的C ₆-C ₁₅芳基；和/或，R ^2-2為羥基、鹵素、胺基或C ₁-C ₆烷氧基，優選R ^2-2為羥基、鹵素或胺基，更優選R ^2-2為羥基或鹵素；和/或，R ^2-1a為鹵素；和/或，R ³為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基，優選R ³可為被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基；和/或，R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基或-L-R ^3-1a，優選R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基，更優選R ^3-1和R ^3-2獨立地為甲基或異丙基；和/或，-L-為

；a端與R ^3-1a相連接，b端與C ₆-C ₁₅芳基或“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基相連接；和/或，n1為0、1、2、3、4、5或6；和/或，m1為0、1、2或3；和/或，R ^3-1a為

；和/或，R ^3-1a-1和R ^3-1a-2獨立地為氫或

；和/或，R ^3-1和R ^3-2的個數為2個，且R ^3-1和R ^3-2不同。 The compound of formula A according to claim 1 or a pharmaceutically acceptable salt thereof, wherein when R ¹ is a C ₁ -C ₆ alkyl group, the configuration of the C atom connected to R ¹ is S configuration and/or, R ⁴ is F; and/or, R ³ is

,

or

; and/or, Z is NR ⁵ and/or, R ⁵ is

,

or

, preferably R ⁵ is

or

, more preferably R ⁵ is

and/or, R ^5-1 is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₆ alkoxy substituted or unsubstituted by R ^5-1a , preferably R ^5-1 is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-1a , more preferably R ^5-1 is C ₂ -C ₆ alkenyl; and/or, R ^5-2 is C ₁ -C ₆ alkyl; and/or, R ^5-3 and R ^5-4 are independently hydrogen, or C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a ; and/or, R ¹ is hydrogen; and/or, R ² is C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^2-2 , preferably R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; and /or, R ^2-2 is hydroxyl, halogen, amino or C ₁ -C ₆ alkoxy, preferably R ^2-2 is hydroxyl, halogen or amino, more preferably R ^2-2 is hydroxyl or halogen; and/ Or, R ^2-1a is halogen; and/or, R ³ is C ₆ -C ₁₅ aryl substituted by R ^3-1 , or "heteroatom selected from N, O and S substituted by R ^3-2 One or more of, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl group, preferably R ³ can be substituted by R ^3-2 " heteroatom is selected from N, O and S One or more of, the number of heteroatoms is 1, 2, 3 or 4" 5-15-membered heteroaryl; and/or, R ^3-1 and R ^3-2 are independently C ₁ -C ₆ Alkyl or -LR ^3-1a , preferably R ^3-1 and R ^3-2 are independently C ₁ -C ₆ alkyl, more preferably R ^3-1 and R ^3-2 are independently methyl or isopropyl ; and/or, -L- is

; The a-end is connected with R ^3-1a , the b-end is connected with C ₆ -C ₁₅ aryl or "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 and/or, n1 is 0, 1, 2, 3, 4, 5 or 6; and/or, m1 is 0, 1, 2 or 3; and/or , R ^3-1a is

and/or, R ^3-1a-1 and R ^3-1a-2 are independently hydrogen or

and/or, the number of R ^3-1 and R ^3-2 is 2, and R ^3-1 and R ^3-2 are different.

如請求項1所述的如式A所示化合物或其藥學上可接受的鹽，其中，所述的如式A所示化合物為如下任一方案，方案1： R ⁴為F； Z為NR ⁵； R ⁵為

、

或

； R ^3-1a-1和R ^3-1a-2獨立地為氫或

；方案2： R ⁴為F； Z為NR ⁵； R ⁵為

或

； R ^5-1為被R ^5-1a取代或未取代的C ₁-C ₆烷基或C ₂-C ₆烯基； R ^5-2為C ₁-C ₆烷基； R ^5-3和R ^5-4獨立地為氫、或被R ^5-1a取代或未取代的C ₁-C ₆烷基； R ^5-1a為被R ^5-1a-1取代或未取代的C ₁-C ₆烷氧基； R ^5-1a-1為C ₁-C ₆烷氧基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基、鹵素、胺基或C ₁-C ₆烷氧基； R ³為被R ^3-1取代或未取代的C ₆-C ₁₅芳基、或被R ^3-2取代或未取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基；方案3： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基、鹵素或胺基； R ³為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為C ₁-C ₆烷基； R ^3-1和R ^3-2的個數為2個，且R ^3-1和R ^3-2不同；方案4： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基或鹵素； R ³為被R ^3-1取代的C ₆-C ₁₅芳基、或被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-1和R ^3-2獨立地為甲基或異丙基； R ^3-1和R ^3-2的個數為2個，且R ^3-1和R ^3-2不同；方案5： R ⁴為F； Z為NR ⁵； R ⁵為

； R ^5-1為C ₂-C ₆烯基； R ¹為氫； R ²為被R ^2-2取代的C ₆-C ₁₅芳基； R ^2-2為羥基或鹵素； R ³為被R ^3-2取代的“雜原子選自N、O和S中的一種或多種，雜原子個數為1、2、3或4個”的5-15元雜芳基； R ^3-2為C ₁-C ₆烷基。 The compound represented by formula A or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula A is any one of the following schemes, Scheme 1: R ⁴ is F; Z is NR ⁵ ^; R5 is

,

or

; R ^3-1a-1 and R ^3-1a-2 are independently hydrogen or

; Scheme 2: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

or

; R ^5-1 is C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl substituted or unsubstituted by R ^5-1a ; R ^5-2 is C ₁ -C ₆ alkyl; R ^5-3 and R ^5-4 is independently hydrogen, or C ₁ -C ₆ alkyl substituted or unsubstituted by R ^5-1a ; R ^5-1a is C ₁ -C ₆ substituted or unsubstituted by R ^5-1a-1 Alkoxy; R ^5-1a-1 is C ₁ -C ₆ alkoxy; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl, Halogen, amino or C ₁ -C ₆ alkoxy; R ³ is a C ₆ -C ₁₅ aryl substituted or unsubstituted by R ^3-1 , or a "heteroatom selected" substituted or unsubstituted by R ^3-2 A 5-15-membered heteroaryl group selected from one or more of N, O and S, the number of heteroatoms is 1, 2, 3 or 4"; R ^3-1 and R ^3-2 are independently C ₁ - C ₆ alkyl; Scheme 3: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

; R ^5-1 is C ₂ -C ₆ alkenyl; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl, halogen or amino; R ³ is a C ₆ -C ₁₅ aryl group substituted by R ^3-1 , or a "hetero atom substituted by R ^3-2 is selected from one or more of N, O and S, and the number of hetero atoms is 1, 2, 3 or 4" 5-15-membered heteroaryl; R ^3-1 and R ^3-2 are independently C ₁ -C ₆ alkyl; R ^3-1 and R ^3-2 are 2 in number, And R ^3-1 and R ^3-2 are different; Scheme 4: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

; R ^5-1 is C ₂ -C ₆ alkenyl; R ¹ is hydrogen; R ² is C ₆ -C ₁₅ aryl substituted by R ^2-2 ; R ^2-2 is hydroxyl or halogen; R ³ is by C ₆ -C ₁₅ aryl substituted by R ^3-1 , or "heteroatoms substituted by R ^3-2 are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4 R ^3-1 and R ^3-2 are independently methyl or isopropyl; the number of R ^3-1 and R ^3-2 is 2, and R ^{3- 1} and R ^3-2 are different; Scheme 5: R ⁴ is F; Z is NR ⁵ ; R ⁵ is

如請求項1-8中任一項所述的如式A所示化合物或其藥學上可接受的鹽，其中，所述的如式A所示化合物為如下任一結構，

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 The compound represented by formula A or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein the compound represented by formula A has any of the following structures,

,

or

.

一種如請求項1-9中任一項所述的如式A所示化合物的製備方法，其中，其為方法一、方法二、方法三或方法四，方法一包括以下步驟：溶劑中，在鹼的存在下，將如式II-1A所示化合物和如式II-2所示化合物進行如下所示的反應，得所述的如式A所示化合物，

；方法二包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式III-1A所示化合物和如式III-2或III-3所示化合物進行如下所示的反應，得所述的如式A所示化合物，

；方法一或方法二中，Z為NR ⁵，R ⁵為

；方法三包括以下步驟：溶劑中，在鹼的存在下，將如式IV-1A所示化合物和IV-2所示化合物進行如下所示的反應，得所述的如式A所示化合物，

；方法三中，Z為NR ⁵，R ⁵為

；方法四包括以下步驟：溶劑中，在鹼和催化劑的存在下，將如式V-1A所示化合物和如式V-2或V-3所示化合物進行如下所示的反應，得所述的如式A所示化合物，

；方法四中，Z為O或NR ⁵，R ⁵為C ₁-C ₆烷基；其中，R ¹、R ²、R ³、R ⁴、R ^5-1、R ^5-3和R ^5-4的定義如請求項1-9中任一項所述。 A method for preparing a compound represented by formula A as described in any one of claims 1-9, wherein, it is method one, method two, method three or method four, and method one comprises the following steps: in a solvent, in a In the presence of a base, the compound shown in formula II-1A and the compound shown in formula II-2 are subjected to the reaction shown below to obtain the compound shown in formula A,

; Method two comprises the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula III-1A and the compound shown in formula III-2 or III-3 are subjected to the reaction shown below to obtain the described The compound shown in formula A,

; In method one or method two, Z is NR ⁵ , and R ⁵ is

The method three comprises the following steps: in a solvent, in the presence of a base, the compound shown in formula IV-1A and the compound shown in IV-2 are subjected to the reaction shown below to obtain the compound shown in formula A,

; In method three, Z is NR ⁵ , and R ⁵ is

; Method four includes the following steps: in a solvent, in the presence of a base and a catalyst, the compound shown in formula V-1A and the compound shown in formula V-2 or V-3 are subjected to the reaction shown below to obtain the described The compound shown in formula A,

; In method 4, Z is O or NR ⁵ , and R ⁵ is C ₁ -C ₆ alkyl; wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5-1 , R ^5-3 and R ^{5- 4} is as defined in any one of claims 1-9.

一種藥物組合物，其包括如請求項1-9中任一項所述的如式A所示化合物或其藥學上可接受的鹽，和藥用輔料；所述的如式A所示化合物或其藥學上可接受的鹽可為治療有效量的。A pharmaceutical composition, which comprises the compound shown in formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, and a pharmaceutical adjuvant; the compound shown in formula A or A pharmaceutically acceptable salt thereof may be in a therapeutically effective amount.

一種如請求項1-9中任一項所述的如式A所示化合物或其藥學上可接受的鹽、或如請求項11所述的藥物組合物在製備激酶調節劑的應用，所述的激酶調節劑可為激酶抑制劑或激酶激動劑，所述的激酶可為KRAS，例如KRAS G12C。A compound shown in formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, or the application of the pharmaceutical composition as described in claim 11 in the preparation of a kinase regulator, the The kinase modulator may be a kinase inhibitor or a kinase agonist, and the kinase may be KRAS, eg KRAS G12C.

一種如請求項1-9中任一項所述的如式A所示化合物或其藥學上可接受的鹽、或如請求項11所述的藥物組合物在製備藥物中的應用；所述的藥物可為預防和/或治療KRAS相關疾病的藥物或用於預防和/或治療癌症的藥物；所述的KRAS優選KRAS G12C；所述的KRAS相關疾病可為癌症；所述的癌症可為肺癌、胰腺癌、胰腺導管癌、大腸癌、結腸癌、直腸癌、闌尾癌、食道鱗狀細胞癌、頭頸鱗狀細胞癌或乳腺癌；所述的癌症可為以KRAS突變為特徵的癌症。 A compound of formula A or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, or the application of the pharmaceutical composition as described in claim 11 in the preparation of medicine; The drug may be a drug for preventing and/or treating KRAS-related diseases or a drug for preventing and/or treating cancer; Described KRAS is preferably KRAS G12C; The KRAS-related disease can be cancer; The cancer can be lung cancer, pancreatic cancer, pancreatic ductal cancer, colorectal cancer, colon cancer, rectal cancer, appendix cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma or breast cancer; the cancer can be KRAS cancer. Cancers characterized by mutations.