TW202227438A - Aromatic compound, preparation method therefor and use thereof - Google Patents
Aromatic compound, preparation method therefor and use thereof Download PDFInfo
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Abstract
Description
本申請要求申請日為2020/11/24的中國專利申請2020113314318的優先權；要求申請日為2021/11/16的中國專利申請2021113580414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 2020113314318 with the filing date of 2020/11/24; and the priority of Chinese patent application 2021113580414 with the filing date of 2021/11/16. 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.
本發明提供了一種芳香化合物、其製備方法及應用。本發明的芳香化合物可作為蛋白酶降解劑和/或抑制劑，對KRAS尤其是KRAS G12C具有良好的降解和/或抑制作用。The invention provides an aromatic compound, its preparation method and application. The aromatic compounds of the present invention can be used as protease degradation agents and/or inhibitors, and have good degradation and/or inhibitory effects on KRAS, especially KRAS G12C.
本發明提供了一種如式I所示化合物或其藥學上可接受的鹽，
在本發明某一方案中，所述的如式I所示化合物或其藥學上可接受的鹽，
其中，標“*”的碳原子為S構型碳原子、R構型碳原子或非手性碳原子；
Y為N或CH；
Z為O或NR
5；
R
5為C
1-C
6烷基、
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：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
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 5-3a取代或未取代的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 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 5-3a In the case of a C 2 -C 6 alkynyl group, 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 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獨立地為被R 5-3a取代的C 2-C 6炔基時，所述的R 5-3a的個數可為1、2或3個。 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 substituted by R 5-3a When 6 alkynyl groups are used, the number of said R 5-3a can be 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 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7獨立地為被R 5-4a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 substituted or unsubstituted by R 5-4a In the case of 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , the second butoxy group or the third butoxy group, preferably a methoxy 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獨立地為被R 5-4a取代或未取代的C 1-C 6烷氧基時，所述的R 5-4a的個數可為1、2或3個。 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 5-4a In the case of 1 -C 6 alkoxy, the number of said R 5-4a can be 1, 2 or 3.
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1-2個”的5-6元單環雜芳基，更優選吡啶基（例如
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獨立地為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟或氯。 In one embodiment: when R 2-2 is independently halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：當R 2-2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。 In a certain scheme: when R 2-2 is independently 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 2-2獨立地為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 independently 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 2-3獨立地為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟或氯。 In one embodiment: when R 2-3 is independently halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：當R 2-3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。 In a certain scheme: when R 2-3 is independently 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 2-3獨立地為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 2-3 is independently 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 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".
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個”的5-6元單環雜芳基，更優選吡啶基（例如
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，優選環丁基（
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（
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11-18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11-18元雜環可為
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（
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（
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（
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（
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（
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：R
5可為甲基、
在某一方案中：當R 6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 6 is independently 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, preferably methyl or tert-butyl.
在某一方案中：當R 7、R 8、R 9和R 10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 7 , R 8 , R 9 and R 10 are independently 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, preferably methyl or tert-butyl.
在某一方案中：當R
7和R
8、R
9和R
10與所連接的N一起獨立地形成“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環時，所述的3-10元雜環可為“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（
在某一方案中：當R 6a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 6a is independently 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, preferably methyl or tert-butyl.
在某一方案中：當R 3-1a-1和R 3-1a-2獨立地為C 3-C 6環烷基時，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，優選環丙基。在某一方案中：當R 6b獨立地為鹵素時，所述的鹵素可為F、Cl。 In a certain scheme: when R 3-1a-1 and R 3-1a-2 are independently C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl can be cyclopropane, cyclo Butane, cyclopentane or cyclohexane, preferably cyclopropyl. In one embodiment: when R 6b is independently halogen, the halogen can be F, Cl.
在某一方案中：當R
3-1和R
3-2獨立地為-L-R
3-1a時，R
3-1和R
3-2位於
在某一方案中：R
3-1a-1和R
3-1a-2獨立地為
在某一方案中：-L-為
在某一方案中：D為苯基、環烷基或“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10元雜環。In a certain scheme: D is a phenyl group, a cycloalkyl group or a 10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3".
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：
在某一方案中：R
2-2和R
2-1a可獨立地為-OH、-F、-Cl、-NH
2、-OMe、
在某一方案中：R
2-1可為
在某一方案中：R
2可為
在某一方案中：-L-可為
在某一方案中：
在某一方案中：R
3-1a可為
在某一方案中：R
3-1a為
在某一方案中：R
3-1和R
3-2可獨立地為OH、Me、Et、CN、
在某一方案中：R
3可為
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原子的構型可為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 can be the S configuration.
在某一方案中：R 4可為F。 In one aspect: R4 can be F.
在某一方案中：R
3可為
在某一方案中：Y可為N。In one scheme: Y can be N.
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C
1-C
6烷基、
在某一方案中：R
5可為
在某一方案中：R
5可為
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可獨立地為氫、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 be independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 1可為C 1-C 6烷基。 In a certain scheme: R 1 can be C 1 -C 6 alkyl.
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可為被R 2-2取代的苯基。 In a certain scheme: R 2 can be phenyl substituted with R 2-2 .
在某一方案中：R
2-2可為羥基、鹵素、胺基、C
1-C
6烷氧基、
在某一方案中：R
2-2可為羥基、鹵素、胺基、
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 3-1取代或未取代的C 6-C 15芳基。 In a certain scheme: R 3 can be C 6 -C 15 aryl substituted or unsubstituted by R 3-1 .
在某一方案中：R 3可為被R 3-1取代的C 6-C 15芳基。 In a certain scheme: R 3 can be C 6 -C 15 aryl substituted with R 3-1 .
在某一方案中：R 3可為被R 3-1取代的苯基。 In a certain scheme: R3 can be phenyl substituted with R3-1 .
在某一方案中：R 3-1和R 3-2可獨立地為羥基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、-L-R 3-1a。 In a certain scheme: R 3-1 and R 3-2 can independently be hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a .
在某一方案中：R
3-1和R
3-2可獨立地為
在某一方案中：R 3-1和R 3-2可獨立地為氰基或C 1-C 6烷基。 In a certain scheme: R 3-1 and R 3-2 can independently be cyano or C 1 -C 6 alkyl.
在某一方案中：R 3-1可為C 1-C 6烷基或-L-R 3-1a。 In a certain scheme: R 3-1 can be C 1 -C 6 alkyl or -LR 3-1a .
在某一方案中：R 3-1可為C 1-C 6烷基。 In a certain scheme: R 3-1 can be C 1 -C 6 alkyl.
在某一方案中：-L-可為
在某一方案中：-L-可為
在某一方案中：-L-可為、
在某一方案中：n8、n9、n10、n11、n12、n13、n14、n15、n16、n17、n18、n19、n20、n21、n22、n23、n24、n25和n26獨立地為0、1、2、3、4、5或6。In one scheme: n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 are independently 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：n1、n2和n3可獨立地為0、1、2、3、4、5或6。In a certain scheme: nl, n2 and n3 can be independently 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：m1和m2可獨立地為0、1、2或3。In a certain scheme: m1 and m2 can be 0, 1, 2 or 3 independently.
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：m3可獨立地為0、1、2或3。In a certain scheme: m3 can be independently 0, 1, 2 or 3.
在某一方案中：m4獨立地為1、2、3、4或5。In an aspect: m4 is independently 1, 2, 3, 4 or 5.
在某一方案中：m5、m6和m7獨立地為0或1，例如0。In a certain scheme: m5, m6 and m7 are independently 0 or 1, eg 0.
在某一方案中：R 3-1a為E3連接酶的配體，其結構例如可為-O-R 3-1a-3或R 3-1a-4。 In a certain scheme: R 3-1a is a ligand of E3 ligase, and its structure can be, for example, -OR 3-1a-3 or R 3-1a-4 .
在某一方案中：R
3-1a-1和R
3-1a-2中的一個獨立地可為氫、C
1-C
6烷基、C
3-C
6環烷基；R
3-1a-1和R
3-1a-2中的另一個為
在某一方案中：R
3-1a-1和R
3-1a-2可獨立地為氫或
在某一方案中：R 3-1和R 3-2的個數可獨立地為1個或2個。 In a certain scheme: the number of R 3-1 and R 3-2 can be independently 1 or 2.
在某一方案中：R 2-2的個數可為2個，且不同。 In a certain scheme: the number of R 2-2 can be 2 and different.
在某一方案中：
R
4為F；
Y為N或CH；
Z為O或NR
5；
R
5為C
1-C
6烷基、
在某一方案中：
R
4為F；
Y為N或CH；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
本發明中，所述的如式I所示化合物可為如下任一結構，
本發明提供了一種上述的如式I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-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所示化合物，
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.
本發明提供了一種藥物組合物，其包括上述如式I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I所示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 I or a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant. 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；黏合劑，如阿拉伯樹膠粉，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.
本發明提供了一種上述如式I所示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。所述的激酶調節劑在體外使用。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 preparing a kinase modulator. The kinase modulator can be a kinase inhibitor or a kinase agonist. The kinase can be KRAS, eg KRAS G12C. The kinase modulators are used in vitro.
本發明提供了一種上述如式I所示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蛋白酶降解劑的應用。所述的蛋白酶降解劑在體外使用。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 protease degrading agent. The protease degrading agent is used in vitro.
本發明提供了一種上述如式I所示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。The present invention provides an application 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 medicine. 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.
本發明提供了一種如式I所示化合物、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，
在本發明某一方案中，所述的如式I所示化合物、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，
其中，標“*”的碳原子為S構型碳原子、R構型碳原子或非手性碳原子；
Y為N或CH；
Z為O或NR
5；
R
5為C
1-C
6烷基、
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：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
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 5-3a取代或未取代的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 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 5-3a In the case of a C 2 -C 6 alkynyl group, 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 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獨立地為被R 5-3a取代的C 2-C 6炔基時，所述的R 5-3a的個數可為1、2或3個。 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 substituted by R 5-3a When 6 alkynyl groups are used, the number of said R 5-3a can be 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 5-1、R 5-2、R 5-3、R 5-4、R 5-6和R 5-7獨立地為被R 5-4a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 substituted or unsubstituted by R 5-4a In the case of 1 -C 6 alkoxy, the C 1 -C 6 alkoxy can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy , the second butoxy group or the third butoxy group, preferably a methoxy 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獨立地為被R 5-4a取代或未取代的C 1-C 6烷氧基時，所述的R 5-4a的個數可為1、2或3個。 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 5-4a In the case of 1 -C 6 alkoxy, the number of said R 5-4a can be 1, 2 or 3.
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1-2個”的5-6元單環雜芳基，更優選吡啶基（例如
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 2-3獨立地為鹵素時，所述的鹵素可為氟、氯、溴或碘，優選氟或氯。 In one embodiment: when R 2-3 is independently halogen, the halogen can be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在某一方案中：當R 2-3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。 In a certain scheme: when R 2-3 is independently 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 2-3獨立地為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 2-3 is independently 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 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".
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個”的5-6元單環雜芳基，更優選吡啶基（例如
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環烷烴可為環丙烷、環丁烷、環戊烷或環己烷，優選環丁基（
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（
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11-18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11-18元雜環可為
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（
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（
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（
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（
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（
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：R
5可為甲基、
在某一方案中：當R 6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 6 is independently 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, preferably methyl or tert-butyl.
在某一方案中：當R 7、R 8、R 9和R 10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 7 , R 8 , R 9 and R 10 are independently 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, preferably methyl or tert-butyl.
在某一方案中：當R
7和R
8、R
9和R
10與所連接的N一起獨立地形成“雜原子選自N、O和S中的一種或多種，雜原子個數為1-3個”的3-10元雜環時，所述的3-10元雜環可為“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（
在某一方案中：當R 6a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 6a is independently 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, preferably methyl or tert-butyl.
在某一方案中：當R 3-1a-1和R 3-1a-2獨立地為C 3-C 6環烷基時，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，優選環丙基。在某一方案中：當R 6b獨立地為鹵素時，所述的鹵素可為F、Cl。 In a certain scheme: when R 3-1a-1 and R 3-1a-2 are independently C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl can be cyclopropane, cyclo Butane, cyclopentane or cyclohexane, preferably cyclopropyl. In one embodiment: when R 6b is independently halogen, the halogen can be F, Cl.
在某一方案中：當R
3-1和R
3-2獨立地為-L-R
3-1a時，R
3-1和R
3-2位於
在某一方案中：R
3-1a-1和R
3-1a-2獨立地為
在某一方案中：-L-為
在某一方案中：D為苯基、環烷基或“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10元雜環。In a certain scheme: D is a phenyl group, a cycloalkyl group or a 10-membered heterocyclic ring with "hetero atoms selected from one or more of N, O and S, and the number of hetero atoms is 1-3".
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：
在某一方案中：R
2-2和R
2-1a可獨立地為-OH、-F、-Cl、-NH
2、-OMe、
在某一方案中：R
2-1可為
在某一方案中：R
2可為
在某一方案中：-L-可為
在某一方案中：
在某一方案中：R
3-1a可為
在某一方案中：R
3-1a為
在某一方案中：R
3-1和R
3-2可獨立地為OH、Me、Et、CN、
在某一方案中：R
3可為
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.
在某一方案中：R
3為
在某一方案中：Y可為N。In one scheme: Y can be N.
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C
1-C
6烷基、
在某一方案中：R
5可為
在某一方案中：R
5可為
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可獨立地為氫、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 be independently hydrogen, or C 1 -C 6 alkyl substituted or unsubstituted by R 5-1a .
在某一方案中：R 1可為C 1-C 6烷基。 In a certain scheme: R 1 can be C 1 -C 6 alkyl.
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可為被R 2-2取代的苯基。 In a certain scheme: R 2 can be phenyl substituted with R 2-2 .
在某一方案中：R
2-2可為羥基、鹵素、胺基、C
1-C
6烷氧基、
在某一方案中：R
2-2可為羥基、鹵素、胺基、
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 3-1取代或未取代的C 6-C 15芳基。 In a certain scheme: R 3 can be C 6 -C 15 aryl substituted or unsubstituted by R 3-1 .
在某一方案中：R 3可為被R 3-1取代的C 6-C 15芳基。 In a certain scheme: R 3 can be C 6 -C 15 aryl substituted with R 3-1 .
在某一方案中：R 3可為被R 3-1取代的苯基。 In a certain scheme: R3 can be phenyl substituted with R3-1 .
在某一方案中：R 3-1和R 3-2可獨立地為羥基、氰基、C 1-C 6烷基、C 1-C 6烷氧基、-L-R 3-1a。 In a certain scheme: R 3-1 and R 3-2 can independently be hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -LR 3-1a .
在某一方案中：R
3-1和R
3-2可獨立地為
在某一方案中：R 3-1和R 3-2可獨立地為氰基或C 1-C 6烷基。 In a certain scheme: R 3-1 and R 3-2 can independently be cyano or C 1 -C 6 alkyl.
在某一方案中：R 3-1可為C 1-C 6烷基或-L-R 3-1a。 In a certain scheme: R 3-1 can be C 1 -C 6 alkyl or -LR 3-1a .
在某一方案中：R 3-1可為C 1-C 6烷基。 In a certain scheme: R 3-1 can be C 1 -C 6 alkyl.
在某一方案中：-L-可為
在某一方案中：-L-可為
在某一方案中：-L-可為、
在某一方案中：n8、n9、n10、n11、n12、n13、n14、n15、n16、n17、n18、n19、n20、n21、n22、n23、n24、n25和n26獨立地為0、1、2、3、4、5或6。In one scheme: n8, n9, n10, n11, n12, n13, n14, n15, n16, n17, n18, n19, n20, n21, n22, n23, n24, n25 and n26 are independently 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：n1、n2和n3可獨立地為0、1、2、3、4、5或6。In a certain scheme: nl, n2 and n3 can be independently 0, 1, 2, 3, 4, 5 or 6.
在某一方案中：m1和m2可獨立地為0、1、2或3。In a certain scheme: m1 and m2 can be 0, 1, 2 or 3 independently.
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：m3可獨立地為0、1、2或3。In a certain scheme: m3 can be independently 0, 1, 2 or 3.
在某一方案中：m4獨立地為1、2、3、4或5。In an aspect: m4 is independently 1, 2, 3, 4 or 5.
在某一方案中：m5、m6和m7獨立地為0或1，例如0。In a certain scheme: m5, m6 and m7 are independently 0 or 1, eg 0.
在某一方案中：R 3-1a為E3連接酶的配體，其結構例如可為-O-R 3-1a-3或R 3-1a-4。 In a certain scheme: R 3-1a is a ligand of E3 ligase, and its structure can be, for example, -OR 3-1a-3 or R 3-1a-4 .
在某一方案中：R
3-1a-1和R
3-1a-2中的一個獨立地可為氫、C
1-C
6烷基、C
3-C
6環烷基；R
3-1a-1和R
3-1a-2中的另一個為
在某一方案中：R
3-1a-1和R
3-1a-2可獨立地為氫或
在某一方案中：R 3-1和R 3-2的個數可獨立地為1個或2個。 In a certain scheme: the number of R 3-1 and R 3-2 can be independently 1 or 2.
在某一方案中：R 2-2的個數可為2個，且不同。 In a certain scheme: the number of R 2-2 can be 2 and different.
在某一方案中：
R
4為F；
Y為N或CH；
Z為O或NR
5；
R
5為C
1-C
6烷基、
在某一方案中：
R
4為F；
Y為N或CH；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
在某一方案中：
R
4為F；
Y為N；
Z為NR
5；
R
5為
本發明中，所述的如式I所示化合物可為如下任一結構，
本發明提供了一種藥物組合物，其包括上述如式I所示化合物、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。The present invention provides a pharmaceutical composition comprising the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its nitrogen oxide, its metabolism Product, its prodrug, its crystal form, or its solvate, and pharmaceutical excipients. The compound shown in 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.
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.
本發明提供了一種上述如式I所示化合物、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。The present invention provides a compound represented by the above formula I, 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. 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.
本發明提供了一種上述如式I所示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蛋白酶降解劑的應用。所述的蛋白酶降解劑在體外使用。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 protease degrading agent. The protease degrading agent is used in vitro.
本發明提供了一種上述如式I所示化合物、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。The present invention provides a compound represented by the above formula I, 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 medicine. 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.
本發明還提供了一種治療KRAS相關疾病的方法，其包括向患者施用治療有效量的上述如式I所示化合物、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。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。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 I, its pharmaceutically acceptable salt, its stereoisomer, 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 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.
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 administering 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手性分離法（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，還可以通過與其它手性化合物成鍵（化學結合等）或成鹽（物理結合等）等方式進行手性拆分獲得。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 salt formation (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、代謝或排泄等。本發明所述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，例如和氨、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 compound of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting the compound of the present invention with an acid, such as: hydrochloride, hydrobromic acid Salt, Sulfate, Pyrosulfate, Bisulfate, Sulfite, Bisulfite, Phosphate, Monohydrogen Phosphate, Dihydrogen Phosphate, Metaphosphate, Pyrophosphate, Nitrate, Acetate, Acetate Acid, Caprate, Caprylate, Formate, Acrylate, Isobutyrate, Caproate, Heptanoate, Oxalate, Malonate, Succinate, Suberate, Benzoate acid salt, 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 ammonia, 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
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元或11-18元的飽和的單環、雙環或稠環，優選3-7元飽和的單環（更優選5-6元飽和的單環）、10或11元的雙環。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 heteroatoms, preferably 3-10 membered or 11-membered, containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. 18-membered saturated monocyclic, bicyclic or fused ring, preferably 3-7-membered saturated monocyclic (more preferably 5-6-membered saturated monocyclic), 10- or 11-membered bicyclic. 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、三唑基、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式A化合物失去一個原子或原子團後的基團；
本發明中，E3連接酶的配體例如可為式A-1至式A-4化合物失去一個原子或原子團後的基團；
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；
本發明中，E3連接酶的配體例如可為以下任意基團；
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組合物。The term "modulator" refers to a composition 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或/和降解作用。The positive improvement effect of the present invention is that the aromatic compound of the present invention has a good inhibitory effect or/and degradation 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N-（2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡喃并[2,3- d]嘧啶-1（2H）-基）-3-甲基苄基）-6-（（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧異吲哚-4-基）胺基）己醯胺
合成路線：
步驟A（Step A）:將2-(2,6-二氧代-哌啶-3-基)-4-氟基-異吲哚-1,3-二酮（200 mg，0.72 mmol)，6-胺基己酸(114 mg，0.87 mmol)與N,N-二異丙基乙胺(185 mg，1.44 mmol)溶於N,N-二甲基甲醯胺(3mL)，反應液在100攝氏度下攪拌5小時。液相層析串聯質譜顯示原料已反應完，經逆相層析純化得到6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）胺基）己酸（283 mg， 黃色固體，收率94%）。MS (ESI) M/Z：388.1[M+H] +。 Step A (Step A): 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (200 mg, 0.72 mmol), 6-Aminohexanoic acid (114 mg, 0.87 mmol) and N,N-diisopropylethylamine (185 mg, 1.44 mmol) were dissolved in N,N-dimethylformamide (3 mL), the reaction solution was in Stir at 100 degrees Celsius for 5 hours. Liquid chromatography tandem mass spectrometry showed that the raw materials had been reacted, and purified by reverse phase chromatography to obtain 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinoline- 4-yl)amino)hexanoic acid (283 mg, yellow solid, 94% yield). MS (ESI) M/Z: 388.1 [M+H] + .
步驟B（Step B）: 往2,6-二氯-5-氟煙酸(21.2 g，75 mmol)的二氯甲烷溶液（250mL）中滴加草醯氯(11.9 g，93 mmol，溶在50mL二氯甲烷中)，接著加入0.3mLN,N-二甲基甲醯胺（DMF）。反應液室溫攪拌過夜後，旋除溶劑。將剩餘的溶在二氧六環中(250 mL)中，並用冰浴控溫到0 攝氏度。接著往反應液中緩慢滴加氨水溶液(含量28-30% 氨，19 mL，112 mmol)。滴加完畢後，反應液在0 攝氏度攪拌30分鐘。然後將反應液的溶劑旋除，剩餘物加入1：1的乙酸乙酯/石油醚混合溶液，並攪拌5分鐘，接著過濾。將過濾的固體用石油醚洗滌，然後把固體真空乾燥，得到產物2,6-二氯-5-氟煙酸醯胺 (16.0 g，74 mmol，白色固體，收率98%)。MS (ESI) M/Z：209.1[M+H] +。 Step B (Step B): To a solution of 2,6-dichloro-5-fluoronicotinic acid (21.2 g, 75 mmol) in dichloromethane (250 mL) was added dropwise oxalic chloride (11.9 g, 93 mmol, dissolved in 50 mL of dichloromethane), followed by 0.3 mL of N,N-dimethylformamide (DMF). After the reaction solution was stirred at room temperature overnight, the solvent was removed by swirl. The remainder was dissolved in dioxane (250 mL) and the temperature was controlled to 0 degrees Celsius with an ice bath. Then, aqueous ammonia solution (content 28-30% ammonia, 19 mL, 112 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at 0°C for 30 minutes. Then the solvent of the reaction solution was spun off, and the residue was added to a 1:1 ethyl acetate/petroleum ether mixed solution, stirred for 5 minutes, and then filtered. The filtered solid was washed with petroleum ether, then the solid was dried in vacuo to give the product 2,6-dichloro-5-fluoronicotinamide (16.0 g, 74 mmol, white solid, 98% yield). MS (ESI) M/Z: 209.1 [M+H] + .
步驟C（Step C）: 冰浴下，往2,6-二氯-5-氟煙酸醯胺(2.5 g，12mmol) 的四氫呋喃 (10 mL)溶液中緩慢加入草醯氯 (1.83 g，14.4 mmol，溶在7mL二氯甲烷中)。反應液在 75 攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加22-胺基-3-甲苯腈 (1.46 g，12 mmol) 的四氫呋喃 (5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-N-（（2-氰基-6-甲基苯基）氨甲醯）-5-氟煙醯胺 (1.4 g，3.9 mmol，收率32% )。MS (ESI) M/Z：367.1[M+H] +。 Step C (Step C): Under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinamide (2.5 g, 12 mmol) in tetrahydrofuran (10 mL) was slowly added oxalic chloride (1.83 g, 14.4 g) mmol, dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 22-amino-3-toluonitrile (1.46 g, 12 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-N-((2-cyano-6-methylphenyl)carbamate)- 5-Fluoronicotinamide (1.4 g, 3.9 mmol, 32% yield). MS (ESI) M/Z: 367.1 [M+H] + .
步驟D（Step D）: 冰浴下，往2,6-二氯-N-（（2-氰基-6-甲基苯基）氨甲醯）-5-氟煙醯胺 (1.4 g，3.9 mmol) 的四氫呋喃 (20 mL)溶液中緩慢滴加雙(三甲基矽烷基)胺基鉀 (KHMDS，1 M的四氫呋喃溶液，8.2 mL，8.2 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。液相層析串聯質譜檢測到有產物生成。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到2-（7-氯-6-氟-2,4-二氧基-3,4-二氫吡啶[2,3-d]嘧啶-1（2H）-基）-3-甲苯腈 (1.1 g，3.3 mmol，收率84% )。MS (ESI) M/Z：331.1[M+H] +。 Step D (Step D): under ice bath, add 2,6-dichloro-N-((2-cyano-6-methylphenyl)carbamoamide)-5-fluoronicotinamide (1.4 g, 3.9 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise potassium bis(trimethylsilyl)amide (KHMDS, 1 M in tetrahydrofuran, 8.2 mL, 8.2 mmol). After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. Product formation was detected by liquid chromatography tandem mass spectrometry. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 2-(7-chloro-6-fluoro-2,4-dioxy-3, 4-Dihydropyridine[2,3-d]pyrimidin-1(2H)-yl)-3-toluonitrile (1.1 g, 3.3 mmol, 84% yield). MS (ESI) M/Z: 331.1 [M+H] + .
步驟E&F（Step D&E）: 往2-（7-氯-6-氟-2,4-二氧基-3,4-二氫吡啶[2,3-d]嘧啶-1（2H）-基）-3-甲苯腈(0.1 g，0.31 mmol)的甲苯(5 mL)中加入N,N-二異丙基乙胺(DIPEA，80 mg，0.62mmol)和三氯氧磷(95 mg，0.62 mmol)。反應液加熱到50 攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品2-（4,7-二氯-6-氟-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-甲苯腈 (0.105 g)，無需純化，直接投入到下一步反應。Step E&F: To 2-(7-chloro-6-fluoro-2,4-dioxy-3,4-dihydropyridin[2,3-d]pyrimidin-1(2H)-yl) -3-Toluonitrile (0.1 g, 0.31 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (DIPEA, 80 mg, 0.62 mmol) and phosphorus oxychloride (95 mg, 0.62 mmol) ). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain the crude product 2-(4,7-dichloro-6-fluoro-2-oxopyridine[2,3-d]pyrimidine-1(2H)- base)-3-toluonitrile (0.105 g), which was directly used in the next reaction without purification.
將2-（4,7-二氯-6-氟-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-甲苯腈(0.105 g, 0.31mmol)溶於DMF (2 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(62 mg， 0.31 mmol)。攪拌下，往上述反應液中滴加DIPEA (0.2 g，9.5 mmol)。滴加完畢反應液攪拌半小時，液相層析串聯質譜監測反應，顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到第三丁基（S）-4-（7-氯-1-（2-氰基-6-甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸酯(0.14 g，0.28mmol，黃色固體，收率90%)。MS (ESI) M/Z：513.4[M+H] +。 2-(4,7-Dichloro-6-fluoro-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-toluonitrile (0.105 g, 0.31 mmol) was dissolved in DMF (2 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (62 mg, 0.31 mmol) was added at room temperature. With stirring, DIPEA (0.2 g, 9.5 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and the reaction was monitored by liquid chromatography tandem mass spectrometry, indicating that the raw materials had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give tert-butyl(S)-4-(7-chloro-1-(2-) cyano-6-methylphenyl)-6-fluoro-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- Carboxylic acid ester (0.14 g, 0.28 mmol, yellow solid, 90% yield). MS (ESI) M/Z: 513.4 [M+H] + .
步驟G（Step G）: 將第三丁基 (S)-4-(7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(0.14 g，0.28 mmol)，2-氟-6-羥基苯硼酸(87 mg，0.56 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，25 mg，0.03 mmol)和KOAc(醋酸鉀，0.14 g，1.4 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(20/1，4 mL) 用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90 攝氏度，在此溫度下攪拌反應5 小時。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到第三丁基（3S）-4-（1-（2-氰基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（100 mg，0.17 mmol，淡黃色固體，收率：57%）。MS (ESI) M/Z：589.6[M+H] +。 Step G (Step G): tert-butyl (S)-4-(7-chloro-1-(2,4-lutidine-3-yl)-6-fluoro-2-carbonyl-1, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.14 g, 0.28 mmol), 2-fluoro-6-hydroxyphenylboronic acid ( 87 mg, 0.56 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 25 mg, 0.03 mmol) and KOAc (potassium acetate, 0.14 g, 1.4 mmol) were mixed together and evacuated on an oil pump and displaced nitrogen several times. Meanwhile, a mixture of dioxane and water (20/1, 4 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give tert-butyl(3S)-4-(1-(2-cyano-6-methylphenyl)-6 -Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-Carboxylate (100 mg, 0.17 mmol, pale yellow solid, yield: 57%). MS (ESI) M/Z: 589.6 [M+H] + .
步驟H（Step H）: 將（3S）-第三丁基4-（1-（2-氰基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2-二氫吡啶基[2，3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸酯(160 mg，0.27 mmol)溶於氨甲醇（7M，3 mL）溶液中，加入雷尼鎳（20 mg)，抽真空並置換氫氣數次，然後在氫氣環境下攪拌反應16小時。質譜監測到所有的原料轉化成產物，矽藻土過濾得溶液，濃縮得產品（3S）-第三丁基4-（1-（2-（胺基甲基）-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2-二氫吡啶基[ 2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸酯(110 mg，0.18 mmol，黃色固體，收率68%)。MS (ESI) M/Z：593.1[M+H] +。 Step H: (3S)-tert-butyl 4-(1-(2-cyano-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene) yl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (160 mg, 0.27 mmol) was dissolved in Raney nickel (20 mg) was added to ammonia methanol (7M, 3 mL) solution, evacuated and replaced with hydrogen several times, and then the reaction was stirred under hydrogen atmosphere for 16 hours. Mass spectrometry monitored the conversion of all starting materials to product, and the solution was filtered through diatomaceous earth and concentrated to give the product (3S)-tert-butyl 4-(1-(2-(aminomethyl)-6-methylphenyl) -6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperidine Azine-1-carboxylate (110 mg, 0.18 mmol, yellow solid, 68% yield). MS (ESI) M/Z: 593.1 [M+H] + .
步驟I（Step I）:將（3S）-第三丁基4-（1-（2-（胺基甲基）-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2-二氫吡啶基[ 2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸酯(110 mg，0.18 mmol)與HATU(N,N,N,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲，69 mg，0.18 mmol)和6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜多林-4-基）胺基）己酸（(70 mg，0.18 mmol）溶於無水二氯甲烷（2 mL)中，室溫下攪拌反應6小時。質譜檢測到所有原料轉化為產物，逆相層析純化（已腈：水(千分之一甲酸））得到產物（3S）-第三丁基4-（1-（2-（（6-（（2-（2,6-二氧代哌啶-3-基l）-1,3-二氧異吲哚-4-基）胺基）六胺基）甲基 ）-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪- 1-羧酸酯（100 mg，黃色固體，收率57%)。Step I (Step I): (3S)-tert-butyl 4-(1-(2-(aminomethyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro- 6-Hydroxyphenyl)-2-oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.18 mmol) with HATU (N,N,N,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, 69 mg, 0.18 mmol) and 6-(( 2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxadolin-4-yl)amino)hexanoic acid ((70 mg, 0.18 mmol) in anhydrous dichloromethane (2 mL), the reaction was stirred at room temperature for 6 hours. Mass spectrometry detected that all the raw materials were converted into products, and purified by reverse phase chromatography (nitrile: water (1/1000 formic acid)) to obtain the product (3S)-third butyl base 4-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino )hexaamino)methyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2, 3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, yellow solid, 57% yield).
步驟J&K（Step J&K）: 將(（3S）-第三丁基4-（1-（2-（（6-（（2-（2,6-二氧代哌啶-3-基l）-1,3-二氧異吲哚-4-基）胺基）六胺基）甲基 ）-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪- 1-羧酸酯 (0.1 g，0.10 mmol) 溶於二氯甲烷 (2 mL)，然後加入1mL三氟乙酸。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於2mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，50 g，0.4 mmol)和丙烯醯氯(15 mg，0.1 mmol)。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效液相純化得到N-（2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡喃并[2,3- d]嘧啶-1（2H）-基）-3-甲基苄基）-6-（（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧異吲哚-4-基）胺基）己醯胺（32 mg，0.11 mmol，淡黃色固體，收率：34%）。MS (ESI) M/Z：916.4[M+H] +。 Step J&K (Step J&K): ((3S)-tert-butyl 4-(1-(2-((6-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxisoindol-4-yl)amino)hexaamino)methyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl) -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.1 g, 0.10 mmol) in dichloro Methane (2 mL), then 1 mL of trifluoroacetic acid was added. The reaction solution was stirred for 1 hour at 20 degrees Celsius. Liquid chromatography tandem mass spectrometry showed that the raw materials had been reacted. Stop the reaction, and the solvent was spun off under reduced pressure, and the crude product was re-used with dichloromethane. Methane was azeotroped twice. The crude product was redissolved in 2 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 50 g, 0.4 mmol) and acryl chloride (15 mg, 0.1 mmol) were added to the reaction solution. mmol). The reaction solution was stirred for 2 hours at 20 degrees Celsius. LCMS showed that the raw material was completely converted into the product. The reaction was stopped, and the solvent was removed. The crude product was purified by high performance liquid phase to obtain N-(2-(4-((S)-4 -Propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyrano[2,3-d]pyrimidine- 1(2H)-yl)-3-methylbenzyl)-6-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4 -yl)amino)hexanamide (32 mg, 0.11 mmol, pale yellow solid, yield: 34%). MS (ESI) M/Z: 916.4 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.24 (s, 1H), 8.32 – 8.03 (m, 1H), 7.87 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.26 (dd, J = 16.8, 6.1 Hz, 3H), 7.17 (s, 1H), 7.04 (dd, J = 24.9, 7.7 Hz, 2H), 6.92 – 6.78 (m, 1H), 6.78 – 6.62 (m, 2H), 6.50 (s, 1H), 6.27 – 6.11 (m, 1H), 5.75 (d, J = 11.6 Hz, 1H), 5.05 (dd, J = 12.6, 5.2 Hz, 1H), 4.81 (d, J = 130.7 Hz, 1H), 4.49 – 4.24 (m, 2H), 4.15 (s, 2H), 3.91 (dd, J = 14.1, 5.1 Hz, 1H), 3.73 (dd, J = 37.0, 23.5 Hz, 1H), 3.51 (d, J = 8.3 Hz, 1H), 3.24 (d, J = 6.3 Hz, 2H), 3.13 (s, 1H), 2.87 (dd, J = 18.0, 4.9 Hz, 1H), 2.07 – 2.00 (m, 1H), 1.88 (s, 3H), 1.71 (s, 1H), 1.49 (d, J = 6.5 Hz, 2H), 1.41 (d, J = 5.0 Hz, 2H), 1.30 (s, 3H), 1.21 (d, J = 22.4 Hz, 5H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.24 (s, 1H), 8.32 – 8.03 (m, 1H), 7.87 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.26 (dd, J = 16.8, 6.1 Hz, 3H), 7.17 (s, 1H), 7.04 (dd, J = 24.9, 7.7 Hz, 2H), 6.92 – 6.78 (m, 1H), 6.78 – 6.62 (m, 2H), 6.50 (s, 1H), 6.27 – 6.11 (m, 1H), 5.75 (d, J = 11.6 Hz, 1H), 5.05 (dd, J = 12.6, 5.2 Hz, 1H), 4.81 (d, J = 130.7 Hz, 1H), 4.49 – 4.24 (m, 2H), 4.15 (s, 2H), 3.91 (dd, J = 14.1, 5.1 Hz, 1H), 3.73 (dd, J = 37.0, 23.5 Hz, 1H), 3.51 (d, J = 8.3 Hz, 1H), 3.24 (d, J = 6.3 Hz, 2H), 3.13 (s, 1H), 2.87 (dd, J = 18.0, 4.9 Hz, 1H) , 2.07 – 2.00 (m, 1H), 1.88 (s, 3H), 1.71 (s, 1H), 1.49 (d, J = 6.5 Hz, 2H), 1.41 (d, J = 5.0 Hz, 2H), 1.30 ( s, 3H), 1.21 (d, J = 22.4 Hz, 5H).
實施例 2：合成2-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-N-（4-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）胺基）丁基）-3-甲基苯甲醯胺
合成路線：
步驟A（Step A）: 把2,6-二氯-5-氟煙腈(50 g，263.0 mmol)加入到250mL的濃硫酸中。反應液50攝氏度室溫攪拌過3個小時，把反應液倒入到冰水中，用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品產物2,6-二氯-5-氟煙酸醯胺 (50.0 g，74 mmol，白色固體，收率91.4%)。MS (ESI) M/Z：209.1；211.1[M+H] +。 Step A: 2,6-Dichloro-5-fluoronicotinonitrile (50 g, 263.0 mmol) was added to 250 mL of concentrated sulfuric acid. The reaction solution was stirred at room temperature at 50 degrees Celsius for 3 hours, poured into ice water, extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product 2,6-dichloro -5-Fluoronicotinamide (50.0 g, 74 mmol, white solid, 91.4% yield). MS (ESI) M/Z: 209.1; 211.1 [M+H] + .
步驟B（Step B）: 冰浴下，往2,6-二氯-5-氟煙酸醯胺(50 g，240mmol)的二氯乙烷(500 mL)溶液中緩慢加入草醯氯 (36.63 g，288.5 mmol，溶在150 mL二氯甲烷中)。反應液在 80 攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下接著往反應液中滴加2-胺基-3-甲基苯甲酸甲酯(51.56 g，312.5 mmol)的二氯乙烷(100 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。過濾，旋乾得到粗品2-（3-（2,6-二氯-5-氟煙醯基）脲基）-3-甲基苯甲酸甲酯(70 g，175 mmol，收率73% )。MS (ESI) M/Z：399.9; 401.9[M+H] +。 Step B (Step B): Under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid amide (50 g, 240 mmol) in dichloroethane (500 mL) was slowly added oxalic chloride (36.63 oz.) g, 288.5 mmol in 150 mL of dichloromethane). The reaction solution was heated at 80°C for one hour and then stopped. The reaction solution was removed under reduced pressure to remove half of the solvent, and then placed under an ice bath and then added dropwise to the reaction solution 2-amino-3-methylbenzoic acid methyl ester (51.56 g, 312.5 mmol) in dichloroethane (100 mmol). mL) solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Filtration, spin-dried to obtain crude product 2-(3-(2,6-dichloro-5-fluoronicotinyl)ureido)-3-methylbenzoic acid methyl ester (70 g, 175 mmol, yield 73%) . MS (ESI) M/Z: 399.9; 401.9 [M+H] + .
步驟C（Step C）: -78攝氏度度乾冰浴下，往2-（3-（2,6-二氯-5-氟煙醯基）脲基）-3-甲基苯甲酸甲酯( (50 g，125.3 mmol)的四氫呋喃(500 mL)溶液中緩慢滴加雙(三甲基矽烷基)胺基鉀(KHMDS，1 M的四氫呋喃溶液，250.6 mL，250.6 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌3個小時。液相層析串聯質譜檢測到有產物生成。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯/石油醚）得到2-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸甲酯(4.5 g，1.25 mmol，收率9.9% )。MS (ESI) M/Z：364.0; 365.9[M+H] +。 Step C (Step C): under -78 degrees Celsius dry ice bath, add 2-(3-(2,6-dichloro-5-fluoronicotinyl)ureido)-3-methylbenzoate (( 50 g, 125.3 mmol) in tetrahydrofuran (500 mL) was slowly added dropwise potassium bis(trimethylsilyl)amide (KHMDS, 1 M solution in tetrahydrofuran, 250.6 mL, 250.6 mmol). The bath was removed, and the reaction solution was stirred at room temperature for 3 hours. Liquid chromatography tandem mass spectrometry detected product generation. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, Filter and spin dry. The crude product is purified by silica gel column chromatography (mobile phase: 0-50% ethyl acetate/petroleum ether) to obtain 2-(7-chloro-6-fluoro-2,4-dioxo-3,4-di Hydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid methyl ester (4.5 g, 1.25 mmol, 9.9% yield). MS (ESI) M/Z: 364.0 ; 365.9[M+H] + .
步驟D&E（Step D&E）: 往2-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸甲酯(4.5 g，1.25 mmol)的乙腈(50 mL)中加入N,N-二異丙基乙胺 (DIPEA，9.52 g，74.38mmol)和三氯氧磷(11.38g，74.38 mmol)。 反應液加熱到80 攝氏度，攪拌60分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品2-（4,7-二氯-6-氟-2-氧吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸甲酯 (4.5 g)，無需純化，直接投入到下一步反應MS (ESI) M/Z：381.9；383.9[M+H] +。 Step D&E: To 2-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl )-methyl 3-methylbenzoate (4.5 g, 1.25 mmol) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (DIPEA, 9.52 g, 74.38 mmol) and phosphorus oxychloride ( 11.38 g, 74.38 mmol). The reaction solution was heated to 80°C and stirred for 60 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain the crude product 2-(4,7-dichloro-6-fluoro-2-oxypyrido[2,3-d]pyrimidine-1 (2H) -yl)-3-methylbenzoic acid methyl ester (4.5 g), without purification, directly into the next reaction MS (ESI) M/Z: 381.9; 383.9 [M+H] + .
將2-（4,7-二氯-6-氟-2-氧吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸甲酯(4.5 g，11.8mmol)溶於DMF(50mL)中，然後室溫下加入（S）-3-甲基哌嗪-1-羧酸第三丁酯(2.36 mg，11.8 mmol)。攪拌下，往上述反應液中滴加DIPEA(9.14 g，70.8 mmol)。滴加完畢反應液攪拌半小時，液相層析串聯質譜監測反應，顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯/石油醚）第三丁基（S）-4-（7-氯-6-氟-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸鹽(4.0 g，7.34mmol，黃色固體，收率62%)。MS (ESI) M/Z：546.0; 548.0[M+H] +。 Methyl 2-(4,7-dichloro-6-fluoro-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoate (4.5 g, 11.8 mmol) in DMF (50 mL), then (S)-3-methylpiperazine-1-carboxylate tert-butyl ester (2.36 mg, 11.8 mmol) was added at room temperature. With stirring, DIPEA (9.14 g, 70.8 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and the reaction was monitored by liquid chromatography tandem mass spectrometry, indicating that the raw materials had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate/petroleum ether) tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-(methoxycarbonyl) )-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (4.0 g, 7.34 mmol, yellow solid, 62% yield). MS (ESI) M/Z: 546.0; 548.0 [M+H] + .
步驟F（Step F）: 將得到的第三丁基（S）-4-（7-氯-6-氟-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸鹽(2 g，3.67 mmol)，2-氟苯硼酸(1.03 g，7.36 mmol)，Pd(dppf)Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀，268.5 mg，0.37 mmol)和KOAc(醋酸鉀，0.72g，7.36 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，40 mL) 用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90 攝氏度，在此溫度下攪拌反應過夜。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相0-80% 乙酸乙酯/石油醚）得到第三丁基（S）-4-（6-氟-7-（2-氟苯基）-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3- d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（1.5g，2.48 mmol，淡黃色固體，收率：67%）。MS (ESI) M/Z：606.3[M+H] +。 Step F (Step F): The obtained tert-butyl (S)-4-(7-chloro-6-fluoro-1-(2-(methoxycarbonyl)-6-methylphenyl)-2- Oxy-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2 g, 3.67 mmol), 2-fluorophenylboronic acid ( 1.03 g, 7.36 mmol), Pd(dppf)Cl2 ([1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride, 268.5 mg, 0.37 mmol) and KOAc (potassium acetate, 0.72 g) , 7.36 mmol) were mixed together and evacuated on the oil pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 40 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, where the reaction was stirred overnight. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate/petroleum ether) to give tert-butyl(S)-4-(6-fluoro-7-(2-fluorophenyl)-1- (2-(methoxycarbonyl)-6-methylphenyl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine -1-carboxylic acid (1.5 g, 2.48 mmol, pale yellow solid, yield: 67%). MS (ESI) M/Z: 606.3 [M+H] + .
步驟G（Step G）: 將得到的第三丁基（S）-4-（6-氟-7-（2-氟苯基）-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3- d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（1.5g，2.48 mmol）溶於甲醇(4mL)，四氫呋喃（4mL）和水（4mL）的混合溶液中，然後加入一水合氫氧化鋰（0.31g，7.44 mmol）。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示有20%左右的產物，停止反應，加水稀釋用醋酸調pH到3 ，用二氯甲烷萃取兩次，有機相用無水硫酸鈉乾燥，過濾濃縮。減壓旋除掉，粗品經高效液相純化得到（S）-2-（4-（4-（4-（第三丁氧基羰基）-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸（200 mg，0.34 mmol，白色固體，收率：13.6%）。MS (ESI) M/Z：592.3[M+H] + Step G (Step G): The obtained tert-butyl (S)-4-(6-fluoro-7-(2-fluorophenyl)-1-(2-(methoxycarbonyl)-6-methyl) Phenyl)-2-oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (1.5 g, 2.48 mmol) was dissolved in To a mixed solution of methanol (4 mL), tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.31 g, 7.44 mmol). The reaction solution was stirred at 20°C for 1 hour. Liquid chromatography tandem mass spectrometry showed about 20% product, stop the reaction, dilute with water, adjust pH to 3 with acetic acid, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter and concentrate. Spin off under reduced pressure, and the crude product was purified by high performance liquid phase to obtain (S)-2-(4-(4-(4-(3rd-butoxycarbonyl)-2-methylpiperazin-1-yl)-6 -Fluoro-7-(2-fluorophenyl)-2-oxopyrido[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid (200 mg, 0.34 mmol, white solid , yield: 13.6%). MS (ESI) M/Z: 592.3 [M+H] +
步驟H（Step H）: 將得到的（S）-2-（4-（4-（4-（第三丁氧基羰基）-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡啶并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸（100 mg，0.17 mmol）溶於二氯甲烷（5 mL）中，然後加入4-（（4-胺基丁基）胺基）-2-（2,6-二氧代哌啶-3-基）異吲哚啉-1,3-二酮（87.7mg，0.26 mmol）；雙(二甲基胺基)甲叉-三唑[4,5-B]吡啶3-氧化物,六氟磷酸鹽；2-(7-偶氮苯并三氮唑)-N,N,N'''',N''''-四甲基脲六氟磷酸酯(96.9 mg，0.26 mmol，HATU) 最後在混合液中加入N,N-二異丙基乙胺 (DIPEA，52.92 mg，0.51mmol)。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示反應底物反應完全，停止反應，加水淬滅，用二氯甲烷萃取兩次，有機相用無水硫酸鈉乾燥，過濾濃縮。減壓旋除掉，粗產品經矽膠柱層析純化（流動相0-10% 甲醇/二氯甲烷）得到第三丁基（3S）-4-（1-（2-（（4-（（2-（2,6-dioxopiperidin-3-yl）-1,3-dioxoisoindindolin-4-yl）amino）butyl）carbamoyl ）-6-甲基苯基）-6-氟-7-（2-氟苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（100 mg，0.11 mmol，淡黃色油狀物，收率：64.4%）。MS (ESI) M/Z：918.3[M+H] + Step H (Step H): The obtained (S)-2-(4-(4-(4-(3rd-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-fluoro- 7-(2-Fluorophenyl)-2-oxypyrido[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid (100 mg, 0.17 mmol) in dichloromethane (5 mL), then 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketone (87.7 mg, 0.26 mmol); bis(dimethylamino)methylene-triazo[4,5-B]pyridine 3-oxide, hexafluorophosphate; 2-(7-azobenzotris Azole)-N,N,N'''',N''''-tetramethylurea hexafluorophosphate (96.9 mg, 0.26 mmol, HATU) Finally, N,N-diisopropane was added to the mixture Ethylethylamine (DIPEA, 52.92 mg, 0.51 mmol). The reaction solution was stirred at 20 degrees Celsius for 1 hour. Liquid chromatography tandem mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, quenched by adding water, and extracted twice with dichloromethane , the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Spinned off under reduced pressure, the crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane) to obtain tert-butyl (3S)-4- (1-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin-4-yl)amino)butyl)carbamoyl)-6-methylphenyl) -6-Fluoro-7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 -formic acid (100 mg, 0.11 mmol, pale yellow oil, yield: 64.4%). MS (ESI) M/Z: 918.3 [M+H] +
步驟I&J（Step I&J）: 將得到的第三丁基（3S）-4-（1-（2-（（4-（（2-（2,6-dioxopiperidin-3-yl）-1,3-dioxoisoindindolin-4-yl）amino）butyl）carbamoyl ）-6-甲基苯基）-6-氟-7-（2-氟苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（100 mg，0.11 mmol） 溶於二氯甲烷（5 mL）中，然後加入1mL三氟乙酸，反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示反應底物反應完全，停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次，粗品再溶於3mL二氯甲烷中，往反應液中分別加入DIPEA (N,N-二異丙基乙胺，43 mg，0.33 mmol)和丙烯醯氯(10 mg，0.11 mmol)。反應液在零下20攝氏度下攪拌1小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡喃并[2,3-d]嘧啶-1（2H ）-基）-N-（4-（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧代異吲哚啉-4-基）胺基）丁基）-3-甲基苯甲醯胺（37.8 mg，0.04 mmol，淡黃色固體，收率：39%）。MS (ESI) M/Z：871.9[M+H] +。 Step I&J (Step I&J): The obtained tertiary butyl (3S)-4-(1-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindindolin-4-yl)amino)butyl)carbamoyl)-6-methylphenyl)-6-fluoro-7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2 ,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (100 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), then 1 mL of trifluoroacetic acid was added, and the reaction solution was Stir for 1 hour at 20°C. Liquid chromatography tandem mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, the solvent was spun off under reduced pressure, the crude product was azeotroped twice with dichloromethane, the crude product was redissolved in 3 mL of dichloromethane, and added to the reaction solution respectively. DIPEA (N,N-diisopropylethylamine, 43 mg, 0.33 mmol) and allyl chloride (10 mg, 0.11 mmol). The reaction solution was stirred at minus 20 degrees Celsius for 1 hour. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 2-(4-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluorophenyl)- 2-Oxypyrano[2,3-d]pyrimidin-1(2H)-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-4-yl)amino)butyl)-3-methylbenzamide (37.8 mg, 0.04 mmol, pale yellow solid, yield: 39%). MS (ESI) M/Z: 871.9 [M+H] + .
1H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 8.39 – 8.08 (m, 2H), 7.60 – 7.19 (m, 8H), 7.11 – 6.95 (m, 2H), 6.92-6.72 (m, 1H), 6.52-6.37 (m, 1H), 6.25-6.13 (m, 1H), 5.75 (dd, J = 12.8, 2.0 Hz, 1H), 5.04 (dd, J = 12.8, 5.6 Hz, 1H), 4.95-4.64 (m, 1H), 4.47 – 3.90 (m, 3H), 3.76-3.45(m, 2H), 3.27 – 3.12 (m, 3H), 3.09-2.94 (m, 3H), 2.96 – 2.80 (m, 1H), 2.68-2.55 (m, 2H), 2.13-2.04 (m, 3H), 2.04 – 1.96 (m, 1H), 1.49-1.37 (m, 2H), 1.28 (dt, J = 17.6, 8.8 Hz, 6H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 8.39 – 8.08 (m, 2H), 7.60 – 7.19 (m, 8H), 7.11 – 6.95 (m, 2H), 6.92-6.72 (m, 1H), 6.52-6.37 (m, 1H), 6.25-6.13 (m, 1H), 5.75 (dd, J = 12.8, 2.0 Hz, 1H), 5.04 (dd, J = 12.8, 5.6 Hz, 1H) ), 4.95-4.64 (m, 1H), 4.47 – 3.90 (m, 3H), 3.76-3.45(m, 2H), 3.27 – 3.12 (m, 3H), 3.09-2.94 (m, 3H), 2.96 – 2.80 (m, 1H), 2.68-2.55 (m, 2H), 2.13-2.04 (m, 3H), 2.04 – 1.96 (m, 1H), 1.49-1.37 (m, 2H), 1.28 (dt, J = 17.6, 8.8 Hz, 6H).
實施例 3：合成2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡喃并[2,3-d]嘧啶-1（2H ）-基）-N-（2-（2-（（2-（2-，2,6-二氧代哌啶-3-基）-1,3-二氧代異吲哚啉-4-基）胺基）乙氧基）乙基）-3-甲基苯甲醯胺
合成路線：
其合成步驟與實施例2相同。The synthesis steps are the same as those in Example 2.
MS (ESI) M/Z：887.8 [M+H] +。 MS (ESI) M/Z: 887.8 [M+H] + .
1H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 8.44 – 8.04 (m, 2H), 7.60 – 7.17 (m, 8H), 7.04 (dd, J = 25.2, 7.6 Hz, 2H), 6.95-6.71 (m, 1H), 6.55 (t, J = 5.6 Hz, 1H), 6.19 (d, J = 18.4 Hz, 1H), 5.80 – 5.69 (m, 1H), 5.04 (dd, J = 12.4, 5.2 Hz, 1H), 4.84 (d, J = 53.2 Hz, 1H), 4.58 – 3.94 (m, 3H), 3.80 – 3.42 (m, 4H), 3.27-3.20 (m, 3H), 3.19-3.03 (m, 3H), 2.94 – 2.81 (m, 1H), 2.72-2.53 (m, 1H), 2.08-2.04 (m, 3H), 2.03-1.97(m, 1H), 1.34 – 1.20 (m, 5H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 8.44 – 8.04 (m, 2H), 7.60 – 7.17 (m, 8H), 7.04 (dd, J = 25.2, 7.6 Hz, 2H ), 6.95-6.71 (m, 1H), 6.55 (t, J = 5.6 Hz, 1H), 6.19 (d, J = 18.4 Hz, 1H), 5.80 – 5.69 (m, 1H), 5.04 (dd, J = 12.4, 5.2 Hz, 1H), 4.84 (d, J = 53.2 Hz, 1H), 4.58 – 3.94 (m, 3H), 3.80 – 3.42 (m, 4H), 3.27-3.20 (m, 3H), 3.19-3.03 (m, 3H), 2.94 – 2.81 (m, 1H), 2.72-2.53 (m, 1H), 2.08-2.04 (m, 3H), 2.03-1.97(m, 1H), 1.34 – 1.20 (m, 5H) .
實施例 4：合成2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡喃并[2,3-d]嘧啶-1（2H）-基）-N-（4-（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）丁基）-3-甲基苯甲醯胺
合成路線：
步驟F之前的合成與實施例2相同。The synthesis before step F was the same as in Example 2.
步驟F（Step F）: 將第三丁基（S）-4-（7-氯-6-氟-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸鹽(2 g，3.67 mmol)，（2-氟-6-羥基苯基）硼酸(1.42 g，7.36 mmol)，Pd(dppf)Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀，268.5 mg，0.37 mmol)和KOAc(醋酸鉀，0.72g，7.36 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，40 mL) 用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90 攝氏度，在此溫度下攪拌反應過夜。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相0-80% 乙酸乙酯/石油醚）第三丁基（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧-1,2-二氫吡啶基[ 2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（1.0 g，1.61 mmol，淡黃色固體，收率：44%）。MS (ESI) M/Z：622.0[M+H] +。 Step F (Step F): tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-(methoxycarbonyl)-6-methylphenyl)-2-oxo- 1,2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2 g, 3.67 mmol), (2-fluoro-6-hydroxy phenyl)boronic acid (1.42 g, 7.36 mmol), Pd(dppf)Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 268.5 mg, 0.37 mmol) and KOAc ( Potassium acetate, 0.72 g, 7.36 mmol) were mixed together and evacuated on the oil pump and displaced nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 40 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, where the reaction was stirred overnight. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate/petroleum ether) tert-butyl(3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl) -1-(2-(Methoxycarbonyl)-6-methylphenyl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methyl Piperazine-1-carboxylic acid (1.0 g, 1.61 mmol, pale yellow solid, yield: 44%). MS (ESI) M/Z: 622.0 [M+H] + .
步驟G（Step G）: 將得到的第三丁基（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-（甲氧羰基）-6-甲基苯基）-2-氧-1,2-二氫吡啶基[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（1.0 g，1.61 mmol）溶於二氯甲烷（10 mL）中，分別加入甲氧基甲基次溴酸鹽(338 mg，2.42 mmol)，DIPEA(N,N-二異丙基乙胺，623 mg，4.83 mmol)，在室溫下下攪拌4小時。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，二氯甲烷萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相0-80% 乙酸乙酯/石油醚）得到第三丁基（3S）-4-（6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-1-（2-（甲氧基羰基）-6-甲基苯基）-2-氧代-1,2 -二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（1.0 g，1.50 mmol，黃色固體，收率：93%）。MS (ESI) M/Z：666.2[M+H] +。 Step G (Step G): The obtained tert-butyl (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(methoxycarbonyl)- 6-Methylphenyl)-2-oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (1.0 g, 1.61 mmol ) was dissolved in dichloromethane (10 mL), methoxymethyl hypobromite (338 mg, 2.42 mmol), DIPEA (N,N-diisopropylethylamine, 623 mg, 4.83 mmol) were added respectively , and stirred at room temperature for 4 hours. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate/petroleum ether) to give tert-butyl(3S)-4-(6-fluoro-7-(2-fluoro-6-(methoxy)) methoxy)phenyl)-1-(2-(methoxycarbonyl)-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine -4-yl)-3-methylpiperazine-1-carboxylic acid (1.0 g, 1.50 mmol, yellow solid, yield: 93%). MS (ESI) M/Z: 666.2 [M+H] + .
步驟H（Step H）: 第三丁基（3S）-4-（6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-1-（2-（甲氧基羰基）-6-甲基苯基）-2-氧代-1,2 -二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（500 mg，0.85 mmol）溶於甲醇 (4 mL)，四氫呋喃（4 mL）和水（4 mL）的混合溶液中，然後加入一水合氫氧化鋰（107mg，2.55 mmol）。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示有20%左右的產物，停止反應。加水稀釋用醋酸調pH到3 ，用二氯甲烷萃取兩次，有機相用無水硫酸鈉乾燥，過濾濃縮。減壓旋除掉，粗品經高效液相純化得到2-（4-（（S）-4-（第三丁氧基羰基）-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-2-氧吡咯并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸（100 mg，0.15 mmol，白色固體，收率：18%）。MS (ESI) M/Z：652.0[M+H] +。 Step H: tert-butyl(3S)-4-(6-fluoro-7-(2-fluoro-6-(methoxymethoxy)phenyl)-1-(2-(methyl) oxycarbonyl)-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (500 mg, 0.85 mmol) was dissolved in a mixed solution of methanol (4 mL), tetrahydrofuran (4 mL) and water (4 mL), then lithium hydroxide monohydrate (107 mg, 2.55 mmol) was added. The reaction solution was stirred at 20°C for 1 hour. Liquid chromatography tandem mass spectrometry showed about 20% product, and the reaction was stopped. It was diluted with water and adjusted to pH 3 with acetic acid, extracted twice with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Spin off under reduced pressure, and the crude product was purified by high performance liquid phase to obtain 2-(4-((S)-4-(3-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-fluoro- 7-(2-Fluoro-6-(methoxymethoxy)phenyl)-2-oxopyrrolo[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid ( 100 mg, 0.15 mmol, white solid, yield: 18%). MS (ESI) M/Z: 652.0 [M+H] + .
步驟I（Step I）: 將得到的2-（4-（（S）-4-（第三丁氧基羰基）-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-2-氧吡咯并[2,3-d]嘧啶-1（2H）-基）-3-甲基苯甲酸（100 mg, 0.15 mmol）溶於二氯甲烷（5 mL）中，然後加入4-（（4-胺基丁基）胺基）-2-（2,6-二氧代哌啶-3-基）異吲哚啉-1,3-二酮（61.9mg，0.18 mmol）；雙(二甲基胺基)甲叉-三唑[4,5-B]吡啶3-氧化物，六氟磷酸鹽；2-(7-偶氮苯并三氮唑)-N,N,N'''',N''''-四甲基脲六氟磷酸酯(68.4 mg，0.18 mmol，HATU) 最後在混合液中加入N,N-二異丙基乙胺 (DIPEA，34.56 mg，0.27mmol)。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示反應底物反應完全，停止反應，加水淬滅，用二氯甲烷萃取兩次，有機相用無水硫酸鈉乾燥，過濾濃縮。減壓旋除掉，粗產品經矽膠柱層析純化（流動相0-10% 甲醇/二氯甲烷）第三丁基（3S）-4-（1-（2-（（4-（（2-（2,6-dioxopiperidin-3-yl）-1,3-dioxoisoindindolin-4-yl）amino）butyl）carbamoyl ）-6-甲基苯基）-6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3 -甲基哌嗪-1-羧酸酯（60 mg, 0.06 mmol, 淡黃色油狀物，收率：40%）。MS (ESI) M/Z：978.2[M+H] + Step I (Step I): The obtained 2-(4-((S)-4-(the third butoxycarbonyl)-2-methylpiperazin-1-yl)-6-fluoro-7-( 2-Fluoro-6-(methoxymethoxy)phenyl)-2-oxopyrrolo[2,3-d]pyrimidin-1(2H)-yl)-3-methylbenzoic acid (100 mg, 0.15 mmol) in dichloromethane (5 mL), then 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindium was added Doline-1,3-dione (61.9 mg, 0.18 mmol); bis(dimethylamino)methylene-triazo[4,5-B]pyridine 3-oxide, hexafluorophosphate; 2- (7-Azobenzotriazole)-N,N,N'''',N''''-tetramethylurea hexafluorophosphate (68.4 mg, 0.18 mmol, HATU) finally in the mixture N,N-Diisopropylethylamine (DIPEA, 34.56 mg, 0.27 mmol) was added. The reaction solution was stirred at 20°C for 1 hour. Liquid chromatography tandem mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, quenched by adding water, extracted twice with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Spin off under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase 0-10% methanol/dichloromethane) tert-butyl (3S)-4-(1-(2-((4-((2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin-4-yl)amino)butyl)carbamoyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6 -(Methoxymethoxy)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate acid ester (60 mg, 0.06 mmol, pale yellow oil, yield: 40%). MS (ESI) M/Z: 978.2[M+H] +
步驟J&K（Step J&K）: 第三丁基（3S）-4-（1-（2-（（4-（（2-（2,6-dioxopiperidin-3-yl）-1,3-dioxoisoindindolin-4-yl）amino）butyl）carbamoyl ）-6-甲基苯基）-6-氟-7-（2-氟-6-（甲氧基甲氧基）苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3 -甲基哌嗪-1-羧酸酯（60 mg, 0.06 mmol）溶於二氯甲烷（5 mL）中，然後加入1mL三氟乙酸，反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示反應底物反應完全，停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次，粗品再溶於3mL二氯甲烷中，往反應液中分別加入DIPEA (N,N-二異丙基乙胺，22 mg，0.18 mmol)和丙烯醯氯(5.5 mg，0.06 mmol)。反應液在零下20攝氏度下攪拌1小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡喃并[2,3-d]嘧啶-1（2H）-基）-N-（4-（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）丁基）-3-甲基苯甲醯胺（9.2 mg，0.01 mmol，淡黃色固體，收率：17%）。MS (ESI) M/Z：887.8[M+H] +。 Step J&K (Step J&K): Tertiary Butyl(3S)-4-(1-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindindolin-4 -yl)amino)butyl)carbamoyl)-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-(methoxymethoxy)phenyl)-2-oxo-1, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL), Then 1 mL of trifluoroacetic acid was added, and the reaction solution was stirred at 20 degrees Celsius for 1 hour. Liquid chromatography tandem mass spectrometry showed that the reaction substrate was completely reacted, the reaction was stopped, the solvent was spun off under reduced pressure, the crude product was azeotroped twice with dichloromethane, the crude product was redissolved in 3 mL of dichloromethane, and added to the reaction solution respectively. DIPEA (N,N-diisopropylethylamine, 22 mg, 0.18 mmol) and allyl chloride (5.5 mg, 0.06 mmol). The reaction solution was stirred at minus 20 degrees Celsius for 1 hour. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 2-(4-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyl) Phenyl)-2-oxopyrano[2,3-d]pyrimidin-1(2H)-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxisoindolin-4-yl)amino)butyl)-3-methylbenzamide (9.2 mg, 0.01 mmol, pale yellow solid, yield: 17%). MS (ESI) M/Z: 887.8 [M+H] + .
1H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.14 (d, J = 8.4 Hz, 1H), 8.32 – 8.09 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.35 (d, J = 5.2 Hz, 2H), 7.33-7.24 (m, 1H), 7.10-7.03 (m, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.90-6.77 (m, 1H), 6.76 – 6.65 (m, 2H), 6.50 (s, 1H), 6.24-6.09 (m, 1H), 5.75 (d, J = 10.4 Hz, 1H), 5.05 (dd, J = 12.4, 5.2 Hz, 1H), 4.81 (brs, 1H), 4.47 – 3.87 (m, 3H), 3.67-3.54 (m, 2H), 3.22 (brs, 3H), 3.11-2.96 (m, 3H), 2.95-2.81 (m, 1H), 2.69 – 2.55 (m, 1H), 2.07-1.96 (m, 4H), 1.54-1.41 (m, 2H), 1.41-1.32 (m, 2H), 1.29 – 1.22 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.14 (d, J = 8.4 Hz, 1H), 8.32 – 8.09 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.35 (d, J = 5.2 Hz, 2H), 7.33-7.24 (m, 1H), 7.10-7.03 (m, 1H), 7.00 (d, J = 6.8 Hz , 1H), 6.90-6.77 (m, 1H), 6.76 – 6.65 (m, 2H), 6.50 (s, 1H), 6.24-6.09 (m, 1H), 5.75 (d, J = 10.4 Hz, 1H), 5.05 (dd, J = 12.4, 5.2 Hz, 1H), 4.81 (brs, 1H), 4.47 – 3.87 (m, 3H), 3.67-3.54 (m, 2H), 3.22 (brs, 3H), 3.11-2.96 ( m, 3H), 2.95-2.81 (m, 1H), 2.69 – 2.55 (m, 1H), 2.07-1.96 (m, 4H), 1.54-1.41 (m, 2H), 1.41-1.32 (m, 2H), 1.29 – 1.22 (m, 3H).
實施例 5：合成2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡喃并[2,3-d]嘧啶 -1（2H）-基）-N-（2-（2-（（2-（2,6-二氧代哌啶-3-基）-1,3-二氧代異吲哚啉-4-基）胺基）乙氧基）乙基）- 3-甲基苯甲醯胺
合成路線：
其合成步驟與實施例2相同。The synthesis steps are the same as those in Example 2.
MS (ESI) M/Z：903.9 [M+H] +。 MS (ESI) M/Z: 903.9 [M+H] + .
1H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.15 (s, 1H), 7.56 – 7.49 (m, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.40-7.24 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.92 – 6.64 (m, 3H), 6.58 (t, J = 5.6 Hz, 1H), 6.28-6.10 (m, 1H), 5.75 (d, J = 10.8 Hz, 1H), 5.05 (dd, J = 13.2, 4.8 Hz, 1H), 4.81 (s, 1H), 4.47-3.98 (m, 3H), 3.67 – 3.49 (m, 4H), 3.43-3.38 (m, 3H), 3.24-3.0 (m, 3H), 2.96-2.81 (m, 1H), 2.69-2.54 (m, 2H), 1.99 (d, J = 5.2 Hz, 4H), 1.30 – 1.23 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.15 (s, 1H), 7.56 – 7.49 (m, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.40- 7.24 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.92 – 6.64 (m, 3H), 6.58 (t, J = 5.6 Hz, 1H) ), 6.28-6.10 (m, 1H), 5.75 (d, J = 10.8 Hz, 1H), 5.05 (dd, J = 13.2, 4.8 Hz, 1H), 4.81 (s, 1H), 4.47-3.98 (m, 3H), 3.67 – 3.49 (m, 4H), 3.43-3.38 (m, 3H), 3.24-3.0 (m, 3H), 2.96-2.81 (m, 1H), 2.69-2.54 (m, 2H), 1.99 ( d, J = 5.2 Hz, 4H), 1.30 – 1.23 (m, 3H).
實施例 6：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異異丙二醇-5-基）胺基）環己烷-1-甲醯胺
合成路線：
步驟A-F與實施例1方法一樣，將StepB中2,2-二甲基吡啶-3-胺基替換為4-胺基-3-異丙基-5-甲苯腈。Steps A-F are the same as those in Example 1, except that the 2,2-lutidine-3-amino group in StepB is replaced with 4-amino-3-isopropyl-5-toluonitrile.
步驟G(StepG):第三丁基（3S）-4-[1-（4-氰基-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-4-基]-3-甲基哌嗪-1-羧酸(4.78 g，7.59 mmol) 溶於甲醇(48.92 mL)於100mL圓底燒瓶，然後將氨甲醇溶液(7 M，30 mL)和雷尼鎳(129.99 mg，1.52 mmol)加入，反應在氫氣環境(4.5atm)下常溫反應16小時。反應液用矽藻土過濾，甲醇洗脫，濃縮得到第三丁基（3S）-4-[1-[4-（胺基甲基）-2-異丙基-6-甲基苯基]-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-4-基]-3-甲基哌嗪-1-羧酸(4.2 g，6.62 mmol，87.22% 收率)。Step G (StepG): tert-butyl (3S)-4-[1-(4-cyano-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro- 6-Hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid (4.78 g, 7.59 mmol) in methanol (48.92 mL) ) in a 100 mL round-bottomed flask, then ammonia methanol solution (7 M, 30 mL) and Raney nickel (129.99 mg, 1.52 mmol) were added, and the reaction was carried out under a hydrogen atmosphere (4.5 atm) at room temperature for 16 hours. The reaction solution was filtered with celite, eluted with methanol, and concentrated to obtain tert-butyl(3S)-4-[1-[4-(aminomethyl)-2-isopropyl-6-methylphenyl] -6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridine[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid ( 4.2 g, 6.62 mmol, 87.22% yield).
步驟H（Step H）：2-（2,6-二氧哌啶-3-基）-5,6-二氟吲哚啉-1,3-二酮（148 mg，0.50 mmol），4-（胺基甲基）環己烷-1-羧酸（79 mg，0.50 mmol），N,N-二異丙基乙胺（194 mg，1.50 mmol），N-甲基吡咯烷酮（2 ml）加入反應瓶中，110℃反應5小時。反應停止後降至室溫，反應液直接通過C18柱色譜純化，用（MeCN/H2O+1‰ HCOOH）洗脫，得到黃色固體產物4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-羧酸（134 mg，0.31 mmol，收率 62%）。MS（ESI） m/z：383.4 [M+H] +。 Step H: 2-(2,6-Dioxypiperidin-3-yl)-5,6-difluoroindoline-1,3-dione (148 mg, 0.50 mmol), 4- (Aminomethyl)cyclohexane-1-carboxylic acid (79 mg, 0.50 mmol), N,N-diisopropylethylamine (194 mg, 1.50 mmol), N-methylpyrrolidone (2 ml) were added In the reaction flask, the reaction was carried out at 110°C for 5 hours. After the reaction was stopped, the temperature was lowered to room temperature, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H2O+1‰HCOOH), to obtain a yellow solid product 4-((2-(2,6-dioxopiperidine- 3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl)cyclohexane-1-carboxylic acid (134 mg, 0.31 mmol, 62% yield). MS (ESI) m/z : 383.4 [M+H] + .
步驟I（Step I）：4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-羧酸（49 mg，0.113 mmol），第三丁基（3S）-4-（1-（4-（胺基甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（60 mg，0.094 mmol），N,N,N’,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲（44 mg，0.113 mmol），N,N-二異丙基乙胺（25 mg，0.189 mmol），N,N-二甲基甲醯胺（2 ml）加入反應瓶中，室溫反應3小時。反應停止，反應液直接通過C18柱色譜純化，用（MeCN/H2O+1‰ HCOOH）洗脫，得到黃色固體產物第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol，收率 50%）。MS（ESI） m/z：1048.7 [M+H] +。 Step I (Step I): 4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methan yl)cyclohexane-1-carboxylic acid (49 mg, 0.113 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methyl) phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3 - Methylpiperazine-1-carboxylate (60 mg, 0.094 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexa Fluorophosphoric acid urea (44 mg, 0.113 mmol), N,N-diisopropylethylamine (25 mg, 0.189 mmol), N,N-dimethylformamide (2 ml) were added to the reaction flask, room temperature The reaction was carried out for 3 hours. The reaction was stopped, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H2O+1‰HCOOH), to obtain a yellow solid product, tert-butyl (3S)-4-(1-(4-((4-( (2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl)cyclohexane-1-carboxylate Amino)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydro Pyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.047 mmol, 50% yield). MS (ESI) m/z : 1048.7 [M+H] + .
步驟J&K（Step J&K）：第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol）溶於二氯甲烷（2 ml）中，然後加入三氟乙酸（1 ml）。反應液在25℃下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於二氯甲烷（2 ml）中，往反應液中分別加入DIPEA（N,N-二異丙基乙胺，31 mg，0.235 mmol）和丙烯醯氯（4.3 mg，0.047 mmol）。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相（ACN/H2O+1‰ HCOOH）純化，得到黃色固體產物N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異異丙二醇-5-基）胺基）環己烷-1-甲醯胺（37.5 mg，0.037 mmol，收率77%）。MS（ESI） m/z：1002.6 [M+H] +。 Step J&K: Tert-Butyl(3S)-4-(1-(4-((4-((2-(2,6-Dioxypiperidin-3-yl)-6-fluoro- 1,3-Dioxisoindol-5-yl)amino)methyl)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6 -Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- The 1-carboxylate (50 mg, 0.047 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 ml), and DIPEA (N,N-diisopropylethylamine, 31 mg, 0.235 mmol) and acryl chloride (4.3 mg, 0.047 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-performance preparative liquid phase (ACN/H2O+1‰ HCOOH) to obtain the yellow solid product N-(4-(4-((S)-4-propenyl-2-methylpiperazin-1-yl)) -6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methyl Benzyl)-4-((2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1,3-dioxoisopropanediol-5-yl)amino)cyclohexane- 1-Carboxamide (37.5 mg, 0.037 mmol, 77% yield). MS (ESI) m/z : 1002.6 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.28 (s, 1H), 8.27 (dt, J= 11.7, 7.4 Hz, 2H), 7.56 (d, J= 10.3 Hz, 1H), 7.26 (dd, J= 15.3, 8.2 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J= 13.3 Hz, 2H), 6.86 (dd, J= 27.4, 16.6 Hz, 1H), 6.76 – 6.65 (m, 2H), 6.20 (dd, J= 16.8, 9.8 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.05 (dd, J= 12.9, 5.4 Hz, 1H), 4.89 (s, 1H), 4.39 (s, 1H), 4.31 – 4.09 (m, 4H), 4.02 (d, J= 14.1 Hz, 1H), 3.64 (d, J= 13.4 Hz, 2H), 3.14 (t, J= 6.1 Hz, 3H), 2.94 – 2.81 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (t, J= 11.9 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.87 – 1.74 (m, 7H), 1.62 (s, 1H), 1.39 (dd, J= 23.6, 11.8 Hz, 2H), 1.31 (dd, J= 10.7, 6.7 Hz, 3H), 1.23 (s, 1H), 1.03 (d, J= 6.7 Hz, 3H), 1.01 – 0.93 (m, 2H), 0.90 (d, J= 6.8 Hz, 3H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.28 (s, 1H), 8.27 (dt, J = 11.7, 7.4 Hz, 2H), 7.56 (d, J = 10.3 Hz, 1H), 7.26 (dd, J = 15.3, 8.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 13.3 Hz, 2H), 6.86 ( dd, J = 27.4, 16.6 Hz, 1H), 6.76 – 6.65 (m, 2H), 6.20 (dd, J = 16.8, 9.8 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.89 (s, 1H), 4.39 (s, 1H), 4.31 – 4.09 (m, 4H), 4.02 (d, J = 14.1 Hz, 1H), 3.64 (d, J = 13.4 Hz, 2H), 3.14 (t, J = 6.1 Hz, 3H), 2.94 – 2.81 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (t, J = 11.9 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.87 – 1.74 (m, 7H), 1.62 (s, 1H), 1.39 (dd, J = 23.6, 11.8 Hz, 2H), 1.31 (dd, J = 10.7, 6.7 Hz, 3H), 1.23 (s, 1H), 1.03 (d, J = 6.7 Hz, 3H), 1.01 – 0.93 (m, 2H), 0.90 (d, J = 6.8 Hz, 3H).
表1：遵循實施例6步驟A-K中所述的操作製備化合物7-17，如下
實施例 18 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚啉-5-基）胺基）甲基）環己烷-1-甲醯胺
合成步驟：
步驟A（Step A）：2-（2,6-二氧哌啶-3-基）-5,6-二氟吲哚啉-1,3-二酮（148 mg，0.50 mmol），4-（胺基甲基）環己烷-1-羧酸（79 mg，0.50 mmol），N,N-二異丙基乙胺（194 mg，1.50 mmol），N-甲基吡咯烷酮（2 ml）加入反應瓶中，110℃反應5小時。反應停止後降至室溫，反應液直接通過C18柱色譜純化，用（MeCN/H2O+1‰ HCOOH）洗脫，得到黃色固體產物4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-羧酸（134 mg，0.31 mmol，收率 62%）。MS（ESI） m/z：383.4 [M+H] +。 Step A: 2-(2,6-Dioxypiperidin-3-yl)-5,6-difluoroindoline-1,3-dione (148 mg, 0.50 mmol), 4- (Aminomethyl)cyclohexane-1-carboxylic acid (79 mg, 0.50 mmol), N,N-diisopropylethylamine (194 mg, 1.50 mmol), N-methylpyrrolidone (2 ml) were added In the reaction flask, the reaction was carried out at 110°C for 5 hours. After the reaction was stopped, the temperature was lowered to room temperature, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H2O+1‰HCOOH), to obtain a yellow solid product 4-((2-(2,6-dioxopiperidine- 3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl)cyclohexane-1-carboxylic acid (134 mg, 0.31 mmol, 62% yield). MS (ESI) m/z : 383.4 [M+H] + .
步驟B（Step B）：4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-羧酸（49 mg，0.113 mmol），第三丁基（3S）-4-（1-（4-（胺基甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（60 mg，0.094 mmol），N,N,N’,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲（44 mg，0.113 mmol），N,N-二異丙基乙胺（25 mg，0.189 mmol），N,N-二甲基甲醯胺（2 ml）加入反應瓶中，室溫反應3小時。反應停止，反應液直接通過C18柱色譜純化，用（MeCN/H2O+1‰ HCOOH）洗脫，得到黃色固體產物第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol，收率 50%）。MS（ESI） m/z：1048.7 [M+H] +。 Step B: 4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methan yl)cyclohexane-1-carboxylic acid (49 mg, 0.113 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methyl) phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3 - Methylpiperazine-1-carboxylate (60 mg, 0.094 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexa Fluorophosphoric acid urea (44 mg, 0.113 mmol), N,N-diisopropylethylamine (25 mg, 0.189 mmol), N,N-dimethylformamide (2 ml) were added to the reaction flask, room temperature The reaction was carried out for 3 hours. The reaction was stopped, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H2O+1‰HCOOH), to obtain a yellow solid product, tert-butyl (3S)-4-(1-(4-((4-( (2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)amino)methyl)cyclohexane-1-carboxylate Amino)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydro Pyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.047 mmol, 50% yield). MS (ESI) m/z : 1048.7 [M+H] + .
步驟C&D（Step C&D）：第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異吲哚-5-基）胺基）甲基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol）溶於二氯甲烷（2 ml）中，然後加入三氟乙酸（1 ml）。反應液在25℃下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於二氯甲烷（2 ml）中，往反應液中分別加入DIPEA（N,N-二異丙基乙胺，31 mg，0.235 mmol）和丙烯醯氯（4.3 mg，0.047 mmol）。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相（ACN/H2O+1‰ HCOOH）純化，得到黃色固體產物N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（（2-（2,6-二氧哌啶-3-基）-6-氟-1,3-二氧異異丙二醇-5-基）胺基）環己烷-1-甲醯胺（37.5 mg，0.037 mmol，收率77%）。MS（ESI） m/z：1002.6 [M+H] +。 Step C&D: tert-butyl(3S)-4-(1-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro- 1,3-Dioxisoindol-5-yl)amino)methyl)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6 -Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- The 1-carboxylate (50 mg, 0.047 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 ml), and DIPEA (N,N-diisopropylethylamine, 31 mg, 0.235 mmol) and acryl chloride (4.3 mg, 0.047 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-performance preparative liquid phase (ACN/H2O+1‰ HCOOH) to obtain the yellow solid product N-(4-(4-((S)-4-propenyl-2-methylpiperazin-1-yl)) -6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methyl Benzyl)-4-((2-(2,6-Dioxypiperidin-3-yl)-6-fluoro-1,3-dioxoisopropanediol-5-yl)amino)cyclohexane- 1-Carboxamide (37.5 mg, 0.037 mmol, 77% yield). MS (ESI) m/z : 1002.6 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.28 (s, 1H), 8.27 (dt, J= 11.7, 7.4 Hz, 2H), 7.56 (d, J= 10.3 Hz, 1H), 7.26 (dd, J= 15.3, 8.2 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J= 13.3 Hz, 2H), 6.86 (dd, J= 27.4, 16.6 Hz, 1H), 6.76 – 6.65 (m, 2H), 6.20 (dd, J= 16.8, 9.8 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.05 (dd, J= 12.9, 5.4 Hz, 1H), 4.89 (s, 1H), 4.39 (s, 1H), 4.31 – 4.09 (m, 4H), 4.02 (d, J= 14.1 Hz, 1H), 3.64 (d, J= 13.4 Hz, 2H), 3.14 (t, J= 6.1 Hz, 3H), 2.94 – 2.81 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (t, J= 11.9 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.87 – 1.74 (m, 7H), 1.62 (s, 1H), 1.39 (dd, J= 23.6, 11.8 Hz, 2H), 1.31 (dd, J= 10.7, 6.7 Hz, 3H), 1.23 (s, 1H), 1.03 (d, J= 6.7 Hz, 3H), 1.01 – 0.93 (m, 2H), 0.90 (d, J= 6.8 Hz, 3H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.28 (s, 1H), 8.27 (dt, J = 11.7, 7.4 Hz, 2H), 7.56 (d, J = 10.3 Hz, 1H), 7.26 (dd, J = 15.3, 8.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 13.3 Hz, 2H), 6.86 ( dd, J = 27.4, 16.6 Hz, 1H), 6.76 – 6.65 (m, 2H), 6.20 (dd, J = 16.8, 9.8 Hz, 1H), 5.80 – 5.73 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.89 (s, 1H), 4.39 (s, 1H), 4.31 – 4.09 (m, 4H), 4.02 (d, J = 14.1 Hz, 1H), 3.64 (d, J = 13.4 Hz, 2H), 3.14 (t, J = 6.1 Hz, 3H), 2.94 – 2.81 (m, 1H), 2.63 – 2.54 (m, 1H), 2.16 (t, J = 11.9 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.87 – 1.74 (m, 7H), 1.62 (s, 1H), 1.39 (dd, J = 23.6, 11.8 Hz, 2H), 1.31 (dd, J = 10.7, 6.7 Hz, 3H), 1.23 (s, 1H), 1.03 (d, J = 6.7 Hz, 3H), 1.01 – 0.93 (m, 2H), 0.90 (d, J = 6.8 Hz, 3H).
表2：遵循上文方法步驟A-D中所述的操作製備化合物19-21，如下
實施例 22 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-2-（2-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）-2-氧乙基）苯基）乙醯胺
合成路線：
步驟A（Step A）：1,4-苯二乙酸（144 mg，0.716 mmol），氯化亞碸（94 mg，0.788 mmol），四氫呋喃（2 ml）加入反應瓶中，室溫反應3小時。向反應體系中加入4-胺基-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（220 mg，0.788 mmol），三乙胺（146 mg，1.432 mmol），室溫反應12小時。反應停止後加入1 mol/L的鹽酸淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品通過C18柱色譜純化，用（MeCN/H2O+1‰ HCOOH）洗脫，得到黃色固體產物2-（4-（2-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）胺基）-2-氧乙基）苯基）乙酸（52 mg，0.116 mmol，收率16%）。MS（ESI） m/z：450.4 [M+H] +。 Step A (Step A): 1,4-phenylenediacetic acid (144 mg, 0.716 mmol), thorium chloride (94 mg, 0.788 mmol), and tetrahydrofuran (2 ml) were added to the reaction flask, and the reaction was carried out at room temperature for 3 hours. To the reaction system was added 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (220 mg, 0.788 mmol), triethylamine (146 mg, 1.432 mmol), and reacted at room temperature for 12 hours. After the reaction was stopped, 1 mol/L hydrochloric acid was added to quench, and ethyl acetate was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by C18 column chromatography eluting with (MeCN/H2O+1‰HCOOH) to give the product 2-(4-(2-((2-(2,6-dioxopiperidin-3-yl) as a yellow solid. )-1,3-dioxoisoquinolin-4-yl)amino)-2-oxoethyl)phenyl)acetic acid (52 mg, 0.116 mmol, 16% yield). MS (ESI) m/z : 450.4 [M+H] + .
步驟B（Step B）：2-（4-（2-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）胺基）-2-氧乙基）苯基）乙酸（52 mg，0.116 mmol），第三丁基（3S）-4-（1-（4-（胺基甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（59 mg，0.093 mmol），N,N,N’,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲（42 mg，0.111 mmol），N,N-二異丙基乙胺（24 mg，0.185 mmol），N,N-二甲基甲醯胺（2 mL）加入反應瓶中，室溫反應3小時。反應停止，反應液直接通過C18柱色譜純化，用（MeCN/H 2O+1‰ HCOOH）洗脫，得到黃色固體產物第三丁基（3S）-4-（1-（4-（（2-（4-（2-）（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）-2-氧乙基）苯基）乙醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol，收率50%）。MS（ESI） m/z：1066.5 [M+H] +。 Step B: 2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)amino )-2-oxoethyl)phenyl)acetic acid (52 mg, 0.116 mmol), tert-butyl(3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6) -methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl) -3-Methylpiperazine-1-carboxylate (59 mg, 0.093 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl ) urea hexafluorophosphate (42 mg, 0.111 mmol), N,N-diisopropylethylamine (24 mg, 0.185 mmol), N,N-dimethylformamide (2 mL) were added to the reaction flask, The reaction was carried out at room temperature for 3 hours. The reaction was stopped, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H 2 O+1‰ HCOOH), to obtain a yellow solid product, tert-butyl (3S)-4-(1-(4-((2 -(4-(2-)((2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl (yl)phenyl)acetamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy -1,2-Dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.047 mmol, 50% yield). MS (ESI) m/z : 1066.5 [M+H] + .
步驟C&D（Step C&D）：第三丁基（3S）-4-（1-（4-（（2-（4-（2-）（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）-2-氧乙基）苯基）乙醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.047 mmol）溶於二氯甲烷（4 mL）中，然後加入三氟乙酸（2 mL）。反應液在25℃下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於二氯甲烷（2 mL）中，往反應液中分別加入DIPEA（N,N-二異丙基乙胺，29 mg，0.223 mmol）和丙烯醯氯（4.0 mg，0.045 mmol）。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相（ACN/H 2O+1‰ HCOOH）純化，得到黃色固體產物N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-2-（2-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異吲哚啉-4-基）胺基）-2-氧乙基）苯基）乙醯胺（25 mg，0.024 mmol，收率51%）。MS（ESI） m/z：1020.6 [M+H] +。 Step C&D (Step C&D): tert-butyl (3S)-4-(1-(4-((2-(4-(2-)((2-(2,6-dioxopiperidine-3-) (yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl)phenyl)acetamido)methyl)-2-isopropyl-6-methyl phenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3- Methylpiperazine-1-carboxylate (50 mg, 0.047 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (2 mL), and DIPEA (N,N-diisopropylethylamine, 29 mg, 0.223 mmol) and allyl chloride (4.0 mg, 0.045 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-performance preparative liquid phase (ACN/H 2 O+1‰ HCOOH) to obtain a yellow solid product N-(4-(4-((S)-4-propenyl-2-methylpiperazine-1- yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5- methylbenzyl)-2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2- Oxyethyl)phenyl)acetamide (25 mg, 0.024 mmol, 51% yield). MS (ESI) m/z : 1020.6 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.15 (s, 1H), 10.21 (s, 1H), 9.85 (s, 1H), 8.55 (t, J= 5.7 Hz, 1H), 8.46 (d, J= 8.4 Hz, 1H), 8.31 – 8.23 (m, 1H), 7.80 (t, J= 7.9 Hz, 1H), 7.60 (d, J= 7.3 Hz, 1H), 7.38 – 7.19 (m, 5H), 7.03 (s, 1H), 6.93 – 6.81 (m, 2H), 6.75 – 6.65 (m, 2H), 6.20 (dd, J= 16.2, 9.3 Hz, 1H), 5.76 (dd, J= 10.5, 2.1 Hz, 1H), 5.13 (dd, J= 12.9, 5.4 Hz, 1H), 4.89 (dd, J= 14.2, 10.5 Hz, 1H), 4.41 (d, J= 12.4 Hz, 1H), 4.27 (t, J= 9.5 Hz, 3H), 4.14 (d, J= 12.9 Hz, 1H), 4.02 (d, J= 13.8 Hz, 1H), 3.80 (s, 2H), 3.26 (dd, J= 10.6, 5.9 Hz, 1H), 3.18 – 3.10 (m, 1H), 2.93 – 2.84 (m, 1H), 2.65 – 2.56 (m, 1H), 2.07 – 2.00 (m, 1H), 1.78 (s, 2H), 1.28 (ddd, J= 19.0, 12.1, 5.7 Hz, 8H), 0.99 (dd, J= 6.5, 2.9 Hz, 3H), 0.87 (dd, J= 6.5, 3.8 Hz, 3H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.15 (s, 1H), 10.21 (s, 1H), 9.85 (s, 1H), 8.55 (t, J = 5.7 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.31 – 8.23 (m, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.38 – 7.19 (m, 5H), 7.03 (s, 1H), 6.93 – 6.81 (m, 2H), 6.75 – 6.65 (m, 2H), 6.20 (dd, J = 16.2, 9.3 Hz, 1H), 5.76 (dd, J = 10.5, 2.1 Hz, 1H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 4.89 (dd, J = 14.2, 10.5 Hz, 1H), 4.41 (d, J = 12.4 Hz, 1H), 4.27 (t, J = 9.5 Hz, 3H), 4.14 (d, J = 12.9 Hz, 1H), 4.02 (d, J = 13.8 Hz, 1H), 3.80 (s, 2H), 3.26 (dd, J = 10.6, 5.9 Hz, 1H), 3.18 – 3.10 (m, 1H), 2.93 – 2.84 (m, 1H), 2.65 – 2.56 (m, 1H), 2.07 – 2.00 (m, 1H), 1.78 (s, 2H), 1.28 (ddd, J = 19.0 , 12.1, 5.7 Hz, 8H), 0.99 (dd, J = 6.5, 2.9 Hz, 3H), 0.87 (dd, J = 6.5, 3.8 Hz, 3H).
實施例 23 ：合成N
1-（4-（4-（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-N4-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異吲哚啉-4-基）環己烷-1,4-二甲醯胺
其合成步驟與實施例22相同。The synthesis procedure is the same as that of Example 22.
MS（ESI） m/z：998.6 [M+H] +。 MS (ESI) m/z : 998.6 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.15 (s, 1H), 10.28 (s, 1H), 9.76 (s, 1H), 8.51 (dd, J= 53.7, 8.4 Hz, 1H), 8.27 (ddd, J= 21.4, 10.9, 5.6 Hz, 2H), 7.87 – 7.78 (m, 1H), 7.61 (t, J= 7.7 Hz, 1H), 7.31 – 7.20 (m, 1H), 7.06 (d, J= 12.2 Hz, 1H), 6.95 (d, J= 8.2 Hz, 1H), 6.92 – 6.77 (m, 1H), 6.76 – 6.57 (m, 2H), 6.20 (dd, J= 16.2, 9.7 Hz, 1H), 5.76 (d, J= 12.3 Hz, 1H), 5.15 (ddd, J= 12.9, 5.4, 2.8 Hz, 1H), 4.88 (d, J= 17.3 Hz, 1H), 4.41 (d, J= 11.7 Hz, 1H), 4.30 – 4.23 (m, 3H), 4.08 (dd, J= 61.5, 13.1 Hz, 1H), 3.67 (dd, J= 30.6, 12.1 Hz, 2H), 2.93 – 2.85 (m, 1H), 2.75 – 2.66 (m, 1H), 2.65 – 2.56 (m, 2H), 2.43 – 2.34 (m, 1H), 2.27 – 2.16 (m, 1H), 2.04 (ddd, J= 20.2, 10.3, 3.9 Hz, 3H), 1.85 (dd, J= 23.4, 9.1 Hz, 5H), 1.69 (s, 1H), 1.63 (s, 1H), 1.55 – 1.40 (m, 3H), 1.31 (dd, J= 10.7, 7.0 Hz, 3H), 1.06 – 0.99 (m, 3H), 0.91 (dd, J= 14.2, 6.8 Hz, 3H)。 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.15 (s, 1H), 10.28 (s, 1H), 9.76 (s, 1H), 8.51 (dd, J = 53.7, 8.4 Hz, 1H), 8.27 ( ddd, J = 21.4, 10.9, 5.6 Hz, 2H), 7.87 – 7.78 (m, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.31 – 7.20 (m, 1H), 7.06 (d, J = 12.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.92 – 6.77 (m, 1H), 6.76 – 6.57 (m, 2H), 6.20 (dd, J = 16.2, 9.7 Hz, 1H), 5.76 (d, J = 12.3 Hz, 1H), 5.15 (ddd, J = 12.9, 5.4, 2.8 Hz, 1H), 4.88 (d, J = 17.3 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H) ), 4.30 – 4.23 (m, 3H), 4.08 (dd, J = 61.5, 13.1 Hz, 1H), 3.67 (dd, J = 30.6, 12.1 Hz, 2H), 2.93 – 2.85 (m, 1H), 2.75 – 2.66 (m, 1H), 2.65 – 2.56 (m, 2H), 2.43 – 2.34 (m, 1H), 2.27 – 2.16 (m, 1H), 2.04 (ddd, J = 20.2, 10.3, 3.9 Hz, 3H), 1.85 (dd, J = 23.4, 9.1 Hz, 5H), 1.69 (s, 1H), 1.63 (s, 1H), 1.55 – 1.40 (m, 3H), 1.31 (dd, J = 10.7, 7.0 Hz, 3H) , 1.06 – 0.99 (m, 3H), 0.91 (dd, J = 14.2, 6.8 Hz, 3H).
實施例 24 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異異丙醇-4-基）-2,7-二氮螺環[3.5]壬烷-2-甲醯胺
合成路線：
步驟A（Step A）：2-（2,6-二氧哌啶-3-基）-4-氟異吲哚啉-1,3-二酮（150 mg，0.543 mmol），2,7-二氮螺環[3.5]壬烷-2-羧酸第三丁酯（148 mg，0.651 mmol），N,N-二異丙基乙胺（210 mg，1.63 mmol），N-甲基吡咯烷酮（2 mL）加入反應瓶中，110℃反應5小時。反應停止後降至室溫，反應液直接通過C18柱色譜純化，用（MeCN/H 2O+1‰ HCOOH）洗脫，得到黃色固體產物7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）-2,7-二氮螺環[3.5]壬烷-2-羧酸第三丁酯（250 mg，0.518 mmol，收率 95%）。MS（ESI） m/z：483.4 [M+H] +。 Step A: 2-(2,6-Dioxypiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (150 mg, 0.543 mmol), 2,7- Diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (148 mg, 0.651 mmol), N,N-diisopropylethylamine (210 mg, 1.63 mmol), N-methylpyrrolidone ( 2 mL) was added to the reaction flask and reacted at 110°C for 5 hours. After the reaction was stopped, the temperature was lowered to room temperature, and the reaction solution was directly purified by C18 column chromatography, eluted with (MeCN/H 2 O + 1‰ HCOOH), to obtain 7-(2-(2,6-dioxopiperidine) as a yellow solid product -3-yl)-1,3-dioxoisoquinolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (250 mg, 0.518 mmol, yield 95%). MS (ESI) m/z : 483.4 [M+H] + .
步驟B&C（Step B&C）：7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）-2,7-二氮螺環[3.5]壬烷-2-羧酸第三丁酯（250 mg，0.518 mmol）溶於二氯甲烷（6 mL）中，然後加入三氟乙酸（3 mL）。反應液在25℃下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於二氯甲烷（5 mL）中，往反應液中加入DIPEA（N,N-二異丙基乙胺，321 mg，2.480 mmol）0攝氏度下攪拌30分鐘，往反應液中加入溶於二氯甲烷的三光氣（48 mg，0.298 mmol）。反應液在室溫下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相（ACN/H 2O+1‰ HCOOH）純化，得到黃色固體產物7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）-2,7-二氮螺環[3.5]壬烷-2-羰基氯（180 mg，0.404 mmol，收率 78%）。MS（ESI） m/z：445.3 [M+H] +。 Step B&C: 7-(2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)-2,7-diazaspiro [3.5] Tert-butyl nonane-2-carboxylate (250 mg, 0.518 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (5 mL), DIPEA (N,N-diisopropylethylamine, 321 mg, 2.480 mmol) was added to the reaction solution, and the mixture was stirred at 0°C for 30 minutes. Triphosgene in dichloromethane (48 mg, 0.298 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-performance preparative liquid phase (ACN/H 2 O+1‰ HCOOH) to obtain a yellow solid product 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Quinolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carbonyl chloride (180 mg, 0.404 mmol, 78% yield). MS (ESI) m/z : 445.3 [M+H] + .
步驟D（Step D）：第三丁基（3S）-4-（1-（4-（胺基甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（50 mg，0.078 mmol），7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）-2,7-二氮螺環[3.5]壬烷-2-羰基氯（45 mg，0.094 mmol），N,N-二異丙基乙胺（51 mg，0.394 mmol），二氯甲烷（2 ml）加入反應瓶中，50℃反應5小時。反應停止後降至室溫，濃縮得到粗產品。粗產品通過C18柱色譜純化，用（MeCN/H 2O+1‰ HCOOH）洗脫，得到黃色固體產物第三丁基（3S）-4-（1-（4-（（7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異異吲哚-4-基）-2,7-二氮螺環[3.5]壬烷-2-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（30 mg，0.028 mmol，收率 36%）。MS（ESI） m/z：1043.6 [M+H] +。 Step D: tert-butyl (3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7- (2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (50 mg, 0.078 mmol), 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)-2,7-diazaspiro Cyclo[3.5]nonane-2-carbonyl chloride (45 mg, 0.094 mmol), N,N-diisopropylethylamine (51 mg, 0.394 mmol), dichloromethane (2 ml) was added to the reaction flask, 50 °C reaction for 5 hours. After the reaction was stopped, it was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by C18 column chromatography eluting with (MeCN/H 2 O + 1‰HCOOH) to give tert-butyl(3S)-4-(1-(4-((7-(2- (2,6-Dioxypiperidin-3-yl)-1,3-dioxisoisoindol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamide yl)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridine [2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (30 mg, 0.028 mmol, 36% yield). MS (ESI) m/z : 1043.6 [M+H] + .
步驟E&F（Step E&F）：第三丁基（3S）-4-（1-（4-（（7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異異吲哚-4-基）-2,7-二氮螺環[3.5]壬烷-2-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸鹽（30 mg，0.028 mmol）溶於二氯甲烷（6 mL）中，然後加入三氟乙酸（2 mL）。反應液在25℃下攪拌2小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於二氯甲烷（3 mL）中，往反應液中分別加入DIPEA（N,N-二異丙基乙胺，17 mg，0.132 mmol）和丙烯醯氯（2.4 mg，0.026 mmol）。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相（ACN/H 2O+1‰ HCOOH）純化，得到黃色固體產物N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-7-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異異丙醇-4-基）-2,7-二氮螺環[3.5]壬烷-2-甲醯胺（9.5 mg，0.009 mmol，收率32 %）。MS（ESI） m/z：997.6 [M+H] +。 Step E&F: Tert-Butyl(3S)-4-(1-(4-((7-(2-(2,6-Dioxypiperidin-3-yl)-1,3-di oxyisoindol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxamido)methyl)-2-isopropyl-6-methylphenyl)- 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxy-1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-3-methylpiperazine -1-Carboxylate (30 mg, 0.028 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at 25°C for 2 hours. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in dichloromethane (3 mL), and DIPEA (N,N-diisopropylethylamine, 17 mg, 0.132 mmol) and acryl chloride (2.4 mg, 0.026 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-performance preparative liquid phase (ACN/H 2 O+1‰ HCOOH) to obtain a yellow solid product N-(4-(4-((S)-4-propenyl-2-methylpiperazine-1- yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5- methylbenzyl)-7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropanol-4-yl)-2,7-diazaspiro [3.5]nonane-2-carboxamide (9.5 mg, 0.009 mmol, 32 % yield). MS (ESI) m/z : 997.6 [M+H] + .
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.37 (s, 1H), 8.40 (s, 1H), 8.26 (ddd, J= 15.7, 13.0, 10.8 Hz, 1H), 7.68 (t, J= 7.7 Hz, 1H), 7.29 (ddd, J= 31.6, 17.0, 10.0 Hz, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 6.94 – 6.79 (m, 2H), 6.73 (d, J= 8.2 Hz, 1H), 6.71 – 6.64 (m, 1H), 6.21 (d, J= 17.3 Hz, 1H), 5.76 (d, J= 11.4 Hz, 1H), 5.32 (s, 1H), 5.09 (dd, J= 12.7, 5.4 Hz, 1H), 4.88 (d, J= 14.3 Hz, 1H), 4.41 (d, J= 11.4 Hz, 1H), 4.27 (d, J= 12.6 Hz, 1H), 4.17 (dd, J= 30.0, 10.1 Hz, 2H), 4.02 (d, J= 12.3 Hz, 1H), 3.62 (s, 3H), 3.21 (s, 3H), 2.88 (dd, J= 22.4, 8.9 Hz, 1H), 2.00 (dd, J= 18.6, 6.8 Hz, 3H), 1.85 (d, J= 15.5 Hz, 5H), 1.45 (dd, J= 12.3, 7.1 Hz, 1H), 1.34 – 1.28 (m, 3H), 1.23 (s, 6H), 1.05 (d, J= 6.6 Hz, 2H), 0.92 (d, J= 5.5 Hz, 2H), 0.85 (t, J= 6.8 Hz, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.37 (s, 1H), 8.40 (s, 1H), 8.26 (ddd, J = 15.7, 13.0, 10.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.29 (ddd, J = 31.6, 17.0, 10.0 Hz, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 6.94 – 6.79 (m, 2H) , 6.73 (d, J = 8.2 Hz, 1H), 6.71 – 6.64 (m, 1H), 6.21 (d, J = 17.3 Hz, 1H), 5.76 (d, J = 11.4 Hz, 1H), 5.32 (s, 1H), 5.09 (dd, J = 12.7, 5.4 Hz, 1H), 4.88 (d, J = 14.3 Hz, 1H), 4.41 (d, J = 11.4 Hz, 1H), 4.27 (d, J = 12.6 Hz, 1H), 4.17 (dd, J = 30.0, 10.1 Hz, 2H), 4.02 (d, J = 12.3 Hz, 1H), 3.62 (s, 3H), 3.21 (s, 3H), 2.88 (dd, J = 22.4 , 8.9 Hz, 1H), 2.00 (dd, J = 18.6, 6.8 Hz, 3H), 1.85 (d, J = 15.5 Hz, 5H), 1.45 (dd, J = 12.3, 7.1 Hz, 1H), 1.34 – 1.28 (m, 3H), 1.23 (s, 6H), 1.05 (d, J = 6.6 Hz, 2H), 0.92 (d, J = 5.5 Hz, 2H), 0.85 (t, J = 6.8 Hz, 1H).
實施例 25 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-2-（2,6-二氧哌啶-3-基）-1,3-二氧異異丙基-4-基）-2,7-二氮螺環[3.5]壬烷-7-甲醯胺
其合成步驟與實施例24相同。The synthesis procedure is the same as that of Example 24.
MS（ESI） m/z：997.6 [M+H] + MS (ESI) m/z : 997.6 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.08 (s, 1H), 10.60 (s, 1H), 8.39 (s, 1H), 8.30 – 8.21 (m, 1H), 7.71 – 7.65 (m, 1H), 7.34 (dd, J = 7.7, 3.4 Hz, 1H), 7.27 – 7.20 (m, 2H), 7.10 (s, 1H), 6.99 (s, 1H), 6.92 – 6.83 (m, 2H), 6.75 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.7 Hz, 1H), 6.25 – 6.16 (m, 1H), 5.76 (d, J = 12.0 Hz, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.88 (d, J = 17.1 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 4.21 (dd, J = 15.2, 6.1 Hz, 2H), 4.02 (d, J = 11.8 Hz, 1H), 3.62 (s, 3H), 3.21 (s, 3H), 2.87 (ddd, J = 16.2, 13.7, 5.3 Hz, 1H), 1.99 (dt, J = 12.0, 6.8 Hz, 3H), 1.85 (d, J = 15.9 Hz, 5H), 1.49 – 1.43 (m, 1H), 1.31 (dd, J = 10.4, 6.9 Hz, 3H), 1.25 – 1.23 (m, 6H), 1.05 (d, J = 6.6 Hz, 2H), 0.92 (d, J = 7.1 Hz, 2H), 0.85 (d, J = 7.0 Hz, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.08 (s, 1H), 10.60 (s, 1H), 8.39 (s, 1H), 8.30 – 8.21 (m, 1H), 7.71 – 7.65 (m, 1H) ), 7.34 (dd, J = 7.7, 3.4 Hz, 1H), 7.27 – 7.20 (m, 2H), 7.10 (s, 1H), 6.99 (s, 1H), 6.92 – 6.83 (m, 2H), 6.75 ( d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.7 Hz, 1H), 6.25 – 6.16 (m, 1H), 5.76 (d, J = 12.0 Hz, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.88 (d, J = 17.1 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.27 (d, J = 13.2 Hz, 1H), 4.21 (dd, J = 15.2, 6.1 Hz, 2H), 4.02 (d, J = 11.8 Hz, 1H), 3.62 (s, 3H), 3.21 (s, 3H), 2.87 (ddd, J = 16.2, 13.7, 5.3 Hz, 1H), 1.99 (dt, J = 12.0, 6.8 Hz, 3H), 1.85 (d, J = 15.9 Hz, 5H), 1.49 – 1.43 (m, 1H), 1.31 (dd, J = 10.4, 6.9 Hz, 3H), 1.25 – 1.23 (m, 6H), 1.05 (d, J = 6.6 Hz, 2H), 0.92 (d, J = 7.1 Hz, 2H), 0.85 (d, J = 7.0 Hz, 1H).
實施例 26 ：合成1-[1-[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]-4-哌啶基]-3-[[4-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3-異丙基-5-甲基-苯基]甲基]脲
其合成步驟與實施例24相同。The synthesis procedure is the same as that of Example 24.
MS（ESI） m/z：971.5 [M+H] + MS (ESI) m/z : 971.5 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.27 (s, 1H), 8.32 – 8.22 (m, 1H), 7.73 – 7.63 (m, 1H), 7.34 (t, J= 8.5 Hz, 2H), 7.27 (dd, J= 15.4, 8.1 Hz, 1H), 7.10 (s, 1H), 6.99 (s, 1H), 6.86 (dd, J= 27.3, 16.8 Hz, 1H), 6.73 (d, J= 8.3 Hz, 1H), 6.69 (t, J= 8.8 Hz, 1H), 6.20 (dd, J= 16.7, 7.8 Hz, 2H), 6.05 (d, J= 7.7 Hz, 1H), 5.76 (d, J= 12.3 Hz, 1H), 5.10 (dd, J= 12.7, 5.4 Hz, 1H), 4.88 (d, J= 18.4 Hz, 1H), 4.41 (d, J= 12.0 Hz, 1H), 4.32 – 4.10 (m, 4H), 4.02 (d, J= 12.5 Hz, 1H), 3.76 – 3.55 (m, 6H), 3.01 (t, J= 11.0 Hz, 2H), 2.93 – 2.80 (m, 1H), 2.64 – 2.53 (m, 2H), 2.08 – 1.97 (m, 1H), 1.92 (d, J= 10.3 Hz, 2H), 1.84 (s, 3H), 1.54 (d, J= 11.6 Hz, 2H), 1.38 – 1.23 (m, 3H), 1.03 (t, J= 18.4 Hz, 3H), 0.91 (dd, J= 18.2, 13.6 Hz, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.27 (s, 1H), 8.32 – 8.22 (m, 1H), 7.73 – 7.63 (m, 1H), 7.34 (t, J = 8.5 Hz, 2H), 7.27 (dd, J = 15.4, 8.1 Hz, 1H), 7.10 (s, 1H), 6.99 (s, 1H), 6.86 (dd, J = 27.3, 16.8 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1H), 6.20 (dd, J = 16.7, 7.8 Hz, 2H), 6.05 (d, J = 7.7 Hz, 1H), 5.76 (d, J = 12.3 Hz, 1H), 5.10 (dd, J = 12.7, 5.4 Hz, 1H), 4.88 (d, J = 18.4 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 4.32 – 4.10 (m, 4H), 4.02 (d, J = 12.5 Hz, 1H), 3.76 – 3.55 (m, 6H), 3.01 (t, J = 11.0 Hz, 2H), 2.93 – 2.80 (m, 1H), 2.64 – 2.53 (m, 2H), 2.08 – 1.97 (m, 1H), 1.92 (d, J = 10.3 Hz, 2H), 1.84 (s, 3H), 1.54 (d, J = 11.6 Hz, 2H), 1.38 – 1.23 (m, 3H), 1.03 (t, J = 18.4 Hz, 3H), 0.91 (dd, J = 18.2, 13.6 Hz, 3H).
實施例 27 ：合成4-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]-N-[[4-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3-異丙基-5-甲基-苯基]甲基]哌啶-1-甲醯胺
其合成步驟與實施例24相同。The synthesis procedure is the same as that of Example 24.
MS（ESI） m/z：971.5 [M+H] + MS (ESI) m/z : 971.5 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.34 (d, J = 62.5 Hz, 2H), 7.57 (dt, J = 14.9, 8.1 Hz, 2H), 7.25 (dt, J = 27.2, 10.8 Hz, 3H), 7.10 (d, J = 15.2 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.98 (s,1H), 6.87 (dd, J = 27.5, 16.5 Hz, 1H), 6.75 – 6.65 (m, 1H), 6.22 (dd, J = 32.1, 9.3 Hz, 2H), 5.75 (t, J = 11.7 Hz, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 4.86 (s, 1H), 4.40 (s, 1H), 4.25 (d, J = 4.9 Hz, 3H), 3.98 (d, J = 12.8 Hz, 2H), 3.71 (d, J = 54.9 Hz, 4H), 2.98 – 2.79 (m, 4H), 2.58 (d, J = 18.4 Hz, 1H), 1.97 (dd, J = 42.8, 7.9 Hz, 4H), 1.83 (s, 2H), 1.45 – 1.21 (m, 6H), 1.05 (d, J = 6.5 Hz, 3H), 0.95 (dd, J = 29.5, 6.2 Hz, 3H), 0.78 (s, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 8.34 (d, J = 62.5 Hz, 2H), 7.57 (dt, J = 14.9, 8.1 Hz, 2H), 7.25 (dt, J = 27.2, 10.8 Hz, 3H), 7.10 (d, J = 15.2 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.98 (s, 1H), 6.87 (dd, J = 27.5, 16.5 Hz, 1H), 6.75 – 6.65 (m, 1H), 6.22 (dd, J = 32.1, 9.3 Hz, 2H), 5.75 (t, J = 11.7 Hz, 1H), 5.05 (dd, J = 12.7, 5.3 Hz , 1H), 4.86 (s, 1H), 4.40 (s, 1H), 4.25 (d, J = 4.9 Hz, 3H), 3.98 (d, J = 12.8 Hz, 2H), 3.71 (d, J = 54.9 Hz , 4H), 2.98 – 2.79 (m, 4H), 2.58 (d, J = 18.4 Hz, 1H), 1.97 (dd, J = 42.8, 7.9 Hz, 4H), 1.83 (s, 2H), 1.45 – 1.21 ( m, 6H), 1.05 (d, J = 6.5 Hz, 3H), 0.95 (dd, J = 29.5, 6.2 Hz, 3H), 0.78 (s, 1H).
實施例 28 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-9-（2-（2,6-二氧哌啶-3-基）-1,3-二氧異異丙醇-4-基）-3,9-二氮螺環-3-甲醯胺
其合成步驟與實施例24相同。The synthesis procedure is the same as that of Example 24.
MS（ESI） m/z：1025.4 [M+H] + MS (ESI) m/z : 1025.4 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.21 (s, 1H), 8.40 (dt, J = 12.3, 5.9 Hz, 1H), 8.27 (dd, J = 22.9, 12.8 Hz, 1H), 8.14 (s, 1H), 7.70 (dd, J = 16.5, 8.8 Hz, 1H), 7.39 – 7.22 (m, 3H), 7.09 (d, J = 12.5 Hz, 1H), 7.00 (s, 1H), 6.92 – 6.81 (m, 1H), 6.75 – 6.63 (m, 2H), 6.20 (dd, J = 16.3, 8.9 Hz, 1H), 5.76 (dd, J = 10.5, 2.2 Hz, 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.88 (d, J = 18.1 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 4.29 (dt, J = 13.7, 7.0 Hz, 3H), 4.08 (dd, J = 60.6, 13.2 Hz, 1H), 3.75 – 3.60 (m, 2H), 3.29 (s, 7H), 2.91 – 2.83 (m, 1H), 2.66 (dd, J = 13.7, 6.6 Hz, 2H), 2.58 (d, J = 16.5 Hz, 4H), 2.53 (d, J = 4.4 Hz, 1H), 2.38 (t, J = 6.9 Hz, 2H), 2.05 – 1.98 (m, 1H), 1.83 (s, 3H), 1.31 (dd, J = 11.6, 6.9 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H), 0.95 – 0.87 (m, 3H). 1H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.21 (s, 1H), 8.40 (dt, J = 12.3, 5.9 Hz, 1H), 8.27 (dd, J = 22.9, 12.8 Hz , 1H), 8.14 (s, 1H), 7.70 (dd, J = 16.5, 8.8 Hz, 1H), 7.39 – 7.22 (m, 3H), 7.09 (d, J = 12.5 Hz, 1H), 7.00 (s, 1H), 6.92 – 6.81 (m, 1H), 6.75 – 6.63 (m, 2H), 6.20 (dd, J = 16.3, 8.9 Hz, 1H), 5.76 (dd, J = 10.5, 2.2 Hz, 1H), 5.09 (dd, J = 12.7, 5.5 Hz, 1H), 4.88 (d, J = 18.1 Hz, 1H), 4.41 (d, J = 10.9 Hz, 1H), 4.29 (dt, J = 13.7, 7.0 Hz, 3H) , 4.08 (dd, J = 60.6, 13.2 Hz, 1H), 3.75 – 3.60 (m, 2H), 3.29 (s, 7H), 2.91 – 2.83 (m, 1H), 2.66 (dd, J = 13.7, 6.6 Hz , 2H), 2.58 (d, J = 16.5 Hz, 4H), 2.53 (d, J = 4.4 Hz, 1H), 2.38 (t, J = 6.9 Hz, 2H), 2.05 – 1.98 (m, 1H), 1.83 (s, 3H), 1.31 (dd, J = 11.6, 6.9 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H), 0.95 – 0.87 (m, 3H).
實施例 29 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-惡吡啉[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄基）-6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜多林-4-基）胺基）己醯胺
合成路線：
步驟A（Step A）: 將（S）-4-（7-氯-1-（4-氰基-2,6-二甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸第三丁酯溶於氨甲醇（7M，10 mL）溶液中，加入雷尼鎳（20 mg)，抽真空並置換氫氣數次，然後在氫氣環境下攪拌反應5小時。質譜監測到所有的原料轉化成產物，矽藻土過濾得溶液，濃縮得產品（3S）-4-（1-（4-（胺基甲基）-2,6-二甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2- 二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯(450 mg，0.74 mmol，黃色固體，收率89%)。MS (ESI) M/Z：607.3[M+H] +。 Step A (Step A): (S)-4-(7-chloro-1-(4-cyano-2,6-dimethylphenyl)-6-fluoro-2-oxo-1,2 - Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester was dissolved in ammonia methanol (7M, 10 mL) solution, raney was added Nickel (20 mg), evacuated and replaced with hydrogen several times, then the reaction was stirred under hydrogen for 5 hours. Mass spectrometry monitored the conversion of all starting materials to product, and the solution was filtered through diatomaceous earth and concentrated to give the product (3S)-4-(1-(4-(aminomethyl)-2,6-dimethylphenyl)- 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine 3-Butyl-1-carboxylate (450 mg, 0.74 mmol, yellow solid, 89% yield). MS (ESI) M/Z: 607.3 [M+H] + .
步驟B（Step B）:將（3S）-4-（1-（4-（胺基甲基）-2,6-二甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧-1,2- 二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯(100 mg,0.165 mmol)與HATU(N,N,N’,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲，69 mg，0.18 mmol)和6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜多林-4-基）胺基）己酸（(63.8 mg，0.165 mmol）溶於DMF（1 mL)中，室溫下攪拌反應6小時。質譜檢測到所有原料轉化為產物，逆相層析純化（已腈：水(千分之一甲酸））得到產物（3S）-4-（1-（4-（（6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜環戊烯-4-基）胺基）己二酸基）-2,6-二甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯（60 mg，0.061 mmol 黃色固體，收率36.9%)。MS (ESI) M/Z：976.4[M+H] + Step B (Step B): (3S)-4-(1-(4-(aminomethyl)-2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6 -Hydroxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg , 0.165 mmol) with HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, 69 mg, 0.18 mmol) and 6 -((2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxadolin-4-yl)amino)hexanoic acid ((63.8 mg, 0.165 mmol) in DMF (1 mL), the reaction was stirred at room temperature for 6 hours. Mass spectrometry detected that all raw materials were converted into products, and purified by reverse phase chromatography (nitrile: water (1/1000 formic acid)) to obtain the product (3S)-4-( 1-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxol-4-yl)amino)adipic acid )-2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydropyridine[2,3-d] Pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (60 mg, 0.061 mmol yellow solid, 36.9% yield). MS (ESI) M/Z: 976.4 [M+H ] +
步驟C（Step C）: 將（3S）-4-（1-（4-（（6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜環戊烯-4-基）胺基）己二酸基）-2,6-二甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代-1,2-二氫吡啶[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯(60 mg，0.06 mmol) 溶於二氯甲烷(2 mL)，然後加入1mL三氟乙酸。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於2mL二氯甲烷中，往反應液中分別加入DIPEA (N,N-二異丙基乙胺，50 g，0.4 mmol)和丙烯醯氯(15 mg，0.1 mmol)。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效液相純化得到N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-惡吡啉[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄基）-6-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧雜多林-4-基）胺基）己醯胺（25.1 mg，0.0027 mmol，淡黃色固體，收率：45%）。MS (ESI) M/Z：930.4[M+H] + Step C (Step C): (3S)-4-(1-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxa Cyclopenten-4-yl)amino)adipate)-2,6-dimethylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxo -1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (60 mg, 0.06 mmol) was dissolved in dichloromethane ( 2 mL), then 1 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20 degrees Celsius for 1 hour. Liquid chromatography tandem mass spectrometry showed that the raw materials had been reacted. Stop the reaction, and the solvent was spun under reduced pressure to remove the crude product. Boil twice. The crude product was redissolved in 2 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 50 g, 0.4 mmol) and acryl chloride (15 mg, 0.1 mmol) were added to the reaction solution. The reaction solution was stirred at 20 degrees Celsius for 2 hours. LCMS showed that the raw materials had been completely converted into products. The reaction was stopped and the solvent was removed. The crude product was purified by high performance liquid phase to obtain N-(4-(4-((S)-4-propene). Acrylo-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxapyrino[2,3-d]pyrimidine-1(2H) -yl)-3,5-dimethylbenzyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxadolin-4-yl) Amino)hexanamide (25.1 mg, 0.0027 mmol, pale yellow solid, yield: 45%). MS (ESI) M/Z: 930.4 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.25 (s, 1H), 8.28 (s, 1H), 7.62 – 7.54 (m, 1H), 7.28 (d, J= 7.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 7.02 (d, J= 6.9 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J= 11.7 Hz, 1H), 6.77 – 6.67 (m, 1H), 6.53 (s, 1H), 6.21 (d, J= 15.7 Hz, 1H), 5.77 (d, J= 7.6 Hz, 1H), 5.05 (dd, J= 12.9, 5.3 Hz, 1H), 4.87 (s, 1H), 4.50 – 3.95 (m, 6H), 3.64 (s, 2H), 2.89 (s, 1H), 2.21 – 2.11 (m, 2H), 2.01 (s, 1H), 1.87 (s, 3H), 1.59 (d, J= 7.0 Hz, 3H), 1.45 (s, 1H), 1.36 – 1.29 (m, 4H), 1.24 (s, 9H), 0.85 (d, J= 6.7 Hz, 2H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 10.25 (s, 1H), 8.28 (s, 1H), 7.62 – 7.54 (m, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.98 (s, 1H), 6.86 (d, J = 11.7 Hz, 1H), 6.77 – 6.67 (m, 1H), 6.53 (s, 1H), 6.21 (d, J = 15.7 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 12.9, 5.3 Hz, 1H ), 4.87 (s, 1H), 4.50 – 3.95 (m, 6H), 3.64 (s, 2H), 2.89 (s, 1H), 2.21 – 2.11 (m, 2H), 2.01 (s, 1H), 1.87 ( s, 3H), 1.59 (d, J = 7.0 Hz, 3H), 1.45 (s, 1H), 1.36 – 1.29 (m, 4H), 1.24 (s, 9H), 0.85 (d, J = 6.7 Hz, 2H ).
表3：遵循實施例29中所述的操作製備化合物30-36，如下
實施例 36 ：合成 (2S，4R)-1-[(2S)-2-[[2-[2-[2-[[4-[6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3，5-二甲基-苯基]甲胺基]-2-氧代-乙氧基]乙氧基]乙醯基]胺基]-3，3-二甲基-丁醯基]-4-羥基-N-[(1S)-1-[4-(4-甲基噻唑-5-基)苯基]乙基]吡咯烷-2-甲醯胺
合成路線：
步驟B（Step B）: 冰浴下，往2,6-二氯-5-氟煙酸(2.0 g, 9.57 mmol)的四氫呋喃(10 mL)溶液中緩慢加入草醯氯(1.46 g， 11.5 mmol，溶在7mL二氯甲烷中)。 反應液在 75 攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加4-胺基-3,5-二甲基苯甲腈(1.40 g，9.57 mmol)的四氫呋喃(20mL)溶液。反應液在攝氏度攪拌一個小時，然後升至室溫（25攝氏度）攪拌一小時。然後旋乾溶劑，再加入10m（石油醚：乙酸乙酯 10：1）超聲五分鐘，抽濾得到2,6-二氯-N-（（（4-氰基-2,6-二甲基苯基）胺基甲醯基）-5-氟煙醯胺（3.2 g，8.4 mmol，收率88%）。MS (ESI) M/Z：381.1[M+H] +。 Step B: Under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol) in tetrahydrofuran (10 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol) , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, then the heating was stopped. The solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 4-amino-3,5-dimethylbenzonitrile (1.40 g, 9.57 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction solution. The reaction solution was stirred at °C for one hour, then warmed to room temperature (25 °C) and stirred for one hour. Then spin to dry the solvent, add 10m (petroleum ether: ethyl acetate 10:1) and sonicate for five minutes, suction filtration to obtain 2,6-dichloro-N-(((4-cyano-2,6-dimethyl Phenyl)aminocarbamoyl)-5-fluoronicotinamide (3.2 g, 8.4 mmol, 88% yield). MS (ESI) M/Z: 381.1 [M+H] + .
步驟C（Step C）: 冰浴下，往2,6-二氯-N-（（（4-氰基-2,6-二甲基苯基）胺基甲醯基）-5-氟煙醯胺(3.2 g，8.4 mmol)的四氫呋喃(30 mL)溶液中緩慢滴加KHMDS(雙(三甲基矽烷基)胺基鉀，1 M的四氫呋喃溶液，16.8 mL，16.8 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。LCMS監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到4-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄腈（1.4 g，4.07 mmol，收率48.5%）。MS (ESI) M/Z：345.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-N-(((4-cyano-2,6-dimethylphenyl)aminocarbamoyl)-5-fluoronicotine To a solution of amide (3.2 g, 8.4 mmol) in tetrahydrofuran (30 mL), KHMDS (potassium bis(trimethylsilyl)amide, 1 M solution in tetrahydrofuran, 16.8 mL, 16.8 mmol) was slowly added dropwise. After that, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. LCMS monitored that all raw materials had been converted into products. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, Filter and spin dry. The crude product is purified by silica gel column chromatography (mobile phase: 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 4-(7-chloro-6-fluoro-2,4-dioxane) Substituted-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3,5-dimethylbenzonitrile (1.4 g, 4.07 mmol, 48.5% yield). MS (ESI) M/Z: 345.1 [M+H] + .
步驟D&E（Step D&E）: 往4-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄腈 (0.572 g，1.663 mmol)的甲苯(10 mL)溶液中加入 DIPEA(N,N-二異丙基乙胺，416 mg，3.22mmol) 和三氯氧磷 (493.6 mg，3.22 mmol)。反應液加熱到50攝氏度，攪拌60分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.83 g，無需純化，直接投入到下一步反應。Step D&E: To 4-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl )-3,5-dimethylbenzonitrile (0.572 g, 1.663 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 416 mg, 3.22 mmol) and oxychloride Phosphorus (493.6 mg, 3.22 mmol). The reaction solution was heated to 50°C and stirred for 60 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.83 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53 g，1.663mmol) 溶於DMF(10 mL)中，然後室溫下加入 (S)-4-N-第三丁氧羰基-2-甲基哌嗪(332.6mg，1.663mmol)。攪拌下，往上述反應液中滴加DIPEA (N,N-二異丙基乙胺，1.07 g，8.3 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到第三丁基(3S)-4-[7-氯-1-(4-氰基-2，6-二甲基-苯基)-6-氟-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯（0.48 g，0.91mmol，淺黃色固體，收率54.7%）。MS (ESI) M/Z：527.2[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.663 mmol) in DMF (10 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (332.6 mg, 1.663 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 1.07 g, 8.3 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give tert-butyl(3S)-4-[7-chloro-1-(4- Cyano-2,6-dimethyl-phenyl)-6-fluoro-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1- Carboxylic acid ester (0.48 g, 0.91 mmol, pale yellow solid, 54.7% yield). MS (ESI) M/Z: 527.2 [M+H] + .
步驟F（Step F）: 將第三丁基(3S)-4-[7-氯-1-(4-氰基-2，6-二甲基-苯基)-6-氟-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯 (0.16 g，0.304 mmol)，2-氟-6-羥基苯硼酸(94.8 mg，0.608mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，22.24 mg，0.03 mmol) 和KOAc(醋酸鉀，0.15 g，1.52 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1, 2 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90 攝氏度，在此溫度下攪拌反應5 小時。LCMS 監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到 第三丁基(3S)-4-[1-(4-氰基-2，6-二甲基-苯基)-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯基）-3-甲基哌嗪-1-羧酸第三丁酯（140mg，0.232 mmol，淡黃色固體，收率：76.3%）。 Step F (Step F): tert-butyl (3S)-4-[7-chloro-1-(4-cyano-2,6-dimethyl-phenyl)-6-fluoro-2-oxo Sub-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (0.16 g, 0.304 mmol), 2-fluoro-6-hydroxyphenylboronic acid (94.8 mg, 0.608 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 22.24 mg, 0.03 mmol ) and KOAc (potassium acetate, 0.15 g, 1.52 mmol) were mixed together and evacuated on a water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 2 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting materials to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give tert-butyl(3S)-4-[1-(4-cyano-2,6-dimethyl-benzene yl)-6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine -1-carboxylate)-3-methylpiperazine-1-carboxylate tert-butyl ester (140 mg, 0.232 mmol, pale yellow solid, yield: 76.3%).
步驟G（Step G）:將第三丁基(3S)-4-[1-(4-氰基-2，6-二甲基-苯基)-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯（140mg，0.232 mmol）溶於MeOH（5ml）中，向體系中加入雷尼鎳（10mg）抽真空並置換氫氣數次，然後在氫氣環境下攪拌反應5小時。質譜監測到所有的原料轉化成產物，矽藻土過濾得溶液，濃縮得產品 第三丁基(3S)-4-[1-[4-(氨甲基)-2，6-二甲基-苯基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯 (120 mg 0.198mmol，黃色固體，收率85%)。MS (ESI) M/Z：607.3[M+H] +。 Step G (Step G): tert-butyl (3S)-4-[1-(4-cyano-2,6-dimethyl-phenyl)-6-fluoro-7-(2-fluoro- 6-Hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (140 mg, 0.232 mmol) was dissolved in In MeOH (5 ml), Raney nickel (10 mg) was added to the system, and the system was evacuated and replaced with hydrogen several times, and then the reaction was stirred under hydrogen atmosphere for 5 hours. Mass spectrometry monitoring showed that all the raw materials were converted into products, the solution was filtered through diatomaceous earth, and concentrated to obtain the product tert-butyl (3S)-4-[1-[4-(aminomethyl)-2,6-dimethyl- Phenyl]-6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperidine Azine-1-carboxylate (120 mg 0.198 mmol, yellow solid, 85% yield). MS (ESI) M/Z: 607.3 [M+H] + .
步驟H（Step H）:將第三丁基(3S)-4-[1-[4-(氨甲基)-2，6-二甲基-苯基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯(120 mg，0.198mmol)溶於DMF(2ml)，向體系中加入2-[2-(羧甲氧基)乙氧基]乙酸（42.22mg，0.237mmol）和 N,N-二異丙基乙胺（76.6mg，0.594mmol）然後在100℃下攪拌過夜，質譜監測到反應完全，反應液冷卻至室溫用流動相（乙腈/水0~100%）純化得到2-[2-[2-[[4-[4-[(2S)-4-第三丁氧基羰基-2-甲基-哌嗪-1-基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3，5-二甲基-苯基]甲胺基]-2-氧代-乙氧基]乙氧基]乙酸（100mg，0.13mmol，淺黃色固體，收率65%）Step H (Step H): tert-butyl (3S)-4-[1-[4-(aminomethyl)-2,6-dimethyl-phenyl]-6-fluoro-7-(2 -Fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (120 mg, 0.198 mmol) was dissolved in DMF (2 ml), and 2-[2-(carboxymethoxy)ethoxy]acetic acid (42.22 mg, 0.237 mmol) and N,N-diisopropylethylamine (76.6 mg) were added to the system. , 0.594 mmol) and then stirred at 100 °C overnight, the mass spectrometry monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and purified with mobile phase (acetonitrile/water 0~100%) to obtain 2-[2-[2-[[4- [4-[(2S)-4-Tertibutoxycarbonyl-2-methyl-piperazin-1-yl]-6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-2 -oxo-pyrido[2,3-d]pyrimidin-1-yl]-3,5-dimethyl-phenyl]methylamino]-2-oxo-ethoxy]ethoxy]acetic acid (100mg, 0.13mmol, light yellow solid, yield 65%)
MS (ESI) M/Z：767.3[M+H] +。 MS (ESI) M/Z: 767.3 [M+H] + .
步驟I（Step I）: 2-[2-[2-[[4-[4-[(2S)-4-第三丁氧基羰基-2-甲基-哌嗪-1-基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3，5-二甲基-苯基]甲胺基]-2-氧代-乙氧基]乙氧基]乙酸（100mg，0.13mmol）溶於二氯甲烷（2ml）攪拌過程中加入三氟乙酸(1ml)體系在室溫下攪拌1小時TLC監測原料消失後旋乾溶劑，再用二氯甲烷（2ml）溶解向溶液中加入 N,N-二異丙基乙胺（76.6mg，0.594mmol）在0℃下加入丙烯醯氯（11.7mg，0.13mmol），攪拌1小時後質譜確認反應完全，旋乾溶劑，加少量水洗滌後用乙酸乙酯萃取，得到有機相後旋乾，快速柱層析(flash)純化（流動相乙腈/水0~100%）得到(2S，4R)-1-[(2S)-2-[[2-[2-[2-[[4-[6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-3，5-二甲基-苯基]甲胺基]-2-氧代-乙氧基]乙氧基]乙醯基]胺基]-3，3-二甲基-丁醯基]-4-羥基-N-[(1S)-1-[4-(4-甲基噻唑-5-基)苯基]乙基]吡咯烷-2-甲醯胺（30mg，0.026mmol，收率20%）。Step I (Step I): 2-[2-[2-[[[4-[4-[(2S)-4-tert-butoxycarbonyl-2-methyl-piperazin-1-yl]-6 -Fluoro-7-(2-Fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-3,5-dimethyl-phenyl] Methylamino]-2-oxo-ethoxy]ethoxy]acetic acid (100mg, 0.13mmol) was dissolved in dichloromethane (2ml) and trifluoroacetic acid (1ml) was added during stirring and the system was stirred at room temperature for 1 After TLC monitoring for the disappearance of raw materials after 1 hour, the solvent was revolved to dryness, and then dissolved in dichloromethane (2 ml). N,N-diisopropylethylamine (76.6 mg, 0.594 mmol) was added to the solution, and acryl chloride (11.7 mmol) was added at 0 °C. mg, 0.13 mmol), after stirring for 1 hour, mass spectrometry confirmed that the reaction was complete, the solvent was spin-dried, washed with a small amount of water, and then extracted with ethyl acetate to obtain an organic phase, spin-dried, and purified by flash column chromatography (mobile phase acetonitrile/ water 0~100%) to obtain (2S, 4R)-1-[(2S)-2-[[2-[2-[2-[[4-[6-fluoro-7-(2-fluoro-6- Hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-3,5-dimethyl-phenyl]methylamino]-2-oxo-ethoxy [methyl]ethoxy]acetyl]amino]-3,3-dimethyl-butyryl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazole-5- yl)phenyl]ethyl]pyrrolidine-2-carboxamide (30 mg, 0.026 mmol, 20% yield).
MS (ESI) M/Z：1147.3[M+H] + MS (ESI) M/Z: 1147.3[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 8.97 (s, 1H), 8.84 – 8.73 (m, 1H), 8.45 (d, J= 34.6 Hz, 2H), 8.31 (s, 2H), 7.42 (d, J= 8.0 Hz, 2H), 7.39 – 7.23 (m, 2H), 7.02 (s, 1H), 6.86 (s, 1H), 6.70 (d, J= 39.6 Hz, 2H), 6.19 (s, 1H), 5.76 (d, J= 10.1 Hz, 1H), 5.26 (d, J= 65.4 Hz, 2H), 4.86 (s, 2H), 4.56 (d, J= 9.5 Hz, 1H), 4.47 (s, 2H), 4.34 – 4.04 (m, 6H), 3.99 (s, 3H), 3.64 (d, J= 14.9 Hz, 8H), 3.09 (s, 1H), 2.64 (s, 1H), 2.45 (s, 2H), 2.37 (s, 1H), 2.02 (d, J= 51.6 Hz, 2H), 1.88 (s, 3H), 1.76 (s, 1H), 1.45 (s, 1H), 1.30 (s, 3H), 1.23 (s, 3H), 0.92 (s, 9H), 0.85 (s, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.97 (s, 1H), 8.84 – 8.73 (m, 1H), 8.45 (d, J = 34.6 Hz, 2H), 8.31 (s, 2H), 7.42 ( d, J = 8.0 Hz, 2H), 7.39 – 7.23 (m, 2H), 7.02 (s, 1H), 6.86 (s, 1H), 6.70 (d, J = 39.6 Hz, 2H), 6.19 (s, 1H) ), 5.76 (d, J = 10.1 Hz, 1H), 5.26 (d, J = 65.4 Hz, 2H), 4.86 (s, 2H), 4.56 (d, J = 9.5 Hz, 1H), 4.47 (s, 2H) ), 4.34 – 4.04 (m, 6H), 3.99 (s, 3H), 3.64 (d, J = 14.9 Hz, 8H), 3.09 (s, 1H), 2.64 (s, 1H), 2.45 (s, 2H) , 2.37 (s, 1H), 2.02 (d, J = 51.6 Hz, 2H), 1.88 (s, 3H), 1.76 (s, 1H), 1.45 (s, 1H), 1.30 (s, 3H), 1.23 ( s, 3H), 0.92 (s, 9H), 0.85 (s, 1H).
表4：遵循實施例36步驟B-I中所述的操作製備化合物37-40，如下
實施例 41 ：合成5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]-N-[[3-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-2，4-二甲基-苯基]甲基]戊醯胺
合成路線
步驟A-G (Step A-G)同實施例1，將2-胺基-3-甲基苯甲腈替換為3-胺基-2,4-二甲基苯甲腈。Steps A-G (Step A-G) are the same as in Example 1, except that 2-amino-3-methylbenzonitrile is replaced with 3-amino-2,4-dimethylbenzonitrile.
步驟H（Step H）：將5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]戊酸 （61.7 mg，0.165 mmol）溶於DMF(2mL)，向體系中加入第三丁基(3S)-4-[1-[3-(氨甲基)-2，6-二甲基-苯基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯（100mg，0.165mmol）N,N,N’,N’-四甲基-O-(7-氮雜苯并三唑-1-基)六氟磷酸脲（68.4mg，0.18mmol）再加入和N,N-二異丙基乙胺（76.6mg，0.594mmol）室溫下攪拌3小時，質譜監測反應完全。flash純化（流動相乙腈/水0~100%）得到第三丁基(3S)-4-[1-[3-[[5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]戊胺基]甲基]-2，6-二甲基-苯基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯（96mg，0.1mmol，收率60%）MS (ESI) M/Z：962.4[M+H] + Step H (Step H): 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino] Valeric acid (61.7 mg, 0.165 mmol) was dissolved in DMF (2 mL), and tert-butyl(3S)-4-[1-[3-(aminomethyl)-2,6-dimethyl- Phenyl]-6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperidine oxazine-1-carboxylate (100 mg, 0.165 mmol) N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (68.4 mg , 0.18 mmol) was added and N,N-diisopropylethylamine (76.6 mg, 0.594 mmol) was stirred at room temperature for 3 hours, and the reaction was completed by mass spectrometry monitoring. flash purification (mobile phase acetonitrile/water 0~100%) gave tert-butyl(3S)-4-[1-[3-[[5-[[2-(2,6-dioxo-3-piperidine pyridyl)-1,3-dioxo-isoindolin-4-yl]amino]pentylamino]methyl]-2,6-dimethyl-phenyl]-6-fluoro-7- (2-Fluoro-6-hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (96 mg, 0.1 mmol, 60% yield) MS (ESI) M/Z: 962.4 [M+H] +
步驟I（Step I）: 第三丁基(3S)-4-[1-[3-[[5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]戊胺基]甲基]-2，6-二甲基-苯基]-6-氟-7-(2-氟-6-羥基-苯基)-2-氧代-吡啶并[2，3-d]嘧啶-4-基]-3-甲基-哌嗪-1-羧酸酯（96mg，0.1mmol）溶於二氯甲烷（2ml）攪拌過程中加入三氟乙酸(1ml)體系在室溫下攪拌1小時TLC監測原料消失後旋乾溶劑，再用二氯甲烷（2ml）溶解向溶液中加入N,N-二異丙基乙胺（76.6mg，0.594mmol）在0℃下加入丙烯醯氯（9.5mg，0.1mmol），攪拌1小時後質譜確認反應完全，旋乾溶劑，加少量水洗滌後用乙酸乙酯萃取，得到有機相後旋乾，flash純化（流動相乙腈/水0~100%）得到5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]-N-[[3-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-2，4-二甲基-苯基]甲基]戊醯胺（39.34mg，0.043mmol，收率43%）Step I (Step I): tert-butyl (3S)-4-[1-[3-[[5-[[2-(2,6-dioxo-3-piperidinyl)-1,3 -Dioxo-isoindolin-4-yl]amino]pentylamino]methyl]-2,6-dimethyl-phenyl]-6-fluoro-7-(2-fluoro-6- Hydroxy-phenyl)-2-oxo-pyrido[2,3-d]pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate (96 mg, 0.1 mmol) in dichloro During the stirring process of methane (2ml), trifluoroacetic acid (1ml) was added to the system, and the system was stirred at room temperature for 1 hour. TLC monitored the disappearance of the raw materials, and then the solvent was spin-dried, and then dissolved in dichloromethane (2ml). Propylethylamine (76.6 mg, 0.594 mmol) was added with acryl chloride (9.5 mg, 0.1 mmol) at 0 °C, and after stirring for 1 hour, mass spectrometry confirmed that the reaction was complete, the solvent was spin-dried, washed with a small amount of water, and extracted with ethyl acetate , after the organic phase was obtained, it was spin-dried and purified by flash (mobile phase acetonitrile/water 0~100%) to obtain 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo substituted-isoindolin-4-yl]amino]-N-[[3-[6-fluoro-7-(2-fluoro-6-hydroxy-phenyl)-4-[(2S)-2- Methyl-4-prop-2-enyl-piperazin-1-yl]-2-oxo-pyrido[2,3-d]pyrimidin-1-yl]-2,4-dimethyl-benzene yl]methyl]pentamamide (39.34 mg, 0.043 mmol, 43% yield)
MS (ESI) M/Z：916.3[M+H] + MS (ESI) M/Z: 916.3[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.54 (s, 2H), 8.36 (d, J= 7.9 Hz, 1H), 8.26 – 8.21 (m, 1H), 7.56 (t, J= 7.8 Hz, 1H), 7.26 (dd, J= 15.4, 8.1 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 7.09 (d, J= 8.7 Hz, 2H), 7.01 (d, J= 7.0 Hz, 1H), 6.76 – 6.72 (m, 1H), 6.66 (t, J= 8.8 Hz, 1H), 6.57 (s, 1H), 5.99 (dd, J= 222.5, 12.7 Hz, 1H), 5.11 – 4.83 (m, 2H), 4.29 (dd, J= 15.1, 5.6 Hz, 2H), 4.18 (dd, J= 15.3, 5.3 Hz, 2H), 2.94 – 2.83 (m, 2H), 2.62 – 2.52 (m, 2H), 2.20 (t, J= 6.5 Hz, 3H), 2.04 (dd, J= 19.0, 13.3 Hz, 2H), 1.94 (d, J= 17.0 Hz, 6H), 1.84 (d, J= 11.2 Hz, 2H), 1.58 (s, 6H), 1.35 – 1.22 (m, 2H), 1.08 – 0.97 (m, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.54 (s, 2H), 8.36 (d, J = 7.9 Hz, 1H), 8.26 – 8.21 (m, 1H), 7.56 ( t, J = 7.8 Hz, 1H), 7.26 (dd, J = 15.4, 8.1 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.01 ( d, J = 7.0 Hz, 1H), 6.76 – 6.72 (m, 1H), 6.66 (t, J = 8.8 Hz, 1H), 6.57 (s, 1H), 5.99 (dd, J = 222.5, 12.7 Hz, 1H) ), 5.11 – 4.83 (m, 2H), 4.29 (dd, J = 15.1, 5.6 Hz, 2H), 4.18 (dd, J = 15.3, 5.3 Hz, 2H), 2.94 – 2.83 (m, 2H), 2.62 – 2.52 (m, 2H), 2.20 (t, J = 6.5 Hz, 3H), 2.04 (dd, J = 19.0, 13.3 Hz, 2H), 1.94 (d, J = 17.0 Hz, 6H), 1.84 (d, J = 11.2 Hz, 2H), 1.58 (s, 6H), 1.35 – 1.22 (m, 2H), 1.08 – 0.97 (m, 1H).
實施例 42 ：合成6-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]-N-[[3-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-2，4-二甲基-苯基]甲基]己醯胺
合成路線同實施例41，將5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]戊酸替換為6-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]己酸。The synthetic route is the same as in Example 41, except that 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino] Valeric acid was replaced with 6-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino]hexanoic acid.
MS (ESI) M/Z：930.5[M+H] + MS (ESI) M/Z: 930.5[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.37 (s, 1H), 8.32 – 8.22 (m, 1H), 8.19 (t, J= 5.6 Hz, 1H), 7.57 (dd, J= 8.4, 7.2 Hz, 1H), 7.27 (dd, J= 15.3, 8.3 Hz, 1H), 7.12 – 7.07 (m, 2H), 7.01 (d, J= 7.0 Hz, 1H), 6.95 – 6.78 (m, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.67 (t, J= 8.9 Hz, 1H), 6.54 (t, J= 5.7 Hz, 1H), 6.20 (dd, J= 16.9, 9.7 Hz, 1H), 5.76 (dd, J= 10.4, 2.2 Hz, 1H), 5.05 (dd, J= 12.8, 5.4 Hz, 1H), 4.88 (d, J= 23.7 Hz, 1H), 4.43 – 4.24 (m, 2H), 4.22 – 3.99 (m, 2H), 3.63 (d, J= 13.1 Hz, 2H), 3.49 – 3.32 (m, 4H), 3.31 – 3.25 (m, 3H), 2.94 – 2.83 (m, 1H), 2.16 (t, J= 7.4 Hz, 1H), 2.03 (ddd, J= 12.7, 8.4, 4.4 Hz, 1H), 1.81 (t, J= 25.5 Hz, 6H), 1.56 (dd, J= 13.1, 5.8 Hz, 3H), 1.38 – 1.26 (m, 4H), 1.02 (t, J= 6.9 Hz, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.37 (s, 1H), 8.32 – 8.22 (m, 1H), 8.19 (t, J = 5.6 Hz, 1H), 7.57 ( dd, J = 8.4, 7.2 Hz, 1H), 7.27 (dd, J = 15.3, 8.3 Hz, 1H), 7.12 – 7.07 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 6.95 – 6.78 (m, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.9 Hz, 1H), 6.54 (t, J = 5.7 Hz, 1H), 6.20 (dd, J = 16.9, 9.7 Hz, 1H), 5.76 (dd, J = 10.4, 2.2 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.88 (d, J = 23.7 Hz, 1H), 4.43 – 4.24 ( m, 2H), 4.22 – 3.99 (m, 2H), 3.63 (d, J = 13.1 Hz, 2H), 3.49 – 3.32 (m, 4H), 3.31 – 3.25 (m, 3H), 2.94 – 2.83 (m, 1H), 2.16 (t, J = 7.4 Hz, 1H), 2.03 (ddd, J = 12.7, 8.4, 4.4 Hz, 1H), 1.81 (t, J = 25.5 Hz, 6H), 1.56 (dd, J = 13.1 , 5.8 Hz, 3H), 1.38 – 1.26 (m, 4H), 1.02 (t, J = 6.9 Hz, 3H).
實施例 43 ：合成2-[3-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]環丁基]-N-[[3-[6-氟-7-(2-氟-6-羥基-苯基)-4-[(2S)-2-甲基-4-丙-2-烯基-哌嗪-1-基]-2-氧代-吡啶并[2，3-d]嘧啶-1-基]-2，4-二甲基-苯基]甲基]乙醯胺
合成路線同實施例41，將5-[[2-(2，6-二氧代-3-哌啶基)-1，3-二氧代-異吲哚啉-4-基]胺基]戊酸替換為2-（3-（（2-（2,6-二氧哌啶-3-基）-1,3-二氧異喹啉-4-基）胺基）環丁基）乙酸。The synthetic route is the same as in Example 41, except that 5-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]amino] Valeric acid was replaced with 2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)amino)cyclobutyl)acetic acid .
MS (ESI) M/Z：928.4[M+H] + MS (ESI) M/Z: 928.4[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 1H), 10.77 – 9.99 (m, 2H), 8.23 (ddd, J= 25.9, 17.5, 9.1 Hz, 2H), 7.59 (dd, J= 15.1, 6.9 Hz, 1H), 7.27 (dd, J= 15.3, 8.1 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.98 (dd, J= 45.4, 8.6 Hz, 1H), 6.86 (dd, J= 27.1, 16.8 Hz, 1H), 6.74 (d, J= 8.4 Hz, 1H), 6.68 (t, J= 8.0 Hz, 1H), 6.45 (dd, J= 30.5, 6.6 Hz, 1H), 6.26 – 6.13 (m, 1H), 5.80 – 5.71 (m, 1H), 5.13 – 5.00 (m, 1H), 4.88 (d, J= 24.0 Hz, 1H), 4.45 – 4.23 (m, 3H), 4.23 – 4.09 (m, 2H), 4.05 – 3.92 (m, 1H), 3.64 (d, J= 13.2 Hz, 2H), 3.17 – 3.03 (m, 1H), 2.96 – 2.85 (m, 1H), 2.65 – 2.51 (m, 4H), 2.45 – 2.39 (m, 1H), 2.33 (dd, J= 21.4, 9.3 Hz, 1H), 2.21 (s, 1H), 2.16 – 2.06 (m, 1H), 2.02 (dd, J= 15.8, 8.5 Hz, 1H), 1.82 (dd, J= 28.5, 22.1 Hz, 6H), 1.68 (d, J= 10.4 Hz, 1H), 1.37 – 1.25 (m, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.77 – 9.99 (m, 2H), 8.23 (ddd, J = 25.9, 17.5, 9.1 Hz, 2H), 7.59 (dd, J = 15.1, 6.9 Hz, 1H), 7.27 (dd, J = 15.3, 8.1 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.98 (dd, J = 45.4, 8.6 Hz, 1H), 6.86 (dd, J = 27.1, 16.8 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 8.0 Hz, 1H), 6.45 (dd, J = 30.5, 6.6 Hz, 1H), 6.26 – 6.13 (m, 1H), 5.80 – 5.71 (m, 1H), 5.13 – 5.00 (m, 1H), 4.88 (d, J = 24.0 Hz, 1H), 4.45 – 4.23 (m, 3H), 4.23 – 4.09 ( m, 2H), 4.05 – 3.92 (m, 1H), 3.64 (d, J = 13.2 Hz, 2H), 3.17 – 3.03 (m, 1H), 2.96 – 2.85 (m, 1H), 2.65 – 2.51 (m, 4H), 2.45 – 2.39 (m, 1H), 2.33 (dd, J = 21.4, 9.3 Hz, 1H), 2.21 (s, 1H), 2.16 – 2.06 (m, 1H), 2.02 (dd, J = 15.8, 8.5 Hz, 1H), 1.82 (dd, J = 28.5, 22.1 Hz, 6H), 1.68 (d, J = 10.4 Hz, 1H), 1.37 – 1.25 (m, 3H).
實施例 44 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（（2-（2,6-二氧哌啶-3-基）-1-氧代異丙酚-4-基）環己烷-1-甲醯胺
合成路線
步驟A（StepA）：將3-（4-羥基-1-氧異喹啉-2-基）哌啶-2,6-二酮（100 mg，0.38mmol)、4-（對甲苯氧基）環己烷-1-羧酸第三丁酯(136mg，0.38mmol)、碳酸鉀((104mg，0.76mmol)，碘化鉀(6.3mg，0.04mmol)溶於N,N-二甲基甲醯胺(2 ml)，在80℃下反應16小時，質譜監測反應完全，加少量水洗滌後用乙酸乙酯萃取，得到有機相後旋乾，flash純化（流動相乙腈/水0~100%）得到第三丁基4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-羧酸酯（132mg，收率78%）。Step A (StepA): 3-(4-Hydroxy-1-oxoisoquinolin-2-yl)piperidine-2,6-dione (100 mg, 0.38 mmol), 4-(p-tolyloxy) Cyclohexane-1-carboxylate tert-butyl ester (136 mg, 0.38 mmol), potassium carbonate ((104 mg, 0.76 mmol), potassium iodide (6.3 mg, 0.04 mmol) in N,N-dimethylformamide ( 2 ml), reacted at 80 ° C for 16 hours, the mass spectrometry monitored the reaction to complete, added a small amount of water to wash and then extracted with ethyl acetate to obtain the organic phase, spin to dry, flash purification (mobile phase acetonitrile/water 0~100%) to obtain the first Tributyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylate (132 mg, yield 78%).
步驟B（StepB）:將第三丁基4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-羧酸酯（132mg，0.3mmol）溶於二氯甲烷（2ml)，然後將三氟乙酸(1ml)加入，在常溫下反應2小時，反應液濃縮得到粗產品4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-羧酸(100mg)。Step B (StepB): tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane- 1-Carboxylic acid ester (132mg, 0.3mmol) was dissolved in dichloromethane (2ml), then trifluoroacetic acid (1ml) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to obtain crude product 4-((2-( 2,6-Dioxypiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylic acid (100 mg).
步驟C（StepC）:將第三丁基（3S）-4-（1-（4-（胺基甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代-1,2-二氫喹唑啉-4-基）-3-甲基哌嗪-1-羧酸鹽（100mg，0.16mmol)，4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-羧酸（61mg，0.16mmol)，2-(7-氮雜苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(60mg, 0.16mmol)，N,N-二異丙基乙胺(41mg，0.32mmol)溶於N,N-二甲基甲醯胺（2ml)，常溫反應1小時，質譜監測反應完全，flash純化（流動相乙腈/水0~100%）得到第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫喹唑啉-4-基）-3-甲基哌嗪-1-羧酸鹽（100mg，收率63%）。Step C (StepC): tert-butyl (3S)-4-(1-(4-(aminomethyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7- (2-Fluoro-6-hydroxyphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.16 mmol) , 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylic acid (61 mg, 0.16 mmol) , 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (60mg, 0.16mmol), N,N-diisopropylethylamine (41mg, 0.32mmol) was dissolved in N,N-dimethylformamide (2ml), reacted at room temperature for 1 hour, the reaction was completed by mass spectrometry, and purified by flash (mobile phase acetonitrile/water 0~100%) to obtain tert-butyl (3S)-4-(1-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoquinolin-4-yl)oxy) ring Hexane-1-carbamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-oxy -1,2-Dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 63% yield).
步驟D&E（StepD&E）:第三丁基（3S）-4-（1-（4-（（4-（（2-（2,6-二氧哌啶-3-基）-1-氧異喹啉-4-基）氧基）環己烷-1-甲醯胺基）甲基）-2-異丙基-6-甲基苯基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧基-1,2-二氫喹唑啉-4-基）-3-甲基哌嗪-1-羧酸鹽（100mg，0.1mmol）溶於二氯甲烷（2ml）攪拌過程中加入三氟乙酸(1ml)體系在室溫下攪拌1小時TLC監測原料消失後旋乾溶劑，再用二氯甲烷（2ml）溶解向溶液中加入 N,N-二異丙基乙胺（76.6mg，0.6mmol）在0℃下加入丙烯醯氯（9.5mg，0.1mmol），攪拌1小時後質譜確認反應完全，旋乾溶劑，加少量水洗滌後用乙酸乙酯萃取，得到有機相後旋乾，flash純化（流動相乙腈/水0~100%）得到N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（（2-（2,6-二氧哌啶-3-基）-1-氧代異丙酚-4-基）環己烷-1-甲醯胺（38mg，0.04mmol，收率40%）。MS (ESI) M/Z：1002.3[M+H] + Step D&E (StepD&E): Tertiary Butyl(3S)-4-(1-(4-((4-((2-(2,6-Dioxypiperidin-3-yl)-1-oxoisoquine olin-4-yl)oxy)cyclohexane-1-carboxamido)methyl)-2-isopropyl-6-methylphenyl)-6-fluoro-7-(2-fluoro-6 -Hydroxyphenyl)-2-oxy-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 0.1 mmol) was dissolved in dichloromethane ( 2ml) During the stirring process, add trifluoroacetic acid (1ml) to the system, stir at room temperature for 1 hour, monitor the disappearance of the raw materials by TLC, spin dry the solvent, and then dissolve it with dichloromethane (2ml) and add N,N-diisopropyl to the solution Ethylamine (76.6 mg, 0.6 mmol) was added with acryl chloride (9.5 mg, 0.1 mmol) at 0 °C, and after stirring for 1 hour, mass spectrometry confirmed that the reaction was complete, the solvent was spin-dried, washed with a small amount of water, and extracted with ethyl acetate to obtain The organic phase was spin-dried and purified by flash (mobile phase acetonitrile/water 0~100%) to obtain N-(4-(4-((S)-4-propenyl-2-methylpiperazin-1-yl)- 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-oxopyridin[2,3-d]pyrimidin-1(2H)-yl)-3-isopropyl-5-methyl Benzyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxopropanol-4-yl)cyclohexane-1-carboxamide (38 mg, 0.04 mmol, 40% yield). MS (ESI) M/Z: 1002.3 [M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 10.98 (s, 1H), 10.31 (s, 1H), 8.45 – 8.16 (m, 2H), 7.47 (dd, J= 10.5, 5.0 Hz, 1H), 7.29 (tt, J= 14.9, 7.5 Hz, 3H), 7.07 (s, 1H), 6.95 (s, 1H), 6.92 – 6.80 (m, 1H), 6.75 – 6.65 (m, 2H), 6.20 (dd, J= 16.3, 9.4 Hz, 1H), 5.76 (d, J= 12.2 Hz, 1H), 5.11 (dt, J= 13.2, 4.4 Hz, 1H), 4.88 (d, J= 17.3 Hz, 1H), 4.75 (s, 1H), 4.56 – 4.10 (m, 7H), 4.02 (d, J= 13.5 Hz, 1H), 3.64 (d, J= 13.8 Hz, 2H), 3.16 – 3.03 (m, 1H), 2.97 – 2.85 (m, 2H), 2.60 (t, J= 20.2 Hz, 2H), 2.48 – 2.41 (m, 1H), 2.39 – 2.22 (m, 1H), 2.15 (d, J= 9.8 Hz, 1H), 2.04 – 1.93 (m, 2H), 1.85 (d, J= 21.6 Hz, 5H), 1.71 – 1.57 (m, 3H), 1.46 – 1.23 (m, 4H), 1.03 (t, J= 6.3 Hz, 3H), 0.91 (s, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.98 (s, 1H), 10.31 (s, 1H), 8.45 – 8.16 (m, 2H), 7.47 (dd, J = 10.5, 5.0 Hz, 1H), 7.29 (tt, J = 14.9, 7.5 Hz, 3H), 7.07 (s, 1H), 6.95 (s, 1H), 6.92 – 6.80 (m, 1H), 6.75 – 6.65 (m, 2H), 6.20 (dd, J = 16.3, 9.4 Hz, 1H), 5.76 (d, J = 12.2 Hz, 1H), 5.11 (dt, J = 13.2, 4.4 Hz, 1H), 4.88 (d, J = 17.3 Hz, 1H), 4.75 ( s, 1H), 4.56 – 4.10 (m, 7H), 4.02 (d, J = 13.5 Hz, 1H), 3.64 (d, J = 13.8 Hz, 2H), 3.16 – 3.03 (m, 1H), 2.97 – 2.85 (m, 2H), 2.60 (t, J = 20.2 Hz, 2H), 2.48 – 2.41 (m, 1H), 2.39 – 2.22 (m, 1H), 2.15 (d, J = 9.8 Hz, 1H), 2.04 – 1.93 (m, 2H), 1.85 (d, J = 21.6 Hz, 5H), 1.71 – 1.57 (m, 3H), 1.46 – 1.23 (m, 4H), 1.03 (t, J = 6.3 Hz, 3H), 0.91 (s, 3H).
實施例 45 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-4-（2-（2,6-二氧哌啶-3-基）-1-氧代異異丙醇-4-氧基）苯甲醯胺
合成路線同實施例44 將4-（對甲苯氧基）環己烷-1-羧酸第三丁酯替換為4-（羥甲基）苯甲酸第三丁酯The synthetic route is the same as in Example 44, except that 4-(p-tolyloxy)cyclohexane-1-carboxylic acid tertiary butyl ester is replaced by 4-(hydroxymethyl) benzoic acid tertiary butyl ester
MS (ESI) M/Z：965.5[M+H] + MS (ESI) M/Z: 965.5[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 10.99 (s, 1H), 9.05 (t, J = 5.9 Hz, 1H), 8.28 (dd, J = 27.8, 18.7 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.59 (t, J = 7.7 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.26 (dd, J = 15.4, 8.1 Hz, 1H), 7.16 (s, 1H), 7.03 (s, 1H), 6.93 – 6.80 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.68 (t, J = 8.8 Hz, 1H), 6.20 (dd, J = 14.8, 9.0 Hz, 1H), 5.81 – 5.70 (m, 1H), 5.33 (s, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.90 (s, 1H), 4.48 (dd, J = 20.1, 11.6 Hz, 3H), 4.35 – 4.24 (m, 2H), 4.05 – 3.97 (m, 1H), 3.64 (d, J = 13.8 Hz, 2H), 3.20 – 3.01 (m, 2H), 2.98 – 2.84 (m, 1H), 2.58 (d, J = 17.6 Hz, 1H), 2.04 – 1.93 (m, 1H), 1.83 (s, 3H), 1.31 (dd, J = 9.9, 6.9 Hz, 3H), 1.25 (d, J = 12.7 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.94 – 0.88 (m, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.99 (s, 1H), 9.05 (t, J = 5.9 Hz, 1H), 8.28 (dd, J = 27.8, 18.7 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.59 (t, J = 7.7 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.26 (dd, J = 15.4, 8.1 Hz, 1H), 7.16 (s, 1H), 7.03 (s, 1H), 6.93 – 6.80 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.68 (t, J = 8.8 Hz, 1H) ), 6.20 (dd, J = 14.8, 9.0 Hz, 1H), 5.81 – 5.70 (m, 1H), 5.33 (s, 2H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.90 (s, 1H), 4.48 (dd, J = 20.1, 11.6 Hz, 3H), 4.35 – 4.24 (m, 2H), 4.05 – 3.97 (m, 1H), 3.64 (d, J = 13.8 Hz, 2H), 3.20 – 3.01 (m, 2H), 2.98 – 2.84 (m, 1H), 2.58 (d, J = 17.6 Hz, 1H), 2.04 – 1.93 (m, 1H), 1.83 (s, 3H), 1.31 (dd, J = 9.9 , 6.9 Hz, 3H), 1.25 (d, J = 12.7 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.94 – 0.88 (m, 3H).
實施例 46 ：合成N-（4-（4-（（S）-4-丙烯醯-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯基）-2-氧代吡啶[2,3-d]嘧啶-1（2H）-基）-3-異丙基-5-甲基苄基）-5-（（2-（2,6-二氧哌啶-3-基）-1-氧代異丙酚-4-基）吡嗪-2-甲醯胺
合成路線同實施例44將4-（對甲苯氧基）環己烷-1-羧酸第三丁酯替換為5-羥基吡嗪-2-羧酸第三丁酯The synthetic route is the same as in Example 44, except that 4-(p-tolyloxy)cyclohexane-1-carboxylate tert-butyl ester is replaced by 5-hydroxypyrazine-2-carboxylate tert-butyl ester
MS (ESI) M/Z：953.4[M+H] + MS (ESI) M/Z: 953.4[M+H] +
1H NMR (500 MHz, DMSO- d 6) δ 10.96 (s, 1H), 10.20 (s, 1H), 9.34 (t, J = 6.5 Hz, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.67 (d, J = 1.0 Hz, 1H), 8.33 – 8.21 (m, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.27 (dd, J = 15.5, 8.0 Hz, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 6.90 – 6.80 (m, 1H), 6.71 (dt, J = 17.5, 9.5 Hz, 2H), 6.20 (dd, J = 16.0, 9.0 Hz, 1H), 5.80 – 5.72 (m, 1H), 5.10 (dd, J = 13.0, 5.0 Hz, 1H), 4.88 (d, J = 18.0 Hz, 1H), 4.48 (d, J = 6.5 Hz, 2H), 4.39 (s, 1H), 4.30 (dd, J = 27.0, 15.5 Hz, 2H), 4.23 – 4.13 (m, 2H), 4.01 (d, J = 13.5 Hz, 1H), 3.74 – 3.59 (m, 2H), 3.55 – 3.43 (m, 1H), 3.18 – 3.01 (m, 1H), 2.93 – 2.84 (m, 1H), 2.34 (dt, J = 13.0, 8.5 Hz, 1H), 2.00 – 1.92 (m, 1H), 1.82 (s, 3H), 1.31 (dd, J = 11.0, 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.95 – 0.88 (m, 3H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.96 (s, 1H), 10.20 (s, 1H), 9.34 (t, J = 6.5 Hz, 1H), 8.72 (d, J = 1.0 Hz, 1H) , 8.67 (d, J = 1.0 Hz, 1H), 8.33 – 8.21 (m, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.27 (dd, J = 15.5, 8.0 Hz, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 6.90 – 6.80 (m, 1H), 6.71 (dt, J = 17.5, 9.5 Hz, 2H), 6.20 (dd, J = 16.0, 9.0 Hz, 1H), 5.80 – 5.72 (m, 1H), 5.10 (dd, J = 13.0, 5.0 Hz, 1H), 4.88 (d, J = 18.0 Hz, 1H), 4.48 (d, J = 6.5 Hz, 2H), 4.39 (s, 1H), 4.30 (dd, J = 27.0, 15.5 Hz, 2H), 4.23 – 4.13 (m, 2H), 4.01 (d, J = 13.5 Hz, 1H), 3.74 – 3.59 (m, 2H), 3.55 – 3.43 (m, 1H), 3.18 – 3.01 (m, 1H), 2.93 – 2.84 (m, 1H), 2.34 ( dt, J = 13.0, 8.5 Hz, 1H), 2.00 – 1.92 (m, 1H), 1.82 (s, 3H), 1.31 (dd, J = 11.0, 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz) , 3H), 0.95 – 0.88 (m, 3H).
實施例 47：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-1-(2,4-二甲基吡啶-3-基)-6-氟-7-(2-氟-6-羥基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟A（Step A）: 往2,6-二氯-5-氟煙酸(21.2 g，75 mmol)的二氯甲烷溶液（250mL）中滴加草醯氯(11.9 g，93 mmol，溶在50mL二氯甲烷中)，接著加入0.3mLN,N-二甲基甲醯胺（DMF）。反應液室溫攪拌過夜後，旋除溶劑。將剩餘的溶在二氧六環中(250 mL)中，並用冰浴控溫到0 攝氏度。接著往反應液中緩慢滴加氨水溶液(含量28-30% 氨，19 mL，112 mmol)。滴加完畢後，反應液在0 攝氏度攪拌30分鐘。然後將反應液的溶劑旋除，剩餘物加入1：1的乙酸乙酯/石油醚混合溶液，並攪拌5分鐘，接著過濾。將過濾的固體用石油醚洗滌，然後把固體真空乾燥，得到產物2,6-二氯-5-氟煙酸醯胺 (16.0 g，74 mmol，白色固體，收率98%)。MS (ESI) M/Z：209.1[M+H] +。 Step A (Step A): To a solution of 2,6-dichloro-5-fluoronicotinic acid (21.2 g, 75 mmol) in dichloromethane (250 mL) was added dropwise oxalic chloride (11.9 g, 93 mmol, dissolved in 50 mL of dichloromethane), followed by 0.3 mL of N,N-dimethylformamide (DMF). After the reaction solution was stirred at room temperature overnight, the solvent was removed by swirl. The remainder was dissolved in dioxane (250 mL) and the temperature was controlled to 0 degrees Celsius with an ice bath. Then, aqueous ammonia solution (content 28-30% ammonia, 19 mL, 112 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at 0°C for 30 minutes. Then the solvent of the reaction solution was spun off, and the residue was added to a 1:1 ethyl acetate/petroleum ether mixed solution, stirred for 5 minutes, and then filtered. The filtered solid was washed with petroleum ether, then the solid was dried in vacuo to give the product 2,6-dichloro-5-fluoronicotinamide (16.0 g, 74 mmol, white solid, 98% yield). MS (ESI) M/Z: 209.1 [M+H] + .
步驟B（Step B）: 冰浴下，往2,6-二氯-5-氟煙酸醯胺(2.5 g，12mmol)的四氫呋喃(10mL)溶液中緩慢加入草醯氯 (1.83 g，14.4 mmol，溶在7mL二氯甲烷中)。反應液在 75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加2,4-二甲基吡啶-3-胺 (1.46 g，12 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-N-((2,4-二甲基吡啶-3-基)胺基甲醯)-5-氟煙酸醯胺 (1.4 g，3.9 mmol，收率32% )。MS (ESI) M/Z：358.1[M+H] +。 Step B: Under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid amide (2.5 g, 12 mmol) in tetrahydrofuran (10 mL) was slowly added oxalic chloride (1.83 g, 14.4 mmol) , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 2,4-lutidine-3-amine (1.46 g, 12 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-N-((2,4-lutidine-3-yl)aminoformamide )-5-fluoronicotinamide (1.4 g, 3.9 mmol, 32% yield). MS (ESI) M/Z: 358.1 [M+H] + .
步驟C（Step C）: 冰浴下，往2,6-二氯-N-((2,4-二甲基吡啶-3-基)胺基甲醯)-5-氟煙酸醯胺 (1.4 g，3.9 mmol) 的四氫呋喃(20 mL)溶液中緩慢滴加雙(三甲基矽烷基)胺基鉀 (KHMDS，1 M的四氫呋喃溶液，8.2 mL，8.2 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。液相層析串聯質譜檢測到有產物生成。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮 (1.1 g，3.3 mmol，收率84% )。MS (ESI) M/Z：321.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-N-((2,4-lutidine-3-yl)aminocarbamide)-5-fluoronicotinic acid amide ( To a solution of 1.4 g, 3.9 mmol) in tetrahydrofuran (20 mL) was slowly added potassium bis(trimethylsilyl)amide (KHMDS, 1 M in tetrahydrofuran, 8.2 mL, 8.2 mmol) dropwise. After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. Product formation was detected by liquid chromatography tandem mass spectrometry. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to give 7-chloro-1-(2,4-lutidine-3-yl)- 6-Fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.1 g, 3.3 mmol, 84% yield). MS (ESI) M/Z: 321.1 [M+H] + .
步驟D&E（Step D&E）: 往7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮 (0.1 g，0.31 mmol)的甲苯(5 mL)中加入N,N-二異丙基乙胺 (DIPEA，80 mg，0.62mmol)和三氯氧磷(95 mg，0.62 mmol)。反應液加熱到50 攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-1-(2,4-二甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮(0.105 g)，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-1-(2,4-lutidine-3-yl)-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione (0.1 g, 0.31 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (DIPEA, 80 mg, 0.62 mmol) and phosphorus oxychloride (95 mg, 0.62 mmol) . The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-1-(2,4-dimethylpyridin-3-yl)-6-fluoropyrido[2, 3-d]pyrimidin-2(1H)-one (0.105 g) was used directly in the next reaction without purification.
將4,7-二氯-1-(2,4-二甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮 (0.105 g, 0.31mmol) 溶於DMF (2 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(62 mg，0.31 mmol)。攪拌下，往上述反應液中滴加DIPEA(0.2 g，9.5 mmol)。滴加完畢反應液攪拌半小時，液相層析串聯質譜監測反應，顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到第三丁基 (S)-4-(7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(0.14 g，0.28mmol， 黃色固體，收率90%)。MS (ESI) M/Z：445.1[M+H] +。 4,7-Dichloro-1-(2,4-lutidine-3-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (0.105 g, 0.31 mmol) in DMF (2 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (62 mg, 0.31 mmol) was added at room temperature. With stirring, DIPEA (0.2 g, 9.5 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and the reaction was monitored by liquid chromatography tandem mass spectrometry, indicating that the raw materials had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give tert-butyl(S)-4-(7-chloro-1-(2, 4-Lutidine-3-yl)-6-fluoro-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 - Carboxylic acid ester (0.14 g, 0.28 mmol, yellow solid, 90% yield). MS (ESI) M/Z: 445.1 [M+H] + .
步驟F（Step F）: 將第三丁基(S)-4-(7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(0.14 g，0.28 mmol)，2-氟-6-羥基苯硼酸(87 mg，0.56 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，25 mg，0.03 mmol)和KOAc (醋酸鉀，0.14 g，1.4 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(20/1，4 mL)用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到第三丁基(3S)-4-(1-(2,4-二甲基吡啶-3-基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯（100 mg，0.17 mmol，淡黃色固體，收率：57%）。MS (ESI) M/Z：579.1[M+H] +。 Step F (Step F): tert-butyl(S)-4-(7-chloro-1-(2,4-lutidine-3-yl)-6-fluoro-2-carbonyl-1, 2-Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.14 g, 0.28 mmol), 2-fluoro-6-hydroxyphenylboronic acid ( 87 mg, 0.56 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 25 mg, 0.03 mmol) and KOAc (potassium acetate, 0.14 g, 1.4 mmol) were mixed together and evacuated on an oil pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (20/1, 4 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give tert-butyl(3S)-4-(1-(2,4-lutidine-3-yl)- 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine -1-Carboxylic acid ester (100 mg, 0.17 mmol, pale yellow solid, yield: 57%). MS (ESI) M/Z: 579.1 [M+H] + .
步驟G&H（Step G&H）:將第三丁基(3S)-4-(1-(2,4-二甲基吡啶-3-基)-6-氟-7-(2-氟-6-羥基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(0.1 g, 0.17 mmol)溶於二氯甲烷(4 mL)，然後加入1mL三氟乙酸。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於2mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，0.11 g，0.85 mmol)和丙烯醯氯(25 mg，0.17 mmol)。反應液在20攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效液相純化得到4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-1-(2,4-二甲基吡啶-3-基)-6-氟-7-(2-氟-6-羥基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（45.5 mg，0.11 mmol，淡黃色固體，收率：49%）。Step G&H: tert-butyl(3S)-4-(1-(2,4-lutidine-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxyl) Phenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.1 g, 0.17 mmol) in in dichloromethane (4 mL), then 1 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Liquid chromatography tandem mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 2 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 0.11 g, 0.85 mmol) and acryl chloride (25 mg, 0.17 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by HPLC to obtain 4-((S)-4-propenyl-2-methylpiperazin-1-yl)-1-(2,4-lutidine-3-yl)-6- Fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (45.5 mg, 0.11 mmol, pale yellow solid, yield: 49%).
MS (ESI) M/Z：533.1[M+H] +。1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.36 – 8.21 (m, 2H), 7.29 (dd, J = 15.3, 8.2 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 6.96 – 6.80 (m, 1H), 6.78 – 6.63 (m, 2H), 6.21 (dd, J = 16.3, 5.9 Hz, 1H), 5.77 (dd, J = 10.4, 2.2 Hz, 1H), 4.92 (s, 1H), 4.46 – 4.23 (m, 2H), 4.20 – 3.97 (m, 1H), 3.78 – 3.43 (m, 2H), 3.30 – 3.01 (m, 1H), 2.09 (d, J = 10.0 Hz, 3H), 1.95 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H)。 MS (ESI) M/Z: 533.1 [M+H] + . 1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.36 – 8.21 (m, 2H), 7.29 (dd, J = 15.3, 8.2 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H) , 6.96 – 6.80 (m, 1H), 6.78 – 6.63 (m, 2H), 6.21 (dd, J = 16.3, 5.9 Hz, 1H), 5.77 (dd, J = 10.4, 2.2 Hz, 1H), 4.92 (s , 1H), 4.46 – 4.23 (m, 2H), 4.20 – 3.97 (m, 1H), 3.78 – 3.43 (m, 2H), 3.30 – 3.01 (m, 1H), 2.09 (d, J = 10.0 Hz, 3H ), 1.95 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H).
實施例 48：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟B（Step B）：冰浴下，往2,6-二氯-5-氟煙酸(2.0 g，9.57mmol)的四氫呋喃(10 mL)溶液中緩慢加入草醯氯(1.46 g，11.5 mmol，溶在7mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加2-異丙基-6-甲基苯胺(1.43 g，9.57 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺（3.6 g，9.37 mmol，收率98%）。MS (ESI) M/Z：385.1[M+H] +。 Step B (Step B): under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol) in tetrahydrofuran (10 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol) , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 2-isopropyl-6-methylaniline (1.43 g, 9.57 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl) Aminoformamide) niacinamide (3.6 g, 9.37 mmol, 98% yield). MS (ESI) M/Z: 385.1 [M+H] + .
步驟C（Step C）:冰浴下，往2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺 (3.6 g，9.37 mmol)的四氫呋喃(20 mL)溶液中緩慢滴加KHMDS(雙(三甲基矽烷基)胺基鉀，1M的四氫呋喃溶液，19.7 mL，19.7 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。LCMS監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮（1.4 g，3.22 mmol，收率34%）。MS (ESI) M/Z：348.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl)aminocarbamide)nicotinamide ( To a solution of 3.6 g, 9.37 mmol) in tetrahydrofuran (20 mL) was slowly added KHMDS (potassium bis(trimethylsilyl)amide, 1 M in tetrahydrofuran, 19.7 mL, 19.7 mmol) dropwise. After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. LCMS monitored that all starting material had been converted to product. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 7-chloro-6-fluoro-1-(2-isopropyl-6-methyl) Phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.4 g, 3.22 mmol, 34% yield). MS (ESI) M/Z: 348.1 [M+H] + .
步驟D&E（Step D&E）：往7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮 (0.5 g，1.44 mmol)的甲苯(10 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，372 mg，2.88mmol)和三氯氧磷(441 mg，2.88 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.53 g，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione (0.5 g, 1.44 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 372 mg, 2.88 mmol) and phosphorus oxychloride (441 mg, 2.88 mmol) ). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.53 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53 g，1.44mmol)溶於DMF(4 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(288 mg，1.44 mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，0.93 g，7.2 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（0.58 g，1.1mmol，黃色固體，收率76%）。MS (ESI) M/Z：531.1[M+H]+。4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.44 mmol) in DMF (4 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (288 mg, 1.44 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 0.93 g, 7.2 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give (S)-4-(7-chloro-6-fluoro-1-(2-) Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid Tributyl ester (0.58 g, 1.1 mmol, yellow solid, 76% yield). MS (ESI) M/Z: 531.1 [M+H]+.
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯 (0.58 g，1.1 mmol)，2-氟-6-羥基苯硼酸(340 mg，2.2 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，90 mg，0.11 mmol)和KOAc(醋酸鉀，0.54 g，5.5 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(20/1，12 mL)用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（420 mg，0.67 mmol，淡黃色固體，收率：61%）。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.58 g, 1.1 mmol), 2-fluoro-6-hydroxyphenylboronic acid (340 mg, 2.2 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 90 mg, 0.11 mmol ) and KOAc (potassium acetate, 0.54 g, 5.5 mmol) were mixed together and evacuated on an oil pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (20/1, 12 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-( 2-Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl acid (420 mg, 0.67 mmol, pale yellow solid, yield: 61%).
MS (ESI) M/Z：606.1[M+H] +。 MS (ESI) M/Z: 606.1 [M+H] + .
步驟G&H（Step G&H）: 將(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.4 g，0.66 mmol)溶於二氯甲烷(6 mL)，然後加入2mL三氟乙酸。反應液在20攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於3mL二氯甲烷中，往反應液中分別加入DIPEA (N,N-二異丙基乙胺，0.43 g，3.3 mmol)和丙烯醯氯(60 mg，0.66 mmol)。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（47.9 mg，0.085 mmol，淡黃色固體，收率：26%）。Step G&H: (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.4 g, 0.66 mmol) was dissolved in Dichloromethane (6 mL), then 2 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 3 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 0.43 g, 3.3 mmol) and acryl chloride (60 mg, 0.66 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 4-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)- 1-(2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (47.9 mg, 0.085 mmol, pale yellow solid, yield: 26%) .
MS (ESI) M/Z：560.1[M+H] +。 MS (ESI) M/Z: 560.1 [M+H] + .
1H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.35 – 8.19 (m, 1H), 7.31 – 7.18 (m, 3H), 7.14 – 7.07 (m, 1H), 6.93 –6.79 (m, 1H), 6.69 (dd, J = 20.7, 8.5 Hz, 2H), 6.25 – 6.13 (m, 1H), 5.77 (dd, J = 10.4, 2.3 Hz, 1H), 4.98 – 4.81 (m, 1H), 4.47 – 3.96 (m, 3H), 3.78 – 3.42 (m, 2H), 3.29 – 3.01 (m, 2H), 1.85 (s, 3H), 1.35 – 1.27 (m, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).1H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.35 – 8.19 (m, 1H), 7.31 – 7.18 (m, 3H), 7.14 – 7.07 (m, 1H), 6.93 –6.79 (m, 1H) ), 6.69 (dd, J = 20.7, 8.5 Hz, 2H), 6.25 – 6.13 (m, 1H), 5.77 (dd, J = 10.4, 2.3 Hz, 1H), 4.98 – 4.81 (m, 1H), 4.47 – 3.96 (m, 3H), 3.78 – 3.42 (m, 2H), 3.29 – 3.01 (m, 2H), 1.85 (s, 3H), 1.35 – 1.27 (m, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).
實施例 49：合成4-((S)-2,4-二甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟B（Step B）:冰浴下，往2,6-二氯-5-氟煙酸醯胺(2.0 g，9.57mmol)的四氫呋喃(10 mL)溶液中緩慢加入草醯氯(1.46 g，11.5 mmol，溶在7mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加2-異丙基-4-甲基-3-胺基吡啶(1.44 g，9.57 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-5-氟-N-((2-異丙基-4-甲基-吡啶-3-基)胺基甲醯)煙酸醯胺（2.4 g，6.23 mmol，收率65%），此粗產品無需純化，直接投入下一步反應。MS (ESI) M/Z：385.1[M+H] +。 Step B (Step B): under ice bath, to 2,6-dichloro-5-fluoronicotinamide (2.0 g, 9.57 mmol) in tetrahydrofuran (10 mL) solution was slowly added oxalic chloride (1.46 g, 11.5 mmol in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 2-isopropyl-4-methyl-3-aminopyridine (1.44 g, 9.57 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methyl-pyridine- 3-yl)aminoformamide)nicotinamide (2.4 g, 6.23 mmol, yield 65%), this crude product does not need to be purified, and is directly put into the next reaction. MS (ESI) M/Z: 385.1 [M+H] + .
步驟C（Step C）:冰浴下，往2,6-二氯-5-氟-N-((2-異丙基-4-甲基-吡啶-3-基)胺基甲醯)煙酸醯胺（2.4 g，6.23 mmol)的四氫呋喃(10 mL)溶液中緩慢滴加雙(三甲基矽烷基)胺基鉀(1M的四氫呋喃溶液，13.1 mL，13.1 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。液相層析串聯質譜監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮（1.5 g，4.3 mmol，收率：69%）。MS (ESI) M/Z：349.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methyl-pyridin-3-yl)aminoformamide) cigarette To a solution of amide (2.4 g, 6.23 mmol) in tetrahydrofuran (10 mL) was slowly added potassium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 13.1 mL, 13.1 mmol) dropwise. After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. Liquid chromatography tandem mass spectrometry monitored the conversion of all starting materials to product. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 7-chloro-6-fluoro-1-(2-isopropyl-4-methyl) Pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g, 4.3 mmol, yield: 69%). MS (ESI) M/Z: 349.1 [M+H] + .
步驟D&E（Step D&E）: 往7-氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.75 g，1.9 mmol)的甲苯(12 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，500 mg，3.8mmol)和三氯氧磷(600 mg，3.8 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.711 g，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4( 1H,3H)-dione (0.75 g, 1.9 mmol) in toluene (12 mL) was added DIPEA (N,N-diisopropylethylamine, 500 mg, 3.8 mmol) and phosphorus oxychloride (600 mg , 3.8 mmol). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido [2,3-d]pyrimidin-2(1H)-one, 0.711 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.711 g, 1.9mmol)溶於DMF(6 mL)中，然後室溫下加入(S)-1,3-二甲基哌嗪(220 mg，1.9 mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，1.23 g，9.5 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（0.31 g，0.7mmol，黃色固體，收率36%）。MS (ESI) M/Z：445.1[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.711 g, 1.9 mmol) was dissolved in DMF (6 mL), then (S)-1,3-dimethylpiperazine (220 mg, 1.9 mmol) was added at room temperature. Under stirring, DIPEA (N,N-diisopropylethylamine, 1.23 g, 9.5 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give (S)-4-(7-chloro-6-fluoro-1-(2-) Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid Tributyl ester (0.31 g, 0.7 mmol, yellow solid, 36% yield). MS (ESI) M/Z: 445.1 [M+H] + .
步驟F（Step F）: 將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯 (0.31 g，0.7 mmol)，2-氟-6-羥基苯硼酸(220 mg，1.4 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，52 mg，0.07 mmol)和KOAc(醋酸鉀，0.34 g，3.5 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(20/1，6 mL)用氮氣除氧15分鐘，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90 攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經高效液相製備純化得到4-((S)-2,4-二甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮（31.6 mg，0.06 mmol，淡黃色固體，收率：26%）。MS (ESI) M/Z：521.1[M+H] +。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.31 g, 0.7 mmol), 2-fluoro-6-hydroxyphenylboronic acid (220 mg, 1.4 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 52 mg, 0.07 mmol ) and KOAc (potassium acetate, 0.34 g, 3.5 mmol) were mixed together and evacuated on an oil pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (20/1, 6 mL) was deoxygenated with nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to obtain 4-((S)-2,4-dimethylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1 -(2-Isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (31.6 mg, 0.06 mmol, pale yellow solid, yield: 26 %). MS (ESI) M/Z: 521.1 [M+H] + .
1H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.25 (dd, J = 18.2, 9.2 Hz, 1H), 7.27 (dd, J = 15.3, 8.2 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 6.76 – 6.63 (m, 2H), 4.92 (d, J = 32.5 Hz, 1H), 4.35 –4.14 (m, 1H), 3.81 – 3.58 (m, 1H), 2.92 – 2.80 (m, 1H), 2.78 – 2.61 (m, 2H), 2.30 – 2.18 (m, 4H), 2.14 –2.02 (m, 1H), 1.89 (d, J = 4.3 Hz, 3H), 1.47 (dd, J = 13.9, 6.7 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.96 –0.88 (m, 3H).1H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.25 (dd, J = 18.2, 9.2 Hz, 1H), 7.27 (dd, J = 15.3, 8.2 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 6.76 – 6.63 (m, 2H), 4.92 (d, J = 32.5 Hz, 1H), 4.35 – 4.14 (m, 1H), 3.81 – 3.58 (m, 1H), 2.92 – 2.80 (m, 1H), 2.78 – 2.61 (m, 2H), 2.30 – 2.18 (m, 4H), 2.14 –2.02 (m, 1H), 1.89 (d, J = 4.3 Hz, 3H), 1.47 (dd, J = 13.9, 6.7 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.96 –0.88 (m, 3H).
實施例 50：合成6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-4-甲基吡啶-3-基)-4-((S)-3-甲基嗎啉代)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例49相同。The synthesis procedure was the same as that of Example 49.
MS (ESI) M/Z：521.1[M+H] +。 MS (ESI) M/Z: 521.1 [M+H] + .
1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.51 – 8.24 (m, 2H), 7.32 – 7.22 (m, 1H), 7.21 – 7.06 (m, 1H), 6.81 – 6.53 (m, 2H), 5.01 – 4.65 (m, 1H), 4.26 – 4.07 (m, 1H), 3.99 – 3.56 (m, 5H), 2.70 (dd, J = 12.8, 6.3 Hz, 1H), 1.97 – 1.83 (m, 3H), 1.55 – 1.37 (m, 3H), 1.12 – 1.02 (m, 3H), 1.00 – 0.83 (m, 3H).1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.51 – 8.24 (m, 2H), 7.32 – 7.22 (m, 1H), 7.21 – 7.06 (m, 1H), 6.81 – 6.53 (m, 2H) ), 5.01 – 4.65 (m, 1H), 4.26 – 4.07 (m, 1H), 3.99 – 3.56 (m, 5H), 2.70 (dd, J = 12.8, 6.3 Hz, 1H), 1.97 – 1.83 (m, 3H) ), 1.55 – 1.37 (m, 3H), 1.12 – 1.02 (m, 3H), 1.00 – 0.83 (m, 3H).
實施例 51：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(3-氟苯氧基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步驟A（Step A）：往2,6-二氯-5-氟煙酸(10 g，35 mmol)的二氯甲烷溶液（200mL）中滴加草醯氯(5.6 g，44 mmol，溶在30 mL二氯甲烷中)，接著加入0.15mLN,N-二甲基甲醯胺（DMF）。反應液室溫攪拌過夜後，旋除溶劑。將剩餘的溶在二氧六環中(200 mL)中，並用冰浴控溫到0攝氏度。接著往反應液中緩慢滴加氨水溶液(含量28-30% 氨，9 mL，53 mmol)。滴加完畢後，反應液在0攝氏度攪拌30分鐘。然後將反應液的溶劑旋除，剩餘物加入1：1的乙酸乙酯/石油醚混合溶液，並攪拌5分鐘，接著過濾。將過濾的固體用石油醚洗滌，然後把固體真空乾燥，得到產物2,6-二氯-5-氟煙酸醯胺 (6 g，28 mmol，白色固體，收率80%)。MS (ESI) M/Z：209.1[M+H] +。 Step A (Step A): To a solution of 2,6-dichloro-5-fluoronicotinic acid (10 g, 35 mmol) in dichloromethane (200 mL) was added dropwise oxalic chloride (5.6 g, 44 mmol, dissolved in 30 mL of dichloromethane), followed by 0.15 mL of N,N-dimethylformamide (DMF). After the reaction solution was stirred at room temperature overnight, the solvent was removed by swirl. The remainder was dissolved in dioxane (200 mL) and the temperature was controlled to 0 degrees Celsius with an ice bath. Then, aqueous ammonia solution (content 28-30% ammonia, 9 mL, 53 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at 0°C for 30 minutes. Then the solvent of the reaction solution was spun off, and the residue was added to a 1:1 ethyl acetate/petroleum ether mixed solution, stirred for 5 minutes, and then filtered. The filtered solid was washed with petroleum ether, then the solid was dried in vacuo to give the product 2,6-dichloro-5-fluoronicotinamide (6 g, 28 mmol, white solid, 80% yield). MS (ESI) M/Z: 209.1 [M+H] + .
步驟B（Step B）：冰浴下，往2,6-二氯-5-氟煙酸醯胺(2 g，10 mmol)的四氫呋喃(20 mL)溶液中緩慢加入草醯氯(1.46 g，11.5 mmol，溶在7 mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加2,4-二甲基苯胺(1.46 g，12 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-N-((2,6-二甲基苯基)胺基甲醯)-5-氟煙酸醯胺 (2.6 g，7.5 mmol，收率75%)。MS (ESI) M/Z：356.2[M+H] +。 Step B (Step B): under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid amide (2 g, 10 mmol) in tetrahydrofuran (20 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Next, a solution of 2,4-dimethylaniline (1.46 g, 12 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-N-((2,6-dimethylphenyl)aminoformamide)-5 - Fluonicotinamide (2.6 g, 7.5 mmol, 75% yield). MS (ESI) M/Z: 356.2 [M+H] + .
步驟C（Step C）：冰浴下，往2,6-二氯-N-((2,6-二甲基苯基)胺基甲醯)-5-氟煙酸醯胺(1.4 g，3.9 mmol)的四氫呋喃(20 mL)溶液中緩慢滴加雙(三甲基矽烷基)胺基鉀(KHMDS，1M的四氫呋喃溶液，8.2 mL，8.2 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。液相層析串聯質譜檢測到有產物生成。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-1-(2,6-二甲基苯基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮 (0.9 g，2.8mmol，收率71% )。MS (ESI) M/Z：320.4[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-N-((2,6-dimethylphenyl)aminocarbamide)-5-fluoronicotinic acid amide (1.4 g, 3.9 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise potassium bis(trimethylsilyl)amide (KHMDS, 1 M in tetrahydrofuran, 8.2 mL, 8.2 mmol). After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. Product formation was detected by liquid chromatography tandem mass spectrometry. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 7-chloro-1-(2,6-dimethylphenyl)-6-fluoro Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.9 g, 2.8 mmol, 71% yield). MS (ESI) M/Z: 320.4 [M+H] + .
步驟D&E（Step D&E）：往7-氯-1-(2,6-二甲基苯基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1 g，3.1 mmol)的甲苯(30 mL)中加入N,N-二異丙基乙胺(DIPEA，0.8 g，6.2mmol)和三氯氧磷(0.95 g，6.2 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-1-(2,6-二甲基苯基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-1-(2,6-dimethylphenyl)-6-fluoropyrido[2,3-d]pyrimidine-2,4(1H,3H)-di To the ketone (1 g, 3.1 mmol) in toluene (30 mL) was added N,N-diisopropylethylamine (DIPEA, 0.8 g, 6.2 mmol) and phosphorus oxychloride (0.95 g, 6.2 mmol). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-1-(2,6-dimethylphenyl)-6-fluoropyrido[2,3-d ]pyrimidin-2(1H)-one, without purification, was directly used in the next reaction.
將4,7-二氯-1-(2,6-二甲基苯基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮(1 g，3.1 mmol)溶於DMF(2 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(620 mg，3.1 mmol)。攪拌下，往上述反應液中滴加DIPEA(2 g，95 mmol)。滴加完畢反應液攪拌半小時，液相層析串聯質譜監測反應，顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到第三丁基(S)-4-(7-氯-1-(2,4-二甲基吡啶-3-基)-6-氟-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(1.4 g，2.8 mmol，黃色固體，收率90%)。MS (ESI) M/Z：502.7[M+H] +。 4,7-Dichloro-1-(2,6-dimethylphenyl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one (1 g, 3.1 mmol) was dissolved in In DMF (2 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (620 mg, 3.1 mmol) was added at room temperature. With stirring, DIPEA (2 g, 95 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and the reaction was monitored by liquid chromatography tandem mass spectrometry, indicating that the raw materials had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give tert-butyl(S)-4-(7-chloro-1-(2, 4-Lutidine-3-yl)-6-fluoro-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 - Carboxylic acid ester (1.4 g, 2.8 mmol, yellow solid, 90% yield). MS (ESI) M/Z: 502.7 [M+H] + .
步驟F（Step F）：將第三丁基(S)-4-(7-氯-1-(2,6-二甲基苯基)-6-氟-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(1.4 g，2.8 mmol)，3-氟苯酚(0.63 g，5.6 mmol)，Cs 2CO 3(碳酸銫，1.82 g，5.6 mmol)溶於二氧六環和水的混合液(10/1,20 mL)然後加熱到90攝氏度，在此溫度下攪拌反應5小時。質譜監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到第三丁基(3S)-4-(1-(2,6-二甲基苯基)-6-氟-7-(3-氟苯氧基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯（1.21 g，2.1 mmol，淡黃色固體，收率：75%）。MS (ESI) M/Z：578.4[M+H] +。 Step F (Step F): tert-butyl (S)-4-(7-chloro-1-(2,6-dimethylphenyl)-6-fluoro-2-carbonyl-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.4 g, 2.8 mmol), 3-fluorophenol (0.63 g, 5.6 mmol), Cs 2 CO 3 (cesium carbonate, 1.82 g, 5.6 mmol) was dissolved in a mixture of dioxane and water (10/1, 20 mL) and heated to 90 degrees Celsius, where the reaction was stirred for 5 hours. Mass spectrometry monitored the conversion of all starting material to product. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give tert-butyl(3S)-4-(1-(2,6-dimethylphenyl)-6-fluoro -7-(3-Fluorophenoxy)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.21 g, 2.1 mmol, pale yellow solid, yield: 75%). MS (ESI) M/Z: 578.4 [M+H] + .
步驟G&H（Step G&H）：將第三丁基(3S)-4-(1-(2,6-二甲基苯基)-6-氟-7-(3-氟苯氧基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸酯(150 mg，0.26 mmol)溶於二氯甲烷(4 mL)，然後加入1mL三氟乙酸。反應液在20攝氏度下攪拌1小時。液相層析串聯質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於2mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，0.17 g，1.3 mmol)和丙烯醯氯(38 mg，0.17 mmol)。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效液相純化得到4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-1-(2,6-二甲基苯基)-6-氟-7-(3-氟苯氧基)吡啶并[2,3-d]嘧啶-2(1H)-酮（79 mg，0.15 mmol，淡黃色固體，收率：57%）。MS (ESI) M/Z：532.5[M+H] +。 Step G&H: tert-butyl(3S)-4-(1-(2,6-dimethylphenyl)-6-fluoro-7-(3-fluorophenoxy)-2- Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.26 mmol) was dissolved in dichloromethane (4 mL), then 1 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Liquid chromatography tandem mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 2 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 0.17 g, 1.3 mmol) and acryl chloride (38 mg, 0.17 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by HPLC to obtain 4-((S)-4-propenyl-2-methylpiperazin-1-yl)-1-(2,6-dimethylphenyl)-6-fluoro-7 -(3-Fluorophenoxy)pyrido[2,3-d]pyrimidin-2(1H)-one (79 mg, 0.15 mmol, pale yellow solid, yield: 57%). MS (ESI) M/Z: 532.5 [M+H] + .
實施例 52：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)--6-氟-7-(2-氟苯氧基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例51相同。The synthesis procedure was the same as in Example 51.
MS (ESI) M/Z：560.4[M+H] +。 MS (ESI) M/Z: 560.4 [M+H] + .
實施例 53：4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)--6-氟-7-(萘-2-基氧基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例51相同。The synthesis procedure was the same as in Example 51.
MS (ESI) M/Z：592.7[M+H] +。 MS (ESI) M/Z: 592.7 [M+H] + .
實施例 54：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)--6-氟-7-(2-氟-6-羥基苯基)-1-(2-甲基萘-6-基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例47相同。The synthesis procedure was the same as in Example 47.
MS (ESI) M/Z：568.5[M+H] +。 MS (ESI) M/Z: 568.5 [M+H] + .
實施例 55：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)--6-氟-7-(2-胺-6-氟苯基)-1-(2-甲基萘-1-基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例47相同。The synthesis procedure was the same as in Example 47.
MS (ESI) M/Z：567.3[M+H] +。 MS (ESI) M/Z: 567.3 [M+H] + .
實施例 56：合成2-（4-（（S）-4-丙烯醯基-2-甲基哌嗪-1-基）-7-（2-胺基-6-氟苯基）-6-氟-2-氧吡喃并[2,3-d]嘧啶 -1（2H）-基）-3-甲基苄腈
合成路線：
其合成步驟與實施例47相同。The synthesis procedure was the same as in Example 47.
MS (ESI) M/Z：542.7[M+H] + MS (ESI) M/Z: 542.7[M+H] +
實施例 57：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟苯基)-1-(2-羥基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
其合成步驟與實施例47相同。The synthesis procedure was the same as in Example 47.
MS (ESI) M/Z：518.4[M+H] + MS (ESI) M/Z: 518.4[M+H] +
實施例 58：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟苯基)-1-(2-甲氧基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
其合成步驟與實施例47相同。The synthesis procedure was the same as in Example 47.
MS (ESI) M/Z：532.7[M+H] + MS (ESI) M/Z: 532.7[M+H] +
實施例 59:合成（S）4-（1-（2,6-二甲基苯基）-6-氟-7-（3-氟苯氧基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸酯
合成路線：
其合成步驟與實施例51相同。The synthesis procedure was the same as in Example 51.
MS (ESI) M/Z：578.6[M+H] + MS (ESI) M/Z: 578.6[M+H] +
實施例 60：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟B（Step B）：冰浴下，往2,6-二氯-5-氟煙酸(2.0 g，9.57mmol)的四氫呋喃(20 mL)溶液中緩慢加入草醯氯(1.46 g，11.5 mmol，溶在7 mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除溶劑，然後重新置於冰浴下加入10 mL四氫呋喃。接著往反應液中滴加2-異丙基-6-甲基苯胺(1.43 g，9.57 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺（3.6 g，9.37 mmol，收率98%）。MS (ESI) M/Z：385.1[M+H] +。 Step B (Step B): under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol) in tetrahydrofuran (20 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol) , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. The solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 2-isopropyl-6-methylaniline (1.43 g, 9.57 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl) Aminoformamide) niacinamide (3.6 g, 9.37 mmol, 98% yield). MS (ESI) M/Z: 385.1 [M+H] + .
步驟C（Step C）：冰浴下，往2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺(3.6 g，9.37 mmol)的四氫呋喃(20 mL)溶液中緩慢滴加KHMDS(雙(三甲基矽烷基)胺基鉀，1M的四氫呋喃溶液，19.7 mL，19.7 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。LCMS監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮（1.4 g, 3.22 mmol, 收率34%）。MS (ESI) M/Z：348.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl)aminocarbamide)nicotinamide ( To a solution of 3.6 g, 9.37 mmol) in tetrahydrofuran (20 mL) was slowly added KHMDS (potassium bis(trimethylsilyl)amide, 1 M in tetrahydrofuran, 19.7 mL, 19.7 mmol) dropwise. After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. LCMS monitored that all starting material had been converted to product. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 7-chloro-6-fluoro-1-(2-isopropyl-6-methyl) Phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.4 g, 3.22 mmol, 34% yield). MS (ESI) M/Z: 348.1 [M+H] + .
步驟D&E（Step D&E）: 往7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.5 g，1.44 mmol)的甲苯(10 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，372 mg，2.88mmol)和三氯氧磷(441 mg，2.88 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.53 g，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione (0.5 g, 1.44 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 372 mg, 2.88 mmol) and phosphorus oxychloride (441 mg, 2.88 mmol) ). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.53 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53 g, 1.44mmol)溶於DMF(4 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(288 mg，1.44 mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，0.93 g，7.2 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（0.58 g，1.1mmol，黃色固體，收率76%）。MS (ESI) M/Z：531.1[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.44 mmol) in DMF (4 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (288 mg, 1.44 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 0.93 g, 7.2 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give (S)-4-(7-chloro-6-fluoro-1-(2-) Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid Tributyl ester (0.58 g, 1.1 mmol, yellow solid, 76% yield). MS (ESI) M/Z: 531.1 [M+H] + .
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.58 g，1.1 mmol)，2-氟-苯硼酸(308 mg，2.2 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，90 mg，0.11 mmol)和KOAc(醋酸鉀，0.54 g，5.5 mmol)混合在一起並加入二氧六環和水的混合液(20/1，12 mL)。反應液置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到(3S)-4-(6-氟-7-(2-氟苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（394.6 mg，0.67 mmol，淡黃色固體，收率：61%）。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.58 g, 1.1 mmol), 2-fluoro-phenylboronic acid (308 mg, 2.2 mmol), Pd(dppf) Cl2CH2Cl2 ( [1,1' - bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 90 mg, 0.11 mmol) and KOAc (potassium acetate, 0.54 g, 5.5 mmol) were mixed together and a mixture of dioxane and water (20/1, 12 mL) was added. The reaction liquid was replaced with nitrogen several times, then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give (3S)-4-(6-fluoro-7-(2-fluorophenyl)-1-(2-isopropyl) (yl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl Ester (394.6 mg, 0.67 mmol, pale yellow solid, yield: 61%).
MS (ESI) M/Z：590.3[M+H] +。 MS (ESI) M/Z: 590.3 [M+H] + .
步驟G&H（Step G&H）: 將(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.39 g，0.66 mmol)溶於二氯甲烷(6 mL)，然後加入2mL三氟乙酸。反應液在20攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於3mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，0.43 g，3.3 mmol)和丙烯醯氯(60 mg，0.66 mmol)。反應液在20攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（46.2 mg, 0.085 mmol, 淡黃色固體，收率：26%）。Step G&H: (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.39 g, 0.66 mmol) was dissolved in Dichloromethane (6 mL), then 2 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 3 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 0.43 g, 3.3 mmol) and acryl chloride (60 mg, 0.66 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 4-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)- 1-(2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (46.2 mg, 0.085 mmol, pale yellow solid, yield: 26%) .
MS (ESI) M/Z：544.3[M+H] +。 MS (ESI) M/Z: 544.3 [M+H] + .
實施例 61：合成4-(-4-丙烯醯-哌嗪-1-基)-1-(2,4-二甲基吡啶-3-基)-6-氟-7-(2-氟-6-羥基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟D&E（Step D&E）：往7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.5 g，1.44 mmol)的甲苯(10 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，372 mg，2.88 mmol)和三氯氧磷(441 mg，2.88 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.53 g，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione (0.5 g, 1.44 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 372 mg, 2.88 mmol) and phosphorus oxychloride (441 mg, 2.88 mmol) ). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.53 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.5 g，1.44 mmol)溶於DMF(10 mL)中，然後室溫下加入第三丁氧羰基哌嗪(268 mg，1.44 mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，0.93 g，7.2 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯（0.566 g，1.1mmol，黃色固體，收率76%）。MS (ESI) M/Z：516.1[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.5 g, 1.44 mmol) in DMF (10 mL), then tert-butoxycarbonylpiperazine (268 mg, 1.44 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 0.93 g, 7.2 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give 4-(7-chloro-6-fluoro-1-(2-isopropyl- 6-Methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.566 g, 1.1 mmol , yellow solid, yield 76%). MS (ESI) M/Z: 516.1 [M+H] + .
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯(0.1 g，0.19 mmol)，2-氟-6-羥基苯硼酸(60.2 mg，0.388 mmol)，Pd(dppf)Cl 2CH 2Cl 2，([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，20 mg，0.027 mmol)和KOAc(醋酸鉀，0.78 g，7.9 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，2 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）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-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯（80 mg，0.135 mmol，淡黃色固體，收率：71%）。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (0.1 g, 0.19 mmol), 2-fluoro-6-hydroxyphenylboronic acid (60.2 mg, 0.388 mmol) , Pd(dppf)Cl 2 CH 2 Cl 2 , ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 20 mg, 0.027 mmol) and KOAc ( Potassium acetate, 0.78 g, 7.9 mmol) were mixed together and evacuated at the water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 2 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give 4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl) (6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.135 mmol, pale yellow solid, yield: 71%).
MS (ESI) M/Z：592.1[M+H] +。 MS (ESI) M/Z: 592.1 [M+H] + .
步驟G&H（Step G&H）：將(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯(80 mg，0.135 mmol)溶於二氯甲烷(1 mL)，然後加入0.5mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於1mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，87 mg，0.67 mmol)和丙烯醯氯(12.2 mg，0.135 mmol)。反應液在20攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-(4-丙烯醯哌嗪-1-基)-6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（28.3 mg，0.052 mmol，淡黃色固體，收率：38%）。Step G&H: (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.135 mmol) was dissolved in dichloromethane (1 mL), then 0.5 mL of trifluoroacetic acid was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 1 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 87 mg, 0.67 mmol) and acryl chloride (12.2 mg, 0.135 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl- 6-Methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (28.3 mg, 0.052 mmol, pale yellow solid, yield: 38%).
MS (ESI) M/Z：546.1[M+H] +。 MS (ESI) M/Z: 546.1 [M+H] + .
實施例 62：4-（4-丙烯醯基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-7-（萘-2-基）吡啶并[2,3-d]嘧啶-2（1H）-酮
合成路線：
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯(200 mg，0.388 mmol)，2-萘硼酸(650 mg，3.88 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，85 mg，0.116 mmol)和KOAc(醋酸鉀，614.7 mg，1.887 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，2 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應16小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到第三丁基4-（6-氟-1-（2-異丙基-6-甲基苯基）-7-（萘-2-基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）哌嗪-1-羧酸第三丁酯（90 mg，0.148 mmol，淡黃色固體，收率：37.1%）。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (200 mg, 0.388 mmol), 2-naphthaleneboronic acid (650 mg, 3.88 mmol), Pd(dppf) Cl2CH2Cl2 ( [1,1' - bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 85 mg, 0.116 mmol) and KOAc (potassium acetate, 614.7 mg, 1.887 mmol) were mixed together and evacuated on a water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 2 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 16 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give tert-butyl 4-(6-fluoro-1-(2-isopropyl-6-methylphenyl)- 7-(Naphthalen-2-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (90 mg , 0.148 mmol, pale yellow solid, yield: 37.1%).
MS (ESI) M/Z：608.3[M+H] +。 MS (ESI) M/Z: 608.3 [M+H] + .
步驟G&H（Step G&H）：將(3S)-4-(6-氟-7-萘基-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯(90mg，0.148 mmol)溶於二氯甲烷(1mL)，然後加入0.5mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於1mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，87mg，0.67 mmol)和丙烯醯氯(14.35 mg，0.158 mmol)。反應液在20攝氏度下攪拌2小時。LCMS 顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-（4-丙烯醯基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-7-（萘-2-基）吡啶并[2,3-d]嘧啶-2（1H）-酮（33.8 mg，0.06 mmol，淡黃色固體，收率：40.5%）。Step G&H: (3S)-4-(6-fluoro-7-naphthyl-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (90 mg, 0.148 mmol) was dissolved in dichloromethane (1 mL) and 0.5 mL of trifluoroacetic acid was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 1 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 87 mg, 0.67 mmol) and acryl chloride (14.35 mg, 0.158 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain 4-(4-propenylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)-7-(naphthalene- 2-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (33.8 mg, 0.06 mmol, pale yellow solid, yield: 40.5%).
MS (ESI) M/Z：562.2[M+H] +。 MS (ESI) M/Z: 562.2 [M+H] + .
實施例 63：合成4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟--7-（萘-2-基）-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(200 mg，0.378 mmol)，2-萘硼酸(130 mg，0.756 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，83 mg，0.11 mmol)和Cs 2CO 3(碳酸銫，246.3 mg，0.756 mmol)混合在一起並加入二氧六環和水的混合液(20/1，12 mL)。反應液置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到（S）-4-（6-氟-1-（2-異丙基-6-甲基苯基）-7-（萘-2-基）-2-氧代-1,2-二氫吡啶基[2,3- d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯（90 mg，0.145 mmol，淡黃色固體，收率：61%）。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (200 mg, 0.378 mmol), 2-naphthaleneboronic acid (130 mg, 0.756 mmol) , Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 83 mg, 0.11 mmol) and Cs 2 CO 3 (Cesium carbonate, 246.3 mg, 0.756 mmol) were mixed together and a mixture of dioxane and water (20/1, 12 mL) was added. The reaction liquid was replaced with nitrogen several times, then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give (S)-4-(6-fluoro-1-(2-isopropyl-6-methylphenyl)- 7-(Naphthalen-2-yl)-2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid third Butyl ester (90 mg, 0.145 mmol, pale yellow solid, yield: 61%).
MS (ESI) M/Z：622.3[M+H] +。 MS (ESI) M/Z: 622.3 [M+H] + .
步驟G&H（Step G&H）：將第三丁基（S）-4-（6-氟-1-（2-異丙基-6-甲基苯基）-7-（萘-2-基）-2-氧代-1,2-二氫吡啶基[2,3- d]嘧啶-4-基）-3-甲基哌嗪-1-羧酸第三丁酯(90 mg，0.145 mmol)溶於二氯甲烷(1 mL)，然後加入0.5mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於3mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，87mg，0.67 mmol)和丙烯醯氯(13.12 mg，0.145 mmol)。反應液在25攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟--7-（萘-2-基）-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（56.5 mg，0.098 mmol，淡黃色固體，收率：67%）。MS (ESI) M/Z：576.3[M+H] +。 Step G&H: Tertiary-butyl(S)-4-(6-fluoro-1-(2-isopropyl-6-methylphenyl)-7-(naphthalen-2-yl)- 2-Oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (90 mg, 0.145 mmol) in in dichloromethane (1 mL) followed by 0.5 mL of trifluoroacetic acid. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 3 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 87 mg, 0.67 mmol) and acryl chloride (13.12 mg, 0.145 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 25°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high-efficiency preparative liquid phase to obtain 4-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(naphthalen-2-yl)-1-( 2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (56.5 mg, 0.098 mmol, pale yellow solid, yield: 67%). MS (ESI) M/Z: 576.3 [M+H] + .
實施例 64：合成4-（4-丙烯醯基哌嗪-1-基）-6-氟-7-（2-氟苯基）-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2（1H）- 酮
合成路線：
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯 (100mg，0.194 mmol)，2-氟-苯硼酸(54 mg，0388 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，42.5 mg，0.058 mmol)和KOAc(醋酸鉀，95 mg，0.97 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，1 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應16小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到4-（6-氟-7-（2-氟苯基）-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- 哌嗪-1-羧酸第三丁酯（56 mg，0.097 mmol，淡黃色固體，收率：50%）。MS (ESI) M/Z：576.3[M+H] +。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (100 mg, 0.194 mmol), 2-fluoro-phenylboronic acid (54 mg, 0388 mmol), Pd (dppf ) Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 42.5 mg, 0.058 mmol) and KOAc (potassium acetate, 95 mg , 0.97 mmol) were mixed together and evacuated at the water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 1 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 16 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give 4-(6-fluoro-7-(2-fluorophenyl)-1-(2-isopropyl-6- Methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-piperazine-1-carboxylate tert-butyl ester (56 mg, 0.097 mmol, pale yellow solid , yield: 50%). MS (ESI) M/Z: 576.3 [M+H] + .
步驟G&H（Step G&H）: 將4-（6-氟-7-（2-氟苯基）-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- 哌嗪-1-羧酸第三丁酯(56mg，0.148 mmol)溶於二氯甲烷(1mL)，然後加入0.5mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於1mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，87 mg，0.67 mmol)和丙烯醯氯(14.35 mg，0.158 mmol)。反應液在20攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-（4-丙烯醯基哌嗪-1-基）-6-氟-7-（2-氟苯基）-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2（1H）- 酮（18.8 mg，0.06 mmol，淡黃色固體，收率：40.5%）。MS (ESI) M/Z：530.2[M+H] +。 Step G&H: 4-(6-Fluoro-7-(2-fluorophenyl)-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidine-4-piperazine-1-carboxylate tert-butyl ester (56 mg, 0.148 mmol) was dissolved in dichloromethane (1 mL), then 0.5 mL of trifluoroacetic acid was added. The liquid was stirred for 1 hour at 25 degrees Celsius. The mass spectrum showed that the raw materials had been reacted. The reaction was stopped, and the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 1 mL of dichloromethane, and the reaction solution DIPEA (N,N-diisopropylethylamine, 87 mg, 0.67 mmol) and propenyl chloride (14.35 mg, 0.158 mmol) were added to it. The reaction was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material The product was obtained. The reaction was stopped, and the solvent was removed. The crude product was purified by high-efficiency preparative liquid phase to obtain 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(2-fluorophenyl)-1- (2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (18.8 mg, 0.06 mmol, pale yellow solid, yield: 40.5%). MS (ESI) M/Z: 530.2 [M+H] + .
實施例 65：4-（4-丙烯醯基哌嗪-1-基）-6-氟-7-（3-氟苯氧基）-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2（1H）-酮
合成路線：
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸第三丁酯(150mg，0.194 mmol)，3-氟-苯酚(98 mg，0388 mmol)，KOAc(醋酸鉀，474.5 mg，0.97 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，3 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應16小時。LCMS 監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到4-（6-氟-7-（3-氟苯氧基）-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- 哌嗪-1-羧酸第三丁酯（90mg，0.152 mmol，淡黃色固體，收率：78.3%）。Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (150 mg, 0.194 mmol), 3-fluoro-phenol (98 mg, 0388 mmol), KOAc (potassium acetate) , 474.5 mg, 0.97 mmol) were mixed together and evacuated at the water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 3 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 16 hours. Conversion of all starting materials to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give 4-(6-fluoro-7-(3-fluorophenoxy)-1-(2-isopropyl-6) -Methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-piperazine-1-carboxylate tert-butyl ester (90 mg, 0.152 mmol, pale yellow solid , yield: 78.3%).
MS (ESI) M/Z：592.3[M+H] +。 MS (ESI) M/Z: 592.3 [M+H] + .
步驟G&H（Step G&H）：將4-（6-氟-7-（3-氟苯氧基）-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- 哌嗪-1-羧酸第三丁酯(90mg，0.152 mmol)溶於二氯甲烷(1mL)，然後加入0.5mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於1mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，58.93mg，0.456 mmol)和丙烯醯氯(13.78 mg，0.152 mmol)。反應液在25攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到4-（4-丙烯醯基哌嗪-1-基）-6-氟-7-（3-氟苯氧基）-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2（1H）-酮（35.6mg，0.065 mmol，淡黃色固體，收率：42.2%）。Step G&H: 4-(6-Fluoro-7-(3-fluorophenoxy)-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2 - Dihydropyrido[2,3-d]pyrimidine-4-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.152 mmol) was dissolved in dichloromethane (1 mL), then 0.5 mL of trifluoroacetic acid was added. The reaction solution was stirred for 1 hour at 25 degrees Celsius. The mass spectrum showed that the raw materials had been reacted. Stop the reaction, and the solvent was rotated under reduced pressure to remove, and the crude product was azeotroped 2 times with dichloromethane. The crude product was redissolved in 1 mL of dichloromethane, and the reaction DIPEA (N,N-diisopropylethylamine, 58.93 mg, 0.456 mmol) and allyl chloride (13.78 mg, 0.152 mmol) were added to the solution. The reaction solution was stirred at 25°C for 2 hours. LCMS showed that the starting material was complete. Converted into product. The reaction was stopped, and the solvent was removed by rotation. The crude product was purified by high-efficiency preparative liquid phase to obtain 4-(4-propenylpiperazin-1-yl)-6-fluoro-7-(3-fluorophenoxy)- 1-(2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (35.6 mg, 0.065 mmol, pale yellow solid, yield: 42.2%) .
MS (ESI) M/Z：546.2[M+H] +。 MS (ESI) M/Z: 546.2 [M+H] + .
實施例 66：合成（S）-4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟-6-羥基苯）-2-氧吡啶并[2,3-d]嘧啶-1（2H ）-基）-3,5-二甲基苄腈
合成路線：
步驟B（Step B）：冰浴下，往2,6-二氯-5-氟煙酸(2.0 g，9.57 mmol)的四氫呋喃(20 mL)溶液中緩慢加入草醯氯(1.46 g, 11.5 mmol，溶在7 mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加4-胺基-3,5-二甲基苯甲腈(1.40 g，9.57 mmol)的四氫呋喃(20mL)溶液。反應液在攝氏度攪拌一個小時，然後升至室溫（25攝氏度）攪拌一小時。然後旋乾溶劑，再加入10m（石油醚：乙酸乙酯 10：1）超聲五分鐘，抽濾得到2,6-二氯-N-（（（4-氰基-2,6-二甲基苯基）胺基甲醯基）-5-氟煙醯胺（3.2 g，8.4 mmol，收率88%）。MS (ESI) M/Z：381.1[M+H] +。 Step B (Step B): To a solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol) in tetrahydrofuran (20 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol) under ice bath , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. The reaction solution was spun off under reduced pressure to remove the solvent, and then placed in an ice bath and added with 10 mL of tetrahydrofuran. Then, a solution of 4-amino-3,5-dimethylbenzonitrile (1.40 g, 9.57 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction solution. The reaction solution was stirred at °C for one hour, then warmed to room temperature (25 °C) and stirred for one hour. Then spin to dry the solvent, add 10m (petroleum ether: ethyl acetate 10:1) and sonicate for five minutes, suction filtration to obtain 2,6-dichloro-N-(((4-cyano-2,6-dimethyl Phenyl)aminocarbamoyl)-5-fluoronicotinamide (3.2 g, 8.4 mmol, 88% yield). MS (ESI) M/Z: 381.1 [M+H] + .
步驟C（Step C）：冰浴下，往2,6-二氯-N-（（（4-氰基-2,6-二甲基苯基）胺基甲醯基）-5-氟煙醯胺(3.2 g，8.4 mmol)的四氫呋喃(30 mL)溶液中緩慢滴加KHMDS(雙(三甲基矽烷基)胺基鉀，1M的四氫呋喃溶液，16.8 mL，16.8 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。LCMS監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到4-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄腈（1.4 g，4.07 mmol，收率48.5%）。MS (ESI) M/Z：345.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-N-(((4-cyano-2,6-dimethylphenyl)aminocarbamoyl)-5-fluoronicotine To a solution of amide (3.2 g, 8.4 mmol) in tetrahydrofuran (30 mL), KHMDS (potassium bis(trimethylsilyl)amide, 1M solution in tetrahydrofuran, 16.8 mL, 16.8 mmol) was slowly added dropwise. , the ice bath is removed, and the reaction solution is stirred overnight at room temperature. LCMS monitors that all raw materials have been converted into products. The reaction solution is quenched with ammonium chloride solution, and extracted with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate and filtered. Spin dry. The crude product is purified by silica gel column chromatography (mobile phase: 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 4-(7-chloro-6-fluoro-2,4-dioxo) -3,4-Dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)-3,5-dimethylbenzonitrile (1.4 g, 4.07 mmol, 48.5% yield). MS ( ESI) M/Z: 345.1 [M+H] + .
步驟D&E（Step D&E）：往4-（7-氯-6-氟-2,4-二氧代-3,4-二氫吡啶并[2,3-d]嘧啶-1（2H）-基）-3,5-二甲基苄腈(0.572 g，1.663 mmol)的甲苯(10 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，416 mg，3.22mmol)和三氯氧磷(493.6 mg，3.22 mmol)。反應液加熱到50攝氏度，攪拌60分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.83 g，無需純化，直接投入到下一步反應。Step D&E: To 4-(7-chloro-6-fluoro-2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl )-3,5-dimethylbenzonitrile (0.572 g, 1.663 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 416 mg, 3.22 mmol) and oxychloride Phosphorus (493.6 mg, 3.22 mmol). The reaction solution was heated to 50°C and stirred for 60 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.83 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53 g，1.663mmol)溶於DMF(10 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(332.6mg，1.663mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，1.07 g，8.3 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到 （S）-4-（7-氯-1-（4-氰基-2,6-二甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸第三丁酯（0.48 g，0.91mmol，淺黃色固體，收率54.7%）。MS (ESI) M/Z：527.2[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.663 mmol) in DMF (10 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (332.6 mg, 1.663 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 1.07 g, 8.3 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give (S)-4-(7-chloro-1-(4-cyano-2). ,6-dimethylphenyl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- 3-Butyl carboxylate (0.48 g, 0.91 mmol, pale yellow solid, 54.7% yield). MS (ESI) M/Z: 527.2 [M+H] + .
步驟F（Step F）：將（S）-4-（7-氯-1-（4-氰基-2,6-二甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸第三丁酯(0.16 g，0.304 mmol)，2-氟-6-羥基苯硼酸(94.8 mg，0.608mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，22.24 mg，0.03 mmol)和KOAc(醋酸鉀，0.15 g，1.52 mmol)混合在一起並在水泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(10/1，2 mL)用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到（S）-4-（7-氯-1-（4-氰基-2,6-二甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸第三丁酯（140mg，0.232 mmol，淡黃色固體，收率：76.3%）。MS (ESI) M/Z：603.2[M+H] +。 Step F: (S)-4-(7-chloro-1-(4-cyano-2,6-dimethylphenyl)-6-fluoro-2-oxo-1,2 - Dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.16 g, 0.304 mmol), 2-fluoro-6-hydroxybenzene Boronic acid (94.8 mg, 0.608 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 22.24 mg , 0.03 mmol) and KOAc (potassium acetate, 0.15 g, 1.52 mmol) were mixed together and evacuated at a water pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (10/1, 2 mL) was added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give (S)-4-(7-chloro-1-(4-cyano-2,6-dimethylphenyl) )-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (140 mg , 0.232 mmol, pale yellow solid, yield: 76.3%). MS (ESI) M/Z: 603.2 [M+H] + .
步驟G&H（Step G&H）：將（S）-4-（7-氯-1-（4-氰基-2,6-二甲基苯基）-6-氟-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶- 4-基）-3-甲基哌嗪-1-羧酸第三丁酯 (40mg，0.066 mmol)溶於二氯甲烷(0.5mL)，然後加入0.3mL三氟乙酸。反應液在25攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於0.5mL二氯甲烷中，往反應液中分別加入DIPEA(N,N-二異丙基乙胺，42.6mg，0.33 mmol)和丙烯醯氯(6 mg，0.066 mmol)。反應液在20攝氏度下攪拌2小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到（S）-4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-7-（2-氟苯基）-2-氧吡啶并[2,3-d]嘧啶-1（2H ）-基）-3,5-二甲基苄腈（19.1 mg，0.052 mmol，黃色固體，收率：78%）。Step G&H: (S)-4-(7-chloro-1-(4-cyano-2,6-dimethylphenyl)-6-fluoro-2-oxo-1,2 -dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.066 mmol) was dissolved in dichloromethane (0.5 mL), Then 0.3 mL of trifluoroacetic acid was added. The reaction solution was stirred at 25°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 0.5 mL of dichloromethane, and DIPEA (N,N-diisopropylethylamine, 42.6 mg, 0.33 mmol) and acryl chloride (6 mg, 0.066 mmol) were added to the reaction solution, respectively. The reaction solution was stirred at 20°C for 2 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain (S)-4-(4-(4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluorophenyl)- 2-Oxypyrido[2,3-d]pyrimidin-1(2H)-yl)-3,5-dimethylbenzonitrile (19.1 mg, 0.052 mmol, yellow solid, yield: 78%).
MS (ESI) M/Z：557.2[M+H] +。 MS (ESI) M/Z: 557.2 [M+H] + .
實施例 67：4-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(4-胺基-2-氟苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
合成路線：
步驟A（Step A）：將（S）-第三丁基4-（7-氯-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- -3-甲基哌嗪-1-羧酸基酯(100 mg，0.19 mmol)溶解在二氯甲烷(2 mL)中並加入三氟乙酸(1 mL)並在室溫下攪拌1小時， 液相層析串聯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，加入二氯甲烷(1 mL)，DIPEA(N,N-二異丙基乙胺)(73.2 g，0.57 mmol)和丙烯醯氯(34 mg，0.38 mmol)並在室溫下攪拌2小時，液相層析串聯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（S）-4-（4-丙烯醯基-2-甲基哌嗪-1-基）-7-氯-6-氟-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2-酮（74.4 mg, 黃色固體，收率81.1%）。MS (ESI) M/Z：484.1[M+H] + Step A (Step A): (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1, 2-Dihydropyrido[2,3-d]pyrimidine-4--3-methylpiperazine-1-carboxylate (100 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL) and added Trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. After monitoring by liquid chromatography tandem mass spectrometry showed the disappearance of the starting material, dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and dichloromethane (10 mL) was added again. Concentrate under reduced pressure until dichloromethane and trifluoroacetic acid are completely removed, add dichloromethane (1 mL), DIPEA (N,N-diisopropylethylamine) (73.2 g, 0.57 mmol) and acryl chloride (34 mg, 0.38 mmol) and stirred at room temperature for 2 hours, after liquid chromatography tandem mass spectrometry monitoring 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 (5 mL). ) to obtain (S)-4-(4-propenyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-6-methyl) ylphenyl)pyrido[2,3-d]pyrimidin-2-one (74.4 mg, yellow solid, 81.1% yield). MS (ESI) M/Z: 484.1 [M+H] +
步驟B（Step B）將（S）-4-（4-丙烯醯基-2-甲基哌嗪-1-基）-7-氯-6-氟-1-（2-異丙基-6-甲基苯基）吡啶并[2,3-d]嘧啶-2-酮(74 mg，0.15 mmol)，3-氟-4-（4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基）苯胺(54 mg，0.23 mmol)，碳酸鈉(78 mg，0.75 mmol)溶解在用氮氣氣置換空氣15分鐘的1,4-二氧六環和水混合溶液（1 mL，4/1）中，加入Pd(PPh 3) 4(10 mg，0.008mg)再次用氮氣氣置換空氣，並在90℃下攪拌4h。液相層析串聯質譜監測顯示原料消失後，用乙酸乙酯(2×40mL)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-((S)-4-丙烯醯-2-甲基哌嗪-1-基)-6-氟-7-(4-胺基-2-氟苯基)-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮（40 mg，淡黃色固體，收率47.8%）。MS (ESI) M/Z：559.2[M+H] + Step B (Step B) will (S)-4-(4-propenyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-6 -Methylphenyl)pyrido[2,3-d]pyrimidin-2-one (74 mg, 0.15 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboran-2-yl)aniline (54 mg, 0.23 mmol), and sodium carbonate (78 mg, 0.75 mmol) were dissolved in 1,4-dioxane and nitrogen displacing the air for 15 min. To the water mixed solution (1 mL, 4/1), Pd(PPh 3 ) 4 (10 mg, 0.008 mg) was added to replace the air with nitrogen again, and the mixture was stirred at 90° C. for 4 h. After monitoring by liquid chromatography tandem mass spectrometry 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-((S)-4-propenyl-2-methylpiperazin-1-yl)-6-fluoro-7-(4-amino-2-fluorophenyl)-1- (2-Isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (40 mg, pale yellow solid, 47.8% yield). MS (ESI) M/Z: 559.2[M+H] +
實施例 68：（S）-N-（4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2- 二氫吡啶并[2,3-d]嘧啶-7-基）-3-氟苯基）-3-（2-甲氧基乙氧基）丙醯胺
合成路線：
步驟A（Step A）將（S）-第三丁基4-（7-氯-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶并[2,3-d]嘧啶-4- -3-甲基哌嗪-1-羧酸基酯(400 mg，0.76 mmol)，3-氟-4-（4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基）苯胺(269 mg，1.13 mmol)，碳酸鈉(399.0 mg，3.80 mmol)溶解在用氮氣氣置換空氣15分鐘的1,4-二氧六環和水混合溶液（1 mL，4/1）中，加入Pd(PPh 3) 4(44 mg，0.038mg)，再次用氮氣氣置換空氣，並在90℃下攪拌4h。液相層析串聯質譜監測顯示原料消失後，用乙酸乙酯(2×40mL)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（S）4-（7-（4-胺基-2-氟苯基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶基-第三丁基[2， 3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（400 mg，淡黃色固體，收率87.1%）。MS (ESI) M/Z：605.3[M+H] + Step A (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2 -Dihydropyrido[2,3-d]pyrimidine-4--3-methylpiperazine-1-carboxylate (400 mg, 0.76 mmol), 3-fluoro-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaboran-2-yl)aniline (269 mg, 1.13 mmol), sodium carbonate (399.0 mg, 3.80 mmol) were dissolved in nitrogen replacing air for 15 min To a mixed solution of 1,4-dioxane and water (1 mL, 4/1), Pd(PPh 3 ) 4 (44 mg, 0.038 mg) was added, the air was replaced with nitrogen gas again, and the mixture was heated at 90 °C. Stir for 4h. After liquid chromatography tandem mass spectrometry monitoring shows the disappearance of the raw materials, extract twice with ethyl acetate (2×40mL), wash the organic layer with brine, dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The crude product is purified by preparation yields (S) 4-(7-(4-amino-2-fluorophenyl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2 -Dihydropyridyl-tert-butyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (400 mg, pale yellow solid, yield 87.1%). MS ( ESI) M/Z: 605.3[M+H] +
步驟B（Step B）將（S）4-（7-（4-胺基-2-氟苯基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶基-第三丁基[2， 3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(38 mg，0.06 mmol)，3-丁氧基丙酸(11 mg，0.075 mmol)，BOP(33 mg，0.075 mmol)，DINAP(24 mg，0.188 mmol)溶與二氯甲烷中攪拌2h。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（洗脫劑：二氯甲烷/甲醇=20/1）得到合成（S）-第三丁基4-（6-氟-7-（2-氟-4-（3-（2-甲氧基乙氧基）丙醯胺基）苯基）-1-（2-異丙基-6-甲基苯基）-2- 氧代1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（20 mg，白色固體，收率45.0%）。MS (ESI) M/Z：735.3[M+H] + Step B (Step B) will (S) 4-(7-(4-amino-2-fluorophenyl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2 -Oxy-1,2-dihydropyridyl-tert-butyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (38 mg, 0.06 mmol), 3- Butoxypropionic acid (11 mg, 0.075 mmol), BOP (33 mg, 0.075 mmol), DINAP (24 mg, 0.188 mmol) were dissolved in dichloromethane and stirred for 2 h. After 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 (S)-tert-butyl 4-( 6-Fluoro-7-(2-Fluoro-4-(3-(2-methoxyethoxy)propionamido)phenyl)-1-(2-isopropyl-6-methylphenyl) )-2-oxo1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (20 mg, white solid, yield 45.0%) . MS (ESI) M/Z: 735.3[M+H] +
步驟C（Step C）將（S）-第三丁基4-（6-氟-7-（2-氟-4-（3-（2-甲氧基乙氧基）丙醯胺基）苯基）-1-（2-異丙基-6-甲基苯基）-2- 氧代1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(20 mg，0.027 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，液相層析串聯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，加入二氯甲烷(1 mL)，DIPEA(N,N-二異丙基乙胺)(7.0 g，0.054 mmol)和丙烯醯氯( 2.43 mg，0.027 mmol)並在室溫下攪拌2小時，液相層析串聯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A（12.0 mg，黃色固體，收率64.5%）。MS (ESI) M/Z：689.3[M+H] + Step C (S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-4-(3-(2-methoxyethoxy)propionamido)benzene) yl)-1-(2-isopropyl-6-methylphenyl)-2-oxo1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methyl Piperazine-1-carboxylic acid (20 mg, 0.027 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour, monitoring by LC tandem mass spectrometry showed starting material After disappearing, 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 removed, add dichloromethane (1 mL), DIPEA (N,N-diisopropylethylamine) (7.0 g, 0.054 mmol) and acryl chloride (2.43 mg, 0.027 mmol) and stirred at room temperature for 2 hours, after liquid chromatography tandem mass spectrometry monitoring showed the disappearance of the starting material , concentrated under reduced pressure to remove the solvent, and the obtained solid was dissolved in N,N-dimethylformamide (5 mL) to prepare and purify to obtain A (12.0 mg, yellow solid, yield 64.5%). MS (ESI) M/Z: 689.3[M+H] +
實施例 69：（S）-1-（4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2- 二氫吡啶并[2,3-d]嘧啶-7-基）-3-氟苯基）-3-（2-甲氧基乙基）脲
合成路線
步驟A（Step A）:將（S）4-（7-（4-胺基-2-氟苯基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶基-第三丁基[2， 3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(50 mg，0.08 mmol)溶解已腈(1 mL)中並加入DIPEA(41.0 mg，0.32 mmoL)，加入4-硝基苯基（2-甲氧基乙基）胺基甲酸酯（62 mg，0.261 mmol），在90℃反應2h，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（洗脫劑：二氯甲烷/甲醇=20/1）得到合成（S）第三丁基4-（6-氟-7-（2-氟-4-（3-（2-甲氧基乙基）脲基）苯基）-1-（2-異丙基-6-甲基苯基）-2- 氧代1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（30 mg，白色固體，收率50.0%）。MS (ESI) M/Z：706.3[M+H] + Step A (Step A): (S) 4-(7-(4-amino-2-fluorophenyl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)- 2-Oxo-1,2-dihydropyridinyl-tert-butyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (50 mg, 0.08 mmol) was dissolved in Nitrile (1 mL) was added DIPEA (41.0 mg, 0.32 mmol), 4-nitrophenyl(2-methoxyethyl)carbamate (62 mg, 0.261 mmol) was added, and the reaction was carried out at 90 °C 2h, after LCMS monitoring showed the disappearance of the raw materials, 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 (S) tert-butyl 4- (6-Fluoro-7-(2-Fluoro-4-(3-(2-methoxyethyl)ureido)phenyl)-1-(2-isopropyl-6-methylphenyl)- 2-oxo1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (30 mg, white solid, 50.0% yield). MS (ESI) M/Z: 706.3[M+H] +
步驟B（Step B):將（S）第三丁基4-（6-氟-7-（2-氟-4-（3-（2-甲氧基乙基）脲基）苯基）-1-（2-異丙基-6-甲基苯基）-2- 氧代1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(28mg，0.04 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，液相層析串聯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，加入二氯甲烷(1 mL)，DIPEA(N,N-二異丙基乙胺)(10.0 mg，0.076 mmol)和丙烯醯氯(3.60 mg，0.04 mmol)並在室溫下攪拌2小時，液相層析串聯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（S）-1-（4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2- 二氫吡啶并[2,3-d]嘧啶-7-基）-3-氟苯基）-3-（2-甲氧基乙基）脲（24.0 mg, 黃色固體，收率91.0%）。Step B (Step B): (S) tert-butyl 4-(6-fluoro-7-(2-fluoro-4-(3-(2-methoxyethyl)ureido)phenyl)- 1-(2-Isopropyl-6-methylphenyl)-2-oxo1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-Formic acid (28 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour. Concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid, add dichloromethane (10 mL) and concentrate again under reduced pressure until dichloromethane and trifluoroacetic acid are completely removed, add dichloromethane (1 mL), DIPEA (N,N -diisopropylethylamine) (10.0 mg, 0.076 mmol) and acryl chloride (3.60 mg, 0.04 mmol) and stirred at room temperature for 2 hours. After monitoring by liquid chromatography tandem mass spectrometry showed the disappearance of the starting material, it was concentrated under reduced pressure The solvent was removed and the resulting solid was dissolved in N,N-dimethylformamide (5 mL) to prepare and purify (S)-1-(4-(4-(4-propenyl-2-methylpiperidine) oxazin-1-yl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine- 7-yl)-3-fluorophenyl)-3-(2-methoxyethyl)urea (24.0 mg, yellow solid, 91.0% yield).
MS (ESI) M/Z：660.3[M+H] +。 MS (ESI) M/Z: 660.3 [M+H] + .
實施例 70：（S）-1-（4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2- 二氫吡啶并[2,3-d]嘧啶-7-基）-3-氟苯基）-3-（2-（2-甲氧基乙氧基）乙基）脲
合成路線
步驟A（Step A):將（S）4-（7-（4-胺基-2-氟苯基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧-1,2-二氫吡啶基-第三丁基[2， 3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(70 mg，0.11 mmol) 溶解已腈(1 mL)中並加入DIPEA(56.76 mg，0.44 mmoL)，加入4-硝基苯基（2-（2-甲氧基乙氧基）乙基）胺基甲酸酯（62.7 mg，0.22 mmol），在90℃反應2h，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（洗脫劑：二氯甲烷/甲醇=20/1）得到合成（S）-第三丁基4-（6-氟-7-（2-氟-4-（3-（2-（2-甲氧基乙氧基）乙基）脲基）苯基）-1-（2-異丙基-6- 甲基苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸（40 mg，白色固體，收率50.0%）。MS (ESI) M/Z：750.3[M+H] + Step A (Step A): (S) 4-(7-(4-amino-2-fluorophenyl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)- 2-Oxy-1,2-dihydropyridinyl-tert-butyl[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid (70 mg, 0.11 mmol) was dissolved in Nitrile (1 mL) and DIPEA (56.76 mg, 0.44 mmol), 4-nitrophenyl(2-(2-methoxyethoxy)ethyl)carbamate (62.7 mg, 0.22 mmol), reacted at 90 °C for 2 h, after LCMS monitoring showed the disappearance of the raw materials, 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 (S )-tert-butyl 4-(6-fluoro-7-(2-fluoro-4-(3-(2-(2-methoxyethoxy)ethyl)ureido)phenyl)-1- (2-Isopropyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1 - Formic acid (40 mg, white solid, 50.0% yield). MS (ESI) M/Z: 750.3[M+H] +
步驟B（Step B):將（S）-第三丁基4-（6-氟-7-（2-氟-4-（3-（2-（2-甲氧基乙氧基）乙基）脲基）苯基）-1-（2-異丙基-6- 甲基苯基）-2-氧代-1,2-二氫吡啶并[2,3-d]嘧啶-4-基）-3-甲基哌嗪-1-甲酸(40mg，0.05 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，液相層析串聯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，加入二氯甲烷(1 mL)，DIPEA(N,N-二異丙基乙胺)(13 mg，0.1 mmol)和丙烯醯氯(4.50 mg，0.05 mmol)並在室溫下攪拌2小時，液相層析串聯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（S）-1-（4-（4-（4-丙烯醯基-2-甲基哌嗪-1-基）-6-氟-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2- 二氫吡啶并[2,3-d]嘧啶-7-基）-3-氟苯基）-3-（2-（2-甲氧基乙氧基）乙基）脲（20.0 mg，黃色固體，收率91.0%）。MS (ESI) M/Z：704.3[M+H] + Step B (Step B): (S)-tert-butyl 4-(6-fluoro-7-(2-fluoro-4-(3-(2-(2-methoxyethoxy)ethyl) )ureido)phenyl)-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl )-3-methylpiperazine-1-carboxylic acid (40 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour, liquid chromatography After tandem mass spectrometry monitoring showed the disappearance of the raw materials, the mixture was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and dichloromethane (10 mL) was added and concentrated under reduced pressure again until the dichloromethane and trifluoroacetic acid were completely removed, and dichloromethane (10 mL) was added. 1 mL), DIPEA (N,N-diisopropylethylamine) (13 mg, 0.1 mmol) and allyl chloride (4.50 mg, 0.05 mmol) and stirred at room temperature for 2 hours, liquid chromatography tandem mass spectrometry After monitoring showed the disappearance of the starting material, the solvent was removed by concentration under reduced pressure and the obtained solid was dissolved in N,N-dimethylformamide (5 mL) to prepare and purify (S)-1-(4-(4-(4- Acryloyl-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido [2,3-d]pyrimidin-7-yl)-3-fluorophenyl)-3-(2-(2-methoxyethoxy)ethyl)urea (20.0 mg, yellow solid, yield 91.0 %). MS (ESI) M/Z: 704.3[M+H] +
實施例 71：合成（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3-d ]嘧啶-4-基）-N-（2-甲氧基乙基）-3-甲基哌嗪-1-羧醯胺
合成路線：
步驟B（Step B）：冰浴下，往2,6-二氯-5-氟煙酸(2.0 g，9.57mmol)的四氫呋喃(10 mL)溶液中緩慢加入草醯氯(1.46 g，11.5 mmol，溶在7mL二氯甲烷中)。反應液在75攝氏度加熱一個小時，然後停止加熱。反應液減壓旋除一半溶劑，然後重新置於冰浴下加入10mL四氫呋喃。接著往反應液中滴加2-異丙基-6-甲基苯胺(1.43 g，9.57 mmol)的四氫呋喃(5 mL)溶液。反應液在0攝氏度攪拌一個小時，然後用1：1的食鹽水和飽和氯化銨溶液淬滅。用乙酸乙酯萃取2次，有機相用無水硫酸鈉乾燥，過濾，旋乾得到粗品2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺（3.6 g，9.37 mmol，收率98%）。MS (ESI) M/Z：385.1[M+H] +。 Step B (Step B): under ice bath, to a solution of 2,6-dichloro-5-fluoronicotinic acid (2.0 g, 9.57 mmol) in tetrahydrofuran (10 mL) was slowly added oxalic chloride (1.46 g, 11.5 mmol) , dissolved in 7 mL of dichloromethane). The reaction solution was heated at 75°C for one hour, and then the heating was stopped. Half of the solvent was removed from the reaction solution under reduced pressure, and then 10 mL of tetrahydrofuran was added under an ice bath. Then, a solution of 2-isopropyl-6-methylaniline (1.43 g, 9.57 mmol) in tetrahydrofuran (5 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 degrees Celsius for one hour, and then quenched with 1:1 brine and saturated ammonium chloride solution. Extracted twice with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain crude 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl) Aminoformamide) niacinamide (3.6 g, 9.37 mmol, 98% yield). MS (ESI) M/Z: 385.1 [M+H] + .
步驟C（Step C）：冰浴下，往2,6-二氯-5-氟-N-((2-異丙基-6-甲基苯基)胺基甲醯)煙酸醯胺(3.6 g，9.37 mmol)的四氫呋喃(20 mL)溶液中緩慢滴加KHMDS(雙(三甲基矽烷基)胺基鉀，1M的四氫呋喃溶液，19.7 mL，19.7 mmol)。滴加完畢後，冰浴移除，反應液在室溫下攪拌過夜。LCMS監測到所有原料都已經轉化成產物。反應液用氯化銨溶液淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品矽膠柱層析純化（流動相0-50% 乙酸乙酯-乙醇 (3:1)/石油醚）得到7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮（1.4 g，3.22 mmol，收率34%）。MS (ESI) M/Z：348.1[M+H] +。 Step C (Step C): under ice bath, add 2,6-dichloro-5-fluoro-N-((2-isopropyl-6-methylphenyl)aminocarbamide)nicotinamide ( To a solution of 3.6 g, 9.37 mmol) in tetrahydrofuran (20 mL) was slowly added KHMDS (potassium bis(trimethylsilyl)amide, 1 M in tetrahydrofuran, 19.7 mL, 19.7 mmol) dropwise. After the dropwise addition, the ice bath was removed, and the reaction solution was stirred at room temperature overnight. LCMS monitored that all starting material had been converted to product. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-50% ethyl acetate-ethanol (3:1)/petroleum ether) to obtain 7-chloro-6-fluoro-1-(2-isopropyl-6-methyl) Phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.4 g, 3.22 mmol, 34% yield). MS (ESI) M/Z: 348.1 [M+H] + .
步驟D&E（Step D&E）: 往7-氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.5 g，1.44 mmol)的甲苯(10 mL)溶液中加入DIPEA(N,N-二異丙基乙胺，372 mg，2.88mmol)和三氯氧磷(441 mg，2.88 mmol)。反應液加熱到50攝氏度，攪拌50分鐘。停止加熱，反應液直接置於旋轉蒸發儀上旋除溶劑，得到粗品4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮，0.53 g，無需純化，直接投入到下一步反應。Step D&E: To 7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H )-dione (0.5 g, 1.44 mmol) in toluene (10 mL) was added DIPEA (N,N-diisopropylethylamine, 372 mg, 2.88 mmol) and phosphorus oxychloride (441 mg, 2.88 mmol) ). The reaction solution was heated to 50°C and stirred for 50 minutes. The heating was stopped, and the reaction solution was directly placed on a rotary evaporator to remove the solvent to obtain a crude product of 4,7-dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2, 3-d]pyrimidin-2(1H)-one, 0.53 g, was directly used in the next reaction without purification.
將4,7-二氯-6-氟-1-(2-異丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮(0.53 g，1.44mmol)溶於DMF (4 mL)中，然後室溫下加入(S)-4-N-第三丁氧羰基-2-甲基哌嗪(288 mg，1.44 mmol)。攪拌下，往上述反應液中滴加DIPEA(N,N-二異丙基乙胺，0.93 g，7.2 mmol)。滴加完畢反應液攪拌半小時，質譜顯示原料已經消耗完畢。反應液用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾旋乾。粗產品用矽膠柱層析純化（流動相0-80% 乙酸乙酯-乙醇 (3:1)/石油醚）得到 (S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（0.58 g，1.1mmol，黃色固體，收率76%）。MS (ESI) M/Z：531.1[M+H] +。 4,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.53 g, 1.44 mmol) in DMF (4 mL), then (S)-4-N-tert-butoxycarbonyl-2-methylpiperazine (288 mg, 1.44 mmol) was added at room temperature. With stirring, DIPEA (N,N-diisopropylethylamine, 0.93 g, 7.2 mmol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred for half an hour, and mass spectrometry showed that the raw material had been consumed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was purified by silica gel column chromatography (mobile phase 0-80% ethyl acetate-ethanol (3:1)/petroleum ether) to give (S)-4-(7-chloro-6-fluoro-1-(2-) Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid Tributyl ester (0.58 g, 1.1 mmol, yellow solid, 76% yield). MS (ESI) M/Z: 531.1 [M+H] + .
步驟F（Step F）：將(S)-4-(7-氯-6-氟-1-(2-異丙基-6-甲基苯基)-2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.58 g，1.1 mmol)，2-氟-6-羥基苯硼酸(340 mg，2.2 mmol)，Pd(dppf)Cl 2CH 2Cl 2([1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物，90 mg，0.11 mmol)和KOAc(醋酸鉀，0.54 g，5.5 mmol)混合在一起並在油泵抽真空並置換氮氣數次。同時，二氧六環和水的混合液(20/1，12 mL)用氮氣鼓泡15分鐘除氧，然後用注射器加入到上面的反應物中。反應液再置換氮氣數次，然後加熱到90攝氏度，在此溫度下攪拌反應5小時。LCMS監測到所有的原料轉化成產物。反應降溫，用水淬滅，乙酸乙酯萃取。有機相用無水硫酸鈉乾燥，過濾濃縮。粗產品經矽膠柱層析純化（流動相1-5% 甲醇/二氯甲烷）得到(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯（420 mg, 0.67 mmol, 淡黃色固體，收率：61%）。MS (ESI) M/Z：606.1[M+H] +。 Step F (Step F): (S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydro Pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.58 g, 1.1 mmol), 2-fluoro-6-hydroxyphenylboronic acid (340 mg, 2.2 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 90 mg, 0.11 mmol ) and KOAc (potassium acetate, 0.54 g, 5.5 mmol) were mixed together and evacuated on an oil pump and replaced with nitrogen several times. Meanwhile, a mixture of dioxane and water (20/1, 12 mL) was deoxygenated by bubbling nitrogen for 15 minutes and then added to the above reaction by syringe. The reaction solution was replaced with nitrogen several times, and then heated to 90 degrees Celsius, and the reaction was stirred at this temperature for 5 hours. Conversion of all starting material to product was monitored by LCMS. The reaction was cooled, quenched with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (mobile phase 1-5% methanol/dichloromethane) to give (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-( 2-Isopropyl-6-methylphenyl)-2-carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate tert-butyl acid (420 mg, 0.67 mmol, pale yellow solid, yield: 61%). MS (ESI) M/Z: 606.1 [M+H] + .
步驟G&H（Step G&H）: 將(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.3 g，0.495 mmol)溶於二氯甲烷(6 mL)，然後加入2mL三氟乙酸。反應液在20攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於3mL二氯甲烷中，往反應液中分別加入4-硝基苯基（2-甲氧基乙基）胺基甲酸酯(0.119g，0.495mmol)，在冰浴下緩慢加入1M的KHMDS（2ml）。反應液在65攝氏度下攪拌12小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3-d ]嘧啶-4-基）-N-（2-甲氧基乙基）-3-甲基哌嗪-1-羧醯胺（42.3 mg，0.085 mmol，淡黃色固體，收率：14.4%)MS (ESI) M/Z：592.6[M+H] +。 Step G&H: (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.495 mmol) was dissolved in Dichloromethane (6 mL), then 2 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 3 mL of dichloromethane, and 4-nitrophenyl (2-methoxyethyl) carbamate (0.119 g, 0.495 mmol) was added to the reaction solution, and slowly added under an ice bath 1M KHMDS (2ml). The reaction solution was stirred at 65°C for 12 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-oxo-1,2-dihydropyridyl[2,3-d]pyrimidin-4-yl)-N-(2-methoxyethyl)-3-methylpiperazine-1-carboxylate Amine (42.3 mg, 0.085 mmol, pale yellow solid, yield: 14.4%) MS (ESI) M/Z: 592.6 [M+H] + .
實施例 72：合成（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3-d ]嘧啶-4-基）-N-（2-（2-甲氧基乙氧基）乙基）-3-甲基哌嗪-1-羧醯胺
合成路線：
步驟G&H（Step G&H）：將(3S)-4-(6-氟-7-(2-氟-6-羥基苯基)-1-(2-異丙基-6-甲基苯基)- 2-羰基-1,2-二氫吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸第三丁酯(0.3 g，0.495 mmol)溶於二氯甲烷(6 mL)，然後加入2mL三氟乙酸。反應液在20攝氏度下攪拌1小時。質譜顯示原料已反應完。停止反應，溶劑減壓旋除掉，粗品再用二氯甲烷共沸2次。粗品再溶於3mL二氯甲烷中，往反應液中分別加入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（2ml）。反應液在65攝氏度下攪拌12小時。LCMS顯示原料已完全轉化成產物。反應停止，旋除溶劑。粗品經高效製備液相純化得到（3S）-4-（6-氟-7-（2-氟-6-羥基苯基）-1-（2-異丙基-6-甲基苯基）-2-氧代-1,2-二氫吡啶基[2,3-d ]嘧啶-4-基）-N-（2-（2-甲氧基乙氧基）乙基）-3-甲基哌嗪-1-羧醯胺（51.3 mg，0.085 mmol，淡黃色固體，收率：16.3%)MS (ESI) M/Z：636.7[M+H] +。 Step G&H: (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-Carbonyl-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.495 mmol) was dissolved in Dichloromethane (6 mL), then 2 mL of trifluoroacetic acid was added. The reaction solution was stirred at 20°C for 1 hour. Mass spectrometry showed that the starting material had reacted. The reaction was stopped, the solvent was spun off under reduced pressure, and the crude product was azeotroped twice with dichloromethane. The crude product was redissolved in 3 mL of dichloromethane, and 4-nitrophenyl (2-(2-methoxyethoxy)ethyl)carbamate (0.216 g, 0.76 mmol) was added to the reaction solution. , 1 M KHMDS (2 ml) was added slowly under ice bath. The reaction solution was stirred at 65°C for 12 hours. LCMS showed complete conversion of starting material to product. The reaction was stopped and the solvent was spun off. The crude product was purified by high performance preparative liquid phase to obtain (3S)-4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)- 2-oxo-1,2-dihydropyridinyl[2,3-d]pyrimidin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)-3-methyl Piperazine-1-carboxamide (51.3 mg, 0.085 mmol, pale yellow solid, yield: 16.3%) MS (ESI) M/Z: 636.7 [M+H] + .
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
用奈升(nanoliter)級的超聲波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 a nanoliter ultrasonic liquid treatment 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.
4.4. 配製formulate 33 倍times KRAS G12CKRAS G12C 酶溶液，enzyme solution, 66 倍times SOS1SOS1 酶溶液，enzyme solution, 66 倍times GTPGTP 溶液，solution, 33 倍檢測溶液double 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（BellBrook, Cat. No. 3014-1K）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 (BellBrook, Cat. No. 3014-1K) 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 for negative control wells, replace the enzyme solution with 10 μl of 1x reaction buffer. 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倍檢測溶液到反應盤中。1000 rpm離心1 分鐘。Transfer 10 μL of 3x detection solution to the reaction dish. Centrifuge at 1000 rpm for 1 minute.
9.9. 讀數reading
用酶標儀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）。Use the microplate reader SpectraMax Paradigm to continuously read the fluorescence signal value (Ex580/Em620) within 2 hours (read every 5 minutes).
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%。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%.
將數據導入MS Excel並用XLFit excel add-in version5.4.0.8擬合IC 50值； Import data into MS Excel and fit IC50 values with XLFit excel add-in version 5.4.0.8;
擬合公式：Y=Bottom+(Top-Bottom)/(1+(IC 50/X)^HillSlope)。 Fitting formula: Y=Bottom+(Top-Bottom)/(1+(IC 50 /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) 對癌細胞的抑制活性Inhibitory activity against cancer cells , NCI-H358, NCI-H358
檢測方法：Detection method: CTGCTG 方法method
實驗方法： 1.將處於對數生長期的細胞（NCI-H358）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。 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。 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。 Experimental Methods: 1. Cells in logarithmic growth phase (NCI-H358) were resuspended in growth medium and diluted to target density. The above cell suspension was seeded into a 96-well dish at 100 μl per well, and incubated overnight at 37 °C in a 5 % CO 2 incubator. 2. Dissolve the test compound in DMSO to make a stock solution with a concentration of 10 mM. 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. Incubate the cells with the compounds to be tested in a 37 °C, 5 % CO 2 incubator for 72 hours. Equilibrate the 96-well plate at room temperature, add 40 μL of CellTiter-Glo ® reagent (Promega G7573) to each well, mix for 2 minutes, incubate for 60 minutes at room temperature, read the luminescence value with EnVision RMultilabel Reader, and use GraphPad Prism 5.0 software to calculate the compound IC50 .
測試方法testing method (3)(3)
Western Blot protocolWestern Blot protocol
細胞平盤培養： 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。 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。 Cell plate culture: 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, 5 % CO 2 incubator. 2. Dissolve the test compound in DMSO to make a stock solution with a concentration of 10 mM. The stock solutions were first diluted with DMSO to 3 mM, 2 mM, 1 mM, and then diluted with growth medium to 150 μM, 100 μM, and 50 μM, respectively. 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 for 8 hours, 24 hours and 48 hours in a 37°C, 5% CO 2 incubator, 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 min，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 min。 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. Centrifuge the sample at 13,000 rpm, 4°C for 10 min to remove the sediment. For BCA quantification, protein samples were prepared with 4X sample loading buffer and boiled in a water bath at 95°C for 15 min.
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. Develop with Westem ECL developer.
蛋白降解的結果如表1所示。The results of protein degradation are shown in Table 1.
表1
無。none.
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