TW202237597A - Novel degraders of egfr - Google Patents

Novel degraders of egfr Download PDF

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TW202237597A
TW202237597A TW111110183A TW111110183A TW202237597A TW 202237597 A TW202237597 A TW 202237597A TW 111110183 A TW111110183 A TW 111110183A TW 111110183 A TW111110183 A TW 111110183A TW 202237597 A TW202237597 A TW 202237597A
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amino
methyl
bifunctional compound
mmol
phenyl
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潘建峰
大慶 孫
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大陸商上海齊魯製藥研究中心有限公司
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract

The present invention provides a novel bifunctional compound (I) capable of degrading EGFR, a pharmaceutical composition containing the compound, a preparation method and a method for treating cell proliferative diseases such as cancer by using the compound of the present invention.

Description

新型EGFR降解劑Novel EGFR degrader

本發明屬於藥物化學領域，具體涉及一種可降解EGFR的新型雙功能化合物，含有所述化合物的藥物組合物、其製備方法及利用本發明化合物治療EGFR介導的癌症的方法。The invention belongs to the field of medicinal chemistry, and specifically relates to a novel bifunctional compound capable of degrading EGFR, a pharmaceutical composition containing the compound, a preparation method thereof and a method for using the compound of the invention to treat cancer mediated by EGFR.

近些年，基於泛素-蛋白酶體系統(ubiquitin-proteasome system, UPS)的PROTAC技術（Proteolysis Targeting Chimeria）得到了快速的發展。PROTAC技術源於2004年諾貝爾化學獎——以色列科學家Aaron Ciechanover、Avram Hershko和美國科學家Irwin Rose共同發現的細胞降解有害蛋白質，即泛素調節的蛋白質降解過程。In recent years, the PROTAC technology (Proteolysis Targeting Chimeria) based on the ubiquitin-proteasome system (UPS) has been developed rapidly. PROTAC technology originated from the Nobel Prize in Chemistry in 2004 - Israeli scientists Aaron Ciechanover, Avram Hershko and American scientist Irwin Rose jointly discovered that cells degrade harmful proteins, that is, the process of protein degradation regulated by ubiquitin.

PROTAC是一種雙功能的小分子三聯體化合物，可以分為靶蛋白配體、Linker（接頭）、E3連接酶配體（降解決定子）三部分。PROTAC分子進入細胞後，其結構中的目標蛋白（Protein of Interest，POI）配體可特異性地與相應的靶蛋白結合，而另一端可以募集E3連接酶從而形成POI-Linker-E3 ligase三元複合物，其中E3連接酶可介導泛素結合酶E2對POI泛素化。被泛素標記的POI被蛋白酶體識別並降解。PROTAC is a bifunctional small molecule triplet compound, which can be divided into three parts: target protein ligand, Linker (linker), and E3 ligase ligand (degradation determinant). After the PROTAC molecule enters the cell, the protein of interest (POI) ligand in its structure can specifically bind to the corresponding target protein, and the other end can recruit E3 ligase to form a POI-Linker-E3 ligase ternary complex, in which E3 ligase can mediate the ubiquitination of POI by ubiquitin-conjugating enzyme E2. POIs labeled with ubiquitin are recognized and degraded by the proteasome.

理論上PROTAC是事件驅動的藥理作用模式，此過程無需靶蛋白配體長時間佔據結合位點，只需三元複合物短暫的形成便可瞬時完成目標蛋白的泛素化，並且PROTAC分子在細胞內可多次循環利用，因此，與傳統的小分子抑制劑和大分子抗體相比，PROTAC具有明顯的優勢，有望將那些難以成藥的蛋白靶向成藥，並且可能具備用量小、毒性低、不依賴於親和力、可選擇性高、克服靶蛋白突變/過表達引起的耐藥等優點。Theoretically, PROTAC is an event-driven pharmacological mode of action. This process does not require the target protein ligand to occupy the binding site for a long time. It only needs the short-term formation of the ternary complex to complete the ubiquitination of the target protein instantaneously, and the PROTAC molecule is in the cell. Therefore, compared with traditional small-molecule inhibitors and macromolecular antibodies, PROTACs have obvious advantages. It relies on the advantages of affinity, high selectivity, and overcoming drug resistance caused by target protein mutation/overexpression.

EGFR，即表皮生長因子受體（epidermal growth factor receptor），廣泛分佈於哺乳動物上皮細胞、成纖維細胞、膠質細胞等細胞表面。EGFR訊號通路對細胞的生長、增殖和分化等生理過程發揮重要的作用。EGFR突變也是NSCLC患者中最常見的一種突變類型，尤其是在亞洲人群中可以占到40%~50%，因此EGFR一直是製藥產業研究的最熱門靶點之一。EGFR, the epidermal growth factor receptor, is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, EGFR has always been one of the most popular targets for research in the pharmaceutical industry.

目前，上市的EGFR抑制劑有一、二、三代。第一代為可逆的靶向藥物，例如吉非替尼、厄洛替尼、埃克替尼。第二代為不可逆的靶向藥物，例如阿法替尼以及達克替尼。第一、二代靶向藥物雖然療效顯著，但多數患者都會在使用藥物1-2年出現耐藥性。EGFR抑制劑耐藥的患者中，有50%的耐藥與T790M突變有關。第三代EGFR靶向藥物奧希替尼能與EGFR敏感突變的T790M突變位點結合，抑制由於T790M突變引起的腫瘤耐藥，它的問世給更多的肺癌患者帶來了好的生存獲益。然而第三代EGFR抑制劑也由於C797S突變，不可避免地產生耐藥性。Currently, there are one, two, and three generations of EGFR inhibitors on the market. The first generation is reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. The second generation is irreversible targeted drugs, such as afatinib and dacomitinib. Although the first and second generation targeted drugs are effective, most patients will develop drug resistance after 1-2 years of drug use. Among patients with EGFR inhibitor resistance, 50% of drug resistance is related to T790M mutation. The third-generation EGFR-targeted drug osimertinib can bind to the T790M mutation site of the EGFR sensitive mutation and inhibit the tumor drug resistance caused by the T790M mutation. Its advent has brought good survival benefits to more lung cancer patients . However, the third-generation EGFR inhibitors inevitably develop drug resistance due to the C797S mutation.

對於目前奧希替尼的耐藥，尚無成熟的治療手段，基於臨床需求的迫在眉睫，同時基於PROTAC技術的獨特優勢，本發明旨在開發一種可特異性降解EGFR蛋白的雙功能的小分子三聯體化合物。For the current drug resistance of osimertinib, there is no mature treatment method. Based on the imminent clinical needs and the unique advantages of PROTAC technology, the present invention aims to develop a bifunctional small molecule triplex that can specifically degrade EGFR protein. body compound.

本發明提供了一種可以用於降解EGFR的新型雙功能化合物，含有所述化合物的藥物組合物、其製備方法及其用於治療EGFR介導的癌症的用途。The invention provides a novel bifunctional compound that can be used to degrade EGFR, a pharmaceutical composition containing the compound, a preparation method thereof and an application for treating cancer mediated by EGFR.

根據本發明所述的化合物為包含靶向配體、接頭與降解決定子的三聯體化合物，如式（X）所示，

Figure 02_image003
The compound according to the present invention is a triplet compound comprising a targeting ligand, a linker and a degradant, as shown in formula (X),
Figure 02_image003

其中，靶向配體可以特異性結合靶蛋白，如EGFR和/或突變的EGFR，在三聯體化合物中通過共價鍵與接頭相連接；接頭為靶向配體與降解決定子的連接基團，一端與靶向配體共價結合，另一端與降解決定子共價結合；降解決定子能夠結合泛素連接酶，如E3泛素連接酶，與接頭共價結合。Among them, the targeting ligand can specifically bind the target protein, such as EGFR and/or mutated EGFR, and is connected to the linker through a covalent bond in the triplet compound; the linker is the linking group between the targeting ligand and the degron , one end is covalently bound to the targeting ligand, and the other end is covalently bound to the degron; the degron can bind ubiquitin ligase, such as E3 ubiquitin ligase, to covalently bind to the linker.

具體地，本發明提供了一種式（I）所示的雙功能化合物及其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，

Figure 02_image005
，
Figure 02_image007
，式（TL）為靶向配體，通過R 1基團與接頭共價結合，其中， R 1選自
Figure 02_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)-(3-7元雜環烷基)-、6-14元螺雜環基、6-14元橋雜環基、6-14元并雜環基； R 2選自C 6-10芳基、5-12元雜芳基，5-6元雜環烯基、其中所述C 6-10芳基、5-12元雜芳基，5-6元雜環烯基各自獨立任選地被一個或多個R 10基團所取代； R 3選自H、鹵素、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、C 1-4鹵代烷氧基； M選自N或者CR 11； R 4選自H、鹵素、-CN、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基； R 5選自-C(=O)NR bR c、-S(=O) 2R b、-P(=O)R bR c、-P(=O)R bNR cR d、-P(=O)R bOR c、-P(=O)OR bOR c、-P(=S)R bR c、-P(=S)R bNR cR d、-P(=S)R bOR c、-P(=S)OR bOR c、-S(=O) 2NR bR c、-NR cS(=O) 2R b、或-NR bC(O)R c； R 6、R 7、R 8各自獨立地選自H、C 1-4烷基、鹵素、C 3-6環烷基； 或者，R 6、R 7和與其連接的原子一起環化成C 4-6環烷基、4-7元雜環烷基、5-7元雜芳基； 或者R 7、R 8和與其連接的原子一起環化成C 4-6環烷基、4-7元雜環烷基、5-7元雜芳基； 每個R 9獨立選自H、鹵素、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、-C 0-4烷基-NR aR b； 每個R 10獨立選自H、鹵素、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基磺醯基； R 11選自H、鹵素、C 1-4烷基； R a選自H、C 1-4烷基； R b、R c、R d各自獨立地選自H、C 1-4烷基、C 3-6環烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 Specifically, the present invention provides a bifunctional compound represented by formula (I) and its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatized things,
Figure 02_image005
,
Figure 02_image007
, the formula (TL) is a targeting ligand, which is covalently bound to the linker through the R 1 group, wherein, R 1 is selected from
Figure 02_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 Yuan Heterocyclyl; R 2 is selected from C 6-10 aryl, 5-12 member heteroaryl, 5-6 member heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 member heteroaryl The 5-6 membered heterocycloalkenyl groups are each independently and optionally substituted by one or more R 10 groups; R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; M is selected from N or CR 11 ; R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3 -6 cycloalkyl; R 5 is selected from -C(=O)NR b R c , -S(=O) 2 R b , -P(=O)R b R c , -P(=O)R b NR c R d , -P(=O)R b OR c , -P(=O)OR b OR c , -P(=S)R b R c , -P(=S)R b NR c R d , -P(=S)R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C(O)R c ; R 6 , R 7 , and R 8 are each independently selected from H, C 1-4 alkyl, halogen, and C 3-6 cycloalkyl; or, R 6 , R 7 , and The atoms of R 7 and R 8 are cyclized together into C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl; or R 7 , R 8 and the atoms connected to them are cyclized together into C 4-6 cycloalkane base, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl; each R 9 is independently selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy base, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ; each R 10 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3- 6 cycloalkylsulfonyl; R 11 is selected from H, halogen, C 1-4 alkyl; R a is selected from H, C 1-4 alkyl; R b , R c , R d are each independently selected from H , C 1-4 alkyl, C 3-6 cycloalkyl; the linker is a group that is covalently bonded to the R 1 group in the targeting ligand and the degron; the degron is capable of binding to ubiquitin ligase group.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，其中， R 1選自

Figure 02_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)-(3-7元雜環烷基)-、6-14元螺雜環基、6-14元橋雜環基、6-14元并雜環基； R 2選自C 6-10芳基、5-12元雜芳基，5-6元雜環烯基、其中所述C 6-10芳基、5-12元雜芳基，5-6元雜環烯基各自獨立任選地被一個或多個R 10基團所取代； R 3選自H、鹵素、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、C 1-4鹵代烷氧基； M選自N或者CR 11； R 4選自H、鹵素、-CN、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基； R 5選自-C(=O)NR bR c、-S(=O) 2R b、-P(=O)R bR c、-P(=O)R bNR cR d、-P(=O)R bOR c、-P(=O)OR bOR c、-P(=S)R bR c、-P(=S)R bNR cR d、-P(=S)R bOR c、-P(=S)OR bOR c、-S(=O) 2NR bR c、-NR cS(=O) 2R b、或-NR bC(O)R c； R 6、R 7、R 8各自獨立地選自H、C 1-4烷基； 或者，R 6、R 7和與其連接的原子一起環化成C 4-6環烷基、5-7元雜芳基； 或者R 7、R 8和與其連接的原子一起環化成C 4-6環烷基、5-7元雜芳基； 每個R 9獨立選自H、鹵素、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、-C 0-4烷基-NR aR b； 每個R 10獨立選自H、鹵素、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基磺醯基； R 11選自H、鹵素、C 1-4烷基； R a選自H、C 1-4烷基； R b、R c、R d各自獨立地選自H、C 1-4烷基、C 3-6環烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives , where R 1 is selected from
Figure 02_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 Yuan Heterocyclyl; R 2 is selected from C 6-10 aryl, 5-12 member heteroaryl, 5-6 member heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 member heteroaryl The 5-6 membered heterocycloalkenyl groups are each independently and optionally substituted by one or more R 10 groups; R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; M is selected from N or CR 11 ; R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3 -6 cycloalkyl; R 5 is selected from -C(=O)NR b R c , -S(=O) 2 R b , -P(=O)R b R c , -P(=O)R b NR c R d , -P(=O)R b OR c , -P(=O)OR b OR c , -P(=S)R b R c , -P(=S)R b NR c R d , -P(=S)R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C(O)R c ; R 6 , R 7 , and R 8 are each independently selected from H, C 1-4 alkyl; or, R 6 , R 7 and the atoms connected to them are cyclized together to form a C 4-6 ring Alkyl, 5-7 membered heteroaryl; or R 7 , R 8 and the atoms connected to them are cyclized together to form C 4-6 cycloalkyl, 5-7 membered heteroaryl; each R 9 is independently selected from H, Halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ; each R 10 is independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl; R 11 is selected from H, halogen, C 1-4 alkyl ; R is selected from H , C 1-4 alkyl; R b , R c , R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl; the linker is the R 1 group in the targeting ligand A group to which a degron is covalently bound; a degron is a group capable of binding to a ubiquitin ligase.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，其中， R 1選自

Figure 02_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)-(3-7元雜環烷基)-、6-14元螺雜環基、6-14元并雜環基； R 2選自5-6元雜芳基，其中所述5-6元雜芳基任選地被一個或多個R 10基團所取代； R 3選自C 1-4烷氧基； M選自CR 11； R 4選自H、鹵素、C 1-4烷基； R 5選自-P(=O)R bR c、-NR cS(=O) 2R b； R 6、R 7、R 8各自獨立的選自H、C 1-4烷基； 或者，R 6、R 7和與其連接的原子一起環化成5-7元雜芳基； 每個R 9獨立選自H、鹵素、-OH、-NH 2、C 1-4烷基； 每個R 10獨立選自H、C 1-4烷基； R 11選自H、鹵素； R a選自H、C 1-4烷基； R b、R c各自獨立的選自H、C 1-4烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , where R 1 is selected from
Figure 02_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered heterocyclyl; R 2 optional From 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by one or more R 10 groups; R 3 is selected from C 1-4 alkoxy; M is selected from CR 11 ; R 4 is selected from H, halogen, C 1-4 alkyl; R 5 is selected from -P(=O)R b R c , -NR c S(=O) 2 R b ; R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl; or, R 6 , R 7 and the atoms connected to them are cyclized together to form a 5-7 membered heteroaryl; each R 9 is independently selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl; each R 10 is independently selected from H, C 1-4 alkyl; R 11 is selected from H, halogen; R a is selected from H, C 1-4 alkyl ; R b , R c are each independently selected from H, C 1-4 alkyl; the linker is a group that is covalently bonded to the R 1 group in the targeting ligand and the degradant; The group to which the ligase binds.

在本發明的一些方案中，A選自5-6元雜環烷基、5-6元雜環烷基-O-、5-6元雜環烷基-NR a-、-(5-6元雜環烷基)-(5-6元雜環烷基)-、7-11元螺雜環基、8-10元并雜環基。 In some schemes of the present invention, A is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl-O-, 5-6 membered heterocycloalkyl-NR a -, -(5-6 Heterocycloalkyl)-(5-6-membered heterocycloalkyl)-, 7-11-membered spiroheterocyclyl, 8-10-membered heterocyclyl.

在本發明的一些方案中，A選自5-6元氮雜環烷基、5-6元氮雜環烷基-O-、5-6元氮雜環烷基-NR a-、-(5-6元雜環烷基)-(5-6元雜環烷基)-、7-11元螺雜環基、8-10元氮雜并環基。 In some schemes of the present invention, A is selected from 5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl-O-, 5-6 membered azacycloalkyl-NR a -, -( 5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-, 7-11 membered spiroheterocyclyl, 8-10 membered azacyclyl.

在本發明的一些方案中，A選自5-6元氮雜環烷基。In some embodiments of the present invention, A is selected from 5-6 membered azacycloalkyl groups.

在本發明的一些方案中，A選自11元氮雜螺環基。In some embodiments of the present invention, A is selected from 11-membered azaspirocyclyl.

在本發明的一些方案中，A選自8元氮雜并環基。In some aspects of the present invention, A is selected from 8-membered azacyclyl.

在本發明的一些方案中，M選自CH。In some aspects of the invention, M is selected from CH.

在本發明的一些方案中，M選自CF。In some aspects of the invention, M is selected from CF.

在本發明的一些方案中，上述A選自

Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
、
Figure 02_image017
、
Figure 02_image019
、
Figure 02_image021
Figure 02_image023
、
Figure 02_image025
，R a如上文所定義。 In some solutions of the present invention, above-mentioned A is selected from
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
Figure 02_image023
,
Figure 02_image025
, R a is as defined above.

在本發明的一些方案中，上述A選自

Figure 02_image027
。 In some solutions of the present invention, above-mentioned A is selected from
Figure 02_image027
.

在本發明的一些方案中，上述A選自

Figure 02_image029
。 In some solutions of the present invention, above-mentioned A is selected from
Figure 02_image029
.

在本發明的一些方案中，上述式R 1選自

Figure 02_image031
、
Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
、
Figure 02_image017
、
Figure 02_image035
、
Figure 02_image021
Figure 02_image023
或
Figure 02_image025
，R a如上文所定義。 In some schemes of the present invention, the above-mentioned formula R 1 is selected from
Figure 02_image031
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image035
,
Figure 02_image021
Figure 02_image023
or
Figure 02_image025
, R a is as defined above.

在本發明的一些方案中，上述R 1選自

Figure 02_image027
。 In some schemes of the present invention, above-mentioned R 1 is selected from
Figure 02_image027
.

在本發明的一些方案中，上述R 1選自

Figure 02_image029
。 In some schemes of the present invention, above-mentioned R 1 is selected from
Figure 02_image029
.

在本發明的一些方案中，上述A選自

Figure 02_image011
。 In some solutions of the present invention, above-mentioned A is selected from
Figure 02_image011
.

在本發明的一些方案中，上述R 1選自

Figure 02_image011
。 In some schemes of the present invention, above-mentioned R 1 is selected from
Figure 02_image011
.

在本發明的一些方案中，上述R 10選自H、甲基、乙基或二氟甲基。 In some aspects of the present invention, the above R 10 is selected from H, methyl, ethyl or difluoromethyl.

在本發明的一些方案中，上述R 2選自

Figure 02_image040
。 In some schemes of the present invention, above-mentioned R 2 is selected from
Figure 02_image040
.

在本發明的一些方案中，上述R 2選自

Figure 02_image042
、
Figure 02_image044
。 In some schemes of the present invention, above-mentioned R 2 is selected from
Figure 02_image042
,
Figure 02_image044
.

在本發明的一些方案中，上述R 3選自甲氧基。 In some aspects of the present invention, the above-mentioned R 3 is selected from methoxy.

在本發明的一些方案中，上述R 3選自H、甲基、F。 In some solutions of the present invention, the above-mentioned R 3 is selected from H, methyl, and F.

在本發明的一些方案中，上述R 4選自F、Cl、Br或甲基。 In some aspects of the present invention, the above-mentioned R 4 is selected from F, Cl, Br or methyl.

在本發明的一些方案中，上述R 4選自Br。 In some aspects of the present invention, the above-mentioned R 4 is selected from Br.

在本發明的一些方案中，上述R 4選自H。 In some aspects of the present invention, the above-mentioned R 4 is selected from H.

在本發明的一些方案中，上述R 4選自三氟甲基。 In some aspects of the present invention, the above R 4 is selected from trifluoromethyl.

在本發明的一些方案中，上述R 5選自

Figure 02_image046
、
Figure 02_image048
。 In some schemes of the present invention, above-mentioned R 5 is selected from
Figure 02_image046
,
Figure 02_image048
.

在本發明的一些方案中，上述R 5選自

Figure 02_image046
。 In some schemes of the present invention, above-mentioned R 5 is selected from
Figure 02_image046
.

在本發明的一些方案中，上述R 6、R 7、R 8選自H。 In some solutions of the present invention, the above-mentioned R 6 , R 7 , and R 8 are selected from H.

在本發明的一些方案中，上述R 6、R 7、R 8各自獨立的選自CH 3、環丙基、氟。 In some solutions of the present invention, the above-mentioned R 6 , R 7 , and R 8 are each independently selected from CH 3 , cyclopropyl, and fluorine.

在本發明的一些方案中，上述R 6、R 7選自CH 3。 In some solutions of the present invention, the aforementioned R 6 and R 7 are selected from CH 3 .

在本發明的一些方案中，上述R 6選自H，R 7選自CH 3、環丙基、氟。 In some aspects of the present invention, the above-mentioned R 6 is selected from H, and R 7 is selected from CH 3 , cyclopropyl, and fluorine.

在本發明的一些方案中，上述R 6、R 7和與其連接的原子一起環化成吡𠯤環。 In some schemes of the present invention, the above-mentioned R 6 , R 7 and the atoms connected to them are cyclized together to form a pyroxetine ring.

在本發明的一些方案中，上述R 6、R 7和與其連接的原子一起環化成吡啶環。 In some schemes of the present invention, the above-mentioned R 6 , R 7 and the atoms connected to them are cyclized together to form a pyridine ring.

在本發明的一些方案中，所述靶向配體式（TL）選自：

Figure 02_image050
、
Figure 02_image052
、
Figure 02_image054
、
Figure 02_image056
、
Figure 02_image058
、
Figure 02_image060
、
Figure 02_image062
、
Figure 02_image064
、
Figure 02_image066
、
Figure 02_image068
； 所述靶向配體通過
Figure 02_image070
與所述接頭共價結合。 In some aspects of the present invention, the targeting ligand formula (TL) is selected from:
Figure 02_image050
,
Figure 02_image052
,
Figure 02_image054
,
Figure 02_image056
,
Figure 02_image058
,
Figure 02_image060
,
Figure 02_image062
,
Figure 02_image064
,
Figure 02_image066
,
Figure 02_image068
; The targeting ligand is passed
Figure 02_image070
Covalently bound to the linker.

在本發明的一些方案中，所述靶向配體式（TL）選自：

Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
。 In some aspects of the present invention, the targeting ligand formula (TL) is selected from:
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
.

在本發明的一些方案中，所述靶向配體式（TL）選自：

Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
。 In some aspects of the present invention, the targeting ligand formula (TL) is selected from:
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
.

在本發明的一些方案中，所述靶向配體式（TL）選自：

Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
。 In some aspects of the present invention, the targeting ligand formula (TL) is selected from:
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
.

在本發明的一些方案中，所述靶向配體式（TL）選自：

Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
。 In some aspects of the present invention, the targeting ligand formula (TL) is selected from:
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
.

在本發明的一些方案中，上述接頭具有式LA：

Figure 02_image130
或其立體異構體， 其中，p 1選自0-6的整數；p 2選自0-6的整數；p 3選自0-6的整數； U為鍵，或者選自C=O、O、NH或NR 12； 每個Q獨立地選自鍵、CH 2、O、S、NH或NR 12； W為鍵，或者選自C=O、O、NH、NR 12、C≡C； 其中所述R 12選自C 1-4烷基； 所述接頭通過U基團與靶向配體（式TL）中的R 1共價結合，W基團與降解決定子共價結合。 In some aspects of the invention, the aforementioned linker has the formula LA:
Figure 02_image130
or its stereoisomer, wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6; U is a bond, or selected from C=O, O, NH or NR 12 ; each Q is independently selected from a bond, CH 2 , O, S, NH or NR 12 ; W is a bond, or selected from C=O, O, NH, NR 12 , C≡C; Wherein the R 12 is selected from C 1-4 alkyl; the linker is covalently bonded to the R 1 in the targeting ligand (Formula TL) through the U group, and the W group is covalently bonded to the degradant.

在本發明的一些方案中，上述TL-LA選自：

Figure 02_image132
，
Figure 02_image134
，
Figure 02_image136
，
Figure 02_image138
，
Figure 02_image140
，
Figure 02_image142
，
Figure 02_image144
，
Figure 02_image146
，
Figure 02_image148
，
Figure 02_image150
，
Figure 02_image152
， 其中，p 1、p 2、p 3如上述所定義，TL代表靶向配體，不屬於接頭LA，僅代表接頭LA與靶向配體的連接關係；以及式TL具有如上所述的定義。 In some solutions of the present invention, the above-mentioned TL-LA is selected from:
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
, wherein, p 1 , p 2 , and p 3 are as defined above, TL represents the targeting ligand, does not belong to the linker LA, and only represents the connection relationship between the linker LA and the targeting ligand; and the formula TL has the above-mentioned definition .

在本發明的一些方案中，上述TL-LA選自：

Figure 02_image154
、
Figure 02_image156
、
Figure 02_image158
、
Figure 02_image160
、
Figure 02_image162
、
Figure 02_image164
、
Figure 02_image166
、
Figure 02_image168
、
Figure 02_image170
、
Figure 02_image172
、
Figure 02_image174
、
Figure 02_image176
、
Figure 02_image178
、
Figure 02_image180
、
Figure 02_image182
、
Figure 02_image184
、
Figure 02_image186
、
Figure 02_image188
、
Figure 02_image190
、
Figure 02_image192
、
Figure 02_image194
、
Figure 02_image196
、
Figure 02_image198
、
Figure 02_image200
、
Figure 02_image202
、
Figure 02_image204
。 In some solutions of the present invention, the above-mentioned TL-LA is selected from:
Figure 02_image154
,
Figure 02_image156
,
Figure 02_image158
,
Figure 02_image160
,
Figure 02_image162
,
Figure 02_image164
,
Figure 02_image166
,
Figure 02_image168
,
Figure 02_image170
,
Figure 02_image172
,
Figure 02_image174
,
Figure 02_image176
,
Figure 02_image178
,
Figure 02_image180
,
Figure 02_image182
,
Figure 02_image184
,
Figure 02_image186
,
Figure 02_image188
,
Figure 02_image190
,
Figure 02_image192
,
Figure 02_image194
,
Figure 02_image196
,
Figure 02_image198
,
Figure 02_image200
,
Figure 02_image202
,
Figure 02_image204
.

在本發明的一些方案中，上述TL-LA選自：

Figure 02_image206
、
Figure 02_image208
、
Figure 02_image210
、
Figure 02_image212
、
Figure 02_image214
、
Figure 02_image216
、
Figure 02_image218
、
Figure 02_image220
、
Figure 02_image222
、
Figure 02_image224
。 In some solutions of the present invention, the above-mentioned TL-LA is selected from:
Figure 02_image206
,
Figure 02_image208
,
Figure 02_image210
,
Figure 02_image212
,
Figure 02_image214
,
Figure 02_image216
,
Figure 02_image218
,
Figure 02_image220
,
Figure 02_image222
,
Figure 02_image224
.

在本發明的一些方案中，上述接頭具有式LB：

Figure 02_image226
或其立體異構體， 其中，p 1選自0-6的整數；p 2選自0-6的整數；p 3選自0-6的整數，p 4選自0-6的整數；p 5選自0-6的整數； U為鍵，或者選自C=O、O、NH或NR 13； 每個Q獨立地選自鍵、CH 2、O、S、NH或NR 13； W為鍵，或者選自C=O、O、NH、NR 13、C≡C； 其中所述R 13選自C 1-4烷基； 每個Z 1各自獨立地選自不存在、苯基、C 3-6元環烷基、3-6元雜環烷基、5-6元雜芳基，其中所述苯基、C 3-6元環烷基、3-6元雜環烷基、5-6元雜芳基各自獨立任選地被一個或多個R 14基團所取代；每個R 14獨立選自鹵素、C 1-4烷基、羥基； 或每個Z 1各自獨立地選自7-11元氮雜螺環，其中所述7-11元氮雜螺環任選地被一個或多個R 14基團所取代；每個R 14獨立選自鹵素、C 1-4烷基、羥基； 所述接頭通過U基團與靶向配體中的R 1共價結合，W基團與降解決定子共價結合。 In some aspects of the invention, the aforementioned linker has the formula LB:
Figure 02_image226
or its stereoisomer, wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6, and p 4 is selected from an integer of 0-6; p 5 is an integer selected from 0-6; U is a bond, or is selected from C=O, O, NH or NR 13 ; each Q is independently selected from a bond, CH 2 , O, S, NH or NR 13 ; W is Bond, or selected from C=O, O, NH, NR 13 , C≡C; wherein said R 13 is selected from C 1-4 alkyl; each Z 1 is independently selected from nonexistent, phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 Each of the -6- membered heteroaryl groups is independently optionally substituted by one or more R groups; each R is independently selected from halogen, C 1-4 alkyl, hydroxyl; or each Z is independently selected from from 7-11 membered azaspiro rings, wherein the 7-11 membered azaspiro rings are optionally substituted by one or more R groups; each R 14 is independently selected from halogen, C 1-4 alkane group, hydroxyl group; the linker is covalently bonded to R1 in the targeting ligand through the U group, and the W group is covalently bonded to the degradant .

在本發明的一些方案中，上述接頭LB選自：

Figure 02_image228
，
Figure 02_image230
其中，p 1、p 2、p 3、p 4、U、W、Z 1如上述所定義。 In some solutions of the present invention, the above-mentioned linker LB is selected from:
Figure 02_image228
,
Figure 02_image230
Wherein, p 1 , p 2 , p 3 , p 4 , U, W, and Z 1 are as defined above.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image232
，
Figure 02_image234
，
Figure 02_image236
，
Figure 02_image238
，
Figure 02_image240
，
Figure 02_image242
，
Figure 02_image244
， 其中，p 1、p 3、p 4、Z 1如上述所定義，TL代表靶向配體，不屬於接頭LB，僅代表接頭LB與靶向配體的連接關係；以及式TL具有如上所述的定義。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image232
,
Figure 02_image234
,
Figure 02_image236
,
Figure 02_image238
,
Figure 02_image240
,
Figure 02_image242
,
Figure 02_image244
, wherein, p 1 , p 3 , p 4 , and Z 1 are as defined above, TL represents the targeting ligand, does not belong to the linker LB, and only represents the connection relationship between the linker LB and the targeting ligand; and the formula TL has the above the above definition.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image246
、
Figure 02_image248
、
Figure 02_image250
、
Figure 02_image252
、
Figure 02_image254
、
Figure 02_image256
、
Figure 02_image258
、
Figure 02_image260
、
Figure 02_image262
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image246
,
Figure 02_image248
,
Figure 02_image250
,
Figure 02_image252
,
Figure 02_image254
,
Figure 02_image256
,
Figure 02_image258
,
Figure 02_image260
,
Figure 02_image262
.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image264
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image264
.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image266
、
Figure 02_image268
、
Figure 02_image270
； 其中，p 1、p 3、p 4、Z 1如上所述定義。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image266
,
Figure 02_image268
,
Figure 02_image270
; wherein, p 1 , p 3 , p 4 , Z 1 are as defined above.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image272
；其中，p 1、p 2、Z 1如上所述的定義。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image272
; Wherein, p 1 , p 2 , Z 1 are as defined above.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image274
、
Figure 02_image276
、
Figure 02_image278
、
Figure 02_image280
、
Figure 02_image282
、
Figure 02_image284
、
Figure 02_image286
、
Figure 02_image288
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image274
,
Figure 02_image276
,
Figure 02_image278
,
Figure 02_image280
,
Figure 02_image282
,
Figure 02_image284
,
Figure 02_image286
,
Figure 02_image288
.

在本發明的一些方案中，上述TL-LB選自：

Figure 02_image290
、
Figure 02_image292
、
Figure 02_image294
、
Figure 02_image296
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from:
Figure 02_image290
,
Figure 02_image292
,
Figure 02_image294
,
Figure 02_image296
.

在本發明的一些方案中，上述TL-LB選自

Figure 02_image298
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from
Figure 02_image298
.

在本發明的一些方案中，上述TL-LB選自

Figure 02_image300
、
Figure 02_image302
、
Figure 02_image304
、
Figure 02_image306
、
Figure 02_image308
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from
Figure 02_image300
,
Figure 02_image302
,
Figure 02_image304
,
Figure 02_image306
,
Figure 02_image308
.

在本發明的一些方案中，上述TL-LB選自

Figure 02_image310
、
Figure 02_image312
、
Figure 02_image314
、
Figure 02_image316
、
Figure 02_image318
、
Figure 02_image320
、
Figure 02_image322
。 In some solutions of the present invention, the above-mentioned TL-LB is selected from
Figure 02_image310
,
Figure 02_image312
,
Figure 02_image314
,
Figure 02_image316
,
Figure 02_image318
,
Figure 02_image320
,
Figure 02_image322
.

在本發明的一些方案中，所述的降解決定子具有式D1，

Figure 02_image324
或其立體異構體， 其中，每個R 15獨立地選自C 1-4烷基； R 16選自H、氘； 每個R 17獨立地選自鹵素、C 1-4烷基、C 1-4烷氧基、羥基； Z 2選自CH 2或者C=O； Y為鍵、O或者NH；其通過共價鍵與接頭相連； m選自0-3的整數； n選自0-4的整數。 In some aspects of the invention, the degron has the formula D1,
Figure 02_image324
or its stereoisomer, wherein, each R 15 is independently selected from C 1-4 alkyl; R 16 is selected from H, deuterium; each R 17 is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl; Z 2 is selected from CH 2 or C=O; Y is a bond, O or NH; it is connected to the linker through a covalent bond; m is selected from an integer of 0-3; n is selected from 0 An integer of -4.

在本發明的一些方案中，所述的降解決定子D1中的Z 2選自C=O。 In some aspects of the present invention, Z 2 in the degron D1 is selected from C=O.

在本發明的一些方案中，所述的降解決定子D1中Y選自鍵或者NH。In some aspects of the present invention, Y in the degron D1 is selected from a bond or NH.

在本發明的一些方案中，所述的降解決定子D1中Y選自O。In some aspects of the present invention, Y is selected from O in the degron D1.

在本發明的一些方案中，所述的降解決定子D1選自：

Figure 02_image326
，
Figure 02_image328
，
Figure 02_image330
，
Figure 02_image332
。 In some aspects of the present invention, the degron D1 is selected from:
Figure 02_image326
,
Figure 02_image328
,
Figure 02_image330
,
Figure 02_image332
.

在本發明的一些方案中，所述的降解決定子D1選自：

Figure 02_image334
。 In some aspects of the present invention, the degron D1 is selected from:
Figure 02_image334
.

在本發明的一些方案中，所述的降解決定子D1選自：

Figure 02_image336
。 In some aspects of the present invention, the degron D1 is selected from:
Figure 02_image336
.

在本發明的一些方案中，所述的降解決定子D1選自：

Figure 02_image338
、
Figure 02_image340
。 In some aspects of the present invention, the degron D1 is selected from:
Figure 02_image338
,
Figure 02_image340
.

在本發明的一些方案中，所述的降解決定子具有式D2，

Figure 02_image342
或其立體異構體， 其中，每個R 15 ，任意獨立地選自C 1-4烷基； R 16 ，選自H、氘； 每個R 17 ，任意獨立地選自鹵素、C 1-4烷基、C 1-4烷氧基； Y ，為鍵、O或者NH，其通過共價鍵與接頭相連； m選自0-3的整數； n選自0-4的整數。 In some aspects of the invention, the degron has the formula D2,
Figure 02_image342
or its stereoisomers, wherein , each R 15 is independently selected from C 1-4 alkyl; R 16 is selected from H , deuterium; each R 17 is independently selected from halogen, C 1- 4 alkyl, C 1-4 alkoxy; Y , is a bond, O or NH, which is connected to the linker through a covalent bond; m is selected from an integer of 0-3; n is selected from an integer of 0-4.

在本發明的一些方案中，所述的降解決定子D2選自：

Figure 02_image344
。 In some aspects of the present invention, the degron D2 is selected from:
Figure 02_image344
.

在本發明的一些方案中，所述的降解決定子具有式D3，

Figure 02_image346
或其立體異構體， 其中，R 18選自H、C 1-4烷基； 每個R 19任意獨立地選自C 1-4烷基； R 20選自H、C 1-4烷基； q選自0-4的整數； 其中所述降解決定子通過
Figure 02_image070
與所述接頭共價結合。 In some aspects of the invention, the degron has the formula D3,
Figure 02_image346
or its stereoisomer, wherein, R 18 is selected from H, C 1-4 alkyl; each R 19 is independently selected from C 1-4 alkyl; R 20 is selected from H, C 1-4 alkyl ; q is an integer selected from 0-4; wherein the degron is passed
Figure 02_image070
Covalently bound to the linker.

在本發明的一些方案中，所述的降解決定子D3中的R 18選自甲基。 In some aspects of the present invention, R 18 in the degron D3 is selected from methyl.

在本發明的一些方案中，所述的降解決定子D3中的R 20選自甲基。 In some aspects of the present invention, R 20 in the degron D3 is selected from methyl.

在本發明的一些方案中，所述的降解決定子D3選自：

Figure 02_image348
，
Figure 02_image350
，
Figure 02_image352
。 In some aspects of the present invention, the degron D3 is selected from:
Figure 02_image348
,
Figure 02_image350
,
Figure 02_image352
.

在本發明的一些方案中，所述的降解決定子具有式D3 ’，

Figure 02_image354
或其立體異構體， 其中，R 18a選自H、C 1-4烷基； 每個R 19a任意獨立地選自C 1-4烷基、C 1-4烷氧基； R 20a、R 20b任意獨立地選自H、C 1-4烷基； 或者R 20a與R 20b相連接，環化形成C 3-6環烷基； 或者R 19a與R 20a或R 19a與R 20b相連接，環化形成3-6元雜環烷基； r選自0-4的整數； 其中所述降解決定子通過
Figure 02_image070
與所述接頭共價結合。 In some aspects of the invention, the degron has the formula D3 ' ,
Figure 02_image354
or its stereoisomers, wherein, R 18a is selected from H, C 1-4 alkyl; each R 19a is independently selected from C 1-4 alkyl, C 1-4 alkoxy; R 20a , R 20b is independently selected from H, C 1-4 alkyl; or R 20a is connected to R 20b and cyclized to form C 3-6 cycloalkyl; or R 19a is connected to R 20a or R 19a is connected to R 20b , Cyclization to form a 3-6 membered heterocycloalkyl group; r is an integer selected from 0-4; wherein the degron is passed
Figure 02_image070
Covalently bound to the linker.

在本發明的一些方案中，所述的降解決定子D3 ’中的R 18a選自甲基。 In some aspects of the present invention, R 18a in the degron D3 ' is selected from methyl.

在本發明的一些方案中，所述的降解決定子D3 ’中的R 20a、R 20b和與其連接的原子一起環化形成環丙基。 In some aspects of the present invention, R 20a , R 20b in the degron D3 ' and the atoms connected to them are cyclized together to form a cyclopropyl group.

在本發明的一些方案中，所述的降解決定子D3 ’中的R 19a與R 20a和與其連接的原子一起環化，或R 19a與R 20b和與其連接的原子一起環化形成四氫吡喃環。 In some schemes of the present invention, R 19a in the degron D3 ' is cyclized with R 20a and the atom connected to it, or R 19a is cyclized with R 20b and the atom connected to it to form a tetrahydropyridine Nan ring.

在本發明的一些方案中，所述的降解決定子具有式D3 ’，選自：

Figure 02_image356
、
Figure 02_image358
、
Figure 02_image360
。 In some aspects of the invention, the degron has the formula D3 ' and is selected from the group consisting of:
Figure 02_image356
,
Figure 02_image358
,
Figure 02_image360
.

在本發明的一些方案中，所述的降解決定子具有式D4，

Figure 02_image362
或其立體異構體， Y為鍵、或者NH，其通過共價鍵與接頭相連。 In some aspects of the invention, the degron has the formula D4,
Figure 02_image362
or its stereoisomer, Y is a bond, or NH, which is connected to the linker through a covalent bond.

在本發明的一些方案中，所述的降解決定子D4選自：

Figure 02_image364
。 In some aspects of the present invention, the degron D4 is selected from:
Figure 02_image364
.

在本發明的一些方案中，所述的降解決定子具有式D5，

Figure 02_image366
其中，M選自NH、O或者S； V為鍵、NH或者O，其通過共價鍵與接頭相連； 每個R 21各自獨立地選自鹵素； S選自0、1、2或3。 In some aspects of the invention, the degron has the formula D5,
Figure 02_image366
Wherein, M is selected from NH, O or S; V is a bond, NH or O, which is connected to the linker through a covalent bond; each R 21 is independently selected from halogen; S is selected from 0, 1, 2 or 3.

在本發明的一些方案中，所述的降解決定子D5為

Figure 02_image368
。 In some schemes of the present invention, the degradon D5 is
Figure 02_image368
.

在本發明的一些方案中，所述的降解決定子D5為

Figure 02_image370
。 In some schemes of the present invention, the degradant D5 is
Figure 02_image370
.

在本發明的一些方案中，所述的降解決定子D5為

Figure 02_image372
、
Figure 02_image374
、
Figure 02_image376
。 In some schemes of the present invention, the degradant D5 is
Figure 02_image372
,
Figure 02_image374
,
Figure 02_image376
.

在本發明的一些方案中，所述的降解決定子D5為

Figure 02_image378
。 In some schemes of the present invention, the degradant D5 is
Figure 02_image378
.

在本發明的一些方案中，所述的降解決定子D5為

Figure 02_image380
。 In some schemes of the present invention, the degradant D5 is
Figure 02_image380
.

在本發明的一些方案中，所述的降解決定子選自

Figure 02_image382
。 In some aspects of the present invention, the degrons are selected from
Figure 02_image382
.

在本發明的一些方案中，所述的降解決定子選自

Figure 02_image384
。 In some aspects of the present invention, the degrons are selected from
Figure 02_image384
.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物選自以下結構：

Figure 02_image386
，
Figure 02_image388
，
Figure 02_image390
，
Figure 02_image392
。 其中，A、M、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 20、Y、R 15、n、接頭、降解決定子如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives Choose from the following structures:
Figure 02_image386
,
Figure 02_image388
,
Figure 02_image390
,
Figure 02_image392
. Wherein, A, M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , Y, R 15 , n, linker, and degron are as defined above.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，選自以下結構：

Figure 02_image394
，
Figure 02_image396
，
Figure 02_image398
，
Figure 02_image400
其中，M、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 20、Y、R 15、n、接頭與降解決定子如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , selected from the following structures:
Figure 02_image394
,
Figure 02_image396
,
Figure 02_image398
,
Figure 02_image400
Wherein, M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 20 , Y, R 15 , n, linker and degron are as defined above.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，選自式（Ic-A）或（Ic-B）：

Figure 02_image402
、
Figure 02_image404
； 其中，R 6、R 7、R 15、Y、n、接頭與降解決定子如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , selected from formula (Ic-A) or (Ic-B):
Figure 02_image402
,
Figure 02_image404
; wherein, R 6 , R 7 , R 15 , Y, n, linker and degron are as defined above.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，選自式（Ic）：

Figure 02_image406
其中，接頭與降解決定子如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , selected from formula (Ic):
Figure 02_image406
Wherein, linkers and degrons are as defined above.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，選自式（Id）：

Figure 02_image408
其中，接頭與降解決定子如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , selected from the formula (Id):
Figure 02_image408
Wherein, linkers and degrons are as defined above.

在本發明的一些方案中，上述式（I）所示的化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，選自以下結構：

Figure 02_image410
、
Figure 02_image412
、
Figure 02_image414
； 其中，接頭、R 20、Y、R 15、n如上述所定義。 In some schemes of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative , selected from the following structures:
Figure 02_image410
,
Figure 02_image412
,
Figure 02_image414
; wherein, linker, R 20 , Y, R 15 , and n are as defined above.

本發明提供的雙功能化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，其選自：

Figure 02_image416
Figure 02_image418
Figure 02_image420
Figure 02_image422
Figure 02_image424
Figure 02_image426
Figure 02_image428
Figure 02_image430
Figure 02_image432
Figure 02_image434
Figure 02_image436
Figure 02_image438
Figure 02_image440
Figure 02_image442
Figure 02_image444
Figure 02_image446
Figure 02_image448
Figure 02_image450
Figure 02_image452
Figure 02_image454
Figure 02_image456
Figure 02_image458
Figure 02_image460
Figure 02_image462
Figure 02_image464
Figure 02_image466
Figure 02_image468
Figure 02_image470
Figure 02_image472
Figure 02_image474
Figure 02_image476
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The bifunctional compound provided by the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative, it is selected from:
Figure 02_image416
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Figure 02_image781

本發明還提供一種藥物組合物，其含有治療有效量的上述雙功能化合物或其立體異構體、互變異構體、藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物和藥學上可接受的載體。The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above bifunctional compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled Derivatives and pharmaceutically acceptable carriers.

根據本發明的藥物組合物可以配製用於各種常規給藥或特定給藥途徑，如口服給藥、胃腸外給藥和直腸給藥等。口服給藥的劑型，例如片劑、膠囊劑(包括持續釋放或定時釋放處方)、丸劑、散劑、顆粒劑、酏劑、酊劑、混懸液(包括奈米混懸液、微米混懸液、噴霧乾燥分散劑)、糖漿劑和乳劑；胃腸外給藥，例如通過皮下、靜脈內、肌內或胸骨內的注射，或輸注技術(例如作為無菌可注射水溶液或非水溶液或混懸液)；經鼻給藥，例如對鼻黏膜給藥，通過吸入噴霧；局部給藥，例如以乳膏或軟膏的形式；直腸給藥，例如以栓劑的形式。根據本發明的化合物可單獨給藥，但通常會與根據所選擇的給藥途徑和標準藥學操作選擇的藥學載體一起給藥。The pharmaceutical composition according to the present invention can be formulated for various conventional administration or specific administration routes, such as oral administration, parenteral administration, rectal administration and the like. Dosage forms for oral administration, such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; parenteral administration, e.g. by subcutaneous, intravenous, intramuscular or intrasternal injection, or infusion techniques (e.g. as sterile injectable aqueous or non-aqueous solutions or suspensions); Nasally, eg, to the nasal mucosa, by inhalation of a spray; topically, eg, in the form of a cream or ointment; rectally, eg, in the form of suppositories. The compounds according to the invention can be administered alone, but will generally be administered with a pharmaceutical carrier selected with regard to the chosen route of administration and standard pharmaceutical practice.

“藥學上可接受的載體”指本領域通常可接受的用於將生物活性藥劑遞送給動物、特別是哺乳動物的介質，根據給藥方式和劑型的性質包括例如佐劑、賦形劑或賦形物，例如稀釋劑、防腐劑、填充劑、流動調節劑、崩解劑、潤濕劑、乳化劑、助懸劑、甜味劑、調味劑、芳香劑、抗菌劑、抗真菌劑、潤滑劑和分散劑。"Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients or excipients according to the mode of administration and the nature of the dosage form. Diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants agents and dispersants.

藥學上可接受的載體在本發明所屬技術領域具有通常知識者的眼界範圍內可以綜合大量因素進行選擇和配製。其包括但不限於：配製的活性藥劑的類型和性質，要將含有該藥劑的組合物給藥的對象，組合物的預期給藥途徑和目標治療適應症等。藥學上可接受的載體包括含水介質和非水介質這兩者以及多種固體和半固體劑型。除了活性藥劑以外，這樣的載體可以包括許多不同的成分和添加劑，因多種原因(例如穩定活性藥劑、黏合劑等)在處方中包括另外的成分對於本發明所屬技術領域具有通常知識者也是眾所周知的。A pharmaceutically acceptable carrier can be selected and formulated in consideration of a large number of factors within the purview of those skilled in the art to which the present invention pertains. It includes, but is not limited to: the type and nature of the active agent to be formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. Such carriers can include many different ingredients and additives in addition to the active agent, and it is well known to those skilled in the art to which this invention pertains to include additional ingredients in formulations for a variety of reasons (e.g., to stabilize the active agent, binders, etc.). .

用於本發明化合物的給藥方案當然可根據已知的因素改變，例如具體藥劑的藥效學特徵及其給藥的模式和途徑，接受者的物種、年齡、性別、健康、醫學狀況和體重，症狀的性質和程度，共存的治療的種類，治療的頻率，給藥的途徑，患者的腎臟和肝臟的功能，和需要的效果。治療有效劑量的化合物、藥物組合物或其組合取決於對象種類、體重、年齡和個體情況、所治療病症或疾病或其嚴重度。掌握普通技術的醫生、臨床醫生或獸醫能容易確定預防、治療或抑制病症或疾病進展所需的各活性成分有效量。Dosage regimens for compounds of the invention may of course vary according to known factors, such as the pharmacodynamic profile of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient , nature and extent of symptoms, types of concurrent treatments, frequency of treatments, route of administration, patient's renal and hepatic function, and desired effects. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the subject, the condition or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a condition or disease.

本發明還提供上述雙功能化合物或其立體異構體、互變異構體、藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物或上述的藥物組合物在製備治療癌症藥物中的應用。The present invention also provides the above-mentioned bifunctional compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative or the above-mentioned pharmaceutical composition in the preparation of therapeutic Applications in cancer medicine.

表皮生長因子受體EGFR（epidermal growth factor receptor），廣泛分佈於哺乳動物上皮細胞、成纖維細胞、膠質細胞等細胞表面。EGFR訊號通路對細胞的生長、增殖和分化等生理過程發揮重要的作用。EGFR突變也是NSCLC患者中最常見的一種突變類型，尤其是在亞洲人群中可以占到40%~50%。Epidermal growth factor receptor EGFR (epidermal growth factor receptor) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, accounting for 40% to 50%.

因此，本發明還提供了治療癌症的方法，其包括向患者施用治療有效量的上述化合物或其立體異構體、互變異構體、藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物或上述的藥物組合物。上述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宮頸癌、***癌、結腸直腸癌、乳腺癌、胰腺癌、膠質瘤、膠質母細胞瘤，黑色素瘤、白血病、胃癌、子宮內膜癌、肺癌、肝細胞癌、胃腸道間質瘤(GIST)、急性髓細胞白血病(AML)、膽管癌、腎癌、甲狀腺癌、間變性大細胞淋巴瘤、間皮瘤、多發性骨髓瘤、黑色素瘤。Therefore, the present invention also provides a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of the above compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate substances, isotope-labeled derivatives or the above-mentioned pharmaceutical compositions. The above cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrium Cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.

本發明還提供了上述化合物或其立體異構體、互變異構體、藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物或上述的藥物組合物在製備治療EGFR相關癌症藥物中的應用。上述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宮頸癌、***癌、結腸直腸癌、乳腺癌、胰腺癌、膠質瘤、膠質母細胞瘤，黑色素瘤、白血病、胃癌、子宮內膜癌、肺癌、肝細胞癌、胃腸道間質瘤(GIST)、急性髓細胞白血病(AML)、膽管癌、腎癌、甲狀腺癌、間變性大細胞淋巴瘤、間皮瘤、多發性骨髓瘤、黑色素瘤。The present invention also provides the above-mentioned compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative or the above-mentioned pharmaceutical composition in the preparation of the treatment of EGFR Applications in related cancer drugs. The above cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrium Cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.

在本發明的一些方案中，上述癌症為肺癌。In some aspects of the present invention, the aforementioned cancer is lung cancer.

本發明提供的上述雙功能化合物或其立體異構體、互變異構體、藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物或上述的藥物組合物，用於治療癌症，上述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宮頸癌、***癌、結腸直腸癌、乳腺癌、胰腺癌、膠質瘤、膠質母細胞瘤，黑色素瘤、白血病、胃癌、子宮內膜癌、肺癌、肝細胞癌、胃癌、胃腸道間質瘤(GIST)、急性髓細胞白血病(AML)、膽管癌、腎癌、甲狀腺癌、間變性大細胞淋巴瘤、間皮瘤、多發性骨髓瘤、黑色素瘤。The above-mentioned bifunctional compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative or the above-mentioned pharmaceutical composition provided by the present invention is used for Treatment of cancers, including lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, Endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, Multiple myeloma, melanoma.

在本發明的一些方案中，上述癌症為肺癌。In some aspects of the present invention, the aforementioned cancer is lung cancer.

本文所述的化合物可以通過本發明所屬技術領域具有通常知識者已知的方法製備，僅作為一般性舉例，可以使用以下方案製備：The compounds described herein can be prepared by methods known to those of ordinary skill in the art to which the invention pertains, and by way of general example only, the following schemes can be used:

通用方案一：

Figure 02_image783
General plan one:
Figure 02_image783

通用方案二：

Figure 02_image785
General plan two:
Figure 02_image785

如通用方案一中所示，接頭與靶向配體可以先通過化學反應相連接，隨後再加入降解決定子，製備得到本發明的三聯體化合物；或者如通用方案二中所示，接頭先與降解決定子通過化學反應相連接，隨後再加入靶向配體，製備得到本發明的三聯體化合物； 需要說明的是，三聯體化合物中兩個部分相連接時，可以是兩部分分別製備完成後再連接，也可以是先連接，再完成每一部分的合成。例如通用方案一中靶向配體與接頭部分相連接，可以是製備完成的靶向配體與接頭相連接，也可以是靶向配體中的一部分先與接頭相連接，連接完成後，再完成靶向配體本身的製備。 As shown in the general scheme 1, the linker and the targeting ligand can be connected through a chemical reaction first, and then the degradant is added to prepare the triplet compound of the present invention; or as shown in the general scheme 2, the linker is first combined with The degradants are connected through chemical reactions, and then the targeting ligand is added to prepare the triplet compound of the present invention; It should be noted that when the two parts in the triplet compound are connected, the two parts can be prepared separately and then connected, or connected first, and then the synthesis of each part can be completed. For example, in the general scheme 1, the targeting ligand is connected to the linker part. It can be that the prepared targeting ligand is connected to the linker, or a part of the targeting ligand is connected to the linker first. After the connection is completed, then The preparation of the targeting ligand itself is completed.

三聯體化合物中兩個部分的連接，通過常規的化學反應製備得到，如通用方案一、二中的步驟1與步驟2，可以通過親核取代、縮合或者偶聯等反應實現。The connection of the two parts in the triplet compound is prepared by conventional chemical reactions, such as steps 1 and 2 in general schemes 1 and 2, which can be realized by reactions such as nucleophilic substitution, condensation or coupling.

具體的，本發明中的三聯體化合物可通過以下方式製備：Specifically, the triplet compound among the present invention can be prepared in the following manner:

靶向配體與接頭連接後，再與降解決定子連接得到：

Figure 02_image787
；或者接頭與降解決定子連接後，再與靶向配體連接得到：
Figure 02_image789
其中，靶向配體，接頭，降解決定子如上述所定義。 After the targeting ligand is linked to the linker, it is then linked to the degron to obtain:
Figure 02_image787
; or after the linker is connected with the degron, and then connected with the targeting ligand to obtain:
Figure 02_image789
Wherein, targeting ligand, linker and degron are as defined above.

代表性合成路線一：

Figure 02_image791
Representative synthetic route 1:
Figure 02_image791

步驟1接頭中的羧酸與降解決定子中的胺基在縮合試劑的作用下發生縮合反應形成醯胺鍵，常用的縮合劑包括但不限於4-（4,6-二甲氧基三𠯤）-4-甲基嗎福林鹽酸鹽（DMTMM）、二環己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)和1-(3-二甲胺基丙基)-3-乙基碳二亞胺(EDCI)、2-(7-氮雜苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)等。The carboxylic acid in the linker in step 1 and the amine group in the degron undergo a condensation reaction under the action of a condensing reagent to form an amide bond. Commonly used condensing agents include but are not limited to 4-(4,6-dimethoxytrimethonium )-4-methylmorphine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc. .

步驟2靶向配體中的胺基進攻降解決定子的LG基團，LG離去發生親核取代反應製備得到三聯體化合物；其中，LG代表常用離去基團，例如三氟甲磺酸基、甲磺酸基、對甲基苯磺酸基以及氟、溴、碘、氯等鹵素原子。Step 2: The amine group in the targeting ligand attacks the LG group of the degron, and the LG leaves to undergo a nucleophilic substitution reaction to prepare a triplet compound; wherein, LG represents a commonly used leaving group, such as a trifluoromethanesulfonic acid group , methanesulfonic acid group, p-toluenesulfonic acid group, and halogen atoms such as fluorine, bromine, iodine, and chlorine.

以上兩步反應常在鹼的催化下進行，常用的鹼催化劑包括三乙胺、吡啶、N,N-二異丙基乙胺、醋酸鈉、碳酸鈉、碳酸鉀等。The above two-step reactions are often carried out under the catalysis of bases, and commonly used base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate, etc.

代表性合成路線二：Representative synthetic route 2:

步驟1，靶向配體中的胺基進攻接頭中的LG基團，LG離去發生親核取代反應；LG代表常用離去基團，例如三氟甲磺酸根、甲磺酸根、對甲基苯磺酸根以及氟、溴、碘、氯等鹵素原子；接頭中的PG代表常用的胺基保護基團，包括但不限於第三丁氧羰基、苄氧羰基、對甲苯磺醯基、笏甲氧羰基、對甲氧基苄基、苄基、三苯甲基等。Step 1, the amine group in the targeting ligand attacks the LG group in the linker, and LG leaves to undergo a nucleophilic substitution reaction; LG represents a commonly used leaving group, such as trifluoromethanesulfonate, methanesulfonate, p-methyl Benzenesulfonate and halogen atoms such as fluorine, bromine, iodine, chlorine, etc.; PG in the linker represents a commonly used amino protecting group, including but not limited to tertiary butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, Watt A Oxycarbonyl, p-methoxybenzyl, benzyl, trityl, etc.

步驟2，一般情況下在酸性作用下脫除胺基保護基，常用的酸包括但不限於鹽酸、甲酸、三氟乙酸、氫溴酸等。Step 2. Generally, the amino protecting group is removed under the action of acid. Commonly used acids include but are not limited to hydrochloric acid, formic acid, trifluoroacetic acid, hydrobromic acid and the like.

步驟3，靶向配體-接頭中胺基進攻降解決定子中的LG基團，LG離去發生親核取代反應，製備得到三聯體化合物。LG代表常用離去基團，例如三氟甲磺酸根、甲磺酸根、對甲基苯磺酸根以及氟、溴、碘、氯等鹵素原子。In step 3, the amine group in the targeting ligand-linker attacks the LG group in the degron, and the LG group leaves to undergo a nucleophilic substitution reaction to prepare a triplet compound. LG represents a commonly used leaving group, such as trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate, and halogen atoms such as fluorine, bromine, iodine, and chlorine.

步驟1與步驟3常在常在鹼的催化下進行，常用的鹼催化劑包括三乙胺、吡啶、N,N-二異丙基乙胺、醋酸鈉、碳酸鈉、碳酸鉀等。

Figure 02_image793
Steps 1 and 3 are often carried out under the catalysis of bases. Commonly used base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate, etc.
Figure 02_image793

代表性合成路線三：

Figure 02_image795
Representative synthetic route three:
Figure 02_image795

步驟1中，在催化劑的作用下接頭與降解決定子發生偶聯反應，常用的催化劑為雙(三苯基膦)二氯化鈀(Ⅱ)、四(三苯基膦)鈀或[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀和碘化亞銅等。In step 1, under the action of a catalyst, the linker and the degradant undergo a coupling reaction, and the commonly used catalysts are bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium or [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride and cuprous iodide, etc.

隨後步驟2中羥基基團轉化為易離去的基團LG，與靶向配體中的胺基發生親核取代反應生成三聯體化合物。Subsequently, in step 2, the hydroxyl group is converted into an easy-to-leave group LG, which undergoes a nucleophilic substitution reaction with the amine group in the targeting ligand to generate a triplet compound.

本發明中使用的靶向配體，可以參考CN112538072A中相關化合物的製備方法中的靶向配體，相關內容以引用的方式併入本申請。For the targeting ligand used in the present invention, refer to the targeting ligand in the preparation method of related compounds in CN112538072A, and the relevant content is incorporated into this application by reference.

以上反應式中的各個基團變量如上文中所定義。The individual group variables in the above schemes are as defined above.

技術效果：Technical effect:

本發明化合物對Ba/F3 Del19/T790M/C797S EGFR三突變細胞系和Ba/F3 L858R/T790M/C797S EGFR三突變細胞系的細胞增殖有著很好的抑制作用。The compound of the present invention has good inhibitory effect on cell proliferation of Ba/F3 Del19/T790M/C797S EGFR triple mutation cell line and Ba/F3 L858R/T790M/C797S EGFR triple mutation cell line.

本發明化合物能夠顯著地誘導EGFR蛋白的降解。The compound of the present invention can significantly induce the degradation of EGFR protein.

說明和定義：Description and Definitions:

除非另有說明，本文所用的下列術語和短語具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。Unless otherwise stated, the following terms and phrases used herein have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning.

術語“藥學上可接受的”指在合理的醫學判斷範圍內適合與人類和動物的組織接觸使用而無過度的毒性、刺激、過敏反應或其它的問題或併發症，具有合理的收益/風險比的那些化合物、材料、組合物和/或劑型。The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and having a reasonable benefit/risk ratio those compounds, materials, compositions and/or dosage forms.

術語“藥學上可接受的鹽”是指本發明化合物與相對無毒的酸或鹼製備得到的衍生物。這些鹽可以在化合物合成、分離、純化期間就被製備，或者單獨使用經過純化的化合物的游離形式與適合的酸或鹼反應。當化合物中含有相對酸性的官能團時，與鹼金屬、鹼土金屬氫氧化物或有機胺反應得到鹼加成鹽，包括基於鹼金屬與鹼土金屬的陽離子以及無毒的銨、季銨和胺陽離子，還涵蓋胺基酸的鹽等。當化合物中含有相對鹼性的官能團時，與有機酸或無機酸反應得到酸加成鹽。The term "pharmaceutically acceptable salt" refers to derivatives prepared from the compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base. When the compound contains relatively acidic functional groups, it can react with alkali metal, alkaline earth metal hydroxide or organic amine to obtain base addition salts, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations. Salts of amino acids and the like are contemplated. When the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to form an acid addition salt.

本發明所提供的化合物還包括前藥的形式，表示體內迅速轉化得到上式母體化合物的化合物，其可在體內或者體外的環境中通過化學或生化方法被轉換成本發明的化合物，例如借助血液中的水解作用。The compounds provided by the present invention also include the form of prodrugs, which means that the compound can be rapidly transformed into the parent compound of the above formula in vivo, which can be converted into the compound of the present invention by chemical or biochemical methods in an in vivo or in vitro environment, for example, by means of blood of hydrolysis.

本發明的化合物能夠以非溶劑化以及溶劑化形式存在，所述溶劑化物包括水合物形式。一般而言，溶劑化物形式的藥學效果等價於未溶劑化形式，也涵蓋在本發明的範圍內。The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the pharmaceutical effects of the solvated forms are equivalent to those of the unsolvated forms and are also encompassed within the scope of the present invention.

本發明的化合物存在“互變異構體”，術語“互變異構體”是指官能團異構體的一種，其通過一個或多個雙鍵位移而具有不同的連接點，例如，酮和它的烯醇形式是酮-烯醇互變異構體。The compounds of the present invention exist as "tautomers", the term "tautomer" refers to one of functional isomers having different points of attachment by displacement of one or more double bonds, for example, ketones and their The enol form is a keto-enol tautomer.

本發明的化合物存在幾何異構體以及立體異構體，例如順反異構體、對映異構體、非對映異構體、外消旋混合物和其他混合物，所有這些混合物都屬於本發明的範圍之內。The compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which are included in the present invention within the range.

本發明的化合物存在“互變異構體”，術語“互變異構體”是指官能團異構體的一種，其通過一個或多個雙鍵位移而具有不同的連接點，例如，酮和它的烯醇形式是酮-烯醇互變異構體。The compounds of the present invention exist as "tautomers", the term "tautomer" refers to one of functional isomers having different points of attachment by displacement of one or more double bonds, for example, ketones and their The enol form is a keto-enol tautomer.

術語“對映異構體”是指互為鏡像關係的立體異構體。The term "enantiomer" refers to stereoisomers that are mirror images of each other.

術語“非對映異構體”是指分子具有兩個或多個手性中心，並且分子間為非鏡像的關係的立體異構體。The term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and which are in a non-mirror-image relationship.

術語“順反異構體”是指分子中雙鍵或者成環碳原子單鍵不能自由旋轉而存在的構型。The term "cis-trans isomer" refers to the configuration in which the double bond or the single bond of the ring carbon atom in the molecule cannot freely rotate.

除非另有說明，用楔形實線鍵

Figure 02_image797
和楔形虛線鍵
Figure 02_image799
表示一個立體中心的絕對構型，用直形實線鍵
Figure 02_image801
和直形虛線鍵
Figure 02_image803
表示立體中心的相對構型。 Unless otherwise noted, keys with wedge-shaped solid lines
Figure 02_image797
and dotted wedge keys
Figure 02_image799
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure 02_image801
and straight dashed keys
Figure 02_image803
Indicates the relative configuration of the stereocenter.

本發明化合物的立體異構體可以通過手性合成或手性試劑或者其他常規技術製備。例如本發明某化合物的一種對映體，可以通過不對稱催化技術或者手性助劑衍生技術製備得到。或者通過手性拆分技術，從混合物中得到單一立體構型的化合物。或者用手性起始原料，直接製備得到。本發明中的光學純化合物的分離通常是使用製備色譜完成的，採用手性色譜柱，達到分離手性化合物的目的。Stereoisomers of the compounds of the present invention may be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a certain compound of the present invention can be prepared by asymmetric catalytic technology or chiral auxiliary derivatization technology. Alternatively, a compound with a single stereo configuration can be obtained from a mixture by chiral resolution technology. Or it can be directly prepared by using chiral starting materials. The separation of optically pure compounds in the present invention is usually accomplished by using preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.

一般情況下，光學純的化合物作為起始物料參與反應時，其結構中手性原子的立體構型也會發生傳遞，無特殊情況，其構型在反應中視為保持不變，即產物具有與起始物料相同的構型，當光學純混合物參與反應時，生成的化合物也是光學純相應的混合物。例如，( R)-3-甲基嗎福林作為起始物料參與反應，得到的化合物也是 R構型；反式-2, 6-二甲基嗎福林作為起始物料參與反應，得到的化合物為2 S, 6 S與2 R, 6 R構型的外消旋體。 In general, when an optically pure compound is used as a starting material to participate in the reaction, the stereo configuration of the chiral atom in its structure will also be transferred. Without special circumstances, its configuration is considered to remain unchanged during the reaction, that is, the product has the same The same configuration of the starting materials, when the optically pure mixture participates in the reaction, the resulting compound is also the optically pure corresponding mixture. For example, ( R )-3-methylmorpholine participates in the reaction as a starting material, and the obtained compound is also in the R configuration; trans-2, 6-dimethylmorpholine participates in the reaction as a starting material, and the obtained The compound is a racemate of 2 S , 6 S and 2 R , 6 R configuration.

術語“光學純”或“對映體富集”是指該異構體或對映體的含量大於等於60%，或者大於等於70%，或者大於等於80%，或者大於等於90%，或者大於等於95%，或者大於等於96%，或者大於等於97%，或者大於等於98%，或者大於等於99%，或者大於等於99.5%，或者大於等於99.6%，或者大於等於99.7%，或者大於等於99.8%，或者大於等於99.9%。The term "optically pure" or "enantiomerically enriched" means that the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to Equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8 %, or greater than or equal to 99.9%.

化合物的絕對立體構型通過可以通過本領域常規技術手段予以確證。例如單晶X射線衍射法，也可以通過原料的手性結構以及不對稱合成的反應機理來確證化合物的絕對構型。The absolute stereo configuration of the compound can be confirmed by conventional technical means in the art. For example, the single crystal X-ray diffraction method can also confirm the absolute configuration of the compound through the chiral structure of the raw material and the reaction mechanism of the asymmetric synthesis.

本發明還包括同位素標記衍生物。包括氫、碳、氮、氧、磷、硫、氟和氯的同位素，分別例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本發明化合物都屬於發明的範圍。 The invention also includes isotopically labeled derivatives. Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, respectively , 35 S, 18 F and 36 Cl. Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention.

術語“有效預防或治療量”是指本發明化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物以適用於任何醫學治療和/或預防的合理效果/風險比治療障礙的足夠量的化合物。但應認識到，本發明式I所示化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物和組合物的總日用量須由主診醫師在可靠的醫學判斷範圍內作出決定。對於任何具體的患者，具體的治療有效劑量水平鬚根據多種因素而定，所述因素包括所治療的障礙和該障礙的嚴重程度；所採用的具體化合物的活性；所採用的具體組合物；患者的年齡、體重、一般健康狀況、性別和飲食；所採用的具體化合物的給藥時間、給藥途徑和***率；治療持續時間；與所採用的具體化合物組合使用或同時使用的藥物；及醫療領域公知的類似因素。例如，本領域的做法是，化合物的劑量從低於為得到所需治療效果而要求的水平開始，逐漸增加劑量，直到得到所需的效果。一般說來，本發明式I所示化合物或其藥學上可接受的鹽用於哺乳動物特別是人的劑量可以介於0.001～1000mg/kg體重/天，例如介於0.01～100mg/kg體重/天，例如介於 0.01～10mg/kg體重/天。The term "effective prophylactic or therapeutic amount" refers to the compounds of the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives suitable for any A sufficient amount of the compound for medical treatment and/or prophylaxis with a reasonable effect/risk ratio to treat the disorder. However, it should be recognized that the compounds represented by formula I of the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives and compositions The daily dosage must be determined by the attending physician within the scope of reliable medical judgment. For any particular patient, the specific therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; the patient. age, weight, general health, sex, and diet; the timing of administration, route of administration, and rate of excretion of the specific compound employed; duration of treatment; drugs used in combination or concomitantly with the specific compound employed; Similar factors are known in the art. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained. Generally speaking, the dose of the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof for mammals, especially humans, can range from 0.001 to 1000 mg/kg body weight/day, for example, from 0.01 to 100 mg/kg body weight/day. day, for example between 0.01-10 mg/kg body weight/day.

術語“任選被取代的”是指可以被取代，也可以不被取代，除非另有規定，取代基的種類和數目在化學上可以實現的基礎上可以是任意的，例如，術語“可任選地被一個或多個R 0取代”是指可以被一個或多個R 0取代，也可以不被R 0取代。 The term "optionally substituted" means that it can be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical realization, for example, the term "optionally "Optionally substituted by one or more R 0 " means that it may or may not be substituted by one or more R 0 .

當任何變量(例如R 12)在化合物的組成或結構中出現一次以上時，其在每一種情況下的定義都是獨立的。例如，如果一個基團被0-2個R 12所取代，則所述基團可以任選地至多被兩個R 12所取代，並且每種情況下的R 12都有獨立的選項。 When any variable (eg R 12 ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted with 0-2 R 12 , said group may optionally be substituted with up to two R 12 , and there are independent options for each occurrence of R 12 .

當一個連接基團的數量為0時，比如-O(CH 2) nCH 3，n=0表示該連接基團為單鍵，即-OCH 3。 When the number of a linking group is 0, such as -O(CH 2 ) n CH 3 , n=0 means that the linking group is a single bond, ie -OCH 3 .

當一個取代基的鍵可以交叉連接到一個環上的兩個原子時，這種取代基可以與這個環上的任意原子相鍵合。例如，結構單元

Figure 02_image805
表示取代基R 12可以在苯環上的任意一個位置發生取代。 When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, the structural unit
Figure 02_image805
Indicates that the substituent R 12 can be substituted at any position on the benzene ring.

當所列舉的取代基中沒有指明其通過哪一個原子連接到化學結構通式中時，這種取代基可以通過其任何原子相鍵合。例如，吡唑作為取代基，是指吡唑環上任意一個碳原子連接到被取代的基團上；當結構中出現

Figure 02_image807
或者
Figure 02_image809
時，表示該原子為鍵合原子，例如
Figure 02_image811
與
Figure 02_image813
均表示嗎福林環上的N原子為鍵合原子。 When a substituent is listed without specifying which atom it is connected to in the formula, such substituent may be bonded through any atom thereof. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is connected to the substituted group; when the structure appears
Figure 02_image807
or
Figure 02_image809
When , it means that the atom is a bonded atom, for example
Figure 02_image811
and
Figure 02_image813
All indicate that the N atom on the morpholine ring is a bonding atom.

除非另有規定，“環”是指飽和的、部分飽和的或不飽和的單環以及多環，“多環”包括螺環、并環或橋環。代表性的“環”包括被取代或未被取代的環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基、芳基或雜芳基。Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic rings and polycyclic rings, and "polycyclic rings" includes spiro rings, fused rings or bridged rings. Representative "ring" includes substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.

術語“雜”表示取代或未被取代的雜原子以及雜原子的氧化形式，所述雜原子一般選自N、O、S，氧化形式一般包括NO、SO、S(O) 2，氮原子可以是取代的，即NR（R為H或者文中定義的其他取代基）；環上原子的數目通常被定義為環的元數，例如，“3-6元雜環烷基”是指3-6個原子環繞排列而成的環，每個環任選地包含1～3個雜原子，即N、O、S、NO、SO、S(O) 2或NR，每個環任選的被R基團所取代，R為本發明中所定義的任意取代基。 The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, said heteroatoms are generally selected from N, O, S, oxidized forms generally include NO, SO, S(O) 2 , nitrogen atoms can be is substituted, that is, NR (R is H or other substituents defined in the text); the number of atoms on the ring is usually defined as the ring number, for example, "3-6 membered heterocycloalkyl" refers to 3-6 rings arranged around atoms, each ring optionally contains 1 to 3 heteroatoms, namely N, O, S, NO, SO, S(O) 2 or NR, and each ring is optionally replaced by R Substituted by a group, R is any substituent defined in the present invention.

除非另有規定，“環烷基”是指飽和的單環烴基。環烷基優選3-8元單環烷基，更優選3-6元單環烷基，這些單環烷基的實例包括但不限於：環丙基、環丁基、環戊基、環己基、環庚基、環辛基。Unless otherwise specified, "cycloalkyl" means a saturated monocyclic hydrocarbon group. The cycloalkyl group is preferably a 3-8 membered monocycloalkyl group, more preferably a 3-6 membered monocycloalkyl group. Examples of these monocycloalkyl groups include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl.

除非另有規定，“雜環烷基”是指環中包含一定數目雜原子或雜原子團的單雜環烷基，所述雜原子或雜原子團一般選自N、O、S、NO、SO、S(O) 2以及NR。雜環烷基優選3-8元單雜環烷基，更優選3-6元單雜環烷基，這些單雜環烷基的實例包括，但不限於環氧乙烷基、四氫吡咯基、哌啶基、哌𠯤基、嗎福林基、四氫呋喃基、四氫噻吩基、四氫吡喃基、1,3-二氧戊環、1,4-二氧六環等。 Unless otherwise specified, "heterocycloalkyl" refers to a monoheterocycloalkyl group containing a certain number of heteroatoms or heteroatom groups in the ring, and the heteroatoms or heteroatom groups are generally selected from N, O, S, NO, SO, S (O) 2 and NR. The heterocycloalkyl group is preferably a 3-8 membered monoheterocycloalkyl group, more preferably a 3-6 membered monoheterocycloalkyl group. Examples of these monoheterocycloalkyl groups include, but are not limited to, oxiranyl, tetrahydropyrrolyl , piperidinyl, piper-𠯤-yl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.

除非另有規定，“螺環基”是指單環之間共用一個碳原子(稱螺原子)的多環體系，每個單環中均可包含一定數目的雙鍵，螺環基優選5-13元螺環基、6-12元螺環基、或者7-11元螺環基。螺環基的實施例包括但不限於螺[2.2]戊基、螺[2.3]己基、螺[2.4]庚基、螺[2.5]辛基、螺[2.6]壬基、螺[3.3]庚基、螺[3.4]辛基、螺[3.5]壬基、螺[3.6]癸基、螺[4.4]壬基、螺[4.5]癸基、螺[4.6]十一烷基、螺[5.5]十一烷基、螺[5.6]十二烷基、螺[6.6]十三烷基、螺[6.7]十四烷基。Unless otherwise specified, "spirocyclic group" refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between single rings, and each single ring can contain a certain number of double bonds. The spirocyclic group is preferably 5- 13-membered spirocyclyl, 6-12-membered spirocyclyl, or 7-11-membered spirocyclyl. Examples of spirocyclyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl , spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro[5.5]decyl Monoalkyl, spiro[5.6]dodecyl, spiro[6.6]tridecyl, spiro[6.7]tetradecyl.

“螺雜環基”是指螺環骨架結構中的一個或多個碳原子被雜原子或雜原子團取代的螺環基，所述雜原子或雜原子團選自N、O、S、NO、SO、S(O) 2等。螺雜環基優選5-13元螺雜環基、6-12元螺雜環基、7-11元螺雜環基以及7-11元氮雜螺環基。螺雜環基的實施例包括但不限於2-氧雜-7-氮雜螺[5.3]壬烷-7-基、2-氧雜-7-氮雜螺[4.4]壬烷-7-基、2-氧雜-6-氮雜螺[3.3]庚烷-6-基、2-氧雜-8-氮雜螺[4.5]癸烷-8-基、1,4,9-三氮雜螺[5.5]十一烷-9-基、3-氧雜-9-氮雜螺[5.5]十一烷-9-基、2,6-二氮雜螺[3.3]庚烷-2-基、2,7-二氮雜螺[5.3]壬 烷 -7- 基、2,7-二氧雜螺[5.3]壬基、3,9-二氮雜螺[5.5]十一烷-3-基、1-氧雜-4,9-二氮雜螺[5.5]十一烷-9-基、1-氧雜-4,8-二氮雜螺[5.4]癸烷-8-基、3-氮雜螺[5.5]十一烷-3-基、7-氮雜螺[3.5]癸烷-7-基、1-氧雜-4,9-二氮雜螺[5.5]十一烷-4-基、6-氧雜-2,9-二氮雜螺[4.5]癸烷-9-基、9-氧雜-2,6-二氮雜螺[4.5]癸烷-6-基、3-氮雜螺[5.5]十一烷-3-基、4-氧雜-1,9-二氮雜螺[5.5]十一烷-9-基。 "Spiroheterocyclic group" refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic skeleton structure are replaced by a heteroatom or a heteroatom group, and the heteroatom or heteroatom group is selected from N, O, S, NO, SO , S(O) 2 and so on. The spiroheterocyclyl is preferably 5-13 membered spiroheterocyclyl, 6-12 membered spiroheterocyclyl, 7-11 membered spiroheterocyclyl and 7-11 membered azaspirocyclyl. Examples of spiroheterocyclyl include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl , 2-oxa-6-azaspiro[3.3]heptane-6-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 1,4,9-triazepine Spiro[5.5]undecane-9-yl, 3-oxa-9-azaspiro[5.5]undecane-9-yl, 2,6-diazaspiro[3.3]heptane-2-yl , 2,7-diazaspiro[5.3] nonan- 7- yl , 2,7-dioxaspiro[5.3]nonyl, 3,9-diazaspiro[5.5]undecane-3- Base, 1-oxa-4,9-diazaspiro[5.5]undecane-9-yl, 1-oxa-4,8-diazaspiro[5.4]decane-8-yl, 3 -Azaspiro[5.5]undecane-3-yl, 7-azaspiro[3.5]decane-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecane- 4-yl, 6-oxa-2,9-diazaspiro[4.5]decane-9-yl, 9-oxa-2,6-diazaspiro[4.5]decane-6-yl, 3-Azaspiro[5.5]undec-3-yl, 4-oxa-1,9-diazaspiro[5.5]undec-9-yl.

除非另有規定，“橋環基”是指共用兩個不直接連接的碳原子的多環體系，體系中可包含一定數目的雙鍵。橋環基優選4-13元橋環基、5-12元橋環基、6-12元橋環基、6-11元橋環基、7-11元橋環基。橋環基的實施例包括但不限於

Figure 02_image815
、
Figure 02_image817
、
Figure 02_image819
、
Figure 02_image821
、
Figure 02_image823
、
Figure 02_image825
、
Figure 02_image827
等。 Unless otherwise specified, "bridged ring group" refers to a polycyclic ring system sharing two carbon atoms not directly attached, which may contain a certain number of double bonds. The bridged ring group is preferably a 4-13-membered bridged ring group, a 5-12-membered bridged ring group, a 6-12-membered bridged ring group, a 6-11-membered bridged ring group, and a 7-11-membered bridged ring group. Examples of bridged ring groups include, but are not limited to
Figure 02_image815
,
Figure 02_image817
,
Figure 02_image819
,
Figure 02_image821
,
Figure 02_image823
,
Figure 02_image825
,
Figure 02_image827
Wait.

“橋雜環基”是指構成橋環骨架的一個或多個碳原子被雜原子或雜原子團取代的橋環基，所述雜原子或雜原子團選自N、O、S、NO、SO、S(O) 2等。橋雜環基優選4-13元橋雜環基、5-12元橋雜環基、6-12元橋雜環基、6-11元橋雜環基、7-11元橋雜環基。橋雜環基的實施例包括但不限於

Figure 02_image829
、
Figure 02_image831
、
Figure 02_image833
、
Figure 02_image835
、
Figure 02_image837
、
Figure 02_image839
、
Figure 02_image841
等。 "Bridged heterocyclic group" refers to a bridged ring group in which one or more carbon atoms constituting a bridged ring skeleton are replaced by a heteroatom or a heteroatom group, and the heteroatom or a heteroatom group is selected from N, O, S, NO, SO, S(O) 2 etc. The bridged heterocyclic group is preferably a 4-13-membered bridged heterocyclic group, a 5-12-membered bridged heterocyclic group, a 6-12-membered bridged heterocyclic group, a 6-11-membered bridged heterocyclic group, and a 7-11-membered bridged heterocyclic group. Examples of bridged heterocyclyl groups include, but are not limited to
Figure 02_image829
,
Figure 02_image831
,
Figure 02_image833
,
Figure 02_image835
,
Figure 02_image837
,
Figure 02_image839
,
Figure 02_image841
Wait.

除非另有規定，“并環”是指系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的多環基團，其中每個環中可包含一定數目的雙鍵。所述并環優選5-14元并環基，更優選7-12元并環基、更優選8-10元并環基，并環基的實例包括但不限於

Figure 02_image843
、
Figure 02_image845
、
Figure 02_image847
、
Figure 02_image849
、
Figure 02_image851
、
Figure 02_image853
、
Figure 02_image855
、
Figure 02_image857
、
Figure 02_image859
等。 Unless otherwise specified, "merged rings" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein each ring may contain a certain number of double bonds. The ring is preferably a 5-14 membered ring group, more preferably a 7-12 membered ring group, more preferably an 8-10 membered ring group, and examples of a ring group include but are not limited to
Figure 02_image843
,
Figure 02_image845
,
Figure 02_image847
,
Figure 02_image849
,
Figure 02_image851
,
Figure 02_image853
,
Figure 02_image855
,
Figure 02_image857
,
Figure 02_image859
Wait.

“并雜環”是指構成并環骨架的一個或多個碳原子被雜原子或雜原子團取代的并環基，所述雜原子或雜原子團選自N、O、S、NO、SO、S(O) 2等。優選5-14元并雜環基，更優選7-12元并雜環基，更優選8-10元并雜環基，更優選8-10元氮雜并環基，并雜環基的實例包括但不限於

Figure 02_image861
、
Figure 02_image863
、
Figure 02_image865
、
Figure 02_image867
、
Figure 02_image869
、
Figure 02_image871
、
Figure 02_image873
、
Figure 02_image875
等。 "Heterocycle" refers to a ring group in which one or more carbon atoms constituting the skeleton of the ring are replaced by heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are selected from N, O, S, NO, SO, S (O) 2 etc. Preferred 5-14 membered heterocyclic group, more preferably 7-12 membered heterocyclic group, more preferably 8-10 membered heterocyclic group, more preferably 8-10 membered azaheterocyclic group, and examples of heterocyclic group including but not limited to
Figure 02_image861
,
Figure 02_image863
,
Figure 02_image865
,
Figure 02_image867
,
Figure 02_image869
,
Figure 02_image871
,
Figure 02_image873
,
Figure 02_image875
Wait.

環烷基、雜環烷基、芳基、雜芳基均可以與苯環稠合，形成相應的多環結構。例如結構

Figure 02_image877
中，“R 7與R 8可以環化成C 4-6環烷基”即代表了該結構可以是
Figure 02_image879
、
Figure 02_image881
或
Figure 02_image883
；“R 7與R 8可以環化成4-6元雜環烷基”的實施例包括但不僅限於
Figure 02_image885
、
Figure 02_image887
、
Figure 02_image889
、
Figure 02_image891
； “R 7與R 8可以環化成5-7元雜芳基”的實施例包括但不僅限於
Figure 02_image893
、
Figure 02_image895
、
Figure 02_image897
、
Figure 02_image899
、
Figure 02_image901
、
Figure 02_image903
、
Figure 02_image905
。 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can all be fused with a benzene ring to form a corresponding polycyclic structure. example structure
Figure 02_image877
In, "R 7 and R 8 can be cyclized to C 4-6 cycloalkyl" means that the structure can be
Figure 02_image879
,
Figure 02_image881
or
Figure 02_image883
; "R 7 and R 8 can be cyclized into 4-6 membered heterocycloalkyl" embodiments include but are not limited to
Figure 02_image885
,
Figure 02_image887
,
Figure 02_image889
,
Figure 02_image891
; Examples of "R 7 and R 8 can be cyclized into 5-7 membered heteroaryl" include but are not limited to
Figure 02_image893
,
Figure 02_image895
,
Figure 02_image897
,
Figure 02_image899
,
Figure 02_image901
,
Figure 02_image903
,
Figure 02_image905
.

除非另有規定，術語“芳基”是指多不飽和的、芳族的烴基，其可為單環或稠合在一起的多個環。芳基的實例包括但不限於苯基。萘基。Unless otherwise specified, the term "aryl" refers to a polyunsaturated, aromatic hydrocarbon group which may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl. naphthyl.

除非另有規定，術語“雜芳基”意指包含至少一個雜原子或雜原子團（N、O、S、NO、SO、S(O) 2或NR）的穩定的單環或者多環的芳族基團。優選5-12元雜芳基，更優選5、6、7元單環或6、7、8、9或10元雙環雜芳基；優選包含碳原子和1、2、3或4個獨立地選自N、O和S的環雜原子。雜芳基的實例包括但不限於吡咯基、吡唑基、咪唑基、吡𠯤基、㗁唑基、苯并㗁唑基、異㗁唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、異喹啉基、喹㗁啉基、喹啉基。 Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic group containing at least one heteroatom or heteroatom group (N, O, S, NO, SO, S(O) 2 or NR). family group. Preferably 5-12 membered heteroaryl, more preferably 5, 6, 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic heteroaryl; preferably comprising carbon atoms and 1, 2, 3 or 4 independently Ring heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyroxazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, Pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinazolyl, quinolinyl.

除非另有規定，術語“烷基”表示直鏈或支鏈的飽和烴基。優選C 1-6的烷基，更優選C 1-3的烷基，烷基的實例包括但不限於甲基，乙基，正丙基、異丙基、丁基、異丁基、戊基、異戊基、新戊基、正己基等。 Unless otherwise specified, the term "alkyl" means a straight or branched chain saturated hydrocarbon group. Preferred C 1-6 alkyl, more preferably C 1-3 alkyl, examples of alkyl include but not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl , Isopentyl, neopentyl, n-hexyl, etc.

除非另有規定，術語“鹵素”表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

除非另有規定，術語“鹵代烷基”是指一個或多個氫原子被鹵素原子取代的烷基。優選C 1-6鹵代烷基，鹵代烷基的實例包括但不僅限於一氟甲基、二氟甲基、三氟甲基、三氯甲基、三溴甲基、2, 2, 2-三氟乙基，2, 2, 2三氯乙基等。 Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C 1-6 haloalkyl is preferred. Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl base, 2, 2, 2 trichloroethyl etc.

除非另有規定，術語“烷氧基”是指通過氧橋連接的烷基，也即是烷基將羥基中的氫原子取代所得到的基團。優選C 1-6烷氧基，更優選C 1-3烷氧基。烷氧基的實例包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、新戊氧基、正己基氧基等。 Unless otherwise specified, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, that is, a group obtained by replacing a hydrogen atom in a hydroxyl group with an alkyl group. It is preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neo Pentyloxy, n-hexyloxy, etc.

除非另有規定，術語“環烷基氧基”是指通過氧橋連接的環烷基，也即是環烷基取代羥基中的氫原子所得到的基團。環烷基氧基優選3-7元、4-7元、或5-7元環烷氧基。環烷基氧基的實例包括但不限於環丙基氧基、環丁基氧基、環戊烷基氧基、環己基氧基等。Unless otherwise specified, the term "cycloalkyloxy" refers to a cycloalkyl group attached through an oxygen bridge, that is, a group obtained by replacing a hydrogen atom in a hydroxyl group with a cycloalkyl group. Cycloalkyloxy is preferably 3-7-membered, 4-7-membered, or 5-7-membered cycloalkoxy. Examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

除非另有規定，術語“鹵代烷氧基”是指一個或多個氫原子被鹵素原子取代的烷氧基。鹵代烷氧基的實例包括但不限於三氟甲氧基、三氯甲氧基、2, 2, 2-三氟乙氧基、2, 2, 2-三氯乙氧基等。Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, and the like.

除非另有規定，術語“環烯基”是指環中包含一個或多個不飽和碳-碳雙鍵的穩定的單環烴基或多環烴基。這些環烯基的實例包括但不限於環丙烯、環丁烯、環戊烯基、環己烯基、1, 3-環己二烯基、1, 4-環己二烯基等。Unless otherwise specified, the term "cycloalkenyl" refers to a stable monocyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds in the ring. Examples of such cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and the like.

除非另有規定，術語“雜環烯基”是指環中包含1-3個雜原子或雜原子團的環烯基。Unless otherwise specified, the term "heterocycloalkenyl" refers to a cycloalkenyl group containing 1-3 heteroatoms or heteroatom groups in the ring.

特別說明，本文中所有的取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。It is specifically stated that all combinations of substituents and/or variations thereof are permissible herein only if such combinations result in stable compounds.

在本發明實施例中，標題化合物的命名是借助Chemdraw通過化合物結構轉化過來的。若化合物名稱與化合物結構存在不一致的情況，可通過綜合相關訊息和反應路線輔助確定；無法通過其他來確認的，以給出的化合物結構式為準。In the examples of the present invention, the name of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the name of the compound and the structure of the compound, it can be determined by comprehensively related information and reaction routes; if it cannot be confirmed by other methods, the structural formula of the given compound shall prevail.

本發明中部分化合物的製備方法引用了前述類似化合物的製備方法。本發明所屬技術領域具有通常知識者應當知曉，在使用或參照使用其引用的製備方法時，反應物的投料比、反應溶劑、反應溫度等可根據反應物的不同，進行適當的調整。The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those with ordinary knowledge in the technical field of the present invention should know that when using or referring to the referenced preparation method, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be adjusted appropriately according to the different reactants.

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

本發明實施例中使用的縮寫及其對應的化學名稱如下： 縮寫 化學名稱 HATU 2-(7-氮雜苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯 DMAP 4-二甲胺基吡啶 DIEA N,N-二異丙基乙胺 DMSO 二甲基亞碸 DMF N,N-二甲基甲醯胺 NMP N-甲基吡咯烷酮 The abbreviations used in the embodiments of the present invention and their corresponding chemical names are as follows: abbreviation Chemical Name HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DMAP 4-Dimethylaminopyridine DIEA N,N-Diisopropylethylamine DMSO DMSO DMF N,N-Dimethylformamide NMP N-Methylpyrrolidone

下面通過實施例對本發明進行詳細描述，但並不意味著對本發明任何不利限制。The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention.

本發明的化合物結構是通過核磁共振（NMR）或/和液質聯用色譜（LC-MS）來確定的。NMR化學位移（δ）以百萬分之一（ppm）的單位給出。NMR的測定是用Bruker Avance III 400M核磁儀器，測定溶劑為氘代二甲基亞碸（DMSO- d 6），氘代甲醇（CD 3OD）和氘代氯仿（CDCl 3），內標為四甲基矽烷（TMS）。 The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is carried out with Bruker Avance III 400M nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfide (DMSO- d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is four Methylsilane (TMS).

液質聯用色譜LC-MS的測定用Shimadzu LCMS-2020質譜儀（離子源為電噴霧離子化）。HPLC的測定使用Shimadzu LCMS-20高效液相色譜。Shimadzu LCMS-2020 mass spectrometer (the ion source is electrospray ionization) was used for the determination of liquid chromatography-mass chromatography LC-MS. For HPLC measurement, Shimadzu LCMS-20 high performance liquid chromatography was used.

製備高效液相色譜使用Waters 2767-2489 (Xbridge，C18，10 µm，OBD 250cm ×19cm）或Waters 2767-2489 (Sunfire Prep，C18，10 µm，OBD 250cm ×19cm）。Preparative HPLC uses Waters 2767-2489 (Xbridge, C18, 10 µm, OBD 250cm × 19cm) or Waters 2767-2489 (Sunfire Prep, C18, 10 µm, OBD 250cm × 19cm).

薄層層析矽膠板使用煙臺江友矽膠開發有限公司GF254矽膠板或乳山市上邦新材料有限公司GF254矽膠板，TLC採用的規格是0.15 mm~0.20 mm，製備型20 x 20 cm，柱層析一般使用於成化工200~300目矽膠為載體。Thin-layer chromatography silica gel plates use GF254 silica gel plates from Yantai Jiangyou Silicone Rubber Development Co., Ltd. or Rushan Shangbang New Materials Co., Ltd. GF254 silica gel plates. The specifications used by TLC are 0.15 mm to 0.20 mm. Analysis is generally used in 200~300 mesh silica gel as a carrier in Chenghua Chemical Industry.

本發明實施例中的起始原料是已知的並且可以在市場上買到，或者可以採用或按照本領域已知的方法來合成。The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.

在無特殊說明的情況下，本發明的所有反應均在連續的磁力攪拌下，在乾燥氮氣或氬氣氣氛下進行，溶劑為乾燥溶劑，反應溫度單位為攝氏度。Unless otherwise specified, all reactions in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of reaction temperature is Celsius.

實施例1: (2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺

Figure 02_image416
反應流程:
Figure 02_image908
反應步驟： 步驟1：室溫下將喹㗁啉-6-胺（5.0 g, 34.5 mmol）溶於乙酸（150 mL）中，緩慢滴加氯化碘（6.1 g, 37.6 mmol）的乙酸（55 mL）溶液，氬氣氛圍下20℃攪拌2小時至反應完全。反應液直接減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 20/1 ~ 3/1）得到5-碘喹㗁啉-6-胺（6.0 g，收率64%）。 MS (ESI) M/Z: 272.1 [M+H] +. 步驟2：室溫下將5-碘喹㗁啉-6-胺（6.0 g, 22.1 mmol）、二甲基膦氧（2.6 g, 33.2 mmol）和磷酸鉀（7.0 g, 33.2 mmol）溶於N’N-二甲基甲醯胺（100 mL）和水（20 mL）中，加入4,5-雙二苯基膦-9,9-二甲基氧雜蒽（1.2 g, 2.2 mmol）和醋酸鈀（494 mg, 2.2 mmol）。反應液在氬氣氛下加熱至120℃攪拌24小時至反應完全。冷卻至室溫，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 10/1 ~ 1/1）得到(6-胺基喹㗁啉-5-基)二甲基氧化膦（4.0 g，收率82%）。 MS (ESI) M/Z: 221.9 [M+H] +. 步驟3：室溫下將(6-胺基喹㗁啉-5-基)二甲基氧化膦（1.0 g, 4.5 mmol）溶於乙醇（20 mL）中，加入5-溴-2,4-二氯吡啶（2.0 g, 9.0 mmol）和N,N-二異丙基乙胺（3.5 g, 27.1 mmol）。反應液在氬氣保護下加熱至120℃攪拌72小時至反應完全。將反應液冷卻至室溫並減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 10/1 ~ 1/1）得到(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（0.5 g，收率27%）。 MS (ESI) M/Z: 411.9 [M+H] +. 步驟4：將1-溴-2-氟-4-甲氧基-5-硝基苯（5.0 g, 20.1 mmol）和哌𠯤-1-羧酸第三丁酯 （4.1 g, 22.0 mmol）溶於N’N-二甲基甲醯胺（60 mL）中，加入碳酸鉀（8.3 g, 60.0 mmol），升溫至60℃攪拌過夜。反應液用水（300 mL）稀釋後用乙酸乙酯（200 mL×3次）萃取。合併有機相，先用飽和食鹽水（300 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 8/1）得到4-(2-溴-5-甲氧基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（6.9 g，收率83%）。 MS (ESI) M/Z: 416.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 8.22 (s, 1H), 6.58 (s, 1H), 3.96 (s, 3H), 3.64 (t, J= 4.8 Hz, 4H), 3.12 (t, J= 4.8 Hz, 4H), 1.49 (s, 9H). 步驟5：室溫下將4-(2-溴-5-甲氧基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（3.0 g, 7.2 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（2.25 g, 10.8 mmol）溶於二氧六環（60 mL）和水（6 mL）中, 加入碳酸鈉 (2.3 g, 21.6 mmol)和二茂鐵二氯化鈀(587.5 mg, 0.72 mmol)。反應液在氬氣氛圍下加熱至105℃攪拌過夜。將反應液冷卻至室溫，用水（300 mL）稀釋後用乙酸乙酯（200 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/1）得到4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-甲酸第三丁酯（2.4 g，收率80%）。 MS (ESI) M/Z: 418.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 7.93 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 6.60 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.50 (br, 4H), 2.95 (br, 4H), 1.47 (s, 9H). 步驟6：室溫下向4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-甲酸第三丁酯（1.9 g, 4.6 mmol）的甲醇（2 mL）溶液中加入鹽酸二氧六環溶液(12 mL, 4M)。室溫下攪拌18小時後減壓濃縮得到1-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤鹽酸鹽（1.4 g，粗品）。 MS (ESI) M/Z: 318.1 [M+H] +. 步驟7：室溫下向1-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤鹽酸鹽 （1.0 g, 粗品，約2.8 mmol）和6-溴代己酸甲酯（0.6 mL, 3.8 mmol）的N’N-二甲基甲醯胺（41 mL）溶液中加入碳酸銫（3.5 g, 10.8 mmol）。反應液在室溫下攪拌18小時。將反應液用水（200 mL）稀釋後用乙酸乙酯（150 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 19/1）得到6-(4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-基)己酸甲酯（927 mg，收率64%）。 MS (ESI) M/Z: 446.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 7.92 (s, 1H), 7.86 (s, 1H),7.69 (s, 1H), 6.61 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.67 (s, 3H), 3.03 (brs, 4H), 2.52 (brs, 4H), 2.38 (t, J= 7.6 Hz, 2H), 2.32 (t, J= 7.6 Hz, 2H), 1.67-1.60 (m, 4H), 1.54-1.49 (m, 2H). 步驟8：室溫下向6-(4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-基)己酸甲酯（927 mg, 2.1 mmol）的甲醇（20 mL）溶液中加入10%鈀碳催化劑Pd/C （223 mg）。氫氣置換三次後反應體系在15psi氫氣氛圍下攪拌過夜。反應液過濾，濾餅用甲醇（20 mL）洗滌，濾液減壓濃縮得到6-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸甲酯（592 mg，收率68%）。 MS (ESI) M/Z: 416.2 [M+H +]. 步驟9：室溫下向6-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸甲酯（204 mg, 0.49 mmol）和(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（203 mg, 0.49 mmol）的異丙醇（8 mL）溶液中加入三氟乙酸（0.36 mL, 4.9 mmol）。反應液升溫至100℃攪拌36小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 40/1）得到6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸甲酯（277 mg，收率71%）。 MS (ESI) M/Z: 791.2 [M+H] +. 步驟10：室溫下向6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸甲酯（200 mg, 0.25 mmol）的四氫呋喃（2 mL）和水（1 mL）混合溶液中加入氫氧化鋰（32 mg, 0.75 mmol）。反應液在室溫下攪拌2小時，用稀鹽酸將反應液pH值調節至5，得到的混合物直接用反相柱色譜層析純化得到6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸（111 mg，收率57%）。 MS (ESI) M/Z: 777.5 [M+H] +. 步驟11：室溫下將6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己酸（60 mg, 0.077 mmol）, HATU（44 mg, 0.10 mmol）和三乙胺（23 mg ,0.11 mmol）溶於N’N-二甲基甲醯胺（4 mL）中，室溫下攪拌0.1小時後加入 (2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺鹽酸鹽 (34 mg, 0.077 mmol)。反應液在室溫下繼續攪拌3小時，加入水（8 mL），有黃色固體析出，過濾，濾餅用高效液相製備色譜純化得到目標化合物(2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺（35 mg，收率38%）。 MS (ESI) M/Z: 1189.5 [M+H] +. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.97 (s, 1H), 8.84-8.80 (m, 3H), 8.57 (t, J= 6.0 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.79 (s, 1H), 7.57 (br, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.38 (d, J= 8.0 Hz, 2H), 6.84 (s, 1H), 5.14 (d, J= 3.6 Hz, 1H), 4.56 (d, J= 9.2 Hz, 1H), 4.45-4.40 (m, 2H), 4.35 (brs, 1H), 4.21 (d, J= 16.0 Hz, 5.6 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.71-3.63 (m, 2H), 2.87 (br, 4H), 2.51-2.49 (m, 4H), 2.44 (s, 3H), 2.35-2.27 (m, 3H), 2.18-2.13 (m, 1H), 2.10 (s, 3H), 2.03 (s, 3H), 2.10-2.02 (m, 1H), 1.99-1.90 (m, 1H), 1.60-1.40 (m, 4H), 1.35-1.25 (m, 2H), 0.94 (s, 9H). Example 1: (2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) caproylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure 02_image416
Reaction flow:
Figure 02_image908
Reaction steps: Step 1: Dissolve quinolin-6-amine (5.0 g, 34.5 mmol) in acetic acid (150 mL) at room temperature, slowly add iodine chloride (6.1 g, 37.6 mmol) in acetic acid (55 mL) solution, stirred at 20°C for 2 hours under argon atmosphere until the reaction was complete. The reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 ~ 3/1) to obtain 5-iodoquinolin-6-amine (6.0 g , yield 64%). MS (ESI) M/Z: 272.1 [M+H] + . Step 2: Mix 5-iodoquinolin-6-amine (6.0 g, 22.1 mmol), dimethylphosphine oxide (2.6 g, 33.2 mmol) and potassium phosphate (7.0 g, 33.2 mmol) were dissolved in N'N-dimethylformamide (100 mL) and water (20 mL), added 4,5-bisdiphenylphosphine-9, 9-Dimethylxanthene (1.2 g, 2.2 mmol) and palladium acetate (494 mg, 2.2 mmol). The reaction solution was heated to 120° C. under an argon atmosphere and stirred for 24 hours until the reaction was complete. Cool to room temperature and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 ~ 1/1) to obtain (6-aminoquinoline-5-yl)dimethylphosphine oxide (4.0 g, yield 82%). MS (ESI) M/Z: 221.9 [M+H] + . Step 3: Dissolve (6-aminoquinolin-5-yl)dimethylphosphine oxide (1.0 g, 4.5 mmol) in In ethanol (20 mL), add 5-bromo-2,4-dichloropyridine (2.0 g, 9.0 mmol) and N,N-diisopropylethylamine (3.5 g, 27.1 mmol). The reaction solution was heated to 120° C. under argon protection and stirred for 72 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 ~ 1/1) to obtain (6-((5-bromo-2-chloropyrimidin-4-yl)amino )quinolin-5-yl)dimethylphosphine oxide (0.5 g, yield 27%). MS (ESI) M/Z: 411.9 [M+H] + . Step 4: Combine 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (5.0 g, 20.1 mmol) and piper- Dissolve tert-butyl 1-carboxylate (4.1 g, 22.0 mmol) in N'N-dimethylformamide (60 mL), add potassium carbonate (8.3 g, 60.0 mmol), heat up to 60°C and stir overnight . The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 8/1) to obtain 4-(2-bromo-5-methoxy-4-nitrophenyl)piperone-1 - Tertiary butyl carboxylate (6.9 g, 83% yield). MS (ESI) M/Z: 416.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 8.22 (s, 1H), 6.58 (s, 1H), 3.96 (s, 3H), 3.64 (t, J = 4.8 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). Step 5: 4-(2-bromo-5-methoxy- 4-Nitrophenyl)piperone-1-carboxylate tert-butyl ester (3.0 g, 7.2 mmol) and 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (2.25 g, 10.8 mmol) To dioxane (60 mL) and water (6 mL), add sodium carbonate (2.3 g, 21.6 mmol) and ferrocenepalladium dichloride (587.5 mg, 0.72 mmol). The reaction solution was heated to 105 °C under argon atmosphere and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (300 mL) and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4- yl)-4-nitrophenyl)pipera-1-carboxylic acid tert-butyl ester (2.4 g, yield 80%). MS (ESI) M/Z: 418.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 7.93 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 6.60 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.50 (br, 4H), 2.95 (br, 4H), 1.47 (s, 9H). Step 6: 4- (5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperone-1-carboxylic acid tert-butyl ester (1.9 g, 4.6 mmol) Add dioxane hydrochloride solution (12 mL, 4M) to the methanol (2 mL) solution. After stirring at room temperature for 18 hours, concentrate under reduced pressure to obtain 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazolium hydrochloride (1.4 g, crude). MS (ESI) M/Z: 318.1 [M+H] + . Step 7: 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- N'N-dimethylformamide ( 41 mL) solution was added cesium carbonate (3.5 g, 10.8 mmol). The reaction was stirred at room temperature for 18 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (150 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1) to obtain 6-(4-(5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)-4-nitrophenyl)piper-1-yl)hexanoic acid methyl ester (927 mg, yield 64%). MS (ESI) M/Z: 446.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 7.92 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 6.61 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.67 (s, 3H), 3.03 (brs, 4H), 2.52 (brs, 4H), 2.38 (t, J = 7.6 Hz, 2H), 2.32 (t, J = 7.6 Hz, 2H), 1.67-1.60 (m, 4H), 1.54-1.49 (m, 2H). Step 8: To 6-(4-(5-methoxy Dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperone-1-yl)hexanoic acid methyl ester (927 mg, 2.1 mmol) in methanol (20 mL ) solution was added 10% palladium carbon catalyst Pd/C (223 mg). After hydrogen replacement three times, the reaction system was stirred overnight under 15 psi hydrogen atmosphere. The reaction solution was filtered, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure to obtain 6-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piper-1-yl)hexanoic acid methyl ester (592 mg, yield 68%). MS (ESI) M/Z: 416.2 [M+H + ]. Step 9: 6-(4-(4-amino-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)piperone-1-yl)hexanoic acid methyl ester (204 mg, 0.49 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino) To a solution of quinolin-5-yl)dimethylphosphine oxide (203 mg, 0.49 mmol) in isopropanol (8 mL) was added trifluoroacetic acid (0.36 mL, 4.9 mmol). The reaction solution was warmed up to 100°C and stirred for 36 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to obtain 6-(4-(4-((5-bromo -4-((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piper-1-yl)hexanoic acid methyl ester (277 mg, yield 71%). MS (ESI) M/Z: 791.2 [M+H] + . Step 10: 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone Lithium hydroxide (32 mg, 0.75 mmol) was added to a mixed solution of methyl-1-hexanoate (200 mg, 0.25 mmol) in tetrahydrofuran (2 mL) and water (1 mL). The reaction solution was stirred at room temperature for 2 hours, the pH value of the reaction solution was adjusted to 5 with dilute hydrochloric acid, and the resulting mixture was directly purified by reverse phase column chromatography to obtain 6-(4-(4-((5-bromo-4 -((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H- pyrazol-4-yl)phenyl)piper-1-yl)hexanoic acid (111 mg, yield 57%). MS (ESI) M/Z: 777.5 [M+H] + . Step 11: 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)hexanoic acid (60 mg, 0.077 mmol), HATU (44 mg, 0.10 mmol) and triethylamine (23 mg, 0.11 mmol) were dissolved in N'N-dimethylformamide (4 mL) After stirring at room temperature for 0.1 hour, add (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4- Methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide hydrochloride (34 mg, 0.077 mmol). The reaction solution was stirred at room temperature for 3 hours, water (8 mL) was added, a yellow solid precipitated, filtered, and the filter cake was purified by preparative high performance liquid chromatography to obtain the target compound (2S,4R)-1-((S)- 2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)hexylamino)-3,3-dimethylbutyryl)- 4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (35 mg, yield 38%). MS (ESI) M/Z: 1189.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 8.97 (s, 1H), 8.84-8.80 (m, 3H ), 8.57 (t, J = 6.0 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.79 (s , 1H), 7.57 (br, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 5.14 (d, J = 3.6 Hz , 1H), 4.56 (d, J = 9.2 Hz, 1H), 4.45-4.40 (m, 2H), 4.35 (brs, 1H), 4.21 (d, J = 16.0 Hz, 5.6 Hz, 1H), 3.81 (s , 3H), 3.75 (s, 3H), 3.71-3.63 (m, 2H), 2.87 (br, 4H), 2.51-2.49 (m, 4H), 2.44 (s, 3H), 2.35-2.27 (m, 3H ), 2.18-2.13 (m, 1H), 2.10 (s, 3H), 2.03 (s, 3H), 2.10-2.02 (m, 1H), 1.99-1.90 (m, 1H), 1.60-1.40 (m, 4H ), 1.35-1.25 (m, 2H), 0.94 (s, 9H).

實施例2: (2S,4R)-1-((S)-2-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺

Figure 02_image418
反應流程:
Figure 02_image911
反應步驟： 步驟1：室溫下將1-（5-甲氧基-2-（1-甲基-1H-吡唑-4-基）-4-硝基苯基）哌𠯤（2.0 g，6.3 mmol）和DMAP（766 mg，6.3 mmol）加入到二氯甲烷（20 mL）中，攪拌5分鐘，再加入三氟乙酸酐（2.64 g，12.6 mmol），室溫攪拌反應2小時。將反應液減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 20/1 ~ 5/1）得到2,2,2-三氟-1-（4-（5-甲氧基-2-（1-甲基-1H-吡唑-4-基）-4-硝基苯基）哌𠯤-1-基）乙烷-1-酮（2.0克，收率77%）。 MS (ESI) M/Z: 414.1[M+H] +. 步驟2：室溫下將2,2,2-三氟-1-（4-（5-甲氧基-2-（1-甲基-1H-吡唑-4-基）-4-硝基苯基）哌𠯤-1-基）乙烷-1-酮（2.0 g，4.8 mmol）和10%鈀碳（500 mg）加入到乙醇（30 mL）中，在氫氣球氛圍下，升溫到55℃攪拌反應2小時。將反應液冷至室溫，過濾，濾液減壓濃縮得到1-（4-（4-胺基-5-甲氧基-2-（1-甲基-1H-吡唑-4-基）苯基）哌𠯤-1-基）-2,2,2-三氟乙烷-1-酮直接用於下一步反應（1.7克，收率92%）。 MS (ESI) M/Z: 384.1 [M+H] +. 步驟3：室溫下將1-（4-（4-胺基-5-甲氧基-2-（1-甲基-1H-吡唑-4-基）苯基）哌𠯤-1-基）-2,2,2-三氟乙烷-1-酮（1.0 g，2.6 mmol），（6-（（5-溴-2-氯嘧啶-4-基）胺基）喹㗁啉-5-基）二甲基氧膦（859 mg，2.1 mmol）和三氟乙酸（2.96 g，26.0 mmol）依次加入到異丙醇（30 mL）中，氬氣保護下升溫至95℃攪拌反應16小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/1）得到1-（4-（4-（（5-溴-4-（（5-（二甲基磷醯基）喹㗁啉-6-基）胺基）嘧啶-2-基）胺基）-5-甲氧基-2-（1-甲基-1H-吡唑-4-基）苯基）哌𠯤-1-基）-2,2,2-三氟乙基-1-酮（1.5克，收率76%）。 MS (ESI) M/Z: 759.1 [M+H] +. 步驟4：室溫下將1-（4-（4-（（5-溴-4-（（5-（二甲基磷醯基）喹㗁啉-6-基）胺基）嘧啶-2-基）胺基）-5-甲氧基-2-（1-甲基-1H-吡唑-4-基）苯基）哌𠯤-1-基）-2,2,2-三氟乙基-1-酮（2.5 g，3.3 mmol）和氫氧化鉀（1.85 g，33.0 mmol）加入到甲醇（100 mL）和水（10 mL）中，升溫至60℃攪拌反應5小時。將反應液冷卻至室溫，用二氯甲烷（100 mL）稀釋，分液。有機相先用飽和食鹽水（100 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到((6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（1.5克，收率69%）。 MS (ESI) M/Z: 663.0 [M+H] +. 1H NMR (400 MHz, CD 3OD): δ 8.84-8.65 (m, 3H), 8.25-8.11 (m, 1H), 7.93 (d, J= 14.4 Hz, 1H), 7.78 (d, J= 6.0 Hz, 1H), 7.41 (s, 2H), 6.81-6.56 (m, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 2.95-2.87 (m, 4H), 2.85-2.77 (m, 4H), 2.13 (d, J= 4.8 Hz, 3H), 2.08 (s, 3H). 步驟5：室溫下將5-氯戊酸（62 mg, 0.45 mmol）溶於N,N-二甲基甲醯胺（3 mL）中，依次加入HATU（172 mg, 0.45 mmol）和DIEA（135 mg, 1.05 mmol），攪拌30分鐘後，滴加(2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺（150 mg, 0.35 mmol）的N,N-二甲基甲醯胺（2 mL）溶液，繼續室溫攪拌3小時。LCMS監控顯示原料消失，往反應液中加入水（10 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，有機相先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到(2S,4R)-1-((S)-2-(5-氯戊醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（125 mg，收率65%）。 MS (ESI) M/Z: 549.5 [M+H] +. 步驟6：室溫下將(2S,4R)-1-((S)-2-(5-氯戊醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（125 mg, 0.23 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，依次加入碘化鈉（51 mg, 0.34 mmol），DIEA（88 mg, 0.76 mmol）和((6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（151 mg, 0.23 mmol），將反應體系加熱至90℃並攪拌4小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（10 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，有機相先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用反相柱層析純化（洗脫劑：乙腈/10%碳酸氫銨= 11/9）得到終產物(2S,4R)-1-((S)-2-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（15.4 mg，收率6%）。 MS (ESI) M/Z: 1175.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.98 (dd, J= 9.6, 4.4 Hz, 1H), 8.78-8.63 (m, 3H), 8.29 (s, 1H), 8.19 (s, 1H), 7.75-7.51 (m, 3H), 7.43-7.30 (m, 6H), 6.72 (s, 1H), 6.21 (brs, 1H), 4.75 (t, J= 8.0 Hz, 1H), 4.57-4.53 (m, 3H), 4.35 (dd, J= 14.8, 5.2 Hz, 1H), 4.10 (d, J= 11.2 Hz, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 3.60 (d, J= 8.0 Hz, 2H), 3.02 (brs, 4H), 2.67 (s, 3H), 2.54-2. 51 (m, 6H), 2.37-2.15 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.62-1.55 (m, 2H), 1.34-1.21 (m, 2H), 0.94 (s, 9H). Example 2: (2S,4R)-1-((S)-2-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) pentylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure 02_image418
Reaction flow:
Figure 02_image911
Reaction steps: Step 1: Add 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperone (2.0 g, 6.3 mmol) and DMAP (766 mg, 6.3 mmol) were added to dichloromethane (20 mL), stirred for 5 minutes, then trifluoroacetic anhydride (2.64 g, 12.6 mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 ~ 5/1) to obtain 2,2,2-trifluoro-1-(4 -(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperone-1-yl)ethan-1-one (2.0 g, Yield 77%). MS (ESI) M/Z: 414.1[M+H] + . Step 2: 2,2,2-trifluoro-1-(4-(5-methoxy-2-(1-methoxy Base-1H-pyrazol-4-yl)-4-nitrophenyl)piperone-1-yl)ethan-1-one (2.0 g, 4.8 mmol) and 10% palladium on carbon (500 mg) were added to In ethanol (30 mL), under a hydrogen balloon atmosphere, the temperature was raised to 55°C and the reaction was stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene base) piper-1-yl)-2,2,2-trifluoroethane-1-one was directly used in the next reaction (1.7 g, yield 92%). MS (ESI) M/Z: 384.1 [M+H] + . Step 3: Mix 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H- pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (1.0 g, 2.6 mmol), (6-((5-bromo-2 -Chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (859 mg, 2.1 mmol) and trifluoroacetic acid (2.96 g, 26.0 mmol) were sequentially added to isopropanol (30 mL), under the protection of argon, the temperature was raised to 95°C and the reaction was stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 1-(4-(4-((5-bromo -4-((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piperol-1-yl)-2,2,2-trifluoroethyl-1-one (1.5 g, yield 76%). MS (ESI) M/Z: 759.1 [M+H] + . Step 4: 1-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl )quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)-2,2,2-trifluoroethyl-1-one (2.5 g, 3.3 mmol) and potassium hydroxide (1.85 g, 33.0 mmol) were added to methanol (100 mL) and water (10 mL ), heated to 60°C and stirred for 5 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated. The organic phase was washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain ((6-((5-bromo-2-((2-methoxy-5-( 1-Methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethyl Phosphine oxide (1.5 g, yield 69%). MS (ESI) M/Z: 663.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD): δ 8.84-8.65 (m, 3H) , 8.25-8.11 (m, 1H), 7.93 (d, J = 14.4 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.41 (s, 2H), 6.81-6.56 (m, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 2.95-2.87 (m, 4H), 2.85-2.77 (m, 4H), 2.13 (d, J = 4.8 Hz, 3H), 2.08 (s, 3H) . Step 5: Dissolve 5-chlorovaleric acid (62 mg, 0.45 mmol) in N,N-dimethylformamide (3 mL) at room temperature, add HATU (172 mg, 0.45 mmol) and DIEA in sequence (135 mg, 1.05 mmol), after stirring for 30 minutes, dropwise added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl-N-( 4-(4-Methylthiazol-5-yl)benzyl)pyrrolidinyl-2-formamide (150 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL), continued Stir at room temperature for 3 hours. LCMS monitoring showed that the raw materials disappeared, and water (10 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated Wash with brine (20 mL × 3 times), then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain (2S,4R)-1-((S)-2-(5-Chloropentylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole -5-yl)benzyl)pyrrolidine-2-carboxamide (125 mg, yield 65%). MS (ESI) M/Z: 549.5 [M+H] + . Step 6: ( 2S,4R)-1-((S)-2-(5-Chloropentylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide (125 mg , 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium iodide (51 mg, 0.34 mmol), DIEA (88 mg, 0.76 mmol) and ((6-(( 5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidine- 4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (151 mg, 0.23 mmol), the reaction system was heated to 90°C and stirred for 4 hours. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (eluent: acetonitrile/10% ammonium bicarbonate=11/9) to obtain the final product (2S,4R)-1-((S)-2-(5-(4 -(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentylamino)-3,3-dimethylbutyryl)-4-hydroxy-N- (4-(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (15.4 mg, yield 6%). MS (ESI) M/Z: 1175.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.98 (dd, J = 9.6, 4.4 Hz, 1H), 8.78 -8.63 (m, 3H), 8.29 (s, 1H), 8.19 (s, 1H), 7.75-7.51 (m, 3H), 7.43-7.30 (m, 6H), 6.72 (s, 1H), 6.21 (brs , 1H), 4.75 (t, J = 8.0 Hz, 1H), 4.57-4.53 (m, 3H), 4.35 (dd, J = 14.8, 5.2 Hz, 1H), 4.10 (d, J = 11.2 Hz, 1H) , 3.89 (s, 3H), 3.70 (s, 3H), 3.60 (d, J = 8.0 Hz, 2H), 3.02 (brs, 4H), 2.67 (s, 3H), 2.54-2. 51 (m, 6H ), 2.37-2.15 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.62-1.55 (m, 2H), 1.34-1.21 (m, 2H), 0.94 (s, 9H).

實施例3: (2R,4S)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺

Figure 02_image913
反應流程:
Figure 02_image915
反應步驟： 以(2R,4S)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺和6-溴己酸為原料，參照實施例2的步驟製備得到終產物(2R,4S)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺（22 mg）。 MS (ESI) M/Z: 1189.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.56 (s, 1H), 9.01-8.97 (m, 1H), 8.72 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.64-7.57 (m, 2H), 7.42-7.37 (m, 3H), 7.32-7.29 (m, 3H), 6.73 (s, 1H), 6.04-6.01 (d, J= 7.2 Hz, 1H), 4.75-4.72 (m, 1H), 4.64-4.62 (m, 1H), 4.58-4.53 (m, 1H), 4.36-4.29 (m, 2H), 4.16-4.12 (m, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.66-3.62 (m, 1H), 2.92-2.90 (m, 4H), 2.52 (s, 3H), 2.52-2.47 (m, 4H), 2.33-2.28 (m, 2H), 2.24-2.11 (m, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07-1.94 (m, 2H), 1.47-1.42 (m, 4H), 1.32-1.21 (m, 4H), 1.08 (s, 9H). Example 3: (2R,4S)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )caproylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide
Figure 02_image913
Reaction flow:
Figure 02_image915
Reaction steps: With (2R,4S)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl-N-(4-(4-methylthiazole-5- Base) benzyl) pyrrolidinyl-2-formamide and 6-bromohexanoic acid are raw materials, and the final product (2R, 4S)-1-((S)-2-(6 -(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperyl-1-yl)hexylamino)-3,3-dimethylbutyryl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (22 mg). MS (ESI) M/Z: 1189.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.56 (s, 1H), 9.01-8.97 (m, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.64-7.57 ( m, 2H), 7.42-7.37 (m, 3H), 7.32-7.29 (m, 3H), 6.73 (s, 1H), 6.04-6.01 (d, J = 7.2 Hz, 1H), 4.75-4.72 (m, 1H), 4.64-4.62 (m, 1H), 4.58-4.53 (m, 1H), 4.36-4.29 (m, 2H), 4.16-4.12 (m, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.66-3.62 (m, 1H), 2.92-2.90 (m, 4H), 2.52 (s, 3H), 2.52-2.47 (m, 4H), 2.33-2.28 (m, 2H), 2.24-2.11 ( m, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07-1.94 (m, 2H), 1.47-1.42 (m, 4H), 1.32-1.21 (m, 4H), 1.08 (s, 9H).

實施例4: (2S,4R)-1-((S)-2-(7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺

Figure 02_image917
反應流程:
Figure 02_image919
反應步驟： 以(2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺和7-溴庚酸為原料，參照實施例2的步驟製備得到終產物(2S,4R)-1-((S)-2-(7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（37.9 mg）。 MS (ESI) M/Z: 1203.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99 (dd, J= 9.6, 4.4 Hz, 1H), 8.75-8.64 (m, 3H), 8.29 (s, 1H),8.22 (s, 1H), 7.65-7.61 (m, 3H), 7.38-7.33 (m, 6H), 6.73 (s, 1H), 6.12-5.98 (m, 1H), 4.74 (t, J= 8.0 Hz, 1H), 4.63-4.47 (m, 3H), 4.33 (dd, J= 14.8, 5.2 Hz, 1H), 4.12 (d, J= 11.2 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.60 (dd, J= 11.2, 3.6 Hz, 1H), 2.94 (br s, 4H), 2.65-2.25 (m, 9H), 2.21-2.20 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.76-1.40 (m, 6H), 1.32 (brs, 4H), 0.93 (s, 9H). Example 4: (2S,4R)-1-((S)-2-(7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) heptylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure 02_image917
Reaction flow:
Figure 02_image919
Reaction steps: With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- Base) benzyl) pyrrolidinyl-2-formamide and 7-bromoheptanoic acid are raw materials, and the final product (2S, 4R)-1-((S)-2-(7 -(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)heptanylamino)-3,3-dimethylbutyryl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (37.9 mg). MS (ESI) M/Z: 1203.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99 (dd, J = 9.6, 4.4 Hz, 1H), 8.75 -8.64 (m, 3H), 8.29 (s, 1H), 8.22 (s, 1H), 7.65-7.61 (m, 3H), 7.38-7.33 (m, 6H), 6.73 (s, 1H), 6.12-5.98 (m, 1H), 4.74 (t, J = 8.0 Hz, 1H), 4.63-4.47 (m, 3H), 4.33 (dd, J = 14.8, 5.2 Hz, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.60 (dd, J = 11.2, 3.6 Hz, 1H), 2.94 (br s, 4H), 2.65-2.25 (m, 9H), 2.21- 2.20 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.76-1.40 (m, 6H), 1.32 (brs, 4H), 0.93 (s, 9H).

實施例5: (2S,4R)-1-((S)-2-(4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丁醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺

Figure 02_image921
反應流程:
Figure 02_image923
反應步驟： 以(2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷基-2-甲醯胺和4-氯丁酸為原料，參照實施例2的步驟製備得到終產物(2S,4R)-1-((S)-2-(4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丁醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（22.4 mg）。 MS (ESI) M/Z: 1161.2 [M+H +]. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.98 (dd, J= 9.6, 4.0 Hz, 1H), 8.71 (dd, J= 10.0, 2.0 Hz, 2H), 8.66 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.75-7.59 (m, 2H), 7.55-7.44 (m, 2H), 7.38-7.29 (m, 5H), 6.95-6.71 (m, 2H), 4.79 (t, J= 8.0 Hz, 1H), 4.63-4.45 (m, 3H), 4.37 (dd, J= 14.8, 5.2 Hz, 1H), 4.17 (d, J= 11.6 Hz, 1H), 3.90 (s, 3H), 3.75 (d, J= 4.8 Hz, 1H), 3.68 (s, 3H), 3.59 (dd, J= 11.2, 3.2 Hz, 1H), 3.26-2.75 (m, 10H), 2.67-2.47 (m, 5H), 2.36 (d, J= 13.2 Hz, 1H), 2.26-2.17 (m, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 1.99 (brs, 2H), 0.97 (s, 9H). Example 5: (2S,4R)-1-((S)-2-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure 02_image921
Reaction flow:
Figure 02_image923
Reaction steps: With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- Base) benzyl) pyrrolidinyl-2-formamide and 4-chlorobutyric acid are raw materials, and the steps of Example 2 are used to prepare the final product (2S, 4R)-1-((S)-2-(4 -(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (22.4 mg). MS (ESI) M/Z: 1161.2 [M+H + ]. 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.98 (dd, J = 9.6, 4.0 Hz, 1H), 8.71 (dd, J = 10.0, 2.0 Hz, 2H), 8.66 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.75-7.59 (m, 2H), 7.55-7.44 (m, 2H ), 7.38-7.29 (m, 5H), 6.95-6.71 (m, 2H), 4.79 (t, J = 8.0 Hz, 1H), 4.63-4.45 (m, 3H), 4.37 (dd, J = 14.8, 5.2 Hz, 1H), 4.17 (d, J = 11.6 Hz, 1H), 3.90 (s, 3H), 3.75 (d, J = 4.8 Hz, 1H), 3.68 (s, 3H), 3.59 (dd, J = 11.2 , 3.2 Hz, 1H), 3.26-2.75 (m, 10H), 2.67-2.47 (m, 5H), 2.36 (d, J = 13.2 Hz, 1H), 2.26-2.17 (m, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 1.99 (brs, 2H), 0.97 (s, 9H).

實施例6: 4-((2-(2-(2-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image925
反應流程:
Figure 02_image927
反應步驟： 步驟1：室溫下將((6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（50 mg, 0.076 mmol）和 (2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基)胺基甲酸第三丁酯（50 mg, 0.14 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，加入DIEA（39 mg, 0.30 mmol）和催化量的碘化鈉，將反應體系加熱至85℃攪拌5小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（10 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，有機相先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-(2-(2-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙氧基)乙氧基)乙氧基)乙基)胺基甲酸第三丁酯（70 mg，粗品）。 MS (ESI) M/Z: 938.3 [M+H] +. 步驟2：室溫下向(2-(2-(2-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙氧基)乙氧基)乙氧基)乙基)胺基甲酸第三丁酯（90 mg, 約0.096 mmol）的二氯甲烷（2 mL）溶液中加入鹽酸二氧六環溶液(12 mL, 4M)。室溫下攪拌2小時後減壓濃縮得到(6-((2-((4-(4-(2-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)乙基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（60 mg，粗品）。 MS (ESI) M/Z: 838.3 [M+H] +. 步驟3：室溫下將(6-((2-((4-(4-(2-(2-(2-(2-胺基乙氧基)乙氧基)乙氧基)乙基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（60 mg, 約0.072 mmol）和 2-(2,6-二氧哌啶-3-基)-4-氟異吲哚-1,3-二酮（20 mg, 0.72 mmol）溶於DMSO（5 mL）中，加入DIEA（47 mg, 0.36 mmol）和催化量的碘化鈉，將反應體系加熱至110℃攪拌12小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（10 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物4-((2-(2-(2-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（1 mg）。 MS (ESI) M/Z: 1093.7 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.57 (s, 1H), 8.98-8.95 (m, 1H), 8.75 (d, J= 1.2 Hz, 1H), 8.70 (d, J= 1.6 Hz, 1H), 8.29 (s, 1H), 8.20 (s,1H), 7.66 (brs, 2H), 7.52-7.46 (m, 2H), 7.35-7.26 (m, 2H), 7.10 (d, J= 6.8 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.71 (s, 1H), 6.53 (t, J= 5.2 Hz, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.73-3.62 (m, 13H), 3.48-3.43 (m, 2H), 3.0-2.7 (m, 12H), 2.26-2.18 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 2.07-1.95 (m, 2H). Example 6: 4-((2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline-6 -yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl Oxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image925
Reaction flow:
Figure 02_image927
Reaction steps: Step 1: ((6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4- (Piperyl-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) and (2-(2- (2-(2-Bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), add DIEA (39 mg, 0.30 mmol) and a catalytic amount of sodium iodide, heat the reaction system to 85 ° C and stir for 5 hours. LCMS monitoring shows that the raw material disappears, the reaction solution is cooled to room temperature, and water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phase was combined, and the organic phase was washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, Finally concentrated under reduced pressure to obtain (2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) quinoline-6-yl) ) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethoxy )ethoxy)ethoxy)ethyl)tert-butylcarbamate (70 mg, crude). MS (ESI) M/Z: 938.3 [M+H] + . 2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethoxy)ethoxy)ethyl Add dioxane hydrochloride solution (12 mL, 4M) to a solution of tert-butyl oxy)ethyl)carbamate (90 mg, about 0.096 mmol) in dichloromethane (2 mL). Stir at room temperature for 2 Concentration under reduced pressure after 1 hour gave (6-((2-((4-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)piperidine 𠯤-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline ( (6-((((6-(( 2-((4-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)piper-1-yl)-2-methoxy Base-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinolin-5-yl)dimethyloxidation Phosphine hydrochloride (60 mg, about 0.072 mmol) and 2-( 2,6-Dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (20 mg, 0.72 mmol) was dissolved in DMSO (5 mL), and DIEA (47 mg, 0.36 mmol) and a catalytic amount of sodium iodide, the reaction system was heated to 110°C and stirred for 12 hours. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to give the final product 4-((2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piper-1-yl) ethoxy) ethoxy) ethoxy) ethyl) amino) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1 ,3-Diketone (1 mg). MS (ESI) M/Z: 1093.7 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.57 (s, 1H), 8.98-8.95 (m, 1H), 8.75 (d, J = 1.2 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.20 (s,1H), 7.66 (brs, 2H), 7.52-7.46 (m, 2H), 7.35- 7.26 (m, 2H), 7.10 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 6.53 (t, J = 5.2 Hz, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.73-3.62 (m, 13H), 3.48-3.43 (m, 2H), 3.0-2.7 (m, 12H), 2.26-2.18 (m, 2H ), 2.14 (s, 3H), 2.11 (s, 3H), 2.07-1.95 (m, 2H).

實施例7: (2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺

Figure 02_image929
反應流程:
Figure 02_image931
反應步驟： 步驟1：室溫下將1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（400 mg，1.04 mmol），(2-((5-溴-2-氯嘧啶-4-基)胺基)苯基)二甲基氧膦（331 mg，0.92 mmol）和三氟乙酸（296 mg，2.6 mmol）依次加入到異丙醇（20 mL）中，氬氣保護下升溫至95℃攪拌反應16小時。將反應液冷卻至室溫並減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/1）得到1-(4-(4-((5-溴-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑基-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟噻吩-1-酮（510 mg，收率78%）。 MS (ESI) M/Z: 707.4 [M+H] +. 步驟2：室溫下將1-(4-(4-((5-溴-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑基-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟噻吩-1-酮（510 mg，0.72 mmol）和氫氧化鉀（403 mg，7.2 mmol）加入到甲醇（15 mL）和水（6 mL）中，升溫至60℃攪拌反應4小時。將反應液冷卻至室溫，用二氯甲烷（100 mL）稀釋，分液。有機相用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦（370 mg，收率84%）。 MS (ESI) M/Z: 611.2 [M+H] +. 以(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦和(2S,4R)-1-((S)-2-(6-氯己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺為原料，參照實施例2製備得到終產物(2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲醯胺（45.5 mg）。 MS (ESI) M/Z: 1137.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.67 (s, 1H), 8.68 (s, 1H), 8.49-8.45 (m, 1H), 8.22 (d, J= 3.6 Hz, 2H), 7.79 (s, 1H), 7.52 (s, 1H), 7.39-7.29 (m, 7H), 7.03-6.95 (m, 2H), 6.71 (s, 1H), 6.10 (brs, 1H), 4.75 (t, J= 8.0 Hz, 1H), 4.61-4.51 (m, 3H), 4.36-4.31 (m, 1H), 4.10 (d, J= 11.2 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.60-3.57 (m, 1H), 2.98 (br s, 4H), 2.60-2.52 (m, 9H), 2.26-2.13 (m, 4H), 1.86 (s, 3H), 1.83 (s, 3H), 1.75-1.50 (m, 4H), 1.37-1.32 (m, 2H), 0.93 (s, 9H). Example 7: (2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)phenyl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)hexanamide Base)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
Figure 02_image929
Reaction flow:
Figure 02_image931
Reaction steps: Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone- 1-yl)-2,2,2-trifluoroethane-1-one (400 mg, 1.04 mmol), (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl ) Dimethylphosphine oxide (331 mg, 0.92 mmol) and trifluoroacetic acid (296 mg, 2.6 mmol) were sequentially added to isopropanol (20 mL), heated to 95°C under argon protection and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 1-(4-(4-((5-bromo-4-((2-(dimethylphosphonium Acyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazolyl-4-yl)phenyl)piperazol-1 -yl)-2,2,2-trifluorothiophen-1-one (510 mg, yield 78%). MS (ESI) M/Z: 707.4 [M+H] + . Step 2: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphoryl ) phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazolyl-4-yl) phenyl) piper-1-yl )-2,2,2-Trifluorothiophen-1-one (510 mg, 0.72 mmol) and potassium hydroxide (403 mg, 7.2 mmol) were added to methanol (15 mL) and water (6 mL), warmed to The reaction was stirred at 60°C for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl )-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (370 mg, yield 84%). MS (ESI) M/Z: 611.2 [M+H] + . With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide and (2S,4R)-1-((S) -2-(6-Chlorohexylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidin-2 - Formamide is a raw material, and the final product (2S, 4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(5-bromo-4-((5) -(Dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )Piperyl-1-yl)hexylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-Formamide (45.5 mg). MS (ESI) M/Z: 1137.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.67 (s, 1H), 8.68 (s, 1H), 8.49-8.45 (m, 1H) , 8.22 (d, J = 3.6 Hz, 2H), 7.79 (s, 1H), 7.52 (s, 1H), 7.39-7.29 (m, 7H), 7.03-6.95 (m, 2H), 6.71 (s, 1H ), 6.10 (brs, 1H), 4.75 (t, J = 8.0 Hz, 1H), 4.61-4.51 (m, 3H), 4.36-4.31 (m, 1H), 4.10 (d, J = 11.2 Hz, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 3.60-3.57 (m, 1H), 2.98 (br s, 4H), 2.60-2.52 (m, 9H), 2.26-2.13 (m, 4H), 1.86 (s, 3H), 1.83 (s, 3H), 1.75-1.50 (m, 4H), 1.37-1.32 (m, 2H), 0.93 (s, 9H).

實施例8: 4-((2-(2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基-3-氧丙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image933
反應流程:
Figure 02_image935
反應步驟： 室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（50 mg，0.076 mmol）溶於DMF（5 mL）中，依次加入3-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧異吲哚-4-基)胺基)乙氧基)丙酸（43 mg，0.10 mmol）、HATU（57 mg，0.15 mmol）和DIEA（20 mg，0.15 mmol），反應體系加熱至25℃攪拌3小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物4-((2-(2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基-3-氧丙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（26.8 mg，收率33%）。 MS (ESI) M/Z: 1077.9 [M+H] +. 1H NMR (400 MHz, CD 3OD): δ 8.86-8.85 (m, 2H), 8.75-8.61 (m, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.65 (brs, 2H), 7.58-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.01-6.95 (m, 2H), 6.82 (s, 1H), 5.02-4.98 (m, 1H), 3.88 (s, 3H), 3.79-3.76 (m, 4H), 3.72-3.69 (m, 2H), 3.68-3.57 (m, 8H), 3.44-3.42 (m, 2H), 2.91-2.84 (m, 4H), 2.80-2.75 (m, 1H), 2.70-2.61 (m, 4H), 2.17-2.13 (m, 6H), 2.04-1.98 (m, 1H), 1.32-1.28 (m, 1H). Example 8: 4-((2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-yl-3-oxopropane Oxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image933
Reaction flow:
Figure 02_image935
Reaction steps: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazol-4-yl)- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL) and added successively 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)propanoic acid (43 mg, 0.10 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol), the reaction system was heated to 25 ° C and stirred for 3 hours. LCMS monitoring showed that the raw material disappeared, and water (20 mL) was quenched. The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally decompressed Concentration. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphonium Acyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Diketone (26.8 mg, yield 33%). MS (ESI) M/Z: 1077.9 [M+H] + . 1 H NMR (400 MHz, CD 3 OD): δ 8.86-8.85 (m, 2H) , 8.75-8.61 (m, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.65 (brs, 2H), 7.58-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.01 -6.95 (m, 2H), 6.82 (s, 1H), 5.02-4.98 (m, 1H), 3.88 (s, 3H), 3.79-3.76 (m, 4H), 3.72-3.69 (m, 2H), 3.68 -3.57 (m, 8H), 3.44-3.42 (m, 2H), 2.91-2.84 (m, 4H), 2.80-2.75 (m, 1H), 2.70-2.61 (m, 4H), 2.17-2.13 (m, 6H), 2.04-1.98 (m, 1H), 1.32-1.28 (m, 1H).

實施例9: 4-((15-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-15-氧-3,6,9,12-四氧戊癸基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image937
反應流程:
Figure 02_image939
反應步驟： 室溫下將1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)胺基)-3,6,9,12-四氧代十五烷基-15-油酸（120 mg，0.23 mmol），2-(7-氮雜苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（105 mg，0.28 mmol）和N,N-二異丙基乙胺（59 mg，0.46 mmol）溶於DMF（5 mL），攪拌一小時後加入((6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（152 mg，0.23 mmol），繼續攪拌3小時。LCMS監測反應基本結束，反應液過濾，濾液經高效製備液相色譜純化得到終產物4-((15-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基) 哌𠯤-1-基)-15-氧-3,6,9,12-四氧戊癸基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（42 mg，收率16%）。 MS (ESI) M/Z: 1166.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.98-8.94 (m, 1H), 8.88-8.83 (m, 1H), 8.74 (d, J= 1.6 Hz, 1H)，8.70 (d, J= 2.0 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.67 (s, 1H), 7.66-7.56 (m, 2H), 7.51-7.45 (m, 1H), 7.38 (s, 1H), 7.10 (d, J= 6.8 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.65 (s, 1H), 6.50-6.48 (m, 1H), 4.96-4.85 (m, 1H), 3.89 (s, 3H), 3.83-3.80 (t, J= 4.8 Hz, 2H), 3.73-3.64 (m, 18H), 3.55-3.53 (m, 2H), 3.53-3.48 (m, 2H), 2.89 (brs, 4H), 2.67-2.64 (m, 2H), 2.58 (t, J= 6.8 Hz, 2H), 2.24-2.20 (m, 1H), 2.14 (s, 3H), 2.11(s, 3H), 2.02-1.98 (m, 1H), 1.31-1.26 (m, 1H). Example 9: 4-((15-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-15-oxo-3,6,9 ,12-tetraoxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image937
Reaction flow:
Figure 02_image939
Reaction steps: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)-3 ,6,9,12-tetraoxopentadecyl-15-oleic acid (120 mg, 0.23 mmol), 2-(7-azabenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (105 mg, 0.28 mmol) and N,N-diisopropylethylamine (59 mg, 0.46 mmol) were dissolved in DMF (5 mL), stirred for one hour and added ((6 -((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl)phenyl)amino )pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (152 mg, 0.23 mmol), and continued to stir for 3 hours. The reaction was basically completed by LCMS monitoring, and the reaction liquid was filtered, and the filtrate was prepared by high-efficiency Purified by liquid chromatography to obtain the final product 4-((15-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-15-oxo-3, 6,9,12-tetraoxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (42 mg, yield 16%). MS (ESI) M/Z: 1166.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.98-8.94 (m, 1H), 8.88- 8.83 (m, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.67 (s, 1H ), 7.66-7.56 (m, 2H), 7.51-7.45 (m, 1H), 7.38 (s, 1H), 7.10 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H) , 6.65 (s, 1H), 6.50-6.48 (m, 1H), 4.96-4.85 (m, 1H), 3.89 (s, 3H), 3.83-3.80 (t, J = 4.8 Hz, 2H), 3.73-3.64 (m, 18H), 3.55-3.53 (m, 2H), 3.53-3.48 (m, 2H), 2.89 (brs, 4H), 2.67-2.64 (m, 2H), 2.58 ( t, J = 6.8 Hz, 2H), 2.24-2.20 (m, 1H), 2.14 (s, 3H), 2.11(s, 3H), 2.02-1.98 (m, 1H), 1.31-1.26 (m, 1H) .

實施例10: 4-((2-(2-(2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-3-氧丙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image434
反應流程:
Figure 02_image942
反應步驟： 室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（50 mg，0.076 mmol）溶於DMF（5 mL）中，依次加入3-(2-(2-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧異吲哚-4-基)胺基)乙氧基)乙氧基)丙酸（35 mg，0.073 mmol）、HATU（57 mg，0.15 mmol）和DIEA（20 mg，0.15 mmol），反應體系加熱至25℃攪拌3小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物4-((2-(2-(2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-3-氧丙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（23.6 mg，收率29%）。 MS (ESI) M/Z: 1121.9 [M+H] +. 1H NMR (400 MHz, CD 3OD): δ 8.86-8.84 (m, 2H), 8.77-8.57 (m, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.64 (s, 2H), 7.55-7.52 (m, 1H) , 7.47-7.43 (m, 1H), 6.99-6.95 (m, 2H), 6.82 (s, 1H), 5.03-4.98 (m, 1H), 3.88 (s, 3H), 3.78-3.69 (m, 7H), 3.68-3.58 (m, 11H), 3.40 (t, J= 5.2 Hz, 2H), 2.95-2.87 (m, 4H), 2.83-2.78 (m, 1H), 2.73-2.59 (m, 4H), 2.16 (s, 3H), 2.13 (s, 3H), 2.08-1.99 (m, 1H), 1.33-1.28 (m, 1H). Example 10: 4-((2-(2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)- 3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image434
Reaction flow:
Figure 02_image942
Reaction steps: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazol-4-yl)- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL) and added successively 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy )ethoxy)propionic acid (35 mg, 0.073 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol), and the reaction system was heated to 25 °C and stirred for 3 hours. LCMS monitoring showed that the raw material disappeared, and the Water (20 mL) was added to the reaction solution to quench. The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), and then washed with anhydrous sodium sulfate Drying, filtration, and finally concentration under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((2-(2-(2-(3-(4-(4-((5-bromo-4 -((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)piperone-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (23.6 mg, yield 29%). MS (ESI) M/Z: 1121.9 [M+H] + . 1 H NMR (400 MHz , CD 3 OD): δ 8.86-8.84 (m, 2H), 8.77-8.57 (m, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.64 (s, 2H), 7.55-7.52 ( m, 1H) , 7.47-7.43 (m, 1H), 6.99-6.95 (m, 2H), 6.82 (s, 1H), 5.03-4.98 (m, 1H), 3.88 (s, 3H), 3.78-3.69 ( m, 7H), 3.68-3.58 (m, 11H), 3.40 (t, J = 5.2 Hz, 2H), 2.95-2.87 (m, 4H), 2.83-2.78 (m, 1H), 2.73-2.59 (m, 4H), 2.16 (s, 3H), 2.13 (s, 3H), 2.08-1.99 (m, 1H), 1.33-1.28 (m, 1H).

實施例11: 4-((9-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-9-氧化壬基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image436
反應流程:
Figure 02_image945
反應步驟： 室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（50 mg，0.076 mmol）溶於DMF（5 mL）中，依次加入9-((2-(2,6-二氧哌啶-3-基)-1,3-二氧異吲哚-4-基)胺基)壬酸（32 mg，0.075 mmol）、HATU（57 mg，0.15 mmol）和DIEA（20 mg，0.15 mmol），反應體系加熱至25℃攪拌3小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物4-((9-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-9-氧化壬基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（21.5 mg，收率27%）。 MS (ESI) M/Z: 1074.0 [M+H] +. 1H NMR (400 MHz, CD 3OD): δ 8.88-8.85 (m, 2H), 8.74-8.59 (m, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.75-7.57 (m, 3H), 7.53-7.49 (m, 1H), 7.02-6.99 (m, 2H), 6.85 (s, 1H), 5.05-5.00 (m, 1H), 3.89 (s, 3H), 3.80-3.62 (m, 7H), 2.97-2.86 (m, 4H), 2.84-2.60 (m, 3H), 2.43 (t, J= 7.6 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.10-1.99 (m, 2H), 1.67-1.58 (m, 4H), 1.47-1.28 (m, 9H). Example 11: 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-9-oxynonyl)amino) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image436
Reaction flow:
Figure 02_image945
Reaction steps: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazol-4-yl)- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL) and added successively 9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)nonanoic acid (32 mg, 0.075 mmol), HATU ( 57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol), the reaction system was heated to 25°C and stirred for 3 hours. LCMS monitoring showed the disappearance of the starting material, which was quenched by adding water (20 mL) to the reaction solution. The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)- 9-Oxononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.5 mg, yield 27%). MS (ESI) M/Z: 1074.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD): δ 8.88-8.85 (m, 2H), 8.74-8.59 (m, 1H), 8.25 (s , 1H), 7.98 (s, 1H), 7.75-7.57 (m, 3H), 7.53-7.49 (m, 1H), 7.02-6.99 (m, 2H), 6.85 (s, 1H), 5.05-5.00 (m , 1H), 3.89 (s, 3H), 3.80-3.62 (m, 7H), 2.97-2.86 (m, 4H), 2.84-2.60 (m, 3H), 2.43 (t, J = 7.6 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.10-1.99 (m, 2H), 1.67-1.58 (m, 4H), 1.47-1.28 (m, 9H).

實施例12: 4-((2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image438
反應流程:
Figure 02_image948
反應步驟： 步驟1：室溫下將2-(2,6-二氧代哌啶-3-基)-4-((2-(3-羥基丙氧基)乙基)胺基)異吲哚啉-1,3-二酮（100 mg, 0.27 mmol）溶於二氯甲烷（5 mL）中，加入三乙胺（40 mg, 0.40 mmol）。降溫至0℃，緩慢滴加甲磺醯氯（46 mg, 0.40 mmol），0℃下攪拌1小時。TLC監測顯示反應結束，加入飽和碳酸氫鈉水溶液（20 mL）淬滅反應。混合液用二氯甲烷（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法純化得到3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)乙氧基)丙基甲磺酸酯。 MS (ESI) M/Z: 454.3 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（48 mg, 0.073 mmol）和3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)乙氧基)丙基甲磺酸酯（50 mg, 0.11 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，加入DIEA（28.7 mg, 0.22 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（10 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物4-((2-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙氧基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（26.7 mg，收率35%）。 MS (ESI) M/Z: 1020.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.34 (brs, 1H), 10.97 (brs, 1H), 10.39 (brs, 1H), 8.90 (s, 1H), 8.78 (d, J= 1.2 Hz, 1H), 8.71-8.68 (m, 1H), 8.08 (s, 1H), 7.92 (d, J= 9.2 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.58-7.54(m, 1H), 7.39 (s, 1H), 7.16 (d, J = 6.8 Hz, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.75 (s, 1H), 6.54 (t, J= 4.8 Hz, 1H), 5.01-4.96 (m, 1H), 3.90 (s, 3H), 3.74-3.69 (m, 9H), 3.62-3.58 (m, 2H), 3.51-3.49 (m, 2H), 3.40-3.38(m, 1H), 3.28-3.21 (m, 3H), 3.13-3.08 (m, 2H), 3.00-2.92 (m, 2H), 2.81-2.76 (m, 1H), 2.35-2.18 (m, 3H),2.14 (s, 3H), 2.11 (s, 3H). Example 12: 4-((2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)propoxy)ethyl) Amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image438
Reaction flow:
Figure 02_image948
Reaction steps: Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-hydroxypropoxy)ethyl)amino)isoindol at room temperature Indoline-1,3-dione (100 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (40 mg, 0.40 mmol) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (46 mg, 0.40 mmol) dropwise, and stir at 0°C for 1 hour. TLC monitoring showed that the reaction was complete, and saturated aqueous sodium bicarbonate (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- base) amino) ethoxy) propyl methanesulfonate. MS (ESI) M/Z: 454.3 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (48 mg, 0.073 mmol) and 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl Oxy)propyl mesylate (50 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (5 mL), DIEA (28.7 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added , the reaction system was heated to 80 °C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- yl)propoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26.7 mg, yield 35%) . MS (ESI) M/Z: 1020.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.34 (brs, 1H), 10.97 (brs, 1H), 10.39 (brs, 1H), 8.90 (s, 1H), 8.78 (d, J = 1.2 Hz, 1H), 8.71-8.68 (m, 1H), 8.08 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.58-7.54(m, 1H), 7.39 (s, 1H), 7.16 (d, J = 6.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.54 (t, J = 4.8 Hz, 1H), 5.01-4.96 (m, 1H), 3.90 (s, 3H), 3.74-3.69 (m, 9H), 3.62-3.58 (m, 2H), 3.51-3.49 (m, 2H), 3.40-3.38(m, 1H), 3.28-3.21 (m, 3H), 3.13-3.08 (m, 2H), 3.00-2.92 (m, 2H), 2.81- 2.76 (m, 1H), 2.35-2.18 (m, 3H), 2.14 (s, 3H), 2.11 (s, 3H).

實施例13: 5-(4-((1-(4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羰基)苯基)哌啶-4-基)甲基)哌𠯤-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image950
反應流程:
Figure 02_image952
反應步驟： 將4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)哌𠯤-1-基)甲基)哌啶-1-基)苯甲酸（73 mg，0.13 mmol）溶於DMF（5 mL）中，依次加入(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（87 mg，0.13 mmol）、HATU（99 mg，0.26 mmol）和DIEA（67 mg，0.52 mmol），反應體系室溫下攪拌1小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(4-((1-(4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羰基)苯基)哌啶-4-基)甲基)哌𠯤-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（7.2 mg，收率4.6%）。 MS (ESI) M/Z: 1204.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 11.07 (s, 1H), 8.84-8.80 (m, 3H), 8.40 (s, 1H), 8.28 (s, 1H), 8.12(s, 1H), 7.75 (s, 1H), 7.69-7.64 (m, 2H), 7.36-7.32 (m, 3H), 7.27-7.23 (m, 1H), 6.89 (s, 1H), 6.54 (d, J= 8.8 Hz, 2H), 5.09-5.05 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.70-3.68 (m, 4H), 3.51-3.44 (m, 6H), 3.39-3.36 (m, 2H), 2.90-2.83 (m, 6H), 2.67-2.51 (m, 6H), 2.44-2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.19-2.13 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.69-1.64 (m, 3H). Example 13: 5-(4-((1-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-carbonyl)phenyl)piper Pyridin-4-yl)methyl)piperone-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image950
Reaction flow:
Figure 02_image952
Reaction steps: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperone -1-yl)methyl)piperidin-1-yl)benzoic acid (73 mg, 0.13 mmol) was dissolved in DMF (5 mL), and (6-((5-bromo-2-((2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline -5-yl) dimethylphosphine oxide (87 mg, 0.13 mmol), HATU (99 mg, 0.26 mmol) and DIEA (67 mg, 0.52 mmol), and the reaction system was stirred at room temperature for 1 hour. LCMS monitoring showed the disappearance of the starting material, which was quenched by adding water (20 mL) to the reaction solution. The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((1-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-carbonyl)phenyl)piperidin-4-yl)methyl)piperone-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Diketone (7.2 mg, 4.6% yield). MS (ESI) M/Z: 1204.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 11.07 (s, 1H), 8.84-8.80 (m, 3H ), 8.40 (s, 1H), 8.28 (s, 1H), 8.12(s, 1H), 7.75 (s, 1H), 7.69-7.64 (m, 2H), 7.36-7.32 (m, 3H), 7.27- 7.23 (m, 1H), 6.89 (s, 1H), 6.54 (d, J = 8.8 Hz, 2H), 5.09-5.05 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.70 -3.68 (m, 4H), 3.51-3.44 (m, 6H), 3.39-3.36 (m, 2H), 2.90-2.83 (m, 6H), 2.67-2.51 (m, 6H), 2.44-2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.19-2.13 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.69-1.64 (m, 3H).

實施例14: 5-(3-(4-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image954
反應流程:
Figure 02_image956
反應步驟： 步驟1：將2-(哌啶-4-基)乙酸乙酯鹽酸鹽（500 mg, 2.4 mmol）、1-Boc-3-碘氮雜環丁烷（1.05 g, 3.6 mmol）和碘化鈉（36 mg, 0.24 mmol）溶於乙腈（100 mL）中，加入碳酸鉀（1.0 g, 7.2 mmol），反應體系升溫至80℃攪拌16小時。LCMS監測顯示反應結束，反應液冷卻至室溫，倒入到冰水（200 mL）中。混合液用乙酸乙酯（200 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 5:1）純化得到3-(4-(2-乙氧基-2-氧代乙基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（304 mg，收率39%）。 MS (ESI) M/Z: 327.2 [M+H] +. 步驟2：將3-(4-(2-乙氧基-2-氧代乙基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（240 mg, 0.74 mmol）溶於氯化氫二氧六環溶液（3M, 5 mL）中，室溫下攪拌3小時。LCMS監測顯示反應結束，反應液減壓濃縮得到190 mg 2-(1-(氮雜環丁烷-3-基)哌啶-4-基)乙酸乙酯鹽酸鹽。 MS (ESI) M/Z: 227.2 [M+H] +. 步驟3：將2-(1-(氮雜環丁烷-3-基)哌啶-4-基)乙酸乙酯鹽酸鹽（250 mg, 0.95 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟-異吲哚啉-1,3-二酮（263 mg, 0.95 mmol）溶於乙腈（100 mL）中，加入N,N-二異丙基乙胺（245 mg，1.90 mmol），反應體系升溫至85℃攪拌16小時。LCMS監測顯示反應結束，反應液冷卻至室溫，倒入到冰水（200 mL）中。混合液用乙酸乙酯（200 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 1:1）純化得到2-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁烷-3-基)哌啶-4-基)乙酸乙酯（143 mg，收率31%）。 MS (ESI) M/Z: 483.2 [M+H] +. 步驟4：將2-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁烷-3-基)哌啶-4-基)乙酸乙酯（140 mg, 0.29 mmol）溶於水（5 mL）中，降溫至0℃，緩慢滴加濃硫酸（1 mL）。反應體系升溫至100℃下攪拌16小時，LCMS監測顯示反應結束。加入飽和碳酸氫鈉水溶液調節pH值至中性，減壓濃縮，所得殘餘物用高效製備液相色譜純化得到2-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁烷-3-基)哌啶-4-基)乙酸（103 mg，收率78%）。 MS (ESI) M/Z: 455.2 [M+H] +. 步驟5：將2-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁烷-3-基)哌啶-4-基)乙酸（27.7 mg，0.06 mmol）溶於DMF（3 mL）中，依次加入(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（33 mg，0.05 mmol）、HATU（57 mg，0.15 mmol）和DIEA（20 mg，0.15 mmol），反應體系室溫下攪拌2小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(3-(4-(2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（3.6 mg，收率6.6%）。 MS (ESI) M/Z: 1099.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.56 (s, 1H), 8.99-8.96 (m, 1H), 8.74-8.70 (m, 2H), 8.30-8.24 (m, 2H), 8.03 (s,1H), 7.65-7.62 (m, 3H), 7.36 (s, 1H), 6.78 (s, 1H), 6.64 (s, 1H), 6.52 (d, J= 9.4 Hz, 1H), 5.36-5.30 (m, 1H), 4.95-4.90 (m, 1H), 4.11 (t, J= 7.6 Hz, 2H), 3.90 (brs, 4H), 3.73 (brs, 4H), 3.53 (s, 2H), 2.90-2.84 (m, 6H), 2.80-2.72 (m, 2H), 2.29 (d, J= 6.4 Hz, 1H), 2.24-2.20 (m, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 2.02-1.98 (m, 4H), 1.90-1.84 (m, 2H), 1.28-1.25 (m, 3H). Example 14: 5-(3-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image954
Reaction flow:
Figure 02_image956
Reaction steps: Step 1: Mix 2-(piperidin-4-yl) ethyl acetate hydrochloride (500 mg, 2.4 mmol), 1-Boc-3-iodoazetidine (1.05 g, 3.6 mmol) Sodium iodide (36 mg, 0.24 mmol) was dissolved in acetonitrile (100 mL), potassium carbonate (1.0 g, 7.2 mmol) was added, and the reaction system was heated to 80°C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with ethyl acetate (200 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl) Azetidine-1-carboxylate tert-butyl ester (304 mg, yield 39%). MS (ESI) M/Z: 327.2 [M+H] + . Step 2: Add 3-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl)azetidinium Tert-butyl alkane-1-carboxylate (240 mg, 0.74 mmol) was dissolved in hydrogen chloride dioxane solution (3M, 5 mL), and stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain 190 mg of ethyl 2-(1-(azetidin-3-yl)piperidin-4-yl)acetate hydrochloride. MS (ESI) M/Z: 227.2 [M+H] + . Step 3: Ethyl 2-(1-(azetidin-3-yl)piperidin-4-yl)acetate hydrochloride ( 250 mg, 0.95 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (263 mg, 0.95 mmol) in acetonitrile (100 mL), N,N-diisopropylethylamine (245 mg, 1.90 mmol) was added, and the reaction system was heated to 85°C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with ethyl acetate (200 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)ethyl acetate (143 mg, yield 31%). MS (ESI) M/Z: 483.2 [M+H] + . Step 4: 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindoline-5-yl)azetidin-3-yl)piperidin-4-yl)ethyl acetate (140 mg, 0.29 mmol) was dissolved in water (5 mL), cooled To 0 ℃, slowly dropwise added concentrated sulfuric acid (1 mL). The reaction system was heated to 100° C. and stirred for 16 hours, and LCMS monitoring showed that the reaction was complete. Add saturated aqueous sodium bicarbonate to adjust the pH value to neutral, concentrate under reduced pressure, and the resulting residue is purified by high performance preparative liquid chromatography to obtain 2-(1-(1-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)acetic acid (103 mg, yield 78%). MS (ESI) M/Z: 455.2 [M+H] + . Step 5: 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)acetic acid (27.7 mg, 0.06 mmol) was dissolved in DMF (3 mL), and added successively to ( 6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amine yl)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (33 mg, 0.05 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol), The reaction system was stirred at room temperature for 2 hours. LCMS monitoring showed the disappearance of the starting material, which was quenched by adding water (20 mL) to the reaction solution. The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)-2-oxoethyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Phenyl-1,3-dione (3.6 mg, yield 6.6%). MS (ESI) M/Z: 1099.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.56 (s, 1H), 8.99-8.96 (m, 1H), 8.74-8.70 (m, 2H), 8.30-8.24 (m, 2H), 8.03 (s,1H), 7.65-7.62 (m, 3H), 7.36 (s, 1H), 6.78 (s, 1H), 6.64 (s, 1H), 6.52 (d, J = 9.4 Hz, 1H), 5.36-5.30 (m, 1H), 4.95-4.90 (m, 1H), 4.11 (t, J = 7.6 Hz, 2H), 3.90 (brs, 4H), 3.73 ( brs, 4H), 3.53 (s, 2H), 2.90-2.84 (m, 6H), 2.80-2.72 (m, 2H), 2.29 (d, J = 6.4 Hz, 1H), 2.24-2.20 (m, 1H) , 2.14 (s, 3H), 2.11 (s, 3H), 2.02-1.98 (m, 4H), 1.90-1.84 (m, 2H), 1.28-1.25 (m, 3H).

實施例15: 4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)丁醯胺

Figure 02_image958
反應流程:
Figure 02_image960
反應步驟： 將4-氯-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)丁醯胺（100 mg, 0.26 mmol）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（176 mg, 0.26 mmol）和碘化鈉（5 mg, 0.03 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，加入DIEA（68 mg, 0.52 mmol），反應體系升溫至90℃攪拌16小時。LCMS監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物4-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)丁醯胺（10.5 mg，收率4%）。 MS (ESI) M/Z: 1004.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 11.16 (s, 1H), 9.85 (s, 1H), 9.69-9.58 (m, 1H), 8.85 (d, J= 2.0 Hz, 1H), 8.81-8.78 (m, 2H), 8.45-8.43 (m, 2H), 8.29 (s, 1H), 8.05 (s, 1H), 7.89-7.82 (m, 2H), 7.68-7.66 (m, 2H), 6.77 (s, 1H), 5.18-5.13 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.60-3.56 (m, 2H), 3.27-3.22 (m, 6H), 3.00-2.95 (m, 3H), 2.67-2.55 (m, 5H), 2.09-2.06 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H). Example 15: 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amine Base)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-N-(2-(2,6-dioxo piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide
Figure 02_image958
Reaction flow:
Figure 02_image960
Reaction steps: 4-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)butyramide (100 mg, 0.26 mmol), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazol-4-yl) -yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (176 mg, 0.26 mmol) and sodium iodide (5 mg, 0.03 mmol) DIEA (68 mg, 0.52 mmol) was added to N,N-dimethylformamide (5 mL), and the reaction system was heated to 90°C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -N-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide (10.5 mg, yield 4%). MS (ESI) M/Z: 1004.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 11.16 (s, 1H), 9.85 (s, 1H), 9.69-9.58 (m, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.81-8.78 (m, 2H), 8.45-8.43 (m, 2H), 8.29 (s, 1H), 8.05 (s, 1H), 7.89-7.82 (m, 2H), 7.68-7.66 (m, 2H), 6.77 (s, 1H), 5.18-5.13 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H) , 3.60-3.56 (m, 2H), 3.27-3.22 (m, 6H), 3.00-2.95 (m, 3H), 2.67-2.55 (m, 5H), 2.09-2.06 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H).

實施例16: 7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)庚醯胺

Figure 02_image962
反應流程:
Figure 02_image964
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和7-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)庚醯胺為原料，參照實施例15製備得到終產物7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)庚醯胺（34.1 mg）。 MS (ESI) M/Z: 1046.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 11.16 (s, 1H), 9.71 (s, 1H), 9.29 (brs, 1H), 8.86 (s, 1H), 8.82-8.77 (m, 2H), 8.59 (brs, 1H), 8.48 (d, J= 8.0 Hz, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.84-7.81 (m, 2H), 7.65-7.62 (m, 2H), 6.77 (s, 1H), 5.16-5.12 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.25-3.22 (m, 8H), 2.97-2.91 (m, 4H), 2.67-2.55 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.69 (brs, 4H), 1.40 (brs, 4H). Example 16: 7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amine Base)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-N-(2-(2,6-dioxo piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptanamide
Figure 02_image962
Reaction flow:
Figure 02_image964
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide and 7-bromo-N-(2-(2,6-dioxopiperidine- 3-base)-1,3-dioxoisoindoline-4-yl)heptanamide is raw material, and the final product 7-(4-(4-((5-bromo-4 -((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)piper-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -4-yl)heptanamide (34.1 mg). MS (ESI) M/Z: 1046.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 11.16 (s, 1H), 9.71 (s, 1H), 9.29 (brs, 1H), 8.86 (s, 1H), 8.82-8.77 (m, 2H), 8.59 (brs, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.84-7.81 (m, 2H), 7.65-7.62 (m, 2H), 6.77 (s, 1H), 5.16-5.12 (m, 1H), 3.84 (s, 3H), 3.78 (s , 3H), 3.25-3.22 (m, 8H), 2.97-2.91 (m, 4H), 2.67-2.55 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.69 (brs, 4H ), 1.40 (brs, 4H).

實施例17: 3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image966
反應流程:
Figure 02_image968
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和5-(2-(2,6-二氧代哌啶-3-基)-1-氧代異吲哚啉-4-基)戊-4-炔-1-基甲磺酸酯為原料（其製備，參見WO2017176958A1），參照實施例15製備得到終產物3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（15.1 mg）。 MS (ESI) M/Z: 971.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.17 (s, 1H), 10.61 (s, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 8.69-8.65 (m, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 7.59 (d, J= 7.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.30 (s, 1H), 6.75 (s, 1H), 5.34-5.29 (m, 1H), 4.67-4.49  (m, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.74-3.67 (m, 1H), 3.63-3.56 (m, 1H), 3.41-3.36 (m, 2H), 3.26-3.24 (m, 3H), 3.18-3.13 (m, 1H), 2.98-2.91 (m, 2H), 2.87-2.85 (m, 2H), 2.67-2.65 (m, 2H), 2.58-2.10 (m, 8H), 1.27-1.24 (m, 2H). Example 17: 3-(4-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pent-1-yne-1- Base)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image966
Reaction flow:
Figure 02_image968
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide and 5-(2-(2,6-dioxopiperidin-3-yl) -1-Oxoisoindoline-4-yl)pent-4-yn-1-yl methanesulfonate as raw material (for its preparation, see WO2017176958A1), the final product 3-(4- (5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)- 5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pent-1-yn-1-yl)-1-oxoisoind Indolin-2-yl)piperidine-2,6-dione (15.1 mg). MS (ESI) M/Z: 971.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.17 (s, 1H), 10.61 (s, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 8.69-8.65 (m, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.89-7.85 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.30 (s, 1H), 6.75 (s, 1H), 5.34-5.29 (m, 1H), 4.67-4.49 (m, 2H), 3.93 (s, 3H), 3.78 ( s, 3H), 3.74-3.67 (m, 1H), 3.63-3.56 (m, 1H), 3.41-3.36 (m, 2H), 3.26-3.24 (m, 3H), 3.18-3.13 (m, 1H), 2.98-2.91 (m, 2H), 2.87-2.85 (m, 2H), 2.67-2.65 (m, 2H), 2.58-2.10 (m, 8H), 1.27-1.24 (m, 2H).

實施例18: 3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image970
反應流程:
Figure 02_image971
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和5-(2-(2,6-二氧代哌啶-3-基)-1-氧代異吲哚啉-4-基)戊基甲磺酸酯為原料（其製備，參見WO2017176958A1），參照實施例15製備得到終產物3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（17 mg）。 MS (ESI) M/Z: 975.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.17 (s, 1H), 9.62 (s, 1H), 8.73 (d, J= 2.0 Hz, 1H), 8.69 (d, J= 1.6 Hz, 1H), 8.62-8.57 (m, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.75-7.70 (m, 1H), 7.64-7.61 (m, 1H), 7.45-7.40 ( m, 2H), 7.34-7.29 (m, 2H), 6.67 (s, 1H), 5.23-5.18 (m, 1H), 4.47-4.28 (m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.57-3.54 (m, 2H), 3.32-3.26 (m, 1H), 3.20-3.13 (m, 3H), 2.95-2.88 (m, 4H), 2.84-2.78 (m, 1H), 2.66-2.61 (m, 2H), 2.49-2.36 (m, 1H), 2.18-2.15 (m, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.24-1.19 (m, 2H), 0.80-0.74 (m, 4H). Example 18: 3-(4-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentyl)-1-oxo Isoindoline-2-yl)piperidine-2,6-dione
Figure 02_image970
Reaction flow:
Figure 02_image971
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide and 5-(2-(2,6-dioxopiperidin-3-yl) -1-Oxoisoindoline-4-yl)pentyl methanesulfonate as raw material (for its preparation, see WO2017176958A1), the final product 3-(4-(5-(4-( 4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2 -(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentyl)-1-oxoisoindoline-2-yl)piperidine-2,6- Diketones (17 mg). MS (ESI) M/Z: 975.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.17 (s, 1H), 9.62 (s, 1H), 8.73 (d, J = 2.0 Hz , 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.62-8.57 (m, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.75-7.70 (m, 1H), 7.64- 7.61 (m, 1H), 7.45-7.40 (m, 2H), 7.34-7.29 (m, 2H), 6.67 (s, 1H), 5.23-5.18 (m, 1H), 4.47-4.28 (m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.57-3.54 (m, 2H), 3.32-3.26 (m, 1H), 3.20-3.13 (m, 3H), 2.95-2.88 (m, 4H), 2.84-2.78 (m, 1H), 2.66-2.61 (m, 2H), 2.49-2.36 (m, 1H), 2.18-2.15 (m, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.24-1.19 (m, 2H), 0.80-0.74 (m, 4H).

實施例19: 3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image973
反應流程:
Figure 02_image975
反應步驟： 步驟1：室溫下將2-(2,6-二氧代哌啶-3-基)-4-((5-羥基戊基)胺基)異吲哚啉-1,3-二酮（65 mg, 0.18 mmol，製備，參見Journal of Medicinal Chemistry，2020, 192, 112186）溶於二氯甲烷（10 mL）中，加入三乙胺（27 mg, 0.27 mmol）。降溫至0℃，緩慢滴加甲磺醯氯（31 mg, 0.27 mmol），0℃下攪拌1小時。TLC監測顯示反應結束，加入飽和碳酸氫鈉水溶液（20 mL）淬滅反應。混合液用二氯甲烷（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法純化得到5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)戊基甲磺酸酯（65 mg，收率82%）。 MS (ESI) M/Z: 438.0 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（98 mg, 0.15 mmol）和5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)戊基甲磺酸酯（65 mg, 0.15 mmol）溶於乙腈（5 mL）中，加入DIEA（48 mg, 0.37 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌12小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物3-(4-(5-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（20.5 mg，收率35%）。 MS (ESI) M/Z: 1004.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.99 (dd, J= 4.4, 9.6 Hz, 1H), 8.73 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.43 (brs, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.65-7.61 (m, 3H), 7.53-7.47 (m, 1H), 7.34 (s, 1H), 7.10 (d, J= 7.2 Hz, 1H), 6.89 (d, J= 8.8 Hz, 1H), 6.74 (s, 1H), 6.24 (t, J= 5.6 Hz, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.32-3.26 (m, 2H), 2.96 (brs, 4H), 2.91-2.59 (m, 8H), 2.45 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.75-1.67 (m, 4H), 1.51-1.43 (m, 2H). Example 19: 3-(4-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentyl)-1-oxo Isoindoline-2-yl)piperidine-2,6-dione
Figure 02_image973
Reaction flow:
Figure 02_image975
Reaction steps: Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)amino)isoindoline-1,3- Diketone (65 mg, 0.18 mmol, prepared, see Journal of Medicinal Chemistry, 2020, 192, 112186) was dissolved in dichloromethane (10 mL) and triethylamine (27 mg, 0.27 mmol) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (31 mg, 0.27 mmol) dropwise, and stir at 0°C for 1 hour. TLC monitoring showed that the reaction was complete, and saturated aqueous sodium bicarbonate (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amine base) pentyl methanesulfonate (65 mg, yield 82%). MS (ESI) M/Z: 438.0 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (98 mg, 0.15 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate Ester (65 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL), DIEA (48 mg, 0.37 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80°C and stirred for 12 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 3-(4-(5-(4-(4-((5-bromo-4-((5- (Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- yl)phenyl)piper-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.5 mg, yield 35%). MS (ESI) M/Z: 1004.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.99 (dd, J = 4.4, 9.6 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (brs, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.65-7.61 (m, 3H), 7.53-7.47 (m, 1H), 7.34 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 6.24 (t, J = 5.6 Hz, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.32-3.26 (m, 2H), 2.96 (brs, 4H) , 2.91-2.59 (m, 8H), 2.45 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.75-1.67 (m, 4H), 1.51-1.43 (m, 2H).

實施例20: 4-((3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image977
反應流程:
Figure 02_image979
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和2-(2,6-二氧代哌啶-3-基)-4-((3-羥基丙基)胺基)異吲哚啉-1,3-二酮為原料，參照實施例19製備得到終產物4-((3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（6.7 mg）。 MS (ESI) M/Z: 976.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J= 1.6 Hz, 1H), 8.70 (d, J= 1.6 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.66 (brs, 2H), 7.52 (t, J= 6.4 Hz, 1H), 7.34 (s, 1H), 7.14-7.11 (m, 1H), 7.00-6.96 (m, 1H), 6.75 (s, 1H), 6.47 (brs, 1H), 4.94-4.89 (m, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 3.42 (brs, 2H), 3.39-2.58 (m, 12H), 2.14 (s, 3H), 2.11 (s, 3H), 2.00-1.78 (m, 2H), 1.31-1.25 (m, 2H). Example 20: 4-((3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)propyl)amino)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image977
Reaction flow:
Figure 02_image979
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide and 2-(2,6-dioxopiperidin-3-yl)-4- ((3-hydroxypropyl) amino) isoindoline-1,3-dione is a raw material, and the final product 4-((3-(4-(4-((5-bromo -4-((5-(Dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piper-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Diketone (6.7 mg). MS (ESI) M/Z: 976.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.66 (brs, 2H), 7.52 (t, J = 6.4 Hz, 1H) , 7.34 (s, 1H), 7.14-7.11 (m, 1H), 7.00-6.96 (m, 1H), 6.75 (s, 1H), 6.47 (brs, 1H), 4.94-4.89 (m, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 3.42 (brs, 2H), 3.39-2.58 (m, 12H), 2.14 (s, 3H), 2.11 (s, 3H), 2.00-1.78 (m, 2H ), 1.31-1.25 (m, 2H).

實施例21: 3-(4-(3-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙氧基)丙基)-3-甲基-2-氧代-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮

Figure 02_image981
反應流程:
Figure 02_image983
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和3-(4-(3-(3-羥基丙氧基)丙基)-3-甲基-2-氧代-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮（製備參見WO2020113233A1）為原料，參照實施例19製備得到終產物3-(4-(3-(3-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙氧基)丙基)-3-甲基-2-氧代-2,3-二氫-1H-苯并[d]咪唑-1-基)哌啶-2,6-二酮（12.3 mg）。 MS (ESI) M/Z: 1020.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J= 1.2 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.90 (brs, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.37 (brs, 2H), 7.02-6.89 (m, 2H), 6.74 (s, 1H), 6.67 (d, J= 8.0 Hz, 1H), 5.26-5.21 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.66-3.64 (m, 3H), 3.53-3.47 (m, 2H), 3.42-3.37 (m, 2H), 3.13-2.71 (m, 12H), 2.66-2.59 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.98-1.86 (m, 6H). Example 21: 3-(4-(3-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propoxy) propane Base)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
Figure 02_image981
Reaction flow:
Figure 02_image983
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide and 3-(4-(3-(3-hydroxypropoxy)propyl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (see WO2020113233A1 for preparation) as raw material, refer to the examples 19 prepared to obtain the final product 3-(4-(3-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl) Amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propoxy) Propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (12.3 mg). MS (ESI) M/Z: 1020.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J = 1.2 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.90 (brs, 1H), 7.69 (d, J = 8.8 Hz, 1H) , 7.37 (brs, 2H), 7.02-6.89 (m, 2H), 6.74 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.26-5.21 (m, 1H), 3.90 (s, 3H ), 3.70 (s, 3H), 3.66-3.64 (m, 3H), 3.53-3.47 (m, 2H), 3.42-3.37 (m, 2H), 3.13-2.71 (m, 12H), 2.66-2.59 (m , 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.98-1.86 (m, 6H).

實施例22: (2S,4R)-1-((S)-2-(7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺

Figure 02_image985
反應流程:
Figure 02_image987
反應步驟： 步驟1：將7-溴庚酸（210 mg，1.0 mmol）溶於DMF（3 mL）中，加入HATU（1.1 g，3.0 mmol）和DIEA（387 mg，3.0 mmol），室溫下攪拌30分鐘後，再滴加(2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺（444 mg，1.0 mmol）的DMF（2 mL）溶液，反應體系室溫下繼續攪拌1小時。LCMS監控顯示原料消失，向反應液中加入水（20 mL）淬滅。混合液用乙酸乙酯（20 mL×3次）萃取。合併有機相，先用飽和食鹽水（20 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2S,4R)-1-((S)-2-(7-溴庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺（200 mg，收率32%）。 MS (ESI) M/Z: 635.3 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（105 mg, 0.16 mmol）和(2S,4R)-1-((S)-2-(7-溴庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺（100 mg, 0.16 mmol）溶於DMF（5 mL）中，加入DIEA（62 mg, 0.48 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物(2S,4R)-1-((S)-2-(7-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺（22.5 mg，收率12%）。 MS (ESI) M/Z: 1217.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.74 (d, J= 1.6 Hz, 1H), 8.71 (d, J= 2.0 Hz, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.72-7.68 (m, 1H), 7.51 (d, J= 7.2 Hz, 1H), 7.39-7.36 (m, 6H), 6.71 (s, 1H), 6.28 (d, J= 8.0 Hz, 1H), 5.12-5.05 (m, 1H), 4.77 (t, J= 8.2 Hz, 1H), 4.62 (d, J= 9.2 Hz, 1H), 4.49 (s, 1H), 4.11 (d, J= 11.6 Hz, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 3.58-5.54 (m, 1H), 3.35-3.15 (m, 5H), 2.91-2.85 (m, 2H), 2.52 (s, 3H), 2.50-2.39 (m, 1H), 2.35-2.27 (m, 2H), 2.24-2.18 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.81-1.72 (m, 4H), 1.63-1.55 (m, 2H), 1.48 (d, J= 7.2 Hz, 3H), 1.39-1.30 (m, 4H), 1.05 (s, 9H). Example 22: (2S,4R)-1-((S)-2-(7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base)heptylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl ) pyrrolidine-2-carboxamide
Figure 02_image985
Reaction flow:
Figure 02_image987
Reaction steps: Step 1: Dissolve 7-bromoheptanoic acid (210 mg, 1.0 mmol) in DMF (3 mL), add HATU (1.1 g, 3.0 mmol) and DIEA (387 mg, 3.0 mmol), at room temperature After stirring for 30 minutes, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl-N-((S)-1-( 4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (444 mg, 1.0 mmol) in DMF (2 mL) solution, the reaction system continued to stir at room temperature for 1 Hour. LCMS monitoring showed the disappearance of the starting material, which was quenched by adding water (20 mL) to the reaction solution. The mixture was extracted with ethyl acetate (20 mL×3 times). The combined organic phases were first washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2S,4R)-1-((S)-2-(7- Bromoheptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) Pyrrolidine-2-carboxamide (200 mg, yield 32%). MS (ESI) M/Z: 635.3 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (105 mg, 0.16 mmol) and (2S,4R)-1-((S)-2-(7-bromoheptylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S )-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (100 mg, 0.16 mmol) was dissolved in DMF (5 mL), and DIEA was added (62 mg, 0.48 mmol) and a catalytic amount of sodium iodide, the reaction system was heated to 80°C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product (2S,4R)-1-((S)-2-(7-(4-(4-(( 5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-yl)heptylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (22.5 mg, yield 12%). MS (ESI) M/Z: 1217.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.72-7.68 ( m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.39-7.36 (m, 6H), 6.71 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 5.12-5.05 (m , 1H), 4.77 (t, J = 8.2 Hz, 1H), 4.62 (d, J = 9.2 Hz, 1H), 4.49 (s, 1H), 4.11 (d, J = 11.6 Hz, 1H), 3.91 (s , 3H), 3.67 (s, 3H), 3.58-5.54 (m, 1H), 3.35-3.15 (m, 5H), 2.91-2.85 (m, 2H), 2.52 (s, 3H), 2.50-2.39 (m , 1H), 2.35-2.27 (m, 2H), 2.24-2.18 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.81-1.72 (m, 4H), 1.63-1.55 (m , 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.39-1.30 (m, 4H), 1.05 (s, 9H).

實施例23: (2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺

Figure 02_image989
反應流程:
Figure 02_image991
反應步驟： 以(2S,4R)-1-((S)-2-胺基-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺、6-溴己酸和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例22的步驟製備得到終產物(2S,4R)-1-((S)-2-(6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己醯胺基)-3,3-二甲基丁醯基)-4-羥基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲醯胺（54.3 mg）。 MS (ESI) M/Z: 1203.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 1.6 Hz, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.68 (brs, 2H), 7.49-7.32 (m, 7H), 6.72 (s, 1H), 6.36-6.18 (m, 1H), 5.12-5.04 (m, 1H), 4.78-4.74 (m, 1H), 4.59 (d, J= 8.8 Hz, 1H), 4.49 (s, 1H), 4.12 (d, J= 11.2 Hz, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.59-3.54 (m, 2H), 3.24-2.90 (m, 5H), 2.90-2.59 (m, 4H), 2.53 (s, 3H), 2.30-2.23 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.85-1.66 (m, 6H), 1.48 (d, J= 6.8 Hz, 3H), 1.40-1.35 (m, 2H), 1.05 (s, 9H). Example 23: (2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )caproylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) Pyrrolidine-2-carboxamide
Figure 02_image989
Reaction flow:
Figure 02_image991
Reaction steps: With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl-N-((S)-1-(4-(4 -methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, 6-bromohexanoic acid and (6-((5-bromo-2-((2-methoxy-5 -(1-methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5-yl) Dimethylphosphine oxide was used as raw material, and the final product (2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4- ((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piperyl-1-yl)hexylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4- Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (54.3 mg). MS (ESI) M/Z: 1203.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.68 (brs, 2H), 7.49-7.32 ( m, 7H), 6.72 (s, 1H), 6.36-6.18 (m, 1H), 5.12-5.04 (m, 1H), 4.78-4.74 (m, 1H), 4.59 (d, J = 8.8 Hz, 1H) , 4.49 (s, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.59-3.54 (m, 2H), 3.24-2.90 (m, 5H ), 2.90-2.59 (m, 4H), 2.53 (s, 3H), 2.30-2.23 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.85-1.66 (m, 6H), 1.48 (d, J = 6.8 Hz, 3H), 1.40-1.35 (m, 2H), 1.05 (s, 9H).

實施例24: 4-((9-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)壬基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image462
反應流程:
Figure 02_image994
反應步驟： 步驟1：將9-胺基壬-1-醇（95 mg, 0.60 mmol）和2-(2,6-二氧代哌啶-3-基)-4-氟-異吲哚啉-1,3-二酮（110 mg, 0.40 mmol）溶於NMP（3 mL）中，加入N,N-二異丙基乙胺（0.1 mL），反應體系升溫至140℃攪拌20分鐘。TLC監測顯示反應結束，反應液冷卻至室溫，倒入到水（10 mL）中。混合液用乙酸乙酯（10 mL×4次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 0:1）純化得到2-(2,6-二氧代哌啶-3-基)-4-((9-羥基壬基)胺基)異吲哚啉-1,3-二酮（80 mg，收率48%）。 MS (ESI) M/Z: 416.2 [M+H] +. 步驟2：室溫下將2-(2,6-二氧代哌啶-3-基)-4-((9-羥基壬基)胺基)異吲哚啉-1,3-二酮（80 mg, 0.19 mmol）溶於二氯甲烷（5 mL）中，加入三乙胺（0.04 mL）。降溫至0℃，緩慢滴加甲磺醯氯（31 mg, 0.27 mmol），0℃下攪拌1小時。TLC監測顯示反應結束，將反應液倒入水（10 mL）中。混合液用乙酸乙酯（10 mL×2次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 5:1）純化得到9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)壬基甲磺酸酯（55 mg，收率58%）。 MS (ESI) M/Z: 494.2 [M+H] +. 步驟3：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（52 mg, 0.08 mmol）和9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)壬基甲磺酸酯（55 mg, 0.11 mmol）溶於乙腈（5 mL）中，加入DIEA（0.04 mL）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌16小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，倒入水（5 mL）中。混合液用二氯甲烷（10 mL×2次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用製備型薄層層析矽膠板（二氯甲烷：甲醇=20：1）純化得到終產物4-((9-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)壬基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（31 mg，收率37%）。 MS (ESI) M/Z: 1060.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J= 1.2 Hz, 1H), 8.70 (d, J= 1.2 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.76 -7.68 (m, 2H), 7.52-7.48 (m, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.09 (d, J= 7.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.73 (s, 1H), 6.25 (t, J= 6.0 Hz, 1H), 4.93-4.89 (m, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 3.29-3.28 (m, 2H), 3.14 (brs, 4H), 2.95-2.66 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.96-1.80 (m, 10H), 1.70-1.64 (m, 4H), 1.47-1.39 (m, 2H). Example 24: 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) nonyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image462
Reaction flow:
Figure 02_image994
Reaction steps: Step 1: Mix 9-aminononan-1-ol (95 mg, 0.60 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-isoindoline -1,3-dione (110 mg, 0.40 mmol) was dissolved in NMP (3 mL), N,N-diisopropylethylamine (0.1 mL) was added, and the reaction system was heated to 140°C and stirred for 20 minutes. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (10 mL). The mixture was extracted with ethyl acetate (10 mL×4 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl base) amino) isoindoline-1,3-dione (80 mg, yield 48%). MS (ESI) M/Z: 416.2 [M+H] + . Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl )amino)isoindoline-1,3-dione (80 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.04 mL) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (31 mg, 0.27 mmol) dropwise, and stir at 0°C for 1 hour. TLC monitoring showed that the reaction was complete, and the reaction solution was poured into water (10 mL). The mixture was extracted with ethyl acetate (10 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 9-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxindolin-4-yl)amino)nonyl methanesulfonate (55 mg, yield 58%). MS (ESI) M/Z: 494.2 [M+H] + . Step 3: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (52 mg, 0.08 mmol) and 9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonylmethanesulfonate Ester (55 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (0.04 mL) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80°C and stirred for 16 hours. LCMS monitoring showed that the starting material disappeared, and the reaction solution was cooled to room temperature and poured into water (5 mL). The mixture was extracted with dichloromethane (10 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography silica gel plate (dichloromethane:methanol=20:1) to obtain the final product 4-((9-(4-(4-((5-bromo-4-((5 -(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- yl)phenyl)piperone-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (31 mg , yield 37%). MS (ESI) M/Z: 1060.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J = 1.2 Hz, 1H), 8.70 (d, J = 1.2 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.76 -7.68 (m, 2H), 7.52-7.48 (m, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.25 (t, J = 6.0 Hz, 1H), 4.93-4.89 (m, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 3.29-3.28 (m, 2H), 3.14 (brs, 4H), 2.95-2.66 ( m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.96-1.80 (m, 10H), 1.70-1.64 (m, 4H), 1.47-1.39 (m, 2H).

實施例25: 4-((7-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image464
反應流程:
Figure 02_image997
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-4-氟異吲哚啉-1,3-二酮、7-胺基庚-1-醇和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例24的步驟製備得到終產物4-((7-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)庚基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（23 mg）。 MS (ESI) M/Z: 1032.3 [M+H] +. 1H NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 11.11 (s, 1H), 9.50 (brs, 1H), 8.87 (d, J= 2.0 Hz, 1H), 8.82 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.50 (brs, 1H), 7.12 (d, J= 8.8 Hz, 1H), 7.05 (d, J= 7.2 Hz, 1H), 6.78 (s, 1H), 6.55 (brs, 1H), 5.09-5.04 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.57-3.54 (m, 2H), 3.37-3.16 (m, 8H), 3.00-2.96 (m, 3H), 2.64-2.56 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.70-1.62 (m, 4H), 1.39 (brs, 6H), 1.24 (brs, 2H). Example 25: 4-((7-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) heptyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image464
Reaction flow:
Figure 02_image997
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, 7-aminoheptan-1-ol and (6-( (5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidine -4-yl) amino) quinoline-5-yl) dimethyl phosphine oxide as raw material, the preparation of the final product 4-((7-(4-(4-((5- Bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piper-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Diketone (23 mg). MS (ESI) M/Z: 1032.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 11.11 (s, 1H), 9.50 (brs, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H ), 7.68 (s, 1H), 7.63-7.59 (m, 1H), 7.50 (brs, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 6.55 (brs, 1H), 5.09-5.04 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.57-3.54 (m, 2H), 3.37-3.16 (m , 8H), 3.00-2.96 (m, 3H), 2.64-2.56 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.70-1.62 (m, 4H), 1.39 (brs, 6H ), 1.24 (brs, 2H).

實施例26: 4-((8-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)辛基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image466
反應流程:
Figure 02_image999
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-4-氟異吲哚啉-1,3-二酮、8-胺基辛-1-醇和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例24的步驟製備得到終產物4-((8-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)辛基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（23 mg）。 MS (ESI) M/Z: 1046.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.26 (s, 1H), 9.28 (s, 1H), 8.83-8.77 (m, 2H), 8.73 8.64 (m, 1H), 8.05-8.02 (m, 2H), 7.69-7.67 (m, 1H), 7.54-7.50 (m, 1H), 7.45-7.42 (m, 2H), 7.10 (d, J= 6.8 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.74 (s, 1H), 4.97-4.92 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.67-3.60 (m, 2H), 3.32-3.24 (m, 6H), 3.07-2.98 (m, 4H), 2.81-2.70 (m, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 1.74-1.69 (m, 4H), 1.47-1.26 (m, 8H). Example 26: 4-((8-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) octyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image466
Reaction flow:
Figure 02_image999
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, 8-aminooct-1-ol and (6-( (5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidine -4-yl) amino) quinoline-5-yl) dimethyl phosphine oxide as raw material, the preparation of the final product 4-((8-(4-(4-((5- Bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piper-1-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Diketone (23 mg). MS (ESI) M/Z: 1046.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.26 (s, 1H), 9.28 (s, 1H), 8.83-8.77 (m, 2H) , 8.73 8.64 (m, 1H), 8.05-8.02 (m, 2H), 7.69-7.67 (m, 1H), 7.54-7.50 (m, 1H), 7.45-7.42 (m, 2H), 7.10 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 4.97-4.92 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.67 -3.60 (m, 2H), 3.32-3.24 (m, 6H), 3.07-2.98 (m, 4H), 2.81-2.70 (m, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 1.74 -1.69 (m, 4H), 1.47-1.26 (m, 8H).

實施例27: 4-((6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image468
反應流程:
Figure 02_image1001
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-4-氟異吲哚啉-1,3-二酮、6-胺基己-1-醇和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例24的步驟製備得到終產物4-((6-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)己基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（22 mg）。 MS (ESI) M/Z: 1018.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 ( d, J= 1.6 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.69 (brs, 1H), 7.54-7.48 (m, 1H), 7.35 (s, 1H), 7.11 (d, J= 7.2 Hz, 1H), 6.91 (d, J= 9.2 Hz, 1H), 6.72 (s, 1H), 6.25-6.23 (m, 1H), 4.94-4.89 (m, 1H), 3.90 (s, 3H), 3.66 (s, 3H), 3.34-3.31 (m, 2H), 3.11-2.60 (m, 12H), 2.15 (s, 3H), 2.11 (s, 3H), 1.72-1.68 (m, 4H), 1.52-1.36 (m, 6H). Example 27: 4-((6-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) hexyl) amino) -2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image468
Reaction flow:
Figure 02_image1001
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, 6-aminohexan-1-ol and (6-( (5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidine -4-yl) amino) quinoline-5-yl) dimethyl phosphine oxide as raw material, the preparation of the final product 4-((6-(4-(4-((5- Bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piper-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - Diketones (22 mg). MS (ESI) M/Z: 1018.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 ( d, J = 1.6 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.69 (brs, 1H), 7.54-7.48 (m, 1H), 7.35 ( s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.72 (s, 1H), 6.25-6.23 (m, 1H), 4.94-4.89 (m , 1H), 3.90 (s, 3H), 3.66 (s, 3H), 3.34-3.31 (m, 2H), 3.11-2.60 (m, 12H), 2.15 (s, 3H), 2.11 (s, 3H), 1.72-1.68 (m, 4H), 1.52-1.36 (m, 6H).

實施例28: 4-((9-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)壬基)氧代)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image470
反應流程:
Figure 02_image1004
反應步驟： 步驟1：將9-溴-1-壬醇（222 mg, 1.0 mmol）和2-(2,6-二氧代哌啶-3-基)-4-羥基-異吲哚啉-1,3-二酮（274 mg, 1.0 mmol）溶於DMF（10 mL）中，加入碳酸氫鈉（168 mg, 2.0 mmol），反應體系升溫至70℃攪拌12小時。TLC監測顯示反應結束，反應液冷卻至室溫，倒入到水（100 mL）中。混合液用乙酸乙酯（50 mL×2次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到2-(2,6-二氧代哌啶-3-基)-4-((9-羥基壬基)氧代)異吲哚啉-1,3-二酮（390 mg，收率93%）。 MS (ESI) M/Z: 417.3 [M+H] +. 後續步驟以2-(2,6-二氧代哌啶-3-基)-4-((9-羥基壬基)氧代)異吲哚啉-1,3-二酮為原料，參照實施例24的製備方法得到終產物4-((9-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)壬基)氧代)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（21.3 mg）。 MS (ESI) M/Z: 1061.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.90 (s, 1H), 12.76 (s, 1H), 11.24 (s, 1H), 9.45 (s, 1H), 8.87-8.82 (m, 1H), 8.79 (d, J= 2.0 Hz, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.89 (s, 2H), 7.75-7.68 (m, 2H), 7.45 (d, J= 7.2 Hz, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 6.70 (s, 1H), 5.02-4.95 (m, 1H), 4.20 (t, J= 6.0 Hz, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.58-3.56 (m, 2H), 3.27-3.18 (m, 2H), 3.10-3.01 (m, 2H), 3.00-2.97 (m, 2H), 2.88-2.86 (m, 2H), 2.83-2.76 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.91-1.87 (m, 2H), 1.57-1.52 (m, 2H), 1.48-1.46 (m, 2H), 1.46-1.34 (m, 10H). Example 28: 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) nonyl) oxo) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image470
Reaction flow:
Figure 02_image1004
Reaction steps: Step 1: Combine 9-bromo-1-nonanol (222 mg, 1.0 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-isoindoline- 1,3-Diketone (274 mg, 1.0 mmol) was dissolved in DMF (10 mL), sodium bicarbonate (168 mg, 2.0 mmol) was added, and the reaction system was heated to 70°C and stirred for 12 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-(2,6-dioxopiperidin-3-yl)- 4-((9-Hydroxynonyl)oxo)isoindoline-1,3-dione (390 mg, yield 93%). MS (ESI) M/Z: 417.3 [M+H] + . Subsequent step with 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl)oxo) Isoindoline-1,3-dione is used as raw material, and the final product 4-((9-(4-(4-((5-bromo-4-((5-(di Phosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene yl)piperone-1-yl)nonyl)oxo)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg). MS (ESI) M/Z: 1061.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.90 (s, 1H), 12.76 (s, 1H), 11.24 (s, 1H), 9.45 (s, 1H), 8.87-8.82 (m, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.89 (s, 2H), 7.75- 7.68 (m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 6.70 (s, 1H), 5.02-4.95 (m, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.58-3.56 (m, 2H), 3.27-3.18 (m, 2H), 3.10-3.01 (m, 2H ), 3.00-2.97 (m, 2H), 2.88-2.86 (m, 2H), 2.83-2.76 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.91-1.87 (m, 2H ), 1.57-1.52 (m, 2H), 1.48-1.46 (m, 2H), 1.46-1.34 (m, 10H).

實施例29: 3-(4-(10-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)癸-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image1006
反應流程:
Figure 02_image1008
反應步驟： 步驟1：將3-(4-溴-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（50 mg, 0.16 mmol），雙(三苯基膦)二氯化鈀(Ⅱ) （43 mg, 0.06 mmol）和碘化亞銅（17 mg, 0.09 mmol）溶於DMF（5 mL）中，氮氣置換3次，再加入DIEA（216 mg, 1.7 mmol）和癸-9-炔-1-醇（213 mg, 1.4 mmol），反應體系升溫至65℃攪拌16小時。TLC監測顯示反應結束，反應液冷卻至室溫，倒入到水（100 mL）中。混合液用乙酸乙酯（50 mL×2次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 0:1）純化得到3-(4-(10-羥基癸-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（34 mg，收率56%）。 MS (ESI) M/Z: 397.2 [M+H] +. 後續步驟以3-(4-(10-羥基癸-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮為原料，參照實施例24的製備方法得到終產物3-(4-(10-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)癸-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（3.9 mg）。 MS (ESI) M/Z: 1041.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74-8.70 (m, 2H), 8.30-8.28 (m, 1H), 8.19 (s, 1H), 7.81-7.32 (m, 8H), 6.72 (s, 1H), 5.29-5.24 (m, 1H), 4.51-4.31 (m, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 2.97-2.82 (m, 6H), 2.71-2.45 (m, 6H), 2.35-2.21 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.53-1.46 (m, 4H), 1.37-1.25 (m, 8H). Example 29: 3-(4-(10-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)dec-1-yn-1-yl )-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image1006
Reaction flow:
Figure 02_image1008
Reaction steps: Step 1: Add 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (50 mg, 0.16 mmol), bis(triphenylphosphine ) Palladium(II) chloride (43 mg, 0.06 mmol) and cuprous iodide (17 mg, 0.09 mmol) were dissolved in DMF (5 mL), replaced with nitrogen for 3 times, then added DIEA (216 mg, 1.7 mmol ) and Dec-9-yn-1-ol (213 mg, 1.4 mmol), the reaction system was heated to 65°C and stirred for 16 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain 3-(4-(10-hydroxydec-1-yn-1-yl)-1-oxoisoind Indoline-2-yl)piperidine-2,6-dione (34 mg, yield 56%). MS (ESI) M/Z: 397.2 [M+H] + . Subsequent step with 3-(4-(10-hydroxydec-1-yn-1-yl)-1-oxoisoindoline-2- Base) piperidine-2,6-dione as raw material, the final product 3-(4-(10-(4-(4-((5-bromo-4-((5- (Dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl )phenyl)piperone-1-yl)dec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.9 mg). MS (ESI) M/Z: 1041.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74-8.70 (m, 2H), 8.30-8.28 (m, 1H), 8.19 (s, 1H), 7.81-7.32 (m, 8H), 6.72 (s, 1H), 5.29-5.24 (m, 1H), 4.51-4.31 (m, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 2.97-2.82 (m, 6H), 2.71-2.45 (m, 6H), 2.35-2.21 (m, 4H), 2.14 (s, 3H) , 2.10 (s, 3H), 1.53-1.46 (m, 4H), 1.37-1.25 (m, 8H).

實施例30: 5-((2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1010
反應流程:
Figure 02_image1012
反應步驟： 步驟1：將2-胺基乙-1-醇（166 mg, 2.7 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟-異吲哚啉-1,3-二酮（500 mg, 1.8 mmol）溶於NMP（10 mL）中，加入N,N-二異丙基乙胺（351 mg, 2.7 mmol），反應體系升溫至140℃攪拌20分鐘。TLC監測顯示反應結束，反應液冷卻至室溫，倒入到水（50 mL）中。混合液用乙酸乙酯（40 mL×4次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 0:1）純化得到2-(2,6-二氧代哌啶-3-基)-5-((2-羥基乙基)胺基)異吲哚啉-1,3-二酮（200 mg，收率35%）。 MS (ESI) M/Z: 318.1 [M+H] +. 後續步驟以2-(2,6-二氧代哌啶-3-基)-5-((2-羥基乙基)胺基)異吲哚啉-1,3-二酮為原料，參照實施例24的製備方法得到終產物5-((2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（5 mg）。 MS (ESI) M/Z: 962.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.19 (s, 1H), 9.58 (brs, 1H), 8.79 (d , J= 1.6 Hz, 1H), 8.75 (d, J= 1.6 Hz, 1H), 8.73-8.69 (m, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.68-7.61 (m, 3H), 7.35 (s, 1H), 6.99-6.95 (m, 2H), 6.70 (s, 1H), 4.98-4.93 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.58-3.50 (m 4H), 3.38-3.32 (m, 4H), 3.30-3.10 (m, 4H), 2.95-2.76 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H). Example 30: 5-((2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1010
Reaction flow:
Figure 02_image1012
Reaction steps: Step 1: Mix 2-aminoethan-1-ol (166 mg, 2.7 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline -1,3-diketone (500 mg, 1.8 mmol) was dissolved in NMP (10 mL), N,N-diisopropylethylamine (351 mg, 2.7 mmol) was added, and the reaction system was heated to 140°C and stirred for 20 minute. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (40 mL×4 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-((2-hydroxyethyl base) amino) isoindoline-1,3-dione (200 mg, yield 35%). MS (ESI) M/Z: 318.1 [M+H] + . Subsequent step with 2-(2,6-dioxopiperidin-3-yl)-5-((2-hydroxyethyl)amino) Isoindoline-1,3-dione is used as raw material, and the final product 5-((2-(4-(4-((5-bromo-4-((5-(di Phosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene yl)piperone-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5 mg). MS (ESI) M/Z: 962.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.19 (s, 1H), 9.58 (brs, 1H), 8.79 (d , J = 1.6 Hz , 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.73-8.69 (m, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.68-7.61 (m, 3H), 7.35 ( s, 1H), 6.99-6.95 (m, 2H), 6.70 (s, 1H), 4.98-4.93 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.58-3.50 (m 4H ), 3.38-3.32 (m, 4H), 3.30-3.10 (m, 4H), 2.95-2.76 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H).

實施例31: 5-((5-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image476
反應流程:
Figure 02_image1014
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5-氟-異吲哚啉-1,3-二酮、5-胺基戊-1-醇和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例24的步驟製備得到終產物5-((5-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（3.2 mg）。 MS (ESI) M/Z: 1004.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.67-7.52 (m, 4H), 7.35 (s, 1H), 6.97 (d, J= 2.4 Hz, 1H), 6.79-6.76 (m, 1H), 6.74 (s, 1H), 4.95-4.90 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.28-3.23 (m, 2H), 3.05 (brs, 4H), 2.92-2.70 (m, 6H), 2.59 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.54-1.47 (m, 4H), 1.34-1.22 (m, 4H). Example 31: 5-((5-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) pentyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image476
Reaction flow:
Figure 02_image1014
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3-dione, 5-aminopentan-1-ol and (6- ((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperyl-1-yl)phenyl)amino) Pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide is raw material, and the final product 5-((5-(4-(4-((5 -Bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl -1H-pyrazol-4-yl)phenyl)piper-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone (3.2 mg). MS (ESI) M/Z: 1004.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.67-7.52 (m, 4H), 7.35 (s, 1H), 6.97 ( d, J = 2.4 Hz, 1H), 6.79-6.76 (m, 1H), 6.74 (s, 1H), 4.95-4.90 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 3.28 -3.23 (m, 2H), 3.05 (brs, 4H), 2.92-2.70 (m, 6H), 2.59 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.54-1.47 (m , 4H), 1.34-1.22 (m, 4H).

實施例32: 4-((5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1016
反應流程:
Figure 02_image1018
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（500 mg, 0.76 mmol）和4-碘哌啶-1-羧酸第三丁酯（705 mg, 2.3 mmol）溶於乙腈（10 mL）中，加入碳酸鉀（312 mg, 2.3 mmol），反應體系升溫至100℃攪拌36小時。TLC監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 1:1）純化得到4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（460 mg，收率72%）。 MS (ESI) M/Z: 846.3 [M+H] +. 步驟2：室溫下向4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（460 mg, 0.54 mmol）的二氯甲烷（5 mL）溶液中加入鹽酸二氧六環溶液（10 mL, 4M）。室溫下攪拌30分鐘後減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽（500 mg，粗品）。 MS (ESI) M/Z: 746.2 [M+H] +. 步驟3：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽（68 mg, 約0.08 mmol）和5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)胺基)戊基甲磺酸酯（60 mg, 0.14 mmol）溶於乙腈（5 mL）中，加入DIEA（35 mg, 0.27 mmol）和催化量的碘化鈉，將反應體系加熱至85℃並攪拌12小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物4-((5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（8.2 mg，收率37%）。 MS (ESI) M/Z: 1087.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J= 1.6 Hz, 1H), 8.70 (d, J= 1.6 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.64 (brs, 3H), 7.53-7.47 (m, 1H), 7.32 (s, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.74 (s, 1H), 6.25 (t, J= 5.4 Hz, 1H), 4.93-4.88 (m, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.31-3.26 (m 2H), 3.11-3.03 (m, 2H), 2.95 (brs, 4H), 2.91-2.74 (m, 4H), 2.72-2.69 (m, 4H), 2.51-2.15 (m, 5H), 2.14 (s, 3H), 2.11 (s, 3H), 1.95-1.88 (m, 2H), 1.53-1.43 (m, 4H), 1.34-1.25 (m, 4H). Example 32: 4-((5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)pentyl Base)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1016
Reaction flow:
Figure 02_image1018
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (500 mg, 0.76 mmol) and 4-iodopiperidine-1-carboxylic acid Tert-butyl ester (705 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (312 mg, 2.3 mmol) was added, and the reaction system was heated to 100°C and stirred for 36 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl) tert-butyl piperidine-1-carboxylate (460 mg, yield 72%). MS (ESI) M/Z: 846.3 [M+H] + . Step 2: 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- To a solution of tert-butyl 1-yl)piperidine-1-carboxylate (460 mg, 0.54 mmol) in dichloromethane (5 mL) was added dioxane hydrochloride solution (10 mL, 4M). After stirring at room temperature for 30 minutes, concentration under reduced pressure gave (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4- (4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphonium oxide hydrochloride ( 500 mg, crude). MS (ESI) M/Z: 746.2 [M+H] + . Step 3: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5 -yl) dimethylphosphonium oxide hydrochloride (68 mg, about 0.08 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-4-yl)amino)pentyl methanesulfonate (60 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and a catalytic amount of sodium iodide were added, The reaction system was heated to 85°C and stirred for 12 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-(4-((5-bromo-4-((5 -(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- Base) phenyl) piper-1-yl) piperidin-1-yl) pentyl) amino) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1, 3-Diketone (8.2 mg, 37% yield). MS (ESI) M/Z: 1087.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.64 (brs, 3H), 7.53-7.47 (m, 1H), 7.32 ( s, 1H), 7.09 (d, J =7.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 6.25 (t, J = 5.4 Hz, 1H), 4.93- 4.88 (m, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.31-3.26 (m 2H), 3.11-3.03 (m, 2H), 2.95 (brs, 4H), 2.91-2.74 (m , 4H), 2.72-2.69 (m, 4H), 2.51-2.15 (m, 5H), 2.14 (s, 3H), 2.11 (s, 3H), 1.95-1.88 (m, 2H), 1.53-1.43 (m , 4H), 1.34-1.25 (m, 4H).

實施例33: 4-((3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)丙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1020
反應流程:
Figure 02_image1022
反應步驟： 以3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-4-基)胺基)丙基甲磺酸酯和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽為原料，參照實施例32的步驟製備得到終產物4-((3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)丙基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（6 mg）。 MS (ESI) M/Z: 1059.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.54 (s, 1H), 8.97-8.93 (m, 1H), 8.73 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 2.0Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.68-7.46 (m, 5H), 7.31 (s, 1H), 7.08 (d, J= 6.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.86-6.83 (m, 1H), 6.76 (s, 1H), 4.90-4.86 (m, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 3.38-3.33 (m, 2H), 3.04-3.01 (m, 6H), 2.87-2.63 (m, 9H), 2.47-2.44 (m, 2H), 2.29-2.23 (m, 2H), 2.14 (s, 3H), 2.11(s, 3H), 1.77-1.64 (m, 4H), 1.33-1.23 (m, 2H). Example 33: 4-((3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)propane Base)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1020
Reaction flow:
Figure 02_image1022
Reaction steps: With 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl methanesulfonic acid Esters and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine-4- Base) piper-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphonium oxide hydrochloride as raw material, prepared according to the steps of Example 32 Obtain final product 4-((3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)propyl )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (6 mg). MS (ESI) M/Z: 1059.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.54 (s, 1H), 8.97-8.93 (m, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.68-7.46 (m, 5H), 7.31 (s, 1H), 7.08 ( d, J = 6.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.86-6.83 (m, 1H), 6.76 (s, 1H), 4.90-4.86 (m, 1H), 3.89 (s , 3H), 3.70 (s, 3H), 3.38-3.33 (m, 2H), 3.04-3.01 (m, 6H), 2.87-2.63 (m, 9H), 2.47-2.44 (m, 2H), 2.29-2.23 (m, 2H), 2.14 (s, 3H), 2.11(s, 3H), 1.77-1.64 (m, 4H), 1.33-1.23 (m, 2H).

實施例34: 3-(4-(5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image1024
反應流程:
Figure 02_image1026
反應步驟： 以5-(2-(2,6-二氧代哌啶-3-基)-1-氧代異吲哚啉-4-基)戊-4-炔-1-基甲磺酸酯和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽為原料，參照實施例32的步驟製備得到終產物3-(4-(5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（10.8 mg）。 MS (ESI) M/Z: 1054.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.04 (s, 1H), 9.67 (s, 1H), 8.80 (s, 1H), 8.79-8.72 (m, 2H), 8.14 (s, 1H), 7.86-7.84 (m, 2H), 7.75 (s, 1H), 7.66-7.64 (m, 1H), 7.58 (d, J= 7.2 Hz, 1H), 7.47 (t, J= 7.6 Hz, 1H), 7.39 (s, 1H), 6.69 (s, 1H), 5.36-5.33 (m, 2H), 4.58-4.41 (m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.26 (brs, 4H), 2.95-2.76 (m, 5H), 2.67-2.60 (m, 2H), 2.54-2.34 (m, 6H), 2.24-2.20 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.31-1.25 (m, 6H). Example 34: 3-(4-(5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl )pent-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image1024
Reaction flow:
Figure 02_image1026
Reaction steps: With 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)pent-4-yn-1-ylmethanesulfonic acid Esters and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine-4- Base) piper-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphonium oxide hydrochloride as raw material, prepared according to the steps of Example 32 Obtain final product 3-(4-(5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl) Pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.8 mg). MS (ESI) M/Z: 1054.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.04 (s, 1H), 9.67 (s, 1H), 8.80 (s, 1H), 8.79 -8.72 (m, 2H), 8.14 (s, 1H), 7.86-7.84 (m, 2H), 7.75 (s, 1H), 7.66-7.64 (m, 1H), 7.58 (d, J = 7.2 Hz, 1H ), 7.47 (t, J = 7.6 Hz, 1H), 7.39 (s, 1H), 6.69 (s, 1H), 5.36-5.33 (m, 2H), 4.58-4.41 (m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.26 (brs, 4H), 2.95-2.76 (m, 5H), 2.67-2.60 (m, 2H), 2.54-2.34 (m, 6H), 2.24-2.20 (m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.31-1.25 (m, 6H).

實施例35: 5-(3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1028
反應流程:
Figure 02_image1030
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽（110 mg, 0.13 mmol）和3-碘氮雜環丁烷-1-羧酸第三丁酯（209 mg, 0.74 mmol）溶於乙腈（10 mL）中，加入碳酸鉀（102 mg, 0.74 mmol），反應體系升溫至100℃攪拌5天。TLC監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。所得殘餘物用製備型薄層層析矽膠板純化得到3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（90 mg，收率77%）。 MS (ESI) M/Z: 901.3 [M+H] +. 步驟2：將3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（90 mg, 0.10 mmol）溶於二氯甲烷（5 mL）中，加入三氟乙酸（10 mL），室溫下攪拌30分鐘。LCMS監測顯示反應結束，反應液減壓濃縮得到(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的三氟乙酸鹽（50 mg，收率55%）。 MS (ESI) M/Z: 801.3 [M+H] +. 步驟3：室溫下將(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物三氟乙酸鹽（25 mg, 0.03 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（25 mg, 0.09 mmol）溶於DMSO（5 mL）中，加入DIEA（12 mg, 0.09 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(3-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（11.4 mg，收率35%）。 MS (ESI) M/Z: 1057.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.23 (s, 1H), 8.80 (d, J= 1.2 Hz, 1H), 8.75 (d, J= 1.6 Hz, 1H), 8.86-8.72 (m, 1H), 8.58 (brs, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.69-7.60 (m, 2H), 7.52-7.50 (m, 1H), 7.43 (s, 1H), 6.82 (d, J= 1.2 Hz, 1H), 6.71 (s, 1H), 6.60-6.57 (m, 1H), 4.97-4.92 (m, 1H), 4.19-4.08 (m, 4H), 3.84 (s, 3H), 3.79 (s, 3H), 3.69-3.65 (m, 1H), 3.57-3.51 (m, 2H), 3.35-3.27 (m, 6H), 2.93-2.68 (m, 5H), 2.49 (m, 4H), 2.30-2.27 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H). Example 35: 5-(3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)azepine Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1028
Reaction flow:
Figure 02_image1030
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-( Piperidin-4-yl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphonium oxide hydrochloride (110 mg, 0.13 mmol) and tertiary butyl 3-iodoazetidine-1-carboxylate (209 mg, 0.74 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (102 mg, 0.74 mmol) was added, and the reaction system was heated Stir at 100°C for 5 days. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography silica gel plate to obtain 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline-6- Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) piperidine -1-yl) tert-butyl azetidine-1-carboxylate (90 mg, yield 77%). MS (ESI) M/Z: 901.3 [M+H] + . Step 2: 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)piperidin-1-yl)azetidine-1-carboxylate tert-butyl ester (90 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL ), and stirred at room temperature for 30 minutes. LCMS monitoring showed that the reaction was over, and the reaction solution was concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperone-4-yl) 1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline -5-yl)trifluoroacetic acid salt of dimethylphosphorus oxide (50 mg, yield 55%). MS (ESI) M/Z: 801.3 [M+H] + . Step 3: (6-((2-((4-(4-(1-(azetidin-3-yl )piperidin-4-yl)piper-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidine -4-yl)amino)quinolin-5-yl)dimethylphosphonium oxide trifluoroacetate (25 mg, 0.03 mmol) and 2-(2,6-dioxopiperidin-3-yl )-5-fluoroisoindoline-1,3-dione (25 mg, 0.09 mmol) was dissolved in DMSO (5 mL), added DIEA (12 mg, 0.09 mmol) and a catalytic amount of sodium iodide, and The reaction system was heated to 60°C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(4-(4-((5-bromo-4-((5- (Dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl ) phenyl) piper-1-yl) piperidin-1-yl) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) isoindoline -1,3-dione (11.4 mg, yield 35%). MS (ESI) M/Z: 1057.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.23 (s, 1H), 8.80 (d, J = 1.2 Hz, 1H), 8.75 (d , J = 1.6 Hz, 1H), 8.86-8.72 (m, 1H), 8.58 (brs, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.69-7.60 (m, 2H), 7.52- 7.50 (m, 1H), 7.43 (s, 1H), 6.82 (d, J = 1.2 Hz, 1H), 6.71 (s, 1H), 6.60-6.57 (m, 1H), 4.97-4.92 (m, 1H) , 4.19-4.08 (m, 4H), 3.84 (s, 3H), 3.79 (s, 3H), 3.69-3.65 (m, 1H), 3.57-3.51 (m, 2H), 3.35-3.27 (m, 6H) , 2.93-2.68 (m, 5H), 2.49 (m, 4H), 2.30-2.27 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H).

實施例36: 5-(4-((4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1032
反應流程:
Figure 02_image1034
反應步驟： 步驟1：室溫下將2-(2,6-二氧代哌啶-3-基)-5-(4-(羥甲基)哌啶-1-基)異吲哚啉-1,3-二酮（100 mg, 0.27 mmol，製備參見WO2018140809A1）溶於二氯甲烷（5 mL）中，加入三乙胺（81.5 mg, 0.81 mmol）。降溫至0℃，緩慢滴加甲磺醯氯（34 mg, 0.30 mmol），0℃下攪拌1小時。TLC監測顯示反應結束。反應液用二氯甲烷（20 mL）稀釋後，用飽和碳酸氫鈉水溶液（10 mL×2次）洗滌，有機相用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 5:1）純化得到(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-5-基)哌啶-4-基)甲基甲磺酸酯（52 mg，收率42%）。 MS (ESI) M/Z: 450.1 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽（86 mg, 約0.10 mmol）和(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-5-基)哌啶-4-基)甲基甲磺酸酯（52 mg, 0.12 mmol）溶於乙腈（5 mL）中，加入DIEA（45 mg, 0.35 mmol）和催化量的碘化鈉，將反應體系加熱至85℃並攪拌12小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(4-((4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（2.2 mg，收率2%）。 MS (ESI) M/Z: 1099.1 [M+H] +. 1H NMR (400 MHz, CD 3OD): δ 8.88-8.77 (m, 3H), 8.29 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.55 (brs, 2H), 7.00 (d, J= 2.0 Hz, 1H), 6.89-6.80 (m, 2H), 5.08-5.06 (m, 1H), 3.94 (s, 3H), 3.89-3.81 (m, 2H), 3.70 (s, 3H), 3.68-3.53 (m, 4H), 3.52-3.46 (m, 4H), 3.26-3.24 (m, 2H), 3.17-3.13 (m, 4H), 2.89-2.48 (m, 1H), 2.76-2.69 (m, 2H), 2.61-2.49 (m, 2H), 2.50-2.22 (m, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 2.12-2.04 (m, 5H), 1.99-1.97 (m, 2H), 1.88-1.78 (m, 1H). Example 36: 5-(4-((4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)methyl Base) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1032
Reaction flow:
Figure 02_image1034
Reaction steps: Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline- 1,3-Diketone (100 mg, 0.27 mmol, see WO2018140809A1 for preparation) was dissolved in dichloromethane (5 mL), and triethylamine (81.5 mg, 0.81 mmol) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (34 mg, 0.30 mmol) dropwise, and stir at 0°C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL×2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain (1-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindoline-5-yl)piperidin-4-yl)methyl methanesulfonate (52 mg, yield 42%). MS (ESI) M/Z: 450.1 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5 -yl) dimethylphosphonium oxide hydrochloride (86 mg, about 0.10 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indolin-5-yl)piperidin-4-yl)methyl methanesulfonate (52 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL), DIEA (45 mg, 0.35 mmol) and a catalytic amount of iodine were added NaCl, the reaction system was heated to 85°C and stirred for 12 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((4-(4-(4-((5-bromo-4-((5 -(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- Base) phenyl) piper-1-yl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindole Phenyl-1,3-dione (2.2 mg, yield 2%). MS (ESI) M/Z: 1099.1 [M+H] + . 1 H NMR (400 MHz, CD 3 OD): δ 8.88-8.77 (m, 3H), 8.29 (s, 1H), 7.95 (s, 1H ), 7.78 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.55 (brs, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.89-6.80 (m, 2H), 5.08 -5.06 (m, 1H), 3.94 (s, 3H), 3.89-3.81 (m, 2H), 3.70 (s, 3H), 3.68-3.53 (m, 4H), 3.52-3.46 (m, 4H), 3.26 -3.24 (m, 2H), 3.17-3.13 (m, 4H), 2.89-2.48 (m, 1H), 2.76-2.69 (m, 2H), 2.61-2.49 (m, 2H), 2.50-2.22 (m, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 2.12-2.04 (m, 5H), 1.99-1.97 (m, 2H), 1.88-1.78 (m, 1H).

實施例37: 5-(4-((9-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image488
反應流程:
Figure 02_image1037
反應步驟： 步驟1：室溫下向9-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,9-二氮雜螺[5.5]十一烷-3-羧酸第三丁酯（346 mg, 0.71 mmol，製備參見CN112538072A）的二氯甲烷（2 mL）溶液中加入鹽酸二氧六環溶液（12 mL, 4M）。室溫下攪拌2小時後減壓濃縮得到3-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,9-二氮雜螺[5.5]十一烷鹽酸鹽（458 mg，粗品）。 MS (ESI) M/Z: 386.2 [M+H] +. 步驟2：室溫下將3-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,9-二氮雜螺[5.5]十一烷鹽酸鹽（458 mg，粗品）和DMAP（342 mg，2.8 mmol）加入到二氯甲烷（10 mL）中，攪拌5分鐘，再加入三氟乙酸酐（588 mg，2.8 mmol），室溫攪拌反應2小時。將反應液減壓濃縮得到2,2,2-三氟-1-(9-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)乙烷-1-酮（382 mg，粗品）。 MS (ESI) M/Z: 482.3 [M+H] +. 步驟3：室溫下將2,2,2-三氟-1-(9-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)乙烷-1-酮（382 mg，粗品）和10%鈀碳（50 mg）加入到甲醇（15 mL）中，氫氣置換三次後，室溫下攪拌反應2小時。過濾，濾液減壓濃縮得到1-(9-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)-2,2,2-三氟乙烷-1-酮（371 mg，粗品）。 MS (ESI) M/Z: 452.2 [M+H] +. 步驟4：室溫下將1-(9-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)-2,2,2-三氟乙烷-1-酮（371 mg，粗品），(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（310 mg，0.75 mmol）和三氟乙酸（857 mg，7.5 mmol）依次加入到異丙醇（10 mL）中，氬氣保護下升溫至100℃攪拌反應16小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用製備TLC板純化得到1-(9-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)-2,2,2-三氟乙基-1-酮（277 mg，四步收率47%）。 MS (ESI) M/Z: 827.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 9.02-8.98 (m, 1H), 8.73 (d, J= 1.6  Hz, 1H), 8.70 (d, J= 1.6 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.68-7.61 (m, 3H), 7.34 (s, 1H), 6.72 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.68-3.64 (m, 2H), 3.57 (brs, 2H), 2.90-2.83 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H), 1.64 (brs, 8H). 步驟5：室溫下將1-(9-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)-2,2,2-三氟乙基-1-酮（237 mg，0.29 mmol）和氫氧化鉀（160 mg，2.9 mmol）加入到甲醇（10 mL）和水（4 mL）中，升溫至60℃攪拌反應4小時。將反應液冷卻至室溫，用二氯甲烷（20 mL）稀釋，分液。有機相先用飽和食鹽水（20 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(3,9-二氮雜螺[5.5]十一烷-3-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（174 mg，收率83%）。 MS (ESI) M/Z: 731.2 [M+H] +. 步驟6：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(3,9-二氮雜螺[5.5]十一烷-3-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（54 mg, 0.074 mmol）和(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-5-基)哌啶-4-基)甲基甲磺酸酯（50 mg, 0.11 mmol）溶於乙腈（5 mL）中，加入DIEA（29 mg, 0.22 mmol）和催化量的碘化鈉，將反應體系加熱至85℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(4-((9-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-3,9-二氮雜螺[5.5]十一烷-3-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（18.2 mg，收率23%）。 MS (ESI) M/Z: 1084.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.35 (s, 1H), 12.55 (brs, 1H), 8.80 (d, J= 1.2 Hz, 1H), 8.76-8.72 (m, 2H), 8.05 (d, J= 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.69-7.64 (m, 2H), 7.58 (d, J= 9.2 Hz, 1H), 7.46 (s, 1H), 6.92 (d, J= 0.8 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J= 8.0 Hz, 1H), 4.96-4.91 (m, 1H), 3.85 (s, 6H), 3.63-3.38 (m, 6H), 3.10-3.05 (m, 2H), 2.96-2.75 (m, 8H), 2.39 (brs, 2H), 2.29 (brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.98 (brs, 6H), 1.79-1.69 (m, 5H). Example 37: 5-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3- Base) methyl) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image488
Reaction flow:
Figure 02_image1037
Reaction steps: Step 1: 9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-di Add dioxane hydrochloride solution (12 mL, 4M). Stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 3-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9- Diazaspiro[5.5]undecane hydrochloride (458 mg, crude). MS (ESI) M/Z: 386.2 [M+H] + . Step 2: 3-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- 4-Nitrophenyl)-3,9-diazaspiro[5.5]undecane hydrochloride (458 mg, crude) and DMAP (342 mg, 2.8 mmol) were added to dichloromethane (10 mL) , stirred for 5 minutes, then added trifluoroacetic anhydride (588 mg, 2.8 mmol), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 2,2,2-trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitro phenyl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (382 mg, crude). MS (ESI) M/Z: 482.3 [M+H] + . Step 3: 2,2,2-Trifluoro-1-(9-(5-methoxy-2-(1-methyl yl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (382 mg, crude ) and 10% palladium on carbon (50 mg) were added to methanol (15 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain 1-(9-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-di Azaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethane-1-one (371 mg, crude). MS (ESI) M/Z: 452.2 [M+H] + . Step 4: 1-(9-(4-amino-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethane-1-one (371 mg, crude ), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (310 mg, 0.75 mmol) and trifluoroacetic acid (857 mg , 7.5 mmol) were sequentially added to isopropanol (10 mL), heated to 100°C under the protection of argon and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified with a preparative TLC plate to obtain 1-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9 - Diazaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethyl-1-one (277 mg, 47% yield over four steps). MS (ESI) M/Z: 827.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 9.02-8.98 (m, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.68-7.61 (m, 3H), 7.34 (s, 1H), 6.72 ( s, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.68-3.64 (m, 2H), 3.57 (brs, 2H), 2.90-2.83 (m, 4H), 2.14 (s, 3H) , 2.11 (s, 3H), 1.64 (brs, 8H). Step 5: 1-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3, 9-diazaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethyl-1-one (237 mg, 0.29 mmol) and potassium hydroxide (160 mg, 2.9 mmol) Added to methanol (10 mL) and water (4 mL), heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated. The organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1 -Methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undecyl-3-yl)phenyl)amino)pyrimidin-4-yl)amino )quinolin-5-yl)dimethylphosphine oxide (174 mg, yield 83%). MS (ESI) M/Z: 731.2 [M+H] + . Step 6: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline -5-yl)dimethylphosphine oxide (54 mg, 0.074 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperidin-4-yl)methyl mesylate (50 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (29 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added , the reaction system was heated to 85 °C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((9-(4-((5-bromo-4-((5-(di Phosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base)-3,9-diazaspiro[5.5]undecyl-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (18.2 mg, yield 23%). MS (ESI) M/Z: 1084.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.35 (s, 1H), 12.55 (brs, 1H), 8.80 (d, J = 1.2 Hz , 1H), 8.76-8.72 (m, 2H), 8.05 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.69-7.64 (m, 2H), 7.58 ( d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 6.92 (d, J = 0.8 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.96- 4.91 (m, 1H), 3.85 (s, 6H), 3.63-3.38 (m, 6H), 3.10-3.05 (m, 2H), 2.96-2.75 (m, 8H), 2.39 (brs, 2H), 2.29 ( brs, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.98 (brs, 6H), 1.79-1.69 (m, 5H).

實施例38: 5-(4-((5-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image490
反應流程:
Figure 02_image1040
反應步驟： 步驟1：將1-溴-2-氟-4-甲氧基-5-硝基苯（250 mg, 1.0 mmol）和六氫吡咯[3,4-c]吡咯-2(1H)-羧酸第三丁酯 （233 mg, 1.1 mmol）溶於N’N-二甲基甲醯胺（10 mL）中，加入碳酸鉀（414 mg, 3.0 mmol），升溫至60℃攪拌過夜。反應液用水（50 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，先用飽和食鹽水（50 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用乙酸乙酯打漿純化得到5-(2-溴-5-甲氧基-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-羧酸第三丁酯（280 mg，收率63%）。 MS (ESI) M/Z: 442.1 [M+H] +. 步驟2：室溫下將5-(2-溴-5-甲氧基-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-羧酸第三丁酯（280 mg, 0.63 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（197 mg, 0.95 mmol）溶於二氧六環（10 mL）和水（2 mL）中, 加入磷酸鉀（267 mg, 1.26mmol）和二茂鐵二氯化鈀（46 mg, 0.06 mmol）。反應液在氬氣氛圍下加熱至110℃攪拌12小時。將反應液冷卻至室溫，用水（50 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用乙酸乙酯打漿純化得到5-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-羧酸第三丁酯（170 mg，收率60%）。 MS (ESI) M/Z: 444.2 [M+H] +. 步驟3：室溫下向5-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-羧酸第三丁酯（170 mg, 0.38 mmol）的二氯甲烷（2 mL）溶液中加入鹽酸二氧六環溶液(8 mL, 4M)。室溫下攪拌2小時後減壓濃縮得到2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)八氫吡咯[3,4-c]吡咯鹽酸鹽（164 mg，粗品）。 MS (ESI) M/Z: 344.2 [M+H] +. 步驟4：室溫下將2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)八氫吡咯[3,4-c]吡咯鹽酸鹽（20 mg, 約0.046 mmol）和(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-5-基)哌啶-4-基)甲基甲磺酸酯（36 mg, 0.08 mmol）溶於乙腈（10 mL）中，加入DIEA（16 mg, 0.12 mmol）和催化量的碘化鈉，將反應體系加熱至85℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，用水（50 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用製備級TLC板純化得到2-(2,6-二氧代哌啶-3-基)-5-(4-((5-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)異吲哚啉-1,3-二酮（21 mg，收率65%）。 MS (ESI) M/Z: 697.3 [M+H] +. 步驟5：室溫下將2-(2,6-二氧代哌啶-3-基)-5-(4-((5-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)異吲哚啉-1,3-二酮（21 mg, 0.03 mmol）和10%鈀碳（10 mg）加入到四氫呋喃（6 mL）中，氫氣置換三次後，室溫下攪拌反應2小時。過濾，濾液減壓濃縮得到5-(4-((5-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（18 mg，收率90%）。 MS (ESI) M/Z: 667.3 [M+H] +. 步驟6：室溫下將5-(4-((5-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（18 mg，0.027 mmol），(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（12 mg，0.029 mmol）和三氟乙酸（34 mg，0.3 mmol）依次加入到異丙醇（4 mL）中，氬氣保護下升溫至95℃攪拌反應16小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用高效製備液相色譜純化得到終產物5-(4-((5-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)六氫吡咯[3,4-c]吡咯-2(1H)-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（6.6 mg，收率23%）。 MS (ESI) M/Z: 1042.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.37 (s, 1H), 13.04 (s, 1H), 8.9 (dd, J= 8.8, 1.2 Hz, 2H), 8.13 (s, 1H), 8.05 (s, 1H), 7.71-7.66 (m, 3H), 7.39 (s, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 6.70 (d, J= 8.4 Hz, 2H), 4.96-4.91 (m, 1H), 4.02 (brs, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.67-3.61 (m, 2H), 3.60-3.50 (m, 2H), 3.49-3.38 (m, 2H), 3.19 (brs, 4H), 3.11(d, J= 9.6 Hz, 4H), 2.70-2.56 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H), 2.06-1.96 (m, 4H), 1.70-1.50 (m, 1H). Example 38: 5-(4-((5-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl )methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image490
Reaction flow:
Figure 02_image1040
Reaction steps: Step 1: Combine 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (250 mg, 1.0 mmol) and hexahydropyrrole[3,4-c]pyrrole-2(1H) - Dissolve tertiary butyl carboxylate (233 mg, 1.1 mmol) in N'N-dimethylformamide (10 mL), add potassium carbonate (414 mg, 3.0 mmol), heat up to 60°C and stir overnight. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by beating with ethyl acetate to obtain 5-(2-bromo-5-methoxy-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid Tributyl ester (280 mg, yield 63%). MS (ESI) M/Z: 442.1 [M+H] + . Step 2: 5-(2-Bromo-5-methoxy-4-nitrophenyl)hexahydropyrrole[3,4 -c] tertiary butyl pyrrole-2(1H)-carboxylate (280 mg, 0.63 mmol) and 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (197 mg, 0.95 mmol) were dissolved in di To oxane (10 mL) and water (2 mL), add potassium phosphate (267 mg, 1.26 mmol) and ferrocene palladium dichloride (46 mg, 0.06 mmol). The reaction solution was heated to 110°C under an argon atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by beating with ethyl acetate to obtain 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3, 4-c] tert-butyl pyrrole-2(1H)-carboxylate (170 mg, yield 60%). MS (ESI) M/Z: 444.2 [M+H] + . Step 3: 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- 4-Nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-tert-butyl carboxylate (170 mg, 0.38 mmol) in dichloromethane (2 mL) was added dihydrochloride Hexane solution (8 mL, 4M). Stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)octahydropyrrole[3 ,4-c]pyrrole hydrochloride (164 mg, crude). MS (ESI) M/Z: 344.2 [M+H] + . Step 4: 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- 4-nitrophenyl)octahydropyrrole[3,4-c]pyrrole hydrochloride (20 mg, about 0.046 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl methanesulfonate (36 mg, 0.08 mmol) was dissolved in acetonitrile (10 mL), and DIEA (16 mg, 0.12 mmol) and a catalytic amount of sodium iodide, the reaction system was heated to 85°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, and the reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified on a preparative TLC plate to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((5-(5-methoxy-2-(1-methoxy Base-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)isoind Indoline-1,3-dione (21 mg, 65% yield). MS (ESI) M/Z: 697.3 [M+H] + . Step 5: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((5- (5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl )methyl)piperidin-1-yl)isoindoline-1,3-dione (21 mg, 0.03 mmol) and 10% palladium on carbon (10 mg) were added to tetrahydrofuran (6 mL), hydrogen was replaced three times Afterwards, the reaction was stirred at room temperature for 2 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain 5-(4-((5-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydro Pyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Diketone (18 mg, 90% yield). MS (ESI) M/Z: 667.3 [M+H] + . Step 6: 5-(4-((5-(4-amino-5-methoxy-2-(1-methyl Base-1H-pyrazol-4-yl)phenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione (18 mg, 0.027 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino )quinolin-5-yl)dimethylphosphine oxide (12 mg, 0.029 mmol) and trifluoroacetic acid (34 mg, 0.3 mmol) were sequentially added to isopropanol (4 mL), and the temperature was raised to The reaction was stirred at 95°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((5-(4-((5-bromo-4-((5-( Dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (6.6 mg, yield 23%). MS (ESI) M/Z: 1042.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.37 (s, 1H), 13.04 (s, 1H), 8.9 (dd, J = 8.8, 1.2 Hz, 2H), 8.13 (s, 1H), 8.05 (s, 1H), 7.71-7.66 (m, 3H), 7.39 (s, 1H), 7.34 (s, 1H), 6.95 (s, 1H), 6.70 (d, J = 8.4 Hz, 2H), 4.96-4.91 (m, 1H), 4.02 (brs, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.67-3.61 (m, 2H) , 3.60-3.50 (m, 2H), 3.49-3.38 (m, 2H), 3.19 (brs, 4H), 3.11(d, J = 9.6 Hz, 4H), 2.70-2.56 (m, 4H), 2.14 (s , 3H), 2.11 (s, 3H), 2.06-1.96 (m, 4H), 1.70-1.50 (m, 1H).

實施例39: 4-((5-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image492
反應流程:
Figure 02_image1043
反應步驟： 步驟1：室溫下將4-(哌啶-4-基)哌𠯤-1-羧酸第三丁酯（2.0 g, 7.4 mmol）、1-溴-2-氟-4-甲氧基-5-硝基苯（1.9 g, 7.4 mmol）溶於DMF（50 mL）中，加入碳酸鉀（2.1 g, 15.0 mmol）。將反應體系加熱至60℃並攪拌過夜。LCMS監控顯示原料消失。將反應液冷卻至室溫，倒入水（250 mL）中，用乙酸乙酯萃取（200 mL × 2）。合併有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，最後減壓濃縮，殘留物用矽膠柱層析純化（石油醚/乙酸乙酯=1/1）得到4-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)哌𠯤-1-羧酸第三丁酯（1.9 g，收率51%）。 MS (ESI) M/Z: 499.2 [M+H] +. 步驟2：室溫下將4-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)哌𠯤-1-羧酸第三丁酯（1.9 g, 3.8 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（0.95 g, 4.6 mmol）溶於二氧六環（50 mL）和水（10 mL）中, 加入磷酸鉀 (1.6 g, 7.6 mmol)和二茂鐵二氯化鈀(0.28g, 0.38 mmol)，反應液在氮氣氛圍下加熱至110℃攪拌過夜。LCMS監測反應結束，將反應液冷卻至室溫，用水（300 mL）稀釋後用乙酸乙酯（200 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/1）得到4-(1-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌啶-4-基)哌𠯤-1-羧酸第三丁酯（1.3 g，收率68%）。 MS (ESI) M/Z: 501.3 [M+H] +. 後續步驟以4-(1-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌啶-4-基)哌𠯤-1-羧酸第三丁酯為原料，參照實施例37的製備方法得到終產物4-((5-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（8.0 mg）。 MS (ESI) M/Z: 1087.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.32 (s, 1H), 10.74 (brs, 1H), 9.41 (s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.70-8.64 (m, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.58-7.48 (m, 4H), 7.15 (d, J= 7.2 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 6.68 (s, 1H), 4.99-4.93 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.83-3.79 (m, 2H), 3.37-3.06 (m, 9H), 2.96-2.86 (m, 2H), 2.82-2.64 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.91-1.88 (m, 4H), 1.78-1.56 (m, 6H). Example 39: 4-((5-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piper-1-yl)pentyl Base)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image492
Reaction flow:
Figure 02_image1043
Reaction steps: Step 1: tert-butyl 4-(piperidin-4-yl)piperone-1-carboxylate (2.0 g, 7.4 mmol), 1-bromo-2-fluoro-4-methyl Oxy-5-nitrobenzene (1.9 g, 7.4 mmol) was dissolved in DMF (50 mL), and potassium carbonate (2.1 g, 15.0 mmol) was added. The reaction system was heated to 60 °C and stirred overnight. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (250 mL), and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 4-(1-(2- Bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) tert-butyl piper-1-carboxylate (1.9 g, yield 51%). MS (ESI) M/Z: 499.2 [M+H] + . Step 2: 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidine-4 -yl)piperone-1-carboxylate tert-butyl ester (1.9 g, 3.8 mmol) and 1-methyl-4-1H-pyrazole borate pinacol ester (0.95 g, 4.6 mmol) were dissolved in dioxane Ring (50 mL) and water (10 mL), add potassium phosphate (1.6 g, 7.6 mmol) and ferrocene palladium dichloride (0.28 g, 0.38 mmol), the reaction solution was heated to 110 ° C under nitrogen atmosphere and stirred overnight. The completion of the reaction was monitored by LCMS, and the reaction solution was cooled to room temperature, diluted with water (300 mL) and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)-4-nitrophenyl)piperidin-4-yl)tert-butyl piper-1-carboxylate (1.3 g, yield 68%). MS (ESI) M/Z: 501.3 [M+H] + . Subsequent step with 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4 -Nitrophenyl) piperidin-4-yl) tertiary butyl piper-1-carboxylate is raw material, and the preparation method of referring to embodiment 37 obtains final product 4-((5-(4-(1-( 4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- (1-Methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperone-1-yl)pentyl)amino)-2-(2,6-dioxopiper pyridin-3-yl) isoindoline-1,3-dione (8.0 mg). MS (ESI) M/Z: 1087.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.32 (s, 1H), 10.74 (brs, 1H), 9.41 (s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.70-8.64 (m, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.58-7.48 (m, 4H ), 7.15 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 4.99-4.93 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.83-3.79 (m, 2H), 3.37-3.06 (m, 9H), 2.96-2.86 (m, 2H), 2.82-2.64 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.91-1.88 (m, 4H), 1.78-1.56 (m, 6H).

實施例40: 4-((5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)氧代)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image494
反應流程:
Figure 02_image1046
反應步驟： 步驟1：室溫下將2-(2,6-二氧代哌啶-3-基)-4-((5-羥戊基)氧代)異吲哚啉-1,3-二酮（16 mg, 0.044 mmol，製備參見CN112552293A）溶於二氯甲烷（10 mL）中，加入DIEA（17 mg, 0.13 mmol）。降溫至0℃，緩慢滴加甲磺醯氯（6 mg, 0.05 mmol），0℃下攪拌19小時。TLC監測顯示反應結束。反應液用二氯甲烷（10 mL）稀釋後，用飽和碳酸氫鈉水溶液（10 mL×2次）洗滌，有機相用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用製備TLC板（二氯甲烷：甲醇= 30:1）純化得到5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)氧代)戊基甲磺酸酯（10 mg，收率52%）。 MS (ESI) M/Z: 439.1 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽（17 mg, 約0.02 mmol）和5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)氧代)戊基甲磺酸酯（10 mg, 0.023 mmol）溶於乙腈（5 mL）中，加入碳酸鉀（10 mg, 0.072 mmol）和催化量的碘化鈉，將反應體系加熱至90℃並攪拌16小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物4-((5-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)氧代)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（5.1 mg，收率21%）。 MS (ESI) M/Z: 1088.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 8.85-8.76 (m, 4H), 8.22 (s, 1H), 7.86-7.83 (m, 1H), 7.76-7.72 (m, 1H), 7.67-7.62 (m, 2H), 7.51 (d, J= 8.0 Hz, 1H), 7.29-7.25 (m, 1H), 6.75 (s, 1H), 5.03-4.99 (m, 1H), 4.25-4.22 (m, 2H), 3.90 (s, 3H), 3.80-3.64 (m, 6H), 3.55- 3.47 (m, 2H), 3.44-3.39 (m, 2H), 3.33-3.22 (s, 8H), 3.17-2.99 (m, 4H), 2.86-2.70 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H), 2.02-1.94 (m, 4H), 1.77-1.70 (m, 2H). Example 40: 4-((5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)pentyl Base) oxo)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image494
Reaction flow:
Figure 02_image1046
Reaction steps: Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)oxo)isoindoline-1,3- Diketone (16 mg, 0.044 mmol, see CN112552293A for preparation) was dissolved in dichloromethane (10 mL), and DIEA (17 mg, 0.13 mmol) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (6 mg, 0.05 mmol) dropwise, and stir at 0°C for 19 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate (10 mL×2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate (dichloromethane: methanol = 30:1) to give 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoind Indoline-4-yl)oxo)pentyl methanesulfonate (10 mg, yield 52%). MS (ESI) M/Z: 439.1 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5 -yl) dimethylphosphonium oxide hydrochloride (17 mg, about 0.02 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-4-yl)oxo)pentyl methanesulfonate (10 mg, 0.023 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (10 mg, 0.072 mmol) and a catalytic amount of sodium iodide were added, The reaction system was heated to 90°C and stirred for 16 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-(4-((5-bromo-4-((5 -(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- Base) phenyl) piper-1-yl) piperidin-1-yl) pentyl) oxo)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1, 3-Diketone (5.1 mg, yield 21%). MS (ESI) M/Z: 1088.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 8.85-8.76 (m, 4H), 8.22 (s, 1H), 7.86-7.83 (m, 1H), 7.76-7.72 (m, 1H), 7.67-7.62 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.29-7.25 (m, 1H), 6.75 (s, 1H), 5.03 -4.99 (m, 1H), 4.25-4.22 (m, 2H), 3.90 (s, 3H), 3.80-3.64 (m, 6H), 3.55- 3.47 (m, 2H), 3.44-3.39 (m, 2H) , 3.33-3.22 (s, 8H), 3.17-2.99 (m, 4H), 2.86-2.70 (m, 4H), 2.14 (s, 3H), 2.11 (s, 3H), 2.02-1.94 (m, 4H) , 1.77-1.70 (m, 2H).

實施例41: 3-(4-(6-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)己-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image496
反應流程:
Figure 02_image1049
反應步驟： 以3-(4-(6-羥己基-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（製備參見WO202191575A1）和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物鹽酸鹽為原料，參照實施例40的步驟製備得到30.4 mg終產物3-(4-(6-(4-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)己-1-炔-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮。 MS (ESI) M/Z: 1068.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.29 (s, 1H), 10.57 (brs, 1H), 10.24 (s, 1H), 8.83 (s, 1H), 8.76 (s, 1H), 8.62 (d, J= 7.2 Hz, 1H), 8.04 (s, 1H), 7.89 (brs, 1H), 7.82 (d, J= 7.6 Hz, 1H), 7.58 (d, J= 7.6 Hz, 2H), 7.48-7.44 (m, 3H), 6.66 (s, 1H), 5.28-5.23 (m, 1H), 4.58-4.42 (m, 2H), 3.80 (brs, 6H), 3.65-3.45 (m, 3H), 3.30-3.25 (m, 8H), 3.10-3.02 (m, 4H), 2.91-2.84 (m, 4H), 2.60-2.54 (m, 6H), 2.14 (s, 3H), 2.10 (s, 3H), 2.10-2.03 (m, 2H), 1.71-1.65 (m, 2H). Example 41: 3-(4-(6-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl )hex-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image496
Reaction flow:
Figure 02_image1049
Reaction steps: 3-(4-(6-hydroxyhexyl-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (for preparation see WO202191575A1 ) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine-4- Base) piper-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoline-5-yl) dimethylphosphonium oxide hydrochloride as raw material, prepared according to the steps of Example 40 30.4 mg of final product 3-(4-(6-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amine) was obtained Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piperidine-1-yl) piperidine-1- base) hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. MS (ESI) M/Z: 1068.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.29 (s, 1H), 10.57 (brs, 1H), 10.24 (s, 1H), 8.83 (s, 1H), 8.76 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.89 (brs, 1H), 7.82 (d, J = 7.6 Hz, 1H) , 7.58 (d, J = 7.6 Hz, 2H), 7.48-7.44 (m, 3H), 6.66 (s, 1H), 5.28-5.23 (m, 1H), 4.58-4.42 (m, 2H), 3.80 (brs , 6H), 3.65-3.45 (m, 3H), 3.30-3.25 (m, 8H), 3.10-3.02 (m, 4H), 2.91-2.84 (m, 4H), 2.60-2.54 (m, 6H), 2.14 (s, 3H), 2.10 (s, 3H), 2.10-2.03 (m, 2H), 1.71-1.65 (m, 2H).

實施例42: 3-(4-(6-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)己基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image498
反應流程:
Figure 02_image1052
反應步驟： 以3-(4-(6-羥己基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（製備參見WO202191575A1）和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌𠯤-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲磷氧化物為原料，參照實施例40的步驟製備得到3.3 mg終產物3-(4-(6-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)己基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮。 MS (ESI) M/Z: 1072.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.26 (s, 1H), 10.80 (brs, 1H), 9.13 (brs, 1H), 8.84 (s, 1H), 8.76 (d, J= 0.8 Hz, 1H), 8.69-8.65 (m, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.77 (d, J= 7.2 Hz, 1H), 7.69 (s, 1H), 7.52 (d, J= 9.2 Hz, 2H), 7.46 (d, J= 7.6 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 6.68 (s, 1H), 5.29-5.24 (m, 1H), 4.48-4.31 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.34-3.21 (m, 4H), 3.03-2.89 (m, 6H), 2.7-2.69 (m, 7H), 2.28-2.22 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 2.09-2.04 (m, 2H), 1.78-1.62 (m, 6H), 1.44-1.28 (m, 6H). Example 42: 3-(4-(6-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino) )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperone-1-yl )hexyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image498
Reaction flow:
Figure 02_image1052
Reaction steps: With 3-(4-(6-hydroxyhexyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (see WO202191575A1 for preparation) and (6-((5 -Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piper-1-yl)piperidin-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphonium oxide as raw material, referring to the steps of Example 40 to prepare 3.3 mg of the final product 3-(4-( 6-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piper-1-yl)hexyl)-1-oxoisoind Indoline-2-yl)piperidine-2,6-dione. MS (ESI) M/Z: 1072.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.26 (s, 1H), 10.80 (brs, 1H), 9.13 (brs, 1H), 8.84 (s, 1H), 8.76 (d, J = 0.8 Hz, 1H), 8.69-8.65 (m, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.52 (d, J = 9.2 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 5.29-5.24 (m, 1H), 4.48-4.31 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.34-3.21 (m, 4H), 3.03-2.89 (m, 6H), 2.7-2.69 (m, 7H), 2.28-2.22 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 2.09-2.04 (m, 2H), 1.78-1.62 (m, 6H), 1.44-1.28 (m, 6H).

實施例43: 4-((8-(2-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯[3,4-c]并吡唑-5(4H)-基)辛基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image500
反應流程:
Figure 02_image1055
反應步驟： 步驟1：室溫下將1-溴-2-氟-4-甲氧基-5-硝基苯（1.5 g, 6.0 mmol）、2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-羧酸第三丁酯（1.3 g, 6.0 mmol）溶於DMF（50 mL）中，加入碳酸鉀（1.7 g, 12.0 mmol）。將反應體系加熱至85℃並攪拌18小時。LCMS監控顯示原料消失。將反應液冷卻至室溫，倒入水（100 mL）中，用乙酸乙酯萃取（100 mL × 2）。合併有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，最後減壓濃縮，殘留物用矽膠柱層析純化（石油醚/乙酸乙酯=1/1）得到2-(2-溴-5-甲氧基-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-羧酸第三丁酯（1.6 g，收率61%）。 MS (ESI) M/Z: 439.1 [M+H] +. 步驟2：室溫下將2-(2-溴-5-甲氧基-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-羧酸第三丁酯（1.6 g, 3.6 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（0.76 g, 3.7 mmol）溶於1,4-二氧六環（100 mL）和水（20 mL）中, 加入碳酸銫 (3.6 g, 10.9 mmol)和二茂鐵二氯化鈀(0.27 g, 0.36 mmol)，反應液在氮氣氛圍下加熱至110℃攪拌18小時。LCMS監測反應結束，將反應液冷卻至室溫，旋蒸除去大部分1,4-二氧六環，加水（100 mL）稀釋後用乙酸乙酯（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/1）得到2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-羧酸第三丁酯（1.4 g，收率84%）。 MS (ESI) M/Z: 441.2 [M+H] +. 步驟3：室溫下向2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-羧酸第三丁酯（1.4 g, 3.1 mmol）的二氯甲烷（100 mL）溶液中滴加三氟乙酸（25 mL）。室溫下攪拌2小時後減壓濃縮得到2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,4,5,6-四氫吡咯并[3,4-c]吡唑三氟乙酸鹽（1.1 g，粗品）。 MS (ESI) M/Z: 341.2 [M+H] +. 步驟4：室溫下將2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,4,5,6-四氫吡咯并[3,4-c]吡唑三氟乙酸鹽（1.1 g，粗品）和DMAP（789 mg，6.5 mmol）加入到二氯甲烷（50 mL）中，攪拌5分鐘，再加入三氟乙酸酐（1.4 g，6.5 mmol），室溫攪拌反應2小時。加水（100 mL）淬滅後用二氯甲烷（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/1）得到2,2,2-三氟-1-(2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)乙烷-1-酮（1.1 g，二步收率79%）。 MS (ESI) M/Z: 437.3 [M+H] +. 步驟5：室溫下將2,2,2-三氟-1-(2-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)乙烷-1-酮（1.1 g，2.5 mmol）和10%濕鈀碳（110 mg）加入到二氯甲烷（25 mL）和甲醇（25 mL）的混合溶液中，氫氣球置換三次，室溫下攪拌2小時。LCMS檢測反應完全，過濾，濾液減壓濃縮得到1-(2-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)-2,2,2-三氟乙烷-1-酮（960 mg，收率94%）。 MS (ESI) M/Z: 407.2 [M+H] +. 步驟6：室溫下將1-(2-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)-2,2,2-三氟乙烷-1-酮（960 mg，2.4 mmol），(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（975 mg，2.4 mmol）和三氟乙酸（2.7 g，23.6 mmol）依次加入到正丁醇（25 mL）中，氬氣保護下升溫至110℃攪拌反應16小時。LCMS檢測反應完全，將反應液冷卻至室溫，加水（100 mL）稀釋後用乙酸乙酯（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/1）得到1-(2-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)-2,2,2-三氟乙烷-1-酮（540 mg，收率29%）。 MS (ESI) M/Z: 782.1 [M+H] +. 步驟7：室溫下將1-(2-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯并[3,4-c]吡唑-5(4H)-基)-2,2,2-三氟乙烷-1-酮（540 mg，0.69 mmol）和氫氧化鉀（77 mg，1.4 mmol）加入到甲醇（10 mL）和水（5 mL）中，升溫至60℃攪拌反應2小時。將反應液冷卻至室溫，旋蒸除去大部分甲醇，用乙酸乙酯（50 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(6-((5-溴-2-((4-(5,6-二氫吡咯并[3,4-c]吡唑-2(4H)-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（480 mg，粗品）。 MS (ESI) M/Z: 686.2 [M+H] +. 步驟8：室溫下將(6-((5-溴-2-((4-(5,6-二氫吡咯并[3,4-c]吡唑-2(4H)-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（140 mg, 約0.20 mmol）和8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)辛基甲磺酸酯（98 mg, 0.20 mmol，製備參見專利WO201889736A1）溶於乙腈（25 mL）中，加入DIEA（77 mg, 0.60 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌16小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物4-((8-(2-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-2,6-二氫吡咯[3,4-c]并吡唑-5(4H)-基)辛基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（34 mg，收率16%）。 MS (ESI) M/Z: 1069.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.02 (s, 1H), 9.44 (s, 1H), 8.78-8.73 (m, 3H), 8.59 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.62 (d, J= 9.2 Hz, 1H), 7.53-7.49 (m, 1H),7.19 (s, 1H), 7.10 (d, J= 7.2 Hz, 1H), 7.01 (s, 1H), 6.91-6.86 (m, 2H), 6.68 (s, 1H), 6.25 (brs, 1H), 5.00-4.89 (m, 3H), 4.20-4.06 (m, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 3.37-3.27 (m, 4H), 3.11-2.99 (m, 8H), 2.90-2.73 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.89-1.85 (m, 2H), 1.70-1.65 (m, 2H). Example 43: 4-((8-(2-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole -5(4H)-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image500
Reaction flow:
Figure 02_image1055
Reaction steps: Step 1: Mix 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.5 g, 6.0 mmol), 2,6-dihydropyrrolo[3,4- c] Pyrazole-5(4H)-tert-butylcarboxylate (1.3 g, 6.0 mmol) was dissolved in DMF (50 mL), and potassium carbonate (1.7 g, 12.0 mmol) was added. The reaction system was heated to 85°C and stirred for 18 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 2-(2-bromo-5 -Methoxy-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-tert-butyl carboxylate (1.6 g, yield 61% ). MS (ESI) M/Z: 439.1 [M+H] + . Step 2: 2-(2-Bromo-5-methoxy-4-nitrophenyl)-2,6-dihydro Pyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (1.6 g, 3.6 mmol) and 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (0.76 g , 3.7 mmol) was dissolved in 1,4-dioxane (100 mL) and water (20 mL), cesium carbonate (3.6 g, 10.9 mmol) and ferrocene palladium dichloride (0.27 g, 0.36 mmol ), the reaction solution was heated to 110° C. and stirred for 18 hours under a nitrogen atmosphere. The completion of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, most of the 1,4-dioxane was removed by rotary evaporation, diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazole-4- yl)-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-tert-butyl carboxylate (1.4 g, yield 84%). MS (ESI) M/Z: 441.2 [M+H] + . Step 3: 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- 4-Nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (1.4 g, 3.1 mmol) in dichloromethane (100 mL) solution was added dropwise trifluoroacetic acid (25 mL). Stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,4, 5,6-Tetrahydropyrrolo[3,4-c]pyrazole trifluoroacetate (1.1 g, crude). MS (ESI) M/Z: 341.2 [M+H] + . Step 4: 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)- 4-nitrophenyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole trifluoroacetate (1.1 g, crude) and DMAP (789 mg, 6.5 mmol) were added to Dichloromethane (50 mL), stirred for 5 minutes, then added trifluoroacetic anhydride (1.4 g, 6.5 mmol), stirred at room temperature for 2 hours. Add water (100 mL) to quench and extract with dichloromethane (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to obtain 2,2,2-trifluoro-1-(2-(5-methoxy-2-( 1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethane -1-one (1.1 g, 79% yield in two steps). MS (ESI) M/Z: 437.3 [M+H] + . Step 5: 2,2,2-trifluoro-1-(2-(5-methoxy-2-(1-methoxy Base-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethane-1- Ketone (1.1 g, 2.5 mmol) and 10% wet palladium on carbon (110 mg) were added to a mixed solution of dichloromethane (25 mL) and methanol (25 mL), replaced by a hydrogen balloon three times, and stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(2-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)- 2,6-Dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (960 mg, yield 94%). MS (ESI) M/Z: 407.2 [M+H] + . Step 6: 1-(2-(4-amino-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1- Ketone (960 mg, 2.4 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (975 mg, 2.4 mmol) and trifluoroacetic acid (2.7 g, 23.6 mmol) were sequentially added to n-butanol (25 mL), and the temperature was raised to 110°C under the protection of argon to react with stirring for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 1-(2-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (540 mg, yield 29% ). MS (ESI) M/Z: 782.1 [M+H] + . Step 7: 1-(2-(4-((5-bromo-4-((5-(dimethylphosphoryl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2 ,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (540 mg, 0.69 mmol) and potassium hydroxide (77 mg, 1.4 mmol) was added to methanol (10 mL) and water (5 mL), heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature, most of the methanol was removed by rotary evaporation, and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((4-(5,6-dihydropyrrolo[3,4-c]pyrazole -2(4H)-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline -5-yl) dimethylphosphine oxide (480 mg, crude). MS (ESI) M/Z: 686.2 [M+H] + . Step 8: (6-((5-bromo-2-((4-(5,6-dihydropyrrolo[3, 4-c]pyrazol-2(4H-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl) Amino)quinolin-5-yl)dimethylphosphine oxide (140 mg, about 0.20 mmol) and 8-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindoline-4-yl)amino)octyl methanesulfonate (98 mg, 0.20 mmol, see patent WO201889736A1 for preparation) was dissolved in acetonitrile (25 mL), and DIEA (77 mg, 0.60 mmol ) and a catalytic amount of sodium iodide, the reaction system was heated to 80°C and stirred for 16 hours. LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((8-(2-(4-((5-bromo-4-((5-(di Phosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)octyl)amino)-2-(2,6-dioxopiperidine-3- base) isoindoline-1,3-dione (34 mg, yield 16%). MS (ESI) M/Z: 1069.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.02 (s, 1H), 9.44 (s, 1H), 8.78-8.73 (m, 3H) , 8.59 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.53-7.49 (m, 1H),7.19 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.91-6.86 (m, 2H), 6.68 (s, 1H), 6.25 (brs, 1H), 5.00-4.89 (m, 3H) , 4.20-4.06 (m, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 3.37-3.27 (m, 4H), 3.11-2.99 (m, 8H), 2.90-2.73 (m, 4H) , 2.16 (s, 3H), 2.12 (s, 3H), 1.89-1.85 (m, 2H), 1.70-1.65 (m, 2H).

實施例44: 4-((5-(4-(4-(4-((5-氯-4-((2-(二甲磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image502
反應流程:
Figure 02_image1058
反應步驟： 步驟1：室溫下將1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（0.5 g，1.3 mmol），(2-((2,5-二氯嘧啶-4-基)胺基)苯基)二甲基氧膦（375 mg，1.2 mmol）和三氟乙酸（1.35 g，11.8 mmol）依次加入到異丙醇（20 mL）中，氬氣保護下升溫至100℃攪拌反應16小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用乙酸乙酯打漿純化得到1-(4-(4-((5-氯-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙基-1-酮（480 mg，收率60%）。 MS (ESI) M/Z: 663.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.03 (s, 1H), 8.56-8.52 (m, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.51 (s, 1H), 7.00-6.99 (m, 2H), 6.64 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.79 (brs, 2H), 3.71-3.67 (m, 2H), 2.99-2.94 (m, 4H), 1.86 (s, 3H), 1.83 (s, 3H). 步驟2：室溫下將1-(4-(4-((5-氯-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙基-1-酮（430 mg，0.65 mmol）和氫氧化鉀（363 mg，6.5 mmol）加入到甲醇（10 mL）和水（4 mL）中，升溫至60℃攪拌反應4小時。將反應液冷卻至室溫，用二氯甲烷（20 mL）稀釋，分液。有機相先用飽和食鹽水（20 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦（304 mg，收率69%）。 MS (ESI) M/Z: 567.3 [M+H] +. 後續步驟以(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦為原料，參照實施例32的製備方法得到終產物4-((5-(4-(4-(4-((5-氯-4-((2-(二甲磷醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（20.2 mg）。 MS (ESI) M/Z: 989.4 [M-H] +. 1H NMR (400 MHz, CDCl 3): δ 12.01 (s, 1H), 10.59 (brs, 1H), 10.15 (s, 1H), 8.35-8.31 (m, 1H), 7.87 (d, J= 5.6 Hz, 2H), 7.58-7.50 (m, 2H), 7.42 (s, 1H), 7.17-7.12 (m, 2H), 6.99-6.92 (m, 2H), 6.68 (s, 1H), 6.25 (brs, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.57 (d, J= 10.4 Hz, 2H), 3.39-3.36 (m, 2H), 3.28 (brs, 5H), 2.97-2.86 (m, 4H), 2.80-2.74 (m, 4H), 2.58-2.53 (m, 4H), 2.36-2.27 (m, 6H), 1.86 (s, 3H), 1.83 (s, 3H), 1.78-1.73 (m, 2H), 1.63-1.59 (m, 2H). Example 44: 4-((5-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)piperidin-1-yl)pentyl)amino) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image502
Reaction flow:
Figure 02_image1058
Reaction steps: Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone- 1-yl)-2,2,2-trifluoroethane-1-one (0.5 g, 1.3 mmol), (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl) Dimethylphosphine oxide (375 mg, 1.2 mmol) and trifluoroacetic acid (1.35 g, 11.8 mmol) were sequentially added to isopropanol (20 mL), heated to 100°C under argon protection and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by slurrying with ethyl acetate to obtain 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl) Phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)- 2,2,2-Trifluoroethyl-1-one (480 mg, yield 60%). MS (ESI) M/Z: 663.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.03 (s, 1H), 8.56-8.52 (m, 1H), 8.22 (s, 1H) , 8.10 (s, 1H), 7.84 (s, 1H), 7.51 (s, 1H), 7.00-6.99 (m, 2H), 6.64 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H ), 3.79 (brs, 2H), 3.71-3.67 (m, 2H), 2.99-2.94 (m, 4H), 1.86 (s, 3H), 1.83 (s, 3H). Step 2: Mix 1- (4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- (1-Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethyl-1-one (430 mg, 0.65 mmol) and hydroxide Potassium (363 mg, 6.5 mmol) was added to methanol (10 mL) and water (4 mL), heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated. The organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-chloro-2-((2-methoxy-5-(1 -Methyl-1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (304 mg , yield 69%). MS (ESI) M/Z: 567.3 [M+H] + . Follow up with (2-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide as raw material, obtained by referring to the preparation method of Example 32 Final product 4-((5-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)piperidin-1-yl)pentyl)amino)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20.2 mg). MS (ESI) M/Z: 989.4 [MH] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.01 (s, 1H), 10.59 (brs, 1H), 10.15 (s, 1H), 8.35-8.31 (m, 1H), 7.87 (d, J = 5.6 Hz, 2H), 7.58-7.50 (m, 2H), 7.42 (s, 1H), 7.17-7.12 (m, 2H), 6.99-6.92 (m, 2H ), 6.68 (s, 1H), 6.25 (brs, 1H), 4.94-4.89 (m, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 3.57 (d, J = 10.4 Hz, 2H) , 3.39-3.36 (m, 2H), 3.28 (brs, 5H), 2.97-2.86 (m, 4H), 2.80-2.74 (m, 4H), 2.58-2.53 (m, 4H), 2.36-2.27 (m, 6H), 1.86 (s, 3H), 1.83 (s, 3H), 1.78-1.73 (m, 2H), 1.63-1.59 (m, 2H).

實施例45: 4-((5-(4-(4-((4-((2-(二甲磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image504
反應流程:
Figure 02_image1061
反應步驟： 步驟1：室溫下將1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（714 mg，1.9 mmol），(2-((2-氯-5-甲基嘧啶-4-基)胺基)苯基)二甲基氧膦（500 mg，1.7 mmol）和三氟乙酸（1.94 g，17.0 mmol）依次加入到異丙醇（50 mL）中，氬氣保護下升溫至95℃攪拌反應16小時。將反應液冷卻至室溫，減壓濃縮，所得殘餘物用製備級TLC板純化得到1-(4-(4-((4-((2-(二甲基磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙基-1-酮（690 mg，收率63%）。 MS (ESI) M/Z: 643.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.83 (s, 1H), 9.51 (s, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 7.86 (s, 2H), 7.63-7.57 (m, 2H), 7.20-7.03 (m, 2H), 6.92 (s, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.79 (brs, 4H), 3.01-2.94(m, 4H), 2.13 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H). 步驟2：室溫下將1-(4-(4-((4-((2-(二甲基磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙基-1-酮（500 mg，0.78 mmol）和氫氧化鉀（437 mg，7.8 mmol）加入到甲醇（50 mL）和水（20 mL）中，升溫至60℃攪拌反應4小時。將反應液冷卻至室溫，用二氯甲烷（50 mL）稀釋，分液。有機相先用飽和食鹽水（20 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)-5-甲基嘧啶-4-基)胺基)苯基)二甲基氧化膦（315 mg，收率74%）。 MS (ESI) M/Z: 547.3 [M+H] +. 步驟3：室溫下將(2-((2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)-5-甲基嘧啶-4-基)胺基)苯基)二甲基氧化膦（50 mg, 0.092 mmol）和5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧異吲哚啉-4-基)胺基)戊基甲磺酸酯（60 mg, 0.14 mmol）溶於乙腈（5 mL）中，加入DIEA（35 mg, 0.27 mmol）和催化量的碘化鈉，將反應體系加熱至110℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物4-((5-(4-(4-((4-((2-(二甲磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（10 mg，收率12%）。 MS (ESI) M/Z: 888.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.09 (s, 1H), 10.84 (s, 1H), 8.60-8.56 (m, 1H), 7.90 (d, J= 12.0 Hz, 2H), 7.83 (d, J= 4.8 Hz, 2H), 7.65 (s, 1H), 7.61-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.11 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 7.2 Hz, 1H), 6.95- 6.94 (m, 2H), 6.79 (s, 1H), 6.56-6.52 (m, 1H), 5.07-5.02 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.92 -2.83 (m, 6H), 2.67-2.56 (m, 4H), 2.42-2.33 (m, 2H), 2.06 (s, 3H), 2.02-1.98 (m, 2H), 1.79 (s, 3H), 1.76 (s, 3H), 1.64-1.58 (m, 2H), 1.55-1.51 (m, 2H), 1.42-1.37 (m, 2H), 1.28-1.24 (m, 2H). Example 45: 4-((5-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentyl)amino)-2-(2,6-di Oxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image504
Reaction flow:
Figure 02_image1061
Reaction steps: Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone- 1-yl)-2,2,2-trifluoroethane-1-one (714 mg, 1.9 mmol), (2-((2-chloro-5-methylpyrimidin-4-yl)amino)benzene Dimethylphosphine oxide (500 mg, 1.7 mmol) and trifluoroacetic acid (1.94 g, 17.0 mmol) were sequentially added to isopropanol (50 mL), heated to 95°C under argon protection and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified with a preparative TLC plate to obtain 1-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amine Base)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl) -2,2,2-Trifluoroethyl-1-one (690 mg, yield 63%). MS (ESI) M/Z: 643.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.83 (s, 1H), 9.51 (s, 1H), 8.46 (s, 1H) , 8.18 (s, 1H), 7.86 (s, 2H), 7.63-7.57 (m, 2H), 7.20-7.03 (m, 2H), 6.92 (s, 1H), 3.86 (s, 3H), 3.82 (s , 3H), 3.79 (brs, 4H), 3.01-2.94(m, 4H), 2.13 (s, 3H), 1.83 (s, 3H), 1.80 (s, 3H). Step 2: Mix 1- (4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2 -(1-Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethyl-1-one (500 mg, 0.78 mmol) and hydrogen Potassium oxide (437 mg, 7.8 mmol) was added to methanol (50 mL) and water (20 mL), heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (50 mL), and separated. The organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (315 mg, yield 74%). MS (ESI) M/Z: 547.3 [M+H] + . Step 3: (2-((2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(piper-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (50 mg, 0.092 mmol ) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl methanesulfonate (60 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 110°C and stirred overnight. LCMS monitoring showed that the raw material disappeared, and the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-((4-((2-(dimethylphosphoryl )phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (10 mg, yield 12%). MS (ESI) M/Z: 888.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.09 (s, 1H), 10.84 (s, 1H), 8.60-8.56 (m, 1H), 7.90 (d, J = 12.0 Hz, 2H), 7.83 (d, J = 4.8 Hz, 2H), 7.65 (s, 1H), 7.61-7.57 (m, 1H), 7.52-7.45 (m, 1H ), 7.11 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.95- 6.94 (m, 2H), 6.79 (s, 1H), 6.56-6.52 (m, 1H) , 5.07-5.02 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 2.92-2.83 (m, 6H), 2.67-2.56 (m, 4H), 2.42-2.33 (m, 2H) , 2.06 (s, 3H), 2.02-1.98 (m, 2H), 1.79 (s, 3H), 1.76 (s, 3H), 1.64-1.58 (m, 2H), 1.55-1.51 (m, 2H), 1.42 -1.37 (m, 2H), 1.28-1.24 (m, 2H).

實施例46: 4-((5-(4-(4-(4-((4-((2-(二甲磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image506
反應流程:
Figure 02_image1064
反應步驟： 以(2-((2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)-5-甲基嘧啶-4-基)胺基)苯基)二甲基氧化膦為原料，參照實施例32的步驟製備得到終產物4-((5-(4-(4-(4-((4-((2-(二甲磷醯基)苯基)胺基)-5-甲基嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（9.3 mg）。 MS (ESI) M/Z: 971.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.11 (brs, 1H), 10.83 (s, 1H), 8.60-8.57 (m, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.84 (d, J= 2.4 Hz, 2H), 7.65 (s, 1H), 7.61-7.58 (m, 1H), 7.53-7.46 (m, 1H), 7.11 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 6.8 Hz, 1H), 6.97-6.95 (m, 2H), 6.82 (s, 1H), 6.56-6.53 (m, 1H), 5.08-5.04 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.94-2.85 (m, 8H), 2.62-2.55 (m, 6H), 2.27-2.24 (m, 2H), 2.20-2.15 (m, 1H), 2.07 (s, 3H), 2.04-1.98 (m, 2H), 1.90-1.83 (m, 2H), 1.80 (s, 3H), 1.77 (s, 3H), 1.64-1.58 (m, 2H), 1.49-1.33 (m, 6H), 1.24 (d, J= 1.2 Hz, 2H). Example 46: 4-((5-(4-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)piperidin-1-yl)pentyl)amino )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image506
Reaction flow:
Figure 02_image1064
Reaction steps: With (2-((2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperi-1-yl)phenyl) Amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide was used as raw material, and the final product 4-((5-(4-(4- (4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine-3 -yl) isoindoline-1,3-dione (9.3 mg). MS (ESI) M/Z: 971.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.11 (brs, 1H), 10.83 (s, 1H), 8.60-8.57 (m, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 2.4 Hz, 2H), 7.65 (s, 1H), 7.61-7.58 (m, 1H), 7.53-7.46 (m , 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.97-6.95 (m, 2H), 6.82 (s, 1H), 6.56-6.53 (m, 1H), 5.08-5.04 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.94-2.85 (m, 8H), 2.62-2.55 (m, 6H), 2.27-2.24 (m, 2H), 2.20-2.15 (m, 1H), 2.07 (s, 3H), 2.04-1.98 (m, 2H), 1.90-1.83 (m, 2H), 1.80 (s, 3H), 1.77 (s, 3H) , 1.64-1.58 (m, 2H), 1.49-1.33 (m, 6H), 1.24 (d, J = 1.2 Hz, 2H).

實施例47: 4-((5-(4-(4-(4-((5-氯-4-((2-(二甲磷醯基)苯基)胺基)嘧啶-2-基)胺基)-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image508
反應流程:
Figure 02_image1067
反應步驟： 步驟1：室溫下將2-溴-1-氟-4-硝基苯（5.0 g, 22.8 mmol）、哌𠯤-1-羧酸第三丁酯（4.3 g, 23.0 mmol）溶於DMF（50 mL）中，加入碳酸鉀（9.5 g, 68.8 mmol）。將反應體系加熱至60℃並攪拌過夜。LCMS監控顯示原料消失。將反應液冷卻至室溫，倒入水（300 mL）中，用乙酸乙酯萃取（300 mL × 2）。合併有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，最後減壓濃縮，殘留物用矽膠柱層析純化（石油醚/乙酸乙酯=10/1）得到4-(2-溴-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（6.1 g，收率69%）。 MS (ESI) M/Z: 386.1 [M+H] +. 步驟2：室溫下將4-(2-溴-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（6.0 g, 15.6 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（3.23 g, 15.6 mmol）溶於DMF（50 mL）中, 加入碳酸鈉 (4.9 g, 46.6 mmol)和二茂鐵二氯化鈀(0.6 g, 0.8 mmol)，反應液在氬氣氛圍下加熱至110℃攪拌12小時。LCMS監測反應結束，將反應液冷卻至室溫，加水（500 mL）稀釋後用乙酸乙酯（250 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 40/1）得到4-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（5.3 g，收率88%）。 MS (ESI) M/Z: 388.2 [M+H] +. 步驟3：室溫下向4-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（5.3 g, 13.7 mmol）的二氯甲烷（30 mL）溶液加入5M鹽酸/二氧六環（30 mL，150 mmol），室溫攪拌2小時。LCMS監測原料消失，直接濃縮得到1-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤鹽酸鹽（2.8 g，粗品）。 MS (ESI) M/Z: 288.2 [M+H] +. 步驟4：室溫下將1-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤鹽酸鹽（2.1 g，粗品）和DMAP（1.8 g，14.6 mmol）加入到DMF（50 mL）中，攪拌5分鐘，再加入三氟乙酸酐（3.1 g，14.6 mmol），室溫攪拌過夜。將反應液倒入冰水（300 mL）中，用乙酸乙酯（200 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到2,2,2-三氟-1-(4-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-基)乙烷-1-酮（2.2 g，粗品）。 MS (ESI) M/Z: 384.3 [M+H] +. 步驟5：室溫下將2,2,2-三氟-1-(4-(2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-基)乙烷-1-酮（2.2 g，粗品）和10%濕鈀碳（200 mg）加入到甲醇（30 mL）中，氫氣球置換三次，室溫下攪拌過夜。LCMS檢測反應完全，過濾，濾液減壓濃縮得到1-(4-(4-胺基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（1.55 g，粗品）。 MS (ESI) M/Z: 354.2 [M+H] +. 步驟6：室溫下將1-(4-(4-胺基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（0.35 g，粗品），(2-((2,5-二氯嘧啶-4-基)胺基)苯基)二甲基氧膦（0.32 g，1.0 mmol）和三氟乙酸（0.35 g，3.0 mmol）依次加入到異丙醇（10 mL）中，氬氣保護下升溫至110℃攪拌反應16小時。LCMS檢測反應完全，將反應液冷卻至室溫，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 30/1）得到1-(4-(4-((5-氯-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（420 mg，四步收率29%）。 MS (ESI) M/Z: 633.1 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.19 (s, 1H), 9.28 (s, 1H), 8.58 (s, 1H), 8.18 (s, 2H), 7.84 (s, 1H), 7.66 (d, J= 2.4 Hz, 1H), 7.59-7.57 (m, 1H), 7.46 (d, J= 8.6 Hz, 1H), 7.25 (s, 1H), 7.09-7.05 (m, 2H), 3.88 (s, 3H), 3.74-3.70 (m, 4H), 2.87-2.83 (m, 4H), 1.80 (s, 3H), 1.77 (s, 3H). 步驟7：室溫下將1-(4-(4-((5-氯-4-((2-(二甲基磷醯基)苯基)胺基)嘧啶-2-基)胺基)-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（1.3 g，2.1 mmol）和氫氧化鉀（1.2 g，21.0 mmol）加入到甲醇（15 mL）和水（6 mL）中，升溫至60℃攪拌反應4小時。將反應液冷卻至室溫，加入二氯甲烷（30 mL）稀釋，用飽和食鹽水（20 mL×3次）洗滌。有機相用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((5-氯-2-((3-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦（1.0 g，收率91%）。 MS (ESI) M/Z: 537.2 [M+H] +. 後續步驟以(2-((5-氯-2-((3-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧化膦為原料，參照實施例32的製備方法得到終產物4-((5-(4-(4-(4-((5-氯-4-((2-(二甲磷醯基)苯基)胺基)嘧啶-2-基)胺基)-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（16.9 mg）。 MS (ESI) M/Z: 961.4 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.15 (s, 1H), 11.58 (brs, 1H), 10.10 (s, 1H), 8.48-8.45 (m, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.57-7.50 (m, 3H), 7.39 (d, J= 2.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.20-7.14 (m, 2H), 7.03 (d, J= 8.8 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 6.24 (brs, 1H), 4.94-4.89 (m, 1H), 3.93 (s, 3H), 3.62-3.45 (m, 2H), 3.38 (brs, 4H), 3.24 (brs, 5H), 2.98-2.87 (m, 4H), 2.81-2.73 (m, 4H), 2.71-2.62 (m, 2H), 2.58-2.44 (m, 4H), 2.35-2.24 (m, 2H), 1.89 (s, 3H), 1.85 (s, 3H), 1.78-1.59 (m, 4H). Example 47: 4-((5-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)piperidin-1-yl)pentyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image508
Reaction flow:
Figure 02_image1067
Reaction steps: Step 1: Dissolve 2-bromo-1-fluoro-4-nitrobenzene (5.0 g, 22.8 mmol) and tert-butyl piper-1-carboxylate (4.3 g, 23.0 mmol) at room temperature In DMF (50 mL), potassium carbonate (9.5 g, 68.8 mmol) was added. The reaction system was heated to 60 °C and stirred overnight. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (300 mL), and extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 4-(2-bromo-4 -Nitrophenyl) piper-1-carboxylate tert-butyl ester (6.1 g, yield 69%). MS (ESI) M/Z: 386.1 [M+H] + . Step 2: tert-butyl 4-(2-bromo-4-nitrophenyl)piperone-1-carboxylate (6.0 g, 15.6 mmol) and 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (3.23 g, 15.6 mmol) were dissolved in DMF (50 mL), sodium carbonate (4.9 g, 46.6 mmol) and di Ferrocene palladium dichloride (0.6 g, 0.8 mmol), the reaction solution was heated to 110°C under argon atmosphere and stirred for 12 hours. The completion of the reaction was monitored by LCMS, and the reaction solution was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (250 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=40/1) to obtain 4-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrate phenyl) piper-1-carboxylate tert-butyl (5.3 g, yield 88%). MS (ESI) M/Z: 388.2 [M+H] + . Step 3: 4-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl ) To a solution of tert-butyl piper-1-carboxylate (5.3 g, 13.7 mmol) in dichloromethane (30 mL) was added 5M hydrochloric acid/dioxane (30 mL, 150 mmol), and stirred at room temperature for 2 hours. The disappearance of the starting material was monitored by LCMS, and direct concentration gave 1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperone hydrochloride (2.8 g, crude product). MS (ESI) M/Z: 288.2 [M+H] + . Step 4: 1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl )piperone hydrochloride (2.1 g, crude product) and DMAP (1.8 g, 14.6 mmol) were added to DMF (50 mL), stirred for 5 minutes, then added trifluoroacetic anhydride (3.1 g, 14.6 mmol), room temperature Stir overnight. The reaction solution was poured into ice water (300 mL), and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2,2,2-trifluoro-1-(4-(2-(1-methyl-1H-pyrazol-4-yl)- 4-nitrophenyl)piperone-1-yl)ethan-1-one (2.2 g, crude). MS (ESI) M/Z: 384.3 [M+H] + . Step 5: 2,2,2-trifluoro-1-(4-(2-(1-methyl-1H-pyrazole -4-yl)-4-nitrophenyl)piper-1-yl)ethan-1-one (2.2 g, crude) and 10% wet palladium on carbon (200 mg) were added to methanol (30 mL) , replaced by a hydrogen balloon three times, and stirred overnight at room temperature. LCMS detected that the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(4-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl) -2,2,2-Trifluoroethane-1-one (1.55 g, crude). MS (ESI) M/Z: 354.2 [M+H] + . Step 6: 1-(4-(4-amino-2-(1-methyl-1H-pyrazol-4-yl )phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (0.35 g, crude product), (2-((2,5-dichloropyrimidin-4-yl) Amino)phenyl)dimethylphosphine oxide (0.32 g, 1.0 mmol) and trifluoroacetic acid (0.35 g, 3.0 mmol) were sequentially added to isopropanol (10 mL), heated to 110°C under argon protection and stirred React for 16 hours. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 1-(4-(4-((5-chloro-4-((2-(dimethylphosphonium Acyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2,2 , 2-trifluoroethane-1-one (420 mg, 29% yield over four steps). MS (ESI) M/Z: 633.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.19 (s, 1H), 9.28 (s, 1H), 8.58 (s, 1H) , 8.18 (s, 2H), 7.84 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.59-7.57 (m, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.25 ( s, 1H), 7.09-7.05 (m, 2H), 3.88 (s, 3H), 3.74-3.70 (m, 4H), 2.87-2.83 (m, 4H), 1.80 (s, 3H), 1.77 (s, 3H). Step 7: 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (1.3 g, 2.1 mmol) and potassium hydroxide (1.2 g, 21.0 mmol) were added to methanol (15 mL) and water (6 mL), heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (30 mL), and washed with saturated brine (20 mL×3 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-chloro-2-((3-(1-methyl-1H-pyrazol-4-yl)-4-(piper 𠯤-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.0 g, yield 91%). MS (ESI) M/Z: 537.2 [M+H] + . Subsequent step with (2-((5-chloro-2-((3-(1-methyl-1H-pyrazol-4-yl)- 4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide is a raw material, and the final product 4-(( 5-(4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(1 -Methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (16.9 mg). MS (ESI) M/Z: 961.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.15 (s, 1H), 11.58 (brs, 1H), 10.10 (s, 1H), 8.48 -8.45 (m, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.57-7.50 (m, 3H), 7.39 (d, J = 2.0 Hz, 1H), 7.35-7.29 (m, 2H ), 7.20-7.14 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.24 (brs, 1H), 4.94-4.89 (m, 1H) , 3.93 (s, 3H), 3.62-3.45 (m, 2H), 3.38 (brs, 4H), 3.24 (brs, 5H), 2.98-2.87 (m, 4H), 2.81-2.73 (m, 4H), 2.71 -2.62 (m, 2H), 2.58-2.44 (m, 4H), 2.35-2.24 (m, 2H), 1.89 (s, 3H), 1.85 (s, 3H), 1.78-1.59 (m, 4H).

實施例48: 5-(3-(4-(2-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image510
反應流程:
Figure 02_image1069
反應步驟： 步驟1：室溫下將4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（1.7 g，4.5 mmol），(6-((2,5-二氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（1.5 g，4.1 mmol）和三氟乙酸（4.68 g，41.0 mmol）依次加入到正丁醇（30 mL）中，氬氣保護下升溫至98℃攪拌過夜。將反應液冷卻至室溫，減壓濃縮，加入四氫呋喃（30 mL），然後向溶液中加入三乙胺（1.24 g，12.3 mmol），攪拌10分鐘，加入二碳酸二第三丁酯（900 mg，4.1 mmol），室溫攪拌2小時。向反應液中加入水（30 mL）淬滅，乙酸乙酯（40 mL×2）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 30/ 1）得到4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（2.0 g，收率75%）。 MS (ESI) M/Z: 719.4 [M+H] +. 步驟2：將4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（2.0 g，2.8 mmol）溶於乙酸乙酯（25 mL）中，加入5M鹽酸/二氧六環（18.5 mL，92.5 mmol），室溫攪拌30分鐘。TLC監測原料消失，直接濃縮得到(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（2.0 g，粗品）。 MS (ESI) M/Z: 619.0 [M+H] +. 步驟3：將(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（500 mg，約0.70 mmol）溶於1,2二氯乙烷（20 mL）和N ,N-二甲基甲醯胺（4 mL）中，加入三乙胺（232 mg，2.3 mmol），攪拌5分鐘，然後加入4-(2-氧乙基)哌啶-1-羧酸第三丁酯（347 mg，1.5 mmol），攪拌15分鐘，加入醋酸（0.75 mL），最後加入三乙醯氧基硼氫化鈉（486 mg，2.3 mmol），室溫攪拌2小時。TLC監測原料消失，向反應液加入飽和碳酸氫鈉（20 mL）淬滅，乙酸乙酯（30 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 20/ 1）得到4-(2-(4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-羧酸第三丁酯（380 mg，收率65%）。 MS (ESI) M/Z: 830.3 [M+H] +. 步驟4：將4-(2-(4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-羧酸第三丁酯（380 mg，0.46 mmol）溶於乙酸乙酯（6 mL）中，加入5M鹽酸/二氧六環溶液（3.5 mL），室溫攪拌30分鐘。TLC監測原料消失，直接減壓濃縮得到(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(2-(哌啶-4-基)乙基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（350 mg，粗品）。 MS (ESI) M/Z: 730.4 [M+H] +. 後續步驟以(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(2-(哌啶-4-基)乙基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽為原料，參照實施例35的製備方法得到終產物5-(3-(4-(2-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（25.1 mg）。 MS (ESI) M/Z: 1041.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.78 (s, 1H), 9.14 (dd, J= 9.6, 4.0 Hz, 1H), 8.73 (dd, J= 14.8, 1.8 Hz, 2H), 8.23-8.19 (m, 3H), 7.83 (s, 1H), 7.73-7.60 (m, 2H), 7.55-7.33 (m, 2H), 6.79 (d, J= 2.0 Hz, 1H), 6.73 (s, 1H), 6.53 (dd, J= 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.11 (t, J= 7.2 Hz, 2H), 3.91 (s, 3H), 3.91-3.83 (m, 2H), 3.71 (s, 3H), 3.35 (brs, 2H), 3.30-2.67 (m, 15H), 2.15 (s, 3H), 2.11 (s, 3H), 1.95-1.91 (m, 2H), 1.85 -1.29 (m, 7H). Example 48: 5-(3-(4-(2-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine- 1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image510
Reaction flow:
Figure 02_image1069
Reaction steps: Step 1: Add 4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-carboxy tertiary butyl ester (1.7 g, 4.5 mmol), (6-((2,5-dichloropyrimidin-4-yl) amino) quinolin-5-yl) dimethylphosphine oxide (1.5 g, 4.1 mmol) and trifluoroacetic acid (4.68 g, 41.0 mmol) were sequentially added to n-butanol (30 mL), heated to 98°C under argon protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added tetrahydrofuran (30 mL), then added triethylamine (1.24 g, 12.3 mmol) to the solution, stirred for 10 minutes, added di-tert-butyl dicarbonate (900 mg , 4.1 mmol), stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction liquid to quench, and ethyl acetate (40 mL×2) was extracted. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinone (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1 - Tertiary butyl carboxylate (2.0 g, 75% yield). MS (ESI) M/Z: 719.4 [M+H] + . Step 2: 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-carboxylic acid Dissolve tributyl ester (2.0 g, 2.8 mmol) in ethyl acetate (25 mL), add 5M hydrochloric acid/dioxane (18.5 mL, 92.5 mmol), and stir at room temperature for 30 minutes. TLC monitoring raw material disappears, directly concentrates to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (2.0 g, crude). MS (ESI) M/Z: 619.0 [M+H] + . Step 3: (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyridine Azol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, about 0.70 mmol) was dissolved in 1,2 dichloroethane (20 mL) and N,N-dimethylformamide (4 mL), added triethylamine (232 mg, 2.3 mmol), stirred for 5 minutes, then added tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (347 mg, 1.5 mmol), stirred for 15 minutes, added acetic acid (0.75 mL), and finally triacetyloxy Sodium borohydride (486 mg, 2.3 mmol), stirred at room temperature for 2 hours. The disappearance of the starting material was monitored by TLC, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 4-(2-(4-(4-((5-chloro-4-((5-(dimethyl Phosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base) piperidine-1-yl) ethyl) piperidine-1-carboxylate tert-butyl ester (380 mg, yield 65%). MS (ESI) M/Z: 830.3 [M+H] + . Step 4: Add 4-(2-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester (380 mg, 0.46 mmol) was dissolved in ethyl acetate (6 mL), and 5M hydrochloric acid/dioxane solution (3.5 mL) was added , and stirred at room temperature for 30 minutes. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(2-(piperidin-4-yl)ethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethyloxidation Phosphine hydrochloride (350 mg, crude). MS (ESI) M/Z: 730.4 [M+H] + . Follow up with (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(4-(2-(piperidin-4-yl)ethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline -5-base) dimethylphosphine oxide hydrochloride as raw material, the preparation method of referring to embodiment 35 obtains final product 5-(3-(4-(2-(4-(4-((5-chloro-4 -((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyridine Azol-4-yl)phenyl)piperone-1-yl)ethyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine-3 -yl) isoindoline-1,3-dione (25.1 mg). MS (ESI) M/Z: 1041.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.78 (s, 1H), 9.14 (dd, J = 9.6, 4.0 Hz, 1H), 8.73 (dd, J = 14.8, 1.8 Hz, 2H), 8.23-8.19 (m, 3H), 7.83 (s, 1H), 7.73-7.60 (m, 2H), 7.55-7.33 (m, 2H), 6.79 (d , J = 2.0 Hz, 1H), 6.73 (s, 1H), 6.53 (dd, J = 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.11 (t, J = 7.2 Hz, 2H) , 3.91 (s, 3H), 3.91-3.83 (m, 2H), 3.71 (s, 3H), 3.35 (brs, 2H), 3.30-2.67 (m, 15H), 2.15 (s, 3H), 2.11 (s , 3H), 1.95-1.91 (m, 2H), 1.85 -1.29 (m, 7H).

實施例49: 5-(3-(4-((4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1071
反應流程:
Figure 02_image1073
反應步驟： 步驟1：將(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（500 mg，約0.70 mmol）溶於1,2二氯乙烷（20 mL）和N ,N-二甲基甲醯胺（4 mL）中，加入三乙胺（232 mg，2.3 mmol），攪拌5分鐘，然後加入4-甲醯基哌啶-1-羧酸第三丁酯（325 mg，1.5 mmol），攪拌15分鐘，加入醋酸（0.75 mL），最後加入三乙醯氧基硼氫化鈉（486 mg，2.3 mmol），室溫攪拌2小時。TLC監測原料消失，向反應液加入飽和碳酸氫鈉（20 mL）淬滅，乙酸乙酯（30 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 20/ 1）得到4-((4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-羧酸第三丁酯（420 mg，收率74%）。 MS (ESI) M/Z: 816.4 [M+H] +. 步驟2：將4-((4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-羧酸第三丁酯（420 mg，0.52 mmol）溶於乙酸乙酯（7 mL）中，加入5M鹽酸/二氧六環溶液（3.9 mL），室溫攪拌30分鐘。TLC監測原料消失，直接減壓濃縮得到(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基甲基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（400 mg，粗品）。 MS (ESI) M/Z: 716.5 [M+H] +. 後續步驟以(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基甲基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽為原料，參照實施例35的製備方法得到終產物5-(3-(4-((4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（5.8 mg）。 MS (ESI) M/Z: 1027.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.78 (s, 1H), 9.15 (dd, J= 9.2, 3.6 Hz, 1H), 8.73 (d, J= 14.0 Hz, 2H), 8.26-8.07 (m, 3H), 7.80-7.65 (m, 3H), 7.38 (brs, 2H), 6.79 (s, 1H), 6.74 (s, 1H), 6.53 (d, J= 7.6 Hz, 1H), 4.95-4.91 (m, 1H), 4.11 (t, J= 6.8 Hz, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 3.70-3.49 (m, 4H), 3.36 (brs, 1H), 3.22-2.66 (m, 14H), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.25 (m, 7H). Example 49: 5-(3-(4-((4-(4-((5-chloro-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)methyl)piperidine-1- Base) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1071
Reaction flow:
Figure 02_image1073
Reaction steps: Step 1: (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, about 0.70 mmol) dissolved in 1,2 dichloro In ethane (20 mL) and N,N-dimethylformamide (4 mL), add triethylamine (232 mg, 2.3 mmol), stir for 5 minutes, then add 4-formylpiperidine-1 - Tertiary butyl carboxylate (325 mg, 1.5 mmol), stirred for 15 minutes, added acetic acid (0.75 mL), and finally sodium triacetyloxyborohydride (486 mg, 2.3 mmol), stirred at room temperature for 2 hours. The disappearance of the starting material was monitored by TLC, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=20/1) to obtain 4-((4-(4-((5-chloro-4-((5-(dimethylphosphorus Acyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) piperidine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (420 mg, yield 74%). MS (ESI) M/Z: 816.4 [M+H] + . Step 2: 4-((4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoline (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1 -yl)methyl)piperidine-1-carboxylate tert-butyl ester (420 mg, 0.52 mmol) was dissolved in ethyl acetate (7 mL), added 5M hydrochloric acid/dioxane solution (3.9 mL), room temperature Stir warm for 30 minutes. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(Piperidin-4-ylmethyl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (400 mg, crude). MS (ESI) M/Z: 716.5 [M+H] + . Follow up with (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(4-(piperidin-4-ylmethyl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5-yl ) Dimethylphosphine oxide hydrochloride as a raw material, and the final product 5-(3-(4-((4-(4-((5-chloro-4-((5-( Dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperone-1-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Phenyl-1,3-dione (5.8 mg). MS (ESI) M/Z: 1027.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.78 (s, 1H), 9.15 (dd, J = 9.2, 3.6 Hz, 1H), 8.73 (d, J = 14.0 Hz, 2H), 8.26-8.07 (m, 3H), 7.80-7.65 (m, 3H), 7.38 (brs, 2H), 6.79 (s, 1H), 6.74 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 4.95-4.91 (m, 1H), 4.11 (t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 3.70-3.49 (m, 4H), 3.36 (brs, 1H), 3.22-2.66 (m, 14H), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.25 (m, 7H).

實施例50: 4-((5-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1075
反應流程:
Figure 02_image1077
反應步驟： 步驟1：將1-溴-2-氟-4-甲基-5-硝基苯（2.0 g, 8.6 mmol）和哌𠯤-1-羧酸第三丁酯 （1.9 g, 10.2 mmol）溶於N’N-二甲基甲醯胺（12 mL）中，加入碳酸鉀（2.4 g, 17.1 mmol），升溫至60℃攪拌過夜。反應液用水（100 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，先用飽和食鹽水（50 mL）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 8/1）得到4-(2-溴-5-甲基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（3.2 g，收率93%）。 MS (ESI) M/Z: 400.1 [M+H] +. 步驟2：室溫下將4-(2-溴-5-甲基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（3.2 g, 8.0 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（2.16 g, 10.4 mmol）溶於二氧六環（70 mL）和水（14 mL）中, 加入碳酸鈉 (1.7 g, 16.0 mmol)和二茂鐵二氯化鈀(586 mg, 0.7 mmol)。反應液在氮氣氛圍下加熱至80℃攪拌過夜。將反應液冷卻至室溫，用水（200 mL）稀釋後用乙酸乙酯（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇＝20/1）得到4-(5-甲基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-甲酸第三丁酯（2.1 g，收率66%）。 MS (ESI) M/Z: 402.3 [M+H] +. 步驟3：將鐵粉（1.5 g，27.0 mmol）、二氧化矽（100-200目，3.1 g）和氯化銨（0.9 g，17.0 mmol）加入乙醇（20 mL）和水（20 mL）中，升溫至65℃，加入4-(5-甲基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（1.7 g，4.2 mmol）的四氫呋喃（15 mL）溶液，反應液在65℃攪拌1.5小時。TLC監測原料消失，將反應液倒入飽和食鹽水（100 mL）和乙酸乙酯（200 mL）中。過濾，分液，有機相用飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到4-(4-胺基-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（1.7 g，收率92%）。 MS (ESI) M/Z: 372.2 [M+H] +. 步驟4：室溫下將4-(4-胺基-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（1.0 g，2.7 mmol），(6-((2,5-二氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（830 mg，2.3 mmol）和三氟乙酸（2.5 g，22.4 mmol）依次加入到正丁醇（20 mL）中，氮氣保護下升溫至98℃攪拌過夜。將反應液冷卻至室溫，減壓濃縮，加入四氫呋喃（16 mL），然後向溶液中加入三乙胺（0.68 g，6.7 mmol），攪拌10分鐘，加入二碳酸二第三丁酯（488 mg，2.2 mmol），室溫攪拌2小時。向反應液中加入水（30 mL）淬滅，乙酸乙酯（40 mL×2）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 30/ 1）得到4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（1.0 g，收率66%）。 MS (ESI) M/Z: 703.2 [M+H] +. 步驟5：將4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-羧酸第三丁酯（1.0 g，1.4 mmol）溶於乙酸乙酯（20 mL）中，加入5M鹽酸/二氧六環（11 mL，55.0 mmol），室溫攪拌30分鐘。TLC監測原料消失，直接濃縮得到(6-((5-氯-2-((2-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（1.0 g，粗品）。 MS (ESI) M/Z: 603.6 [M+H] +. 步驟6：將(6- ((5-氯-2- ((2-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（110 mg， 約0.14 mmol）溶於N,N二甲基甲醯胺（20 mL）中，依次加入N,N-二異丙基乙胺（407 mg，3.1 mmol）、5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-4-基)胺基)戊基甲磺酸酯（411 mg，0.94 mmol）和碘化鈉（30 mg），反應液60℃攪拌過夜。TLC監測原料消失，向反應液加入飽和碳酸氫鈉溶液（50 mL）淬滅，二氯甲烷（25 mL×2）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物4-((5-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（15.8 mg，收率12%）。 MS (ESI) M/Z: 944.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.81 (s, 1H), 9.08 (dd, J= 9.6, 4.0 Hz, 1H), 8.74 -8.63 (m, 2H), 8.14 (s, 1H), 7.90 (brs, 1H), 7.77-7.65 (m, 2H), 7.59 (d, J= 9.6 Hz, 1H), 7.54-7.50 (m, 1H), 7.11 (d, J= 7.2 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.66 (s, 1H), 6.25 (t, J= 5.6 Hz, 1H), 4.94-4.90 (m, 1H), 3.82 (s, 3H), 3.32-3.30 (m, 2H), 3.06 (brs, 4H), 2.95-2.52 (m, 8H), 2.28 (s, 3H), 2.12-2.09 (m, 8H), 1.76-1.63 (m, 6H). Example 50: 4-((5-(4-(4-((5-chloro-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methyl-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) pentyl) amino) -2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1075
Reaction flow:
Figure 02_image1077
Reaction steps: Step 1: Combine 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (2.0 g, 8.6 mmol) and tert-butyl piper-1-carboxylate (1.9 g, 10.2 mmol ) was dissolved in N'N-dimethylformamide (12 mL), potassium carbonate (2.4 g, 17.1 mmol) was added, and the temperature was raised to 60°C and stirred overnight. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 8/1) to obtain 4-(2-bromo-5-methyl-4-nitrophenyl)piperone-1- Tertiary butyl carboxylate (3.2 g, yield 93%). MS (ESI) M/Z: 400.1 [M+H] + . Step 2: Dilute 4-(2-bromo-5-methyl-4-nitrophenyl)piperone-1-carboxylic acid at room temperature Tributyl ester (3.2 g, 8.0 mmol) and 1-methyl-4-1H-pyrazoleboronic acid pinacol ester (2.16 g, 10.4 mmol) were dissolved in dioxane (70 mL) and water (14 mL) In, sodium carbonate (1.7 g, 16.0 mmol) and ferrocenepalladium dichloride (586 mg, 0.7 mmol) were added. The reaction solution was heated to 80 °C under nitrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 4-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl) -4-Nitrophenyl)piperone-1-carboxylic acid tert-butyl ester (2.1 g, yield 66%). MS (ESI) M/Z: 402.3 [M+H] + . Step 3: Iron powder (1.5 g, 27.0 mmol), silicon dioxide (100-200 mesh, 3.1 g) and ammonium chloride (0.9 g, 17.0 mmol) into ethanol (20 mL) and water (20 mL), warming up to 65°C, adding 4-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4 -Nitrophenyl) piper-1-carboxylate tert-butyl ester (1.7 g, 4.2 mmol) in tetrahydrofuran (15 mL), and the reaction solution was stirred at 65°C for 1.5 hours. The disappearance of the starting material was monitored by TLC, and the reaction solution was poured into saturated brine (100 mL) and ethyl acetate (200 mL). Filtration, separation, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(4-amino-5-methyl-2-(1-methyl-1H -Pyrazol-4-yl)phenyl)piperone-1-carboxylate tert-butyl ester (1.7 g, yield 92%). MS (ESI) M/Z: 372.2 [M+H] + . Step 4: 4-(4-amino-5-methyl-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piperone-1-carboxylate (1.0 g, 2.7 mmol), (6-((2,5-dichloropyrimidin-4-yl)amino)quinoline-5 -Dimethylphosphine oxide (830 mg, 2.3 mmol) and trifluoroacetic acid (2.5 g, 22.4 mmol) were sequentially added to n-butanol (20 mL), heated to 98°C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added tetrahydrofuran (16 mL), then added triethylamine (0.68 g, 6.7 mmol) to the solution, stirred for 10 minutes, added di-tert-butyl dicarbonate (488 mg , 2.2 mmol), stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction liquid to quench, and ethyl acetate (40 mL×2) was extracted. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinone (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Tertiary butyl carboxylate (1.0 g, yield 66%). MS (ESI) M/Z: 703.2 [M+H] + . Step 5: 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoline-6 -yl) amino) pyrimidin-2-yl) amino) -5-methyl-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piperazine-1-carboxylic acid third Butyl ester (1.0 g, 1.4 mmol) was dissolved in ethyl acetate (20 mL), 5M hydrochloric acid/dioxane (11 mL, 55.0 mmol) was added, and stirred at room temperature for 30 minutes. TLC monitors the disappearance of the raw material, and directly concentrates to obtain (6-((5-chloro-2-((2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (1.0 g, crude). MS (ESI) M/Z: 603.6 [M+H] + . Step 6: (6-((5-chloro-2-((2-methyl-5-(1-methyl-1H-pyrazole -4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide hydrochloride (110 mg , about 0.14 mmol) was dissolved in N,N dimethylformamide (20 mL), and N,N-diisopropylethylamine (407 mg, 3.1 mmol), 5-(2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)pentyl methanesulfonate (411 mg, 0.94 mmol) and sodium iodide (30 mg), and the reaction solution was stirred overnight at 60°C. The disappearance of the starting material was monitored by TLC, and the reaction solution was quenched by adding saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (25 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoline-6- Base) amino) pyrimidin-2-yl) amino) -5-methyl-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) pentyl) Amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (15.8 mg, yield 12%). MS (ESI) M/Z: 944.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.81 (s, 1H), 9.08 (dd, J = 9.6, 4.0 Hz, 1H), 8.74 -8.63 (m, 2H), 8.14 (s, 1H), 7.90 (brs, 1H), 7.77-7.65 (m, 2H), 7.59 (d, J = 9.6 Hz, 1H), 7.54-7.50 (m, 1H ), 7.11 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.25 (t, J = 5.6 Hz, 1H ), 4.94-4.90 (m, 1H), 3.82 (s, 3H), 3.32-3.30 (m, 2H), 3.06 (brs, 4H), 2.95-2.52 (m, 8H), 2.28 (s, 3H), 2.12-2.09 (m, 8H), 1.76-1.63 (m, 6H).

實施例51: 4-((5-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image1079
反應流程:
Figure 02_image1081
反應步驟： 以(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽為原料，參照實施例50的操作製備得到終產物4-((5-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)戊基)胺基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（13.6 mg）。 MS (ESI) M/Z: 960.8 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.77 (s, 1H), 9.14 (dd, J= 9.6, 4.0 Hz, 1H), 8.73 (dd, J= 14.6, 1.8 Hz, 2H), 8.22-8.19 (m, 2H), 7.76 (brs, 1H), 7.68-7.56 (m, 2H), 7.54-7.47 (m, 1H), 7.36 (s, 1H), 7.11 (d, J= 6.8 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.73 (s, 1H), 6.25 (t, J= 5.6 Hz, 1H), 4.95-4.91 (m, 1H), 3.90 (s, 3H), 3.73 (s, 3H), 3.31-3.25 (m, 2H), 3.03 (brs, 4H), 2.94-2.37 (m, 8H), 2.15-2.10 (m, 8H), 1.77-1.66 (m, 6H). Example 51: 4-((5-(4-(4-((5-chloro-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) pentyl) amino) -2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image1079
Reaction flow:
Figure 02_image1081
Reaction steps: With (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinazolin-5-yl) dimethylphosphine oxide hydrochloride as raw material, the operation of referring to Example 50 was prepared to obtain the final product 4-((5 -(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxygen-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (13.6 mg). MS (ESI) M/Z: 960.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.77 (s, 1H), 9.14 (dd, J = 9.6, 4.0 Hz, 1H), 8.73 (dd, J = 14.6, 1.8 Hz, 2H), 8.22-8.19 (m, 2H), 7.76 (brs, 1H), 7.68-7.56 (m, 2H), 7.54-7.47 (m, 1H), 7.36 (s , 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.25 (t, J = 5.6 Hz, 1H), 4.95-4.91 (m, 1H), 3.90 (s, 3H), 3.73 (s, 3H), 3.31-3.25 (m, 2H), 3.03 (brs, 4H), 2.94-2.37 (m, 8H), 2.15-2.10 (m , 8H), 1.77-1.66 (m, 6H).

實施例52: 5-(3-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image513
反應流程:
Figure 02_image1084
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌𠯤-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例35的操作步驟製備得到終產物5-(3-(4-(1-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-4-基)哌𠯤-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（17.8 mg）。 MS (ESI) M/Z: 1075.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.71 (s, 1H), 11.09 (s, 1H), 9.41 (brs, 1H), 8.86 (d, J= 2.0 Hz, 1H), 8.81 (d, J= 1.6 Hz, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.66-7.60 (m, 2H), 6.96 (d, J= 7.6 Hz, 1H), 6.81 (s, 1H), 5.10-5.05 (m, 1H), 4.31-4.26 (m, 2H), 4.07-4.01 (m, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.35-3.28 (m, 2H), 3.23-3.07(m, 8H), 2.90-2.82 (m, 1H), 2.72-2.59 (m, 4H), 2.35-2.28 (m, 3H), 2.19-2.11 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H), 1.87-1.77 (m, 2H). Example 52: 5-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piper-1-yl)azepine Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image513
Reaction flow:
Figure 02_image1084
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piper 𠯤- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide as raw material, prepared with reference to the operation steps of Example 35 Obtain final product 5-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazol-1-yl)azacycle Butan-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (17.8 mg). MS (ESI) M/Z: 1075.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.71 (s, 1H), 11.09 (s, 1H), 9.41 (brs, 1H) , 8.86 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 1.6 Hz, 2H), 8.45 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.66-7.60 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 5.10-5.05 (m, 1H), 4.31-4.26 (m, 2H), 4.07 -4.01 (m, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.35-3.28 (m, 2H), 3.23-3.07(m, 8H), 2.90-2.82 (m, 1H), 2.72 -2.59 (m, 4H), 2.35-2.28 (m, 3H), 2.19-2.11 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H), 1.87-1.77 (m, 2H).

實施例53: 5-(3-(4-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image515
反應流程:
Figure 02_image1087
反應步驟： 步驟1：將(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（1.0 g，約1.5 mmol）溶於1,2二氯乙烷（50 mL）和N,N-二甲基甲醯胺中（10 mL）中，加入三乙胺（500 mg， 5.0 mmol），攪拌5分鐘，再加入4-氧代哌啶-1-羧酸第三丁酯（1.3 g，6.5 mmol），攪拌15分鐘，最後加入醋酸（1.5 mL）和三乙醯氧基硼氫化鈉（1.6 g，7.5 mmol），室溫攪拌過夜。TLC監測原料消失，向反應液中加入飽和碳酸氫鈉溶液（20 mL）淬滅，乙酸乙酯（30 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/ 1）得到4-(4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（840 mg，收率69%）。 MS (ESI) M/Z: 702.7 [M-Boc+H] +. 步驟2：將4-(4-(4-((5-氯-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（840 mg，1.0 mmol）溶於乙酸乙酯（16 mL）中，加入5M鹽酸/二氧六環溶液（8 mL），室溫攪拌30分鐘。TLC監測原料消失，直接減壓濃縮得到(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（800 mg，粗品）。 MS (ESI) M/Z: 702.3 [M+H] +. 後續步驟以(6-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽為原料，參照實施例35的製備方法得到終產物5-(3-(4-(4-(4-((5-氯-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（29.4 mg）。 MS (ESI) M/Z: 1013.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.78 (s, 1H), 9.14 (dd, J= 9.6, 4.0 Hz, 1H), 8.73 (dd, J= 15.6, 2.0 Hz, 2H), 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (brs, 1H), 7.82 (brs, 1H), 7.75-7.63 (m, 3H), 7.59-7.49 (m, 1H), 7.39 (brs, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.74 (s, 1H), 6.55 (dd, J= 8.4, 2.0 Hz, 1H), 4.96-4.92 (m, 1H), 4.25-4.23 (m, 1H), 4.22-4.08 (m, 2H), 3.91 (s, 3H), 3.91-3.87 (m, 2H), 3.70 (brs, 4H), 3.39 (brs, 2H), 3.28-2.67 (m, 12H), 2.15 (s, 3H), 2.11 (s, 3H), 2.08-1.96 (m, 2H), 1.77-1.65 (m, 4H). Example 53: 5-(3-(4-(4-(4-((5-chloro-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)azepine Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image515
Reaction flow:
Figure 02_image1087
Reaction steps: Step 1: (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (1.0 g, about 1.5 mmol) dissolved in 1,2 dichloro Add triethylamine (500 mg, 5.0 mmol) to ethane (50 mL) and N,N-dimethylformamide (10 mL), stir for 5 minutes, then add 4-oxopiperidine-1 - Tertiary butyl carboxylate (1.3 g, 6.5 mmol), stirred for 15 minutes, finally added acetic acid (1.5 mL) and sodium triacetyloxyborohydride (1.6 g, 7.5 mmol), stirred overnight at room temperature. The disappearance of the raw material was monitored by TLC, and saturated sodium bicarbonate solution (20 mL) was added to the reaction solution to quench it, and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 4-(4-(4-((5-chloro-4-((5-(dimethylphosphonium Acyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) piperidine-1-yl) tert-butyl piperidine-1-carboxylate (840 mg, yield 69%). MS (ESI) M/Z: 702.7 [M-Boc+H] + . Step 2: 4-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)piperidine-1-carboxylate tert-butyl ester (840 mg, 1.0 mmol) was dissolved in ethyl acetate (16 mL), added 5M hydrochloric acid/dioxane solution (8 mL), stirred at room temperature 30 minutes. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide hydrochloride (800 mg, crude). MS (ESI) M/Z: 702.3 [M+H] + . Follow up with (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5-yl)di Methylphosphine oxide hydrochloride was used as a raw material, and the final product 5-(3-(4-(4-(4-((5-chloro-4-((5-(dimethylphosphonium Acyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - Diketones (29.4 mg). MS (ESI) M/Z: 1013.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.78 (s, 1H), 9.14 (dd, J = 9.6, 4.0 Hz, 1H), 8.73 (dd, J = 15.6, 2.0 Hz, 2H), 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (brs, 1H), 7.82 (brs, 1H), 7.75-7.63 (m, 3H), 7.59-7.49 (m, 1H), 7.39 (brs, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.74 (s, 1H), 6.55 (dd, J = 8.4, 2.0 Hz, 1H), 4.96 -4.92 (m, 1H), 4.25-4.23 (m, 1H), 4.22-4.08 (m, 2H), 3.91 (s, 3H), 3.91-3.87 (m, 2H), 3.70 (brs, 4H), 3.39 (brs, 2H), 3.28-2.67 (m, 12H), 2.15 (s, 3H), 2.11 (s, 3H), 2.08-1.96 (m, 2H), 1.77-1.65 (m, 4H).

實施例54: 3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯基)胺基)哌啶-2,6-二酮

Figure 02_image517
反應流程:
Figure 02_image1089
反應步驟： 步驟1：將1-溴-4-硝基苯（4.8 g，23.8 mmol）、N-Boc-1,2,5,6-四氫吡啶-4-硼酸頻哪醇酯（7.3 g，23.8 mmol）、Pd(dppf)Cl 2（1.7 g，2.4 mmol）和磷酸鉀（9.85 g，71.3 mmol）依次加入二氧六環/水（40 mL/10 mL）中，氮氣置換三次，升溫至100℃攪拌過夜。LCMS監測原料消失，將反應液冷卻至室溫，加入水（50 mL）稀釋，乙酸乙酯（30 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 5/ 1）得到4-(4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（4.5 g，收率62%）。 MS (ESI) M/Z: 305.1 [M+H] +. 步驟2：室溫下將4-(4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（2.0 g，6.6 mmol）和10%濕鈀碳（350 mg）加入到甲醇/DMF（10 mL/10 mL）中，氫氣置換三次，室溫攪拌過夜。LCMS檢測反應完全，反應液過濾，減壓濃縮得到4-(4-胺基苯基)哌啶-1-羧酸第三丁酯（1.68 g，收率92%）。 MS (ESI) M/Z: 277.2 [M+H] +. 步驟3：室溫下將4-(4-胺基苯基)哌啶-1-羧酸第三丁酯（252 mg, 0.9 mmol）、3-溴哌啶-2,6-二酮（175 mg，0.9 mmol）和碳酸氫鈉（230 mg，2.7 mmol）依次加入DMF（10 mL）中，升溫至50℃攪拌過夜。LCMS監測原料消失，加入水（50 mL）稀釋，乙酸乙酯（30 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 3/ 1）得到4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-羧酸第三丁酯（112 mg，收率32%）。 MS (ESI) M/Z: 388.2 [M+H] +. 步驟4：將4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-羧酸第三丁酯（60 mg， 0.16 mmol）和5M HCl/dioxane（10 mL）加入到DCM（5 mL）中，室溫下攪拌30分鐘。LCMS監測反應完成。反應液減壓濃縮得到3-((4-(哌啶-4-基)苯基)胺基)哌啶-2,6-二酮鹽酸鹽（47 mg，粗品）。 MS (ESI) M/Z: 288.2 [M+H] +. 步驟5：室溫下將3-((4-(哌啶-4-基)苯基)胺基)哌啶-2,6-二酮鹽酸鹽（27 mg，粗品）、碳酸氫鈉（44 mg，0.5 mmol）和溴乙酸第三丁酯（21 mg，0.1 mmol）依從加入到乙腈（6 mL）中，升溫至50℃攪拌過夜。LCMS監測原料消失，加入水（30 mL）稀釋，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用製備級TLC板純化得到2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-基)乙酸第三丁酯（30 mg，二步收率84%）。 MS (ESI) M/Z: 402.3 [M+H] +. 步驟6：將2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-基)乙酸第三丁酯（30 mg，0.075 mmol）和5M HCl/dioxane（5 mL）加入到DCM（5 mL）中，室溫下攪拌1小時。LCMS監測反應完成。反應液減壓濃縮得到2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-基)乙酸鹽酸鹽（25 mg，粗品）。 MS (ESI) M/Z: 346.2 [M+H] +. 步驟7：室溫下將2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)苯基)哌啶-1-基)乙酸鹽酸鹽（25 mg，粗品）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（60 mg，0.09 mmol）、HATU（55 mg，0.14 mmol）和DIEA（28 mg，0.22 mmol）依次加入到DMF（5 mL）中，室溫下攪拌10分鐘。LCMS監測原料消失，加入水（30 mL）稀釋，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯基)胺基)哌啶-2,6-二酮（7.8 mg，二步收率11%）。 MS (ESI) M/Z: 990.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J= 1.6 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.11(brs, 1H), 7.68 (s, 1H), 7.64-7.61 (m, 2H), 7.36 (s, 1H), 7.05 (d, J= 7.6 Hz, 2H), 6.66-6.62 (m, 3H), 4.09-4.05 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.71-3.68 (m, 2H), 3.34 (brs, 2H), 3.10-3.06 (m, 2H), 2.91-2.88 (m, 6H), 2.79-2.70 (m, 2H), 2.56-2.52 (m, 2H), 2.46-2.41 (m, 2H), 2.34-2.28 (m, 2H), 2.24-2.20 (m, 1H), 2.15 (s, 3H), 2.11 (s, 3H), 2.03-2.00 (m, 2H). Example 54: 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione
Figure 02_image517
Reaction flow:
Figure 02_image1089
Reaction steps: Step 1: Mix 1-bromo-4-nitrobenzene (4.8 g, 23.8 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (7.3 g , 23.8 mmol), Pd(dppf)Cl 2 (1.7 g, 2.4 mmol) and potassium phosphate (9.85 g, 71.3 mmol) were sequentially added to dioxane/water (40 mL/10 mL), replaced with nitrogen three times, and the temperature was raised Stir overnight at 100°C. The disappearance of raw materials was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- Tertiary butyl carboxylate (4.5 g, yield 62%). MS (ESI) M/Z: 305.1 [M+H] + . Step 2: 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid at room temperature Tributyl ester (2.0 g, 6.6 mmol) and 10% wet palladium on carbon (350 mg) were added to methanol/DMF (10 mL/10 mL), replaced by hydrogen three times, and stirred overnight at room temperature. LCMS detected that the reaction was complete, and the reaction solution was filtered and concentrated under reduced pressure to obtain tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.68 g, yield 92%). MS (ESI) M/Z: 277.2 [M+H] + . Step 3: tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (252 mg, 0.9 mmol ), 3-bromopiperidine-2,6-dione (175 mg, 0.9 mmol) and sodium bicarbonate (230 mg, 2.7 mmol) were sequentially added to DMF (10 mL), heated to 50°C and stirred overnight. The disappearance of the starting material was monitored by LCMS, diluted with water (50 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 4-(4-((2,6-dioxopiperidin-3-yl)amino) Phenyl)piperidine-1-carboxylic acid tert-butyl ester (112 mg, yield 32%). MS (ESI) M/Z: 388.2 [M+H] + . Step 4: Add 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine- Tert-butyl 1-carboxylate (60 mg, 0.16 mmol) and 5M HCl/dioxane (10 mL) were added to DCM (5 mL), stirred at room temperature for 30 minutes. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (47 mg, crude product). MS (ESI) M/Z: 288.2 [M+H] + . Step 5: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6- Diketone hydrochloride (27 mg, crude product), sodium bicarbonate (44 mg, 0.5 mmol) and tertiary butyl bromoacetate (21 mg, 0.1 mmol) were added into acetonitrile (6 mL) according to the requirements, and the temperature was raised to 50°C Stir overnight. LCMS monitored the disappearance of the starting material, added water (30 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep TLC plate to give 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid third Butyl ester (30 mg, two-step yield 84%). MS (ESI) M/Z: 402.3 [M+H] + . Step 6: Adding 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl) Piperidin-1-yl)-tert-butyl acetate (30 mg, 0.075 mmol) and 5M HCl/dioxane (5 mL) were added to DCM (5 mL) and stirred at room temperature for 1 hour. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid hydrochloride (25 mg ,Crude). MS (ESI) M/Z: 346.2 [M+H] + . Step 7: 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino) Phenyl)piperidin-1-yl)acetic acid hydrochloride (25 mg, crude), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H- Pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (60 mg, 0.09 mmol), HATU (55 mg, 0.14 mmol) and DIEA (28 mg, 0.22 mmol) were sequentially added to DMF (5 mL), and stirred at room temperature for 10 minutes. LCMS monitored the disappearance of the starting material, added water (30 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (7.8 mg, 11% over two steps). MS (ESI) M/Z: 990.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.11(brs, 1H), 7.68 (s, 1H), 7.64-7.61 ( m, 2H), 7.36 (s, 1H), 7.05 (d, J = 7.6 Hz, 2H), 6.66-6.62 (m, 3H), 4.09-4.05 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.71-3.68 (m, 2H), 3.34 (brs, 2H), 3.10-3.06 (m, 2H), 2.91-2.88 (m, 6H), 2.79-2.70 (m, 2H), 2.56 -2.52 (m, 2H), 2.46-2.41 (m, 2H), 2.34-2.28 (m, 2H), 2.24-2.20 (m, 1H), 2.15 (s, 3H), 2.11 (s, 3H), 2.03 -2.00 (m, 2H).

實施例55: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image519
反應流程:
Figure 02_image1092
反應步驟： 步驟1：將2-(哌啶-4-基)乙烷-1-醇 （219.5 mg，1.7 mmol）溶於NMP（5 mL）中，加入2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（500 mg，1.7 mmol，製備參見US202016143A1），微波下升溫至140℃反應5 分鐘。LCMS監測反應結束，將反應液倒入水中，有固體析出，過濾，石油醚淋洗得到2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-(2-羥乙基)哌啶-1-基)異吲哚啉-1,3-二酮（560 mg，收率82%）。 MS (ESI) M/Z: 385.1 [M-H 2O] +. 步驟2：室溫下將2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-(2-羥乙基)哌啶-1-基)異吲哚啉-1,3-二酮（100 mg，0.25 mmol）溶於二氯甲烷（3 mL）中，加入三乙胺（38 mg，0.37 mmol），降溫至0℃，緩慢滴加甲磺醯氯（42.6 mg，0.37 mmol），0℃下攪拌30分鐘。LCMS監測反應結束，反應液用二氯甲烷（15 mL）稀釋，飽和碳酸氫鈉水溶液（20 mL×2）洗滌。合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 2/ 1）得到2-(1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（100 mg，收率84%）。 MS (ESI) M/Z: 482.1 [M+H] +. 步驟3：室溫下將2-(1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（37 mg，0.077 mmol）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（51 mg, 0.077 mmol）溶於乙腈（3 mL）中，加入DIEA（30 mg，0.23 mmol）和催化量的碘化鈉，85℃攪拌反應15小時。LCMS監測原料消失，反應液冷卻至室溫，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（18.7 mg，收率23%）。 MS (ESI) M/Z: 1048.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.73 (s, 1H), 11.11 (s, 1H), 9.53 (brs, 1H), 8.86 (d, J= 1.6 Hz, 1H), 8.82 (d, J= 2.0 Hz, 1H), 8.80 (brs, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.73 (d, J= 11.6 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J= 7.2 Hz, 1H), 6.78 (s, 1H), 5.13-5.08 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69-3.55 (m, 4H), 3.32-3.21 (m, 4H), 3.03-2.85 (m, 4H), 2.62-2.51 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.88-1.79 (m, 2H), 1.75-1.67 (m, 2H), 1.62-1.55 (m, 1H), 1.44-1.35 (m, 2H), 1.29-1.21 (m, 4H). Example 55: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image519
Reaction flow:
Figure 02_image1092
Reaction steps: Step 1: Dissolve 2-(piperidin-4-yl)ethan-1-ol (219.5 mg, 1.7 mmol) in NMP (5 mL), add 2-(2,6-dioxo Piperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (500 mg, 1.7 mmol, see US202016143A1 for preparation), heated to 140°C for 5 minutes under microwave. LCMS monitors the end of the reaction, the reaction solution is poured into water, solids are precipitated, filtered, and washed with petroleum ether to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4- (2-Hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (560 mg, yield 82%). MS (ESI) M/Z: 385.1 [MH 2 O] + . Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4- (2-Hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (100 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), triethylamine (38 mg , 0.37 mmol), cooled to 0°C, slowly added methanesulfonyl chloride (42.6 mg, 0.37 mmol) dropwise, and stirred at 0°C for 30 minutes. The completion of the reaction was monitored by LCMS, and the reaction solution was diluted with dichloromethane (15 mL) and washed with saturated aqueous sodium bicarbonate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 2-(1-(2-(2,6-dioxopiperidin-3-yl)- 6-Fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl methanesulfonate (100 mg, yield 84%). MS (ESI) M/Z: 482.1 [M+H] + . Step 3: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro -1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl methanesulfonate (37 mg, 0.077 mmol), (6-((5-bromo-2-( (2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino) Quinolin-5-yl) dimethylphosphine oxide (51 mg, 0.077 mmol) was dissolved in acetonitrile (3 mL), DIEA (30 mg, 0.23 mmol) and a catalytic amount of sodium iodide were added, and the reaction was stirred at 85°C 15 hours. LCMS monitored the disappearance of raw materials, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl) Ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (18.7 mg, yield 23 %). MS (ESI) M/Z: 1048.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.73 (s, 1H), 11.11 (s, 1H), 9.53 (brs, 1H) , 8.86 (d, J = 1.6 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.80 (brs, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.73 (d, J = 11.6 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 5.13- 5.08 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69-3.55 (m, 4H), 3.32-3.21 (m, 4H), 3.03-2.85 (m, 4H), 2.62- 2.51 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.88-1.79 (m, 2H), 1.75-1.67 (m, 2H), 1.62-1.55 (m, 1H), 1.44- 1.35 (m, 2H), 1.29-1.21 (m, 4H).

實施例56: 5-(4-((4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image521
反應流程:
Figure 02_image1095
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮和哌啶-4-基甲醇為原料，參照實施例55的操作步驟製備得到終產物5-(4-((4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（30.7 mg）。 MS (ESI) M/Z: 1034.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.78 (s, 1H), 11.11 (s, 1H), 9.77 (brs, 1H), 8.87 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.70-7.60 (m, 2H), 7.50 (brs, 1H), 7.09 (d, J= 6.8 Hz, 1H), 6.80 (s, 1H), 5.11-5.06 (m, 1H), 3.84-3.60 (m, 11H), 3.28 (brs, 8H), 3.03-2.86 (m, 3H), 2.63-2.52 (m, 2H), 2.33 (brs, 1H), 2.18 (brs, 1H), 2.06 (s, 3H), 2.02 (s, 3H), 1.90 (brs, 2H), 1.71 (brs, 1H). Example 56: 5-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl) piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image521
Reaction flow:
Figure 02_image1095
Reaction steps: Using 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and piperidin-4-ylmethanol as raw materials, Refer to the operation steps of Example 55 to prepare the final product 5-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)piper Pyridin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (30.7 mg). MS (ESI) M/Z: 1034.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.78 (s, 1H), 11.11 (s, 1H), 9.77 (brs, 1H) , 8.87 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.70-7.60 (m, 2H ), 7.50 (brs, 1H), 7.09 (d, J = 6.8 Hz, 1H), 6.80 (s, 1H), 5.11-5.06 (m, 1H), 3.84-3.60 (m, 11H), 3.28 (brs, 8H), 3.03-2.86 (m, 3H), 2.63-2.52 (m, 2H), 2.33 (brs, 1H), 2.18 (brs, 1H), 2.06 (s, 3H), 2.02 (s, 3H), 1.90 (brs, 2H), 1.71 (brs, 1H).

實施例57: 5-(3-(4-((4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image523
反應流程:
Figure 02_image1098
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦和4-甲醯基哌啶-1-羧酸第三丁酯為原料，參照實施例49的操作步驟製備得到終產物5-(3-(4-((4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（16.1 mg）。 MS (ESI) M/Z: 1070.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.99 (dd, J= 9.6, 4.0 Hz, 1H), 8.72 (dd, J= 12.0, 1.6 Hz, 2H), 8.29 (s, 1H), 8.21 (brs, 2H), 7.80-7.52 (m, 4H), 7.36 (s, 1H), 6.81-6.71 (m, 2H), 6.52 (dd, J= 8.4, 2.0 Hz, 1H), 4.94-4.92 (m, 1H), 4.11 (t, J= 7.6 Hz, 2H), 3.90 (brs, 5H), 3.72 (s, 3H), 3.37-3.33 (m, 1H), 3.22-2.66 (m, 14H), 2.15-2.11  (m, 8H), 1.96-1.89 (m, 5H), 1.45-1.27 (m, 2H). Example 57: 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)methyl)piperidine-1- Base) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image523
Reaction flow:
Figure 02_image1098
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethyl phosphine oxide and tertiary butyl 4-formylpiperidine-1-carboxylate as raw materials, refer to The operation steps of Example 49 prepared the final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline-6- Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl )piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16.1 mg) . MS (ESI) M/Z: 1070.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.99 (dd, J = 9.6, 4.0 Hz, 1H), 8.72 (dd, J = 12.0, 1.6 Hz, 2H), 8.29 (s, 1H), 8.21 (brs, 2H), 7.80-7.52 (m, 4H), 7.36 (s, 1H), 6.81-6.71 (m, 2H ), 6.52 (dd, J = 8.4, 2.0 Hz, 1H), 4.94-4.92 (m, 1H), 4.11 (t, J = 7.6 Hz, 2H), 3.90 (brs, 5H), 3.72 (s, 3H) , 3.37-3.33 (m, 1H), 3.22-2.66 (m, 14H), 2.15-2.11 (m, 8H), 1.96-1.89 (m, 5H), 1.45-1.27 (m, 2H).

實施例58: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image525
反應流程:
Figure 02_image1101
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮和2-(哌啶-4-基)乙烷-1-醇為原料，參照實施例55的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（12.8 mg）。 MS (ESI) M/Z: 1030.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99 (dd, J= 9.6, 4.0 Hz, 1H), 8.73 (dd, J= 13.6, 1.6 Hz, 2H), 8.30 (s, 1H), 8.23 (s, 1H), 8.14 (brs, 1H), 7.77-7.55 (m, 4H), 7.36 (s, 1H), 7.28 (d, J= 2.4 Hz, 1H), 7.05 (dd, J= 8.4, 2.4 Hz, 1H), 6.72 (s, 1H), 4.96-4.93 (m, 1H), 3.98-3.87 (m, 5H), 3.71 (s, 3H), 3.05-2.38 (m, 14H), 2.15 (s, 3H), 2.11 (s, 3H), 1.86-1.82 (m, 2H), 1.68-1.57 (m, 5H), 1.40-1.23 (m, 2H). Example 58: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image525
Reaction flow:
Figure 02_image1101
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione and 2-(piperidin-4-yl)ethane- 1-alcohol as raw material, the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.8 mg). MS (ESI) M/Z: 1030.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99 (dd, J = 9.6, 4.0 Hz, 1H), 8.73 (dd, J = 13.6, 1.6 Hz, 2H), 8.30 (s, 1H), 8.23 (s, 1H), 8.14 (brs, 1H), 7.77-7.55 (m, 4H), 7.36 (s, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.4 Hz, 1H), 6.72 (s, 1H), 4.96-4.93 (m, 1H), 3.98-3.87 (m, 5H) , 3.71 (s, 3H), 3.05-2.38 (m, 14H), 2.15 (s, 3H), 2.11 (s, 3H), 1.86-1.82 (m, 2H), 1.68-1.57 (m, 5H), 1.40 -1.23 (m, 2H).

實施例59: 5-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image527
反應流程:
Figure 02_image1103
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（1.7 g，約2.6 mmol）溶於甲醇（20 mL）和二氯甲烷（5 mL）中，加入2-氧代-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（740 mg，3.1 mmol），室溫攪拌1小時後，冰浴下慢慢加入氰基硼氫化鈉（650 mg，10.3 mmol），再室溫攪拌16小時。TLC監測原料消失，向反應液加入飽和碳酸氫鈉（20 mL）淬滅，乙酸乙酯（40 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇=40/ 1~ 20/ 1）得到2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（810 mg，收率36%）。 MS (ESI) M/Z: 886.5 [M+H] +. 步驟2：將2-(4-(4-((5-溴-4-((5-(二甲基磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（810 mg，0.92 mmol）溶於二氯甲烷（3 mL）中，冰浴下加入三氟乙酸（6 mL），室溫攪拌3小時。TLC監測原料消失，直接減壓濃縮得到(6-((2-((4-(4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸（800 mg，粗品）。 MS (ESI) M/Z: 786.7 [M+H] +. 步驟3：室溫下將(6-((2-((4-(4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸（200 mg，粗品）、2-(2,6-二氧哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（200 mg, 0.68 mmol）溶於N,N-二甲基甲醯胺（6 mL）中，加入碳酸鉀（152 mg，1.1 mmol）和催化量的碘化鈉，75℃攪拌反應16小時。LCMS監測原料消失，反應液冷卻至室溫，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物5-(2-(4-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（28.6 mg，收率12%）。 MS (ESI) M/Z: 1060.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.12 (s, 1H), 8.85-8.81 (m, 3H), 8.44 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.73-7.44 (m, 4H), 6.87 (m, 1H), 5.13-5.08 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.23-3.15 (m, 4H), 2.89-2.85 (m, 8H), 2.66-2.50 (m, 3H), 2.05-2.01 (m, 8H), 1.74-1.64 (m, 6H), 1.25-1.15 (m, 2H). Example 59: 5-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5]nonane- 7-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image527
Reaction flow:
Figure 02_image1103
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (1.7 g, about 2.6 mmol) was dissolved in methanol (20 mL) and dichloro In methane (5 mL), add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (740 mg, 3.1 mmol), stir at room temperature for 1 hour, and place in ice bath Sodium cyanoborohydride (650 mg, 10.3 mmol) was added slowly and stirred at room temperature for 16 hours. The disappearance of the starting material was monitored by TLC, and the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1～20/1) to obtain 2-(4-(4-((5-bromo-4-((5-(di Methylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) tert-butyl phenyl)piper-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (810 mg, yield 36%). MS (ESI) M/Z: 886.5 [M+H] + . Step 2: Dilute 2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinol Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (810 mg, 0.92 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (6 mL ), stirred at room temperature for 3 hours. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperone-1-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinolin-5-yl)dimethyl phosphine oxide trifluoroacetic acid (800 mg, crude). MS (ESI) M/Z: 786.7 [M+H] + . Step 3: (6-((2-((4-(4-(7-azaspiro[3.5]nonane-2 -yl) piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl) Amino)quinolin-5-yl)dimethylphosphine oxide trifluoroacetic acid (200 mg, crude product), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroiso Indoline-1,3-dione (200 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (6 mL), potassium carbonate (152 mg, 1.1 mmol) and a catalytic amount of iodine were added NaCl, stirred at 75°C for 16 hours. LCMS monitored the disappearance of raw materials, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinolin-6-yl ) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -7- Azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (28.6 mg, Yield 12%). MS (ESI) M/Z: 1060.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.12 (s, 1H), 8.85-8.81 (m, 3H), 8.44 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.73-7.44 (m, 4H), 6.87 (m, 1H), 5.13-5.08 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.23-3.15 (m, 4H), 2.89-2.85 (m, 8H), 2.66-2.50 (m, 3H), 2.05-2.01 (m, 8H), 1.74-1.64 (m, 6H), 1.25-1.15 (m, 2H).

實施例60: 5-(3-(1'-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-[4,4'-二哌啶]-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image529
反應流程:
Figure 02_image1105
反應步驟： 步驟1：室溫下將[4,4'-二哌啶]-1-羧酸第三丁酯（1.6 g, 6.0 mmol）、1-溴-2-氟-4-甲氧基-5-硝基苯（1.4 g, 5.6 mmol）溶於DMF（20 mL）中，加入碳酸鉀（0.8 g, 6.0 mmol），室溫攪拌16小時。LCMS監控顯示原料消失。將反應液冷卻至室溫，倒入冰水（100 mL）中，用乙酸乙酯萃取（120 mL × 2）。合併有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，最後減壓濃縮，石油醚結晶純化得到1'-(2-溴-5-甲氧基-4-硝基苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯（1.6 g，收率57%）。 MS (ESI) M/Z: 498.2 [M+H] +. 步驟2：室溫下將1'-(2-溴-5-甲氧基-4-硝基苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯（1.6 g, 3.2 mmol）和1-甲基-4-1H-吡唑硼酸頻那醇酯（0.8 g, 3.8 mmol）溶於二氧六環（10 mL）和水（1 mL）中, 加入磷酸鉀（1.3 g, 6.4 mmol）和二茂鐵二氯化鈀（0.12 g, 0.16 mmol)，反應液在氮氣氛圍下加熱至80℃攪拌16小時。LCMS監測反應結束，將反應液冷卻至室溫，用水（200 mL）稀釋後用乙酸乙酯（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮得到1'-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯（1.3 g，粗品）。 MS (ESI) M/Z: 500.4 [M+H] +. 步驟3：室溫下將1'-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯（1.1 g，粗品）和10%鈀碳（110 mg）加入到甲醇（15 mL）中，在氫氣球氛圍下室溫攪拌4小時。TLC監測顯示原料消失，過濾，濾液減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/乙酸乙酯= 1/1）得到1'-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯（0.75 g，二步收率59%）。 MS (ESI) M/Z: 470.4 [M+H] +. 後續步驟以1'-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-[4,4'-聯哌啶]-1-羧酸第三丁酯為原料，參照實施例35和實施例48的製備方法得到終產物5-(3-(1'-(4-((5-溴-4-((5-(二甲磷醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-[4,4'-二哌啶]-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（33.6 mg）。 MS (ESI) M/Z: 1056.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.68 (s, 1H), 11.09 (s, 1H), 8.84-8.81 (m, 3H), 8.45 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.67-7.65 (m, 1H), 7.56 (s, 2H), 6.81 (d, J= 8.0 Hz, 2H), 6.69-6.67 (m, 1H), 5.10-5.06 (m, 1H), 4.14-4.10 (m, 2H), 3.84-3.79 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.37-3.31 (m, 2H), 3.15-3.12 (m, 2H), 2.91-2.85 (m, 3H), 2.66-2.52 (m, 6H), 2.03 (s, 3H), 1.99 (s, 3H), 1.93-1.70 (m, 6H), 1.35-1.10 (m, 4H). Example 60: 5-(3-(1'-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-dipiperidin]-1-yl)azepine Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image529
Reaction flow:
Figure 02_image1105
Reaction steps: Step 1: Add [4,4'-dipiperidine]-1-carboxylic acid tert-butyl ester (1.6 g, 6.0 mmol), 1-bromo-2-fluoro-4-methoxy -5-Nitrobenzene (1.4 g, 5.6 mmol) was dissolved in DMF (20 mL), potassium carbonate (0.8 g, 6.0 mmol) was added, and stirred at room temperature for 16 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with ethyl acetate (120 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by petroleum ether crystallization to obtain 1'-(2-bromo-5-methoxy-4-nitrophenyl)-[4 ,4'-bipiperidine]-1-carboxylate tert-butyl ester (1.6 g, yield 57%). MS (ESI) M/Z: 498.2 [M+H] + . Step 2: 1'-(2-bromo-5-methoxy-4-nitrophenyl)-[4,4' -Bipiperidine]-tert-butyl carboxylate (1.6 g, 3.2 mmol) and 1-methyl-4-1H-pyrazole borate pinacol ester (0.8 g, 3.8 mmol) were dissolved in dioxane Ring (10 mL) and water (1 mL), add potassium phosphate (1.3 g, 6.4 mmol) and ferrocene palladium dichloride (0.12 g, 0.16 mmol), the reaction solution was heated to 80 ° C under nitrogen atmosphere and stirred 16 hours. The completion of the reaction was monitored by LCMS, and the reaction solution was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 1'-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene base)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (1.3 g, crude product). MS (ESI) M/Z: 500.4 [M+H] + . Step 3: 1'-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) -4-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylate tert-butyl ester (1.1 g, crude product) and 10% palladium on carbon (110 mg) were added to methanol (15 mL) , stirred at room temperature for 4 hours under a hydrogen balloon atmosphere. TLC monitoring showed that the starting material disappeared, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate = 1/1) to obtain 1'-(4-amino-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (0.75 g, di step yield 59%). MS (ESI) M/Z: 470.4 [M+H] + . Subsequent step with 1'-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl ) phenyl)-[4,4'-bipiperidine]-1-carboxylate tert-butyl ester as raw material, the final product 5-(3-(1'- (4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2 -(1-Methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-dipiperidin]-1-yl)azetidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (33.6 mg). MS (ESI) M/Z: 1056.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.68 (s, 1H), 11.09 (s, 1H), 8.84-8.81 (m, 3H) , 8.45 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.67-7.65 (m, 1H), 7.56 (s, 2H), 6.81 (d, J = 8.0 Hz, 2H), 6.69-6.67 (m, 1H), 5.10-5.06 (m, 1H), 4.14-4.10 (m, 2H), 3.84-3.79 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.37-3.31 (m, 2H), 3.15-3.12 (m, 2H), 2.91-2.85 (m, 3H), 2.66-2.52 (m, 6H), 2.03 (s, 3H), 1.99 (s, 3H), 1.93-1.70 (m, 6H), 1.35-1.10 (m, 4H).

實施例61: 5-(3-(4-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image531
反應流程:
Figure 02_image1108
反應步驟： 步驟1：室溫下將(6-胺基-2,3-二甲基苯基)二甲基氧化膦（1.1 g, 5.6 mmol）溶於丙酮（50 mL）中，加入5-溴-2,4-二氯吡啶（1.3 g, 5.6 mmol）和N,N-二異丙基乙胺（1.4 g, 11.2 mmol）。反應液在氮氣保護下加熱至60℃攪拌3小時至反應完全。將反應液冷卻至室溫並減壓濃縮，加入水（50 mL），用乙酸乙酯（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（1.7 g，收率78%）。 MS (ESI) M/Z: 388.0 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（1.7 g，4.4 mmol）溶於正丁醇（50 mL），加入1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（1.7 g，4.4 mmol）和三氟乙酸（5.0 g， 43.7 mmol），氮氣置換2次，升溫至110℃攪拌過夜，LCMS監測反應完畢。將反應液冷卻至室溫並減壓濃縮，加入水（50 mL），用乙酸乙酯（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到1-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（3.2 g，收率99%）。 MS (ESI) M/Z: 735.2 [M+H] +. 步驟3：室溫下將1-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（3.2 g，4.4 mmol）溶於甲醇（50 mL）和水（10 mL）中，加入氫氧化鉀（487 mg，8.7 mmol），氮氣保護下升溫至60℃攪拌1小時，LCMS監測反應結束。將反應液冷卻至室溫並減壓濃縮，加入水（50 mL），用乙酸乙酯/甲醇=10:1（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物（2.2 g，收率79%）。 MS (ESI) M/Z: 639.2 [M+H] +. 步驟4：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物（2.2 g, 3.4 mmol）和4-碘哌啶-1-羧酸第三丁酯（2.1 g, 6.9 mmol）溶於乙腈（10 mL）中，加入碳酸鉀（1.4 g, 10.3 mmol），氮氣置換3次後，反應體系升溫至100℃攪拌4天。LCMS監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。加入水（50 mL），用二氯甲烷（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1~5/1）得到4-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（1.5 g，收率53%）。 MS (ESI) M/Z: 822.3 [M+H] +. 步驟5：將4-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（1.5 g, 1.8 mmol）溶於二氯甲烷（50 mL）中，加入三氟乙酸（10 mL），室溫下攪拌3小時。LCMS監測顯示反應結束，加入水（50 mL），用二氯甲烷（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物的三氟乙酸鹽（1.2 g，粗品）。 MS (ESI) M/Z: 722.3 [M+H] +. 步驟6：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物的三氟乙酸鹽（0.5 g, 粗品）和3-碘氮雜環丁烷-1-羧酸第三丁酯（588 mg, 2.1 mmol）溶於乙腈（50 mL）中，加入碳酸鉀（477 mg, 3.5 mmol），氮氣置換3次後，反應體系升溫至100℃攪拌4天。LCMS監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。加入水（50 mL），用二氯甲烷（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1~5/1）得到3-(4-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（280 mg，二步收率42%）。 MS (ESI) M/Z: 877.3 [M+H] +. 步驟7：將3-(4-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（280 mg, 0.32 mmol）溶於二氯甲烷（50 mL）中，加入三氟乙酸（10 mL），室溫下攪拌3小時。LCMS監測顯示反應結束，加入水（30 mL），用二氯甲烷（30 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物的三氟乙酸鹽（220 mg，粗品）。 MS (ESI) M/Z: 777.3 [M+H] +. 步驟8：室溫下將(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基磷氧化物的三氟乙酸鹽（120 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（43 mg, 0.15 mmol）溶於DMSO（5 mL）和乙腈（5 mL）中，加入DIEA（40 mg, 0.31 mmol），將反應體系加熱至80℃並攪拌16小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(3-(4-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（23.1 mg，收率15%）。 MS (ESI) M/Z: 1033.2 [M+H] +. 1H NMR (400 MHz, CDCl 3/CD 3OD): δ 8.08 (s, 1H), 7.98-7.95 (m, 1H), 7.71-7.64 (m, 4H), 7.50 (s, 1H), 6.86 (s, 1H), 6.77-6.71 (m, 2H), 6.65-6.62 (m, 1H), 4.98-4.95 (m, 1H), 4.26 (t, J= 7.6 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88-3.81 (m, 1H), 3.75-3.50 (m, 4H), 3.28 (brs, 6H), 2.88-2.75 (m, 3H), 2.71-2.59 (m, 2H), 2.40-2.29 (m, 6H), 2.20-2.11 (m, 8H), 2.02 (s, 3H), 1.99 (s, 3H). Example 61: 5-(3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image531
Reaction flow:
Figure 02_image1108
Reaction steps: Step 1: Dissolve (6-amino-2,3-dimethylphenyl) dimethylphosphine oxide (1.1 g, 5.6 mmol) in acetone (50 mL) at room temperature, add 5- Bromo-2,4-dichloropyridine (1.3 g, 5.6 mmol) and N,N-diisopropylethylamine (1.4 g, 11.2 mmol). The reaction solution was heated to 60°C under nitrogen protection and stirred for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, added water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dimethyl phenyl) dimethylphosphine oxide (1.7 g, yield 78%). MS (ESI) M/Z: 388.0 [M+H] + . Step 2: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-di Methylphenyl) dimethylphosphine oxide (1.7 g, 4.4 mmol) was dissolved in n-butanol (50 mL), and 1-(4-(4-amino-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (1.7 g, 4.4 mmol) and trifluoroacetic acid (5.0 g, 43.7 mmol), replaced with nitrogen twice, heated to 110°C and stirred overnight, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure, added water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 1-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl)-2,2,2-trifluoroethane-1-one (3.2 g, yield 99%). MS (ESI) M/Z: 735.2 [M+H] + . Step 3: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) (Piperyl-1-yl)-2,2,2-trifluoroethane-1-one (3.2 g, 4.4 mmol) was dissolved in methanol (50 mL) and water (10 mL), and potassium hydroxide (487 mg, 8.7 mmol), heated to 60°C under nitrogen protection and stirred for 1 hour, and the reaction was monitored by LCMS. The reaction solution was cooled to room temperature and concentrated under reduced pressure, added water (50 mL), and extracted with ethyl acetate/methanol=10:1 (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain (6 -((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide (2.2 g, yield 79%). MS (ESI) M/Z: 639.2 [M+H] + . Step 4: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyridine Azol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide ( 2.2 g, 3.4 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (2.1 g, 6.9 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (1.4 g, 10.3 mmol) was added, and nitrogen replacement After 3 times, the temperature of the reaction system was raised to 100°C and stirred for 4 days. LCMS monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. Add water (50 mL), and extract with dichloromethane (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1~5/1 ) to give 4-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amine Base)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g , yield 53%). MS (ESI) M/Z: 822.3 [M+H] + . Step 5: Add 4-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3, 4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol- 1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 1.8 mmol) was dissolved in dichloromethane (50 mL), added trifluoroacetic acid (10 mL), and stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, water (50 mL) was added, and extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3- Dimethylphenyl) trifluoroacetate salt of dimethylphosphorus oxide (1.2 g, crude). MS (ESI) M/Z: 722.3 [M+H] + . Step 6: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyridine Azol-4-yl)-4-(4-(piperidin-4-yl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethyl Trifluoroacetate salt of phenyl)dimethylphosphorus oxide (0.5 g, crude product) and tert-butyl 3-iodoazetidine-1-carboxylate (588 mg, 2.1 mmol) were dissolved in acetonitrile (50 mL), potassium carbonate (477 mg, 3.5 mmol) was added, and after nitrogen replacement 3 times, the reaction system was heated to 100°C and stirred for 4 days. LCMS monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. Add water (50 mL), and extract with dichloromethane (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1~5/1 ) to obtain 3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)azacycle Butane-1-carboxylate tert-butyl ester (280 mg, 42% yield over two steps). MS (ESI) M/Z: 877.3 [M+H] + . Step 7: 3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl )-3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperidin-1-yl)piperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (280 mg, 0.32 mmol) was dissolved in dichloromethane (50 mL), and trifluoro Acetic acid (10 mL), stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, water (30 mL) was added, and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidin-3-yl )piperidin-4-yl)piper-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide trifluoroacetate (220 mg, crude). MS (ESI) M/Z: 777.3 [M+H] + . Step 8: (6-((2-((4-(4-(1-(azetidin-3-yl )piperidin-4-yl)piper-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidine -4-yl)amino)-2,3-dimethylphenyl)trifluoroacetate salt of dimethylphosphorus oxide (120 mg, crude product) and 2-(2,6-dioxopiperidine- 3-yl)-5-fluoroisoindoline-1,3-dione (43 mg, 0.15 mmol) was dissolved in DMSO (5 mL) and acetonitrile (5 mL), and DIEA (40 mg, 0.31 mmol) was added , the reaction system was heated to 80 °C and stirred for 16 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(4-(4-((5-bromo-4-((2- (Dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piper-1-yl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (23.1 mg, yield 15%). MS (ESI) M/Z: 1033.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 /CD 3 OD): δ 8.08 (s, 1H), 7.98-7.95 (m, 1H), 7.71- 7.64 (m, 4H), 7.50 (s, 1H), 6.86 (s, 1H), 6.77-6.71 (m, 2H), 6.65-6.62 (m, 1H), 4.98-4.95 (m, 1H), 4.26 ( t, J = 7.6 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.88-3.81 (m, 1H), 3.75-3.50 (m, 4H), 3.28 (brs, 6H), 2.88 -2.75 (m, 3H), 2.71-2.59 (m, 2H), 2.40-2.29 (m, 6H), 2.20-2.11 (m, 8H), 2.02 (s, 3H), 1.99 (s, 3H).

實施例62： 5-(3-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-1,4’-雙哌啶-1’-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image533
反應流程:
Figure 02_image1111
反應步驟： 步驟1：將4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（770 mg，1.9 mmol，製備可參考專利WO2021/104441A1）溶於甲醇（20 mL）中，加入10% Pd/C（80 mg）。室溫10公斤氫氣壓下攪拌反應16小時。過濾，濾液減壓濃縮得到4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-羧酸第三丁酯（600 mg，收率84%），直接用於下步反應。 MS (ESI) M/Z: 387.2 [M+H] +. 步驟2：室溫下將4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-羧酸第三丁酯（370 mg，0.96 mmol），(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（357 mg，0.87 mmol）和三氟乙酸（992 mg，8.7 mmol）依次加入到正丁醇（10 mL）中，氮氣保護下升溫至98℃攪拌過夜。將反應液冷卻至室溫，減壓濃縮，加入四氫呋喃（10 mL），然後向溶液中加入三乙胺（90 mg，0.89 mmol），攪拌10分鐘，加入二碳酸二第三丁酯（285 mg，1.3 mmol），室溫攪拌2小時。向反應液中加入水（50 mL）淬滅，乙酸乙酯（50 mL×2）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/ 1）得到4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-羧酸第三丁酯（370 mg，收率56%）。 MS (ESI) M/Z: 761.7 [M+H] +. 步驟3：將4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌啶-1-羧酸第三丁酯（370 mg，0.49 mmol）溶於乙酸乙酯（8 mL）中，加入5M氯化氫/乙酸乙酯溶液（5 mL），室溫攪拌30分鐘。TLC監測原料消失，過濾，濾餅用飽和碳酸鉀溶液調節pH值到9，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌啶-4-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（300 mg，收率93%）。 MS (ESI) M/Z: 661.9 [M+H] +. 後續步驟以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌啶-4-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例35和實施例53的製備方法得到終產物5-(3-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)-1,4’-雙哌啶-1’-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（4 mg）。 MS (ESI) M/Z: 1056.6 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.77 (s, 1H), 8.90-8.80 (m, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.00 (brs, 1H),7.67-7.64 (m, 2H), 7.34-7.26 (m, 2H), 7.10 (s, 1H), 6.83-6.80 (m, 1H), 6.56-6.54 (m, 1H), 4.95-4.93 (m, 1H), 4.20-4.05 (m, 2H), 3.95-3.80 (m, 8H), 3.60-3.40 (m, 4H), 2.85-2.65 (m, 6H), 2.20-2.00 (m, 9H), 2.00-1.60 (m, 6H), 1.30-1.20 (m, 4H). Example 62: 5-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-ylamino)pyrimidin-2-yl)amine Base)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,4'-bispiperidin-1'-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image533
Reaction flow:
Figure 02_image1111
Reaction steps: Step 1: 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,6-dihydropyridine- 1(2H)-tert-butyl carboxylate (770 mg, 1.9 mmol, refer to patent WO2021/104441A1 for preparation) was dissolved in methanol (20 mL), and 10% Pd/C (80 mg) was added. The reaction was stirred at room temperature under 10 kg hydrogen pressure for 16 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain the third 4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylic acid Butyl ester (600 mg, yield 84%) was directly used in the next reaction. MS (ESI) M/Z: 387.2 [M+H] + . Step 2: 4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (370 mg, 0.96 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoline -5-yl) dimethylphosphine oxide (357 mg, 0.87 mmol) and trifluoroacetic acid (992 mg, 8.7 mmol) were sequentially added to n-butanol (10 mL), heated to 98°C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added tetrahydrofuran (10 mL), then added triethylamine (90 mg, 0.89 mmol) to the solution, stirred for 10 minutes, added di-tert-butyl dicarbonate (285 mg , 1.3 mmol), stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction liquid to quench, and ethyl acetate (50 mL×2) was extracted. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=50/1) to obtain 4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1 - Tertiary butyl carboxylate (370 mg, yield 56%). MS (ESI) M/Z: 761.7 [M+H] + . Step 3: 4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylic acid Dissolve tributyl ester (370 mg, 0.49 mmol) in ethyl acetate (8 mL), add 5M hydrogen chloride/ethyl acetate solution (5 mL), and stir at room temperature for 30 minutes. The disappearance of the raw material was monitored by TLC, filtered, the filter cake was adjusted to pH 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl -1H-pyrazol-4-yl)-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide ( 300 mg, yield 93%). MS (ESI) M/Z: 661.9 [M+H] + . Follow up with (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide as raw material, referring to the examples 35 and the preparation method of Example 53 to obtain the final product 5-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-ylamino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,4'-bispiperidin-1'-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4 mg). MS (ESI) M/Z: 1056.6 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.77 (s, 1H), 8.90-8.80 (m, 1H), 8.78 (s, 1H) , 8.73 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.00 (brs, 1H),7.67-7.64 (m, 2H), 7.34-7.26 (m, 2H), 7.10 (s , 1H), 6.83-6.80 (m, 1H), 6.56-6.54 (m, 1H), 4.95-4.93 (m, 1H), 4.20-4.05 (m, 2H), 3.95-3.80 (m, 8H), 3.60 -3.40 (m, 4H), 2.85-2.65 (m, 6H), 2.20-2.00 (m, 9H), 2.00-1.60 (m, 6H), 1.30-1.20 (m, 4H).

實施例63: 5-(4-(3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image535
反應流程:
Figure 02_image1114
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基) 苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的鹽酸鹽（0.5 g, 0.72 mmol）和3-碘氮雜環丁烷-1-羧酸第三丁酯（1.1 g, 3.9 mmol）溶於乙腈（20 mL）中，加入碳酸鉀（521 mg, 3.8 mmol），氮氣置換3次後，反應體系升溫至98℃攪拌3天。TLC監測顯示反應結束，反應液冷卻至室溫，加入飽和碳酸氫鈉溶液（100 mL）淬滅，用二氯甲烷（50 mL×2次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 8/1）得到3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-( 1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-羧酸第三丁酯（230 mg，收率39%）。 MS (ESI) M/Z: 818.6 [M+H] +. 步驟2：將3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-( 1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-羧酸第三丁酯（230 mg，0.28 mmol）溶於乙酸乙酯（5 mL）中，加入5M氯化氫/1,4-二氧六環溶液（5 mL），室溫攪拌30分鐘。TLC監測原料消失，直接減壓濃縮得到(6-((2-((4-(4-(氮雜環丁烷-3-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦的鹽酸鹽（200 mg，粗品）。 MS (ESI) M/Z: 718.2 [M+H] +. 步驟3：將(6-((2-((4-(4-(氮雜環丁烷-3-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（200 mg，粗品）溶於1,2二氯乙烷（10 mL）和N,N-二甲基甲醯胺（2 mL）中，加入三乙胺（118 mg， 1.2 mmol），攪拌5分鐘，再加入4-氧代哌啶-1-羧酸第三丁酯（155 mg，0.78 mmol），攪拌15分鐘，最後加入醋酸（0.4 mL）和三乙醯氧基硼氫化鈉（248 mg，1.2 mmol），室溫攪拌2小時。TLC監測原料消失，向反應液中加入飽和碳酸氫鈉溶液（20 mL）淬滅，乙酸乙酯（30 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/ 1）得到4-(3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基- 2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-羧酸第三丁酯（190 mg，二步收率75%）。 MS (ESI) M/Z: 901.5 [M+H] +. 步驟4：將4-(3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基- 2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-羧酸第三丁酯（190 mg，0.21 mmol）溶於二氯甲烷（10 mL）中，加入三氟乙酸（10 mL），室溫攪拌30分鐘。TLC監測原料消失，直接減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(1-(哌啶-4-基)氮雜環丁烷)- 3-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦的三氟乙酸鹽（200 mg，粗品）。 MS (ESI) M/Z: 801.5 [M+H] +. 步驟5：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(1-(哌啶-4-基)氮雜環丁烷)- 3-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸鹽（200 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（207 mg, 0.75 mmol）溶於DMSO（10 mL）中，加入DIEA（163 mg, 1.3 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入飽和碳酸氫鈉溶液（20 mL）淬滅，乙酸乙酯（15 mL×2）萃取。合併有機相，飽和食鹽水（10 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(4-(3-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（8.5 mg，二步收率3.8%）。 MS (ESI) M/Z: 1057.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.97 (dd, J= 9.6, 4.2 Hz, 1H), 8.73 (dd, J= 12.0 1.8 Hz, 2H), 8.37 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.65-7.40 (m, 3H), 7.38 (s, 1H), 7.06 (dd, J= 8.6, 1.8 Hz, 1H), 6.70 (s, 1H), 4.95 (dd, J= 12.0, 5.2 Hz, 1H), 4.03-3.93 (m, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.55 (brs, 2H), 3.13-2.65 (m, 12H), 2.49 (brs, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 2.07-1.95 (m, 6H). Example 63: 5-(4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)azetidine-1- Base) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image535
Reaction flow:
Figure 02_image1114
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphorus oxide hydrochloride (0.5 g, 0.72 mmol) and 3-iodoazepine Cyclobutane-1-carboxylic acid tert-butyl ester (1.1 g, 3.9 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (521 mg, 3.8 mmol) was added, nitrogen replacement was performed three times, and the temperature of the reaction system was raised to 98 °C and stirred for 3 days. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (100 mL), and extracted with dichloromethane (50 mL×2 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 8/1) to obtain 3- (4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxygen-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)azetidine-1-carboxylic acid tert-butyl ester (230 mg, yield 39%). MS (ESI) M/Z: 818.6 [M+H] + . Step 2: 3-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- base) Azetidine-1-carboxylate tert-butyl ester (230 mg, 0.28 mmol) was dissolved in ethyl acetate (5 mL), and 5M hydrogen chloride/1,4-dioxane solution (5 mL ), and stirred at room temperature for 30 minutes. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((2-((4-(4-(azetidin-3-yl) piper-1-yl)-2-methoxy-5 Salts of -(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide salt (200 mg, crude). MS (ESI) M/Z: 718.2 [M+H] + . Step 3: (6-((2-((4-(4-(azetidin-3-yl)piperone-1- Base)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline-5 -yl) dimethylphosphine oxide hydrochloride (200 mg, crude product) was dissolved in 1,2 dichloroethane (10 mL) and N,N-dimethylformamide (2 mL), and triethyl Amine (118 mg, 1.2 mmol), stirred for 5 minutes, then added tert-butyl 4-oxopiperidine-1-carboxylate (155 mg, 0.78 mmol), stirred for 15 minutes, and finally added acetic acid (0.4 mL) and Sodium triacetyloxyborohydride (248 mg, 1.2 mmol), stirred at room temperature for 2 hours. The disappearance of the raw material was monitored by TLC, and saturated sodium bicarbonate solution (20 mL) was added to the reaction solution to quench it, and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=20/1) to obtain 4-(3-(4-(4-((5-bromo-4-((5-(di Methylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) azetidin-1-yl) piperidine-1-carboxylate tert-butyl ester (190 mg, 75% yield in two steps). MS (ESI) M/Z: 901.5 [M+H] + . Step 4: 4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)azetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (190 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), added trifluoroacetic acid (10 mL), stirred at room temperature for 30 minutes. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(1-(piperidin-4-yl)azetidine)-3-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline- 5-yl) trifluoroacetate salt of dimethylphosphine oxide (200 mg, crude). MS (ESI) M/Z: 801.5 [M+H] + . Step 5: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(1-(piperidin-4-yl)azetidine)-3-yl)piperazol-1-yl)phenyl)amino) pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide trifluoroacetate (200 mg, crude) and 2-(2,6-dioxopiperidin-3-yl) -5-Fluoroisoindoline-1,3-dione (207 mg, 0.75 mmol) was dissolved in DMSO (10 mL), DIEA (163 mg, 1.3 mmol) and a catalytic amount of sodium iodide were added, and the reaction The system was heated to 60°C and stirred overnight. LCMS monitoring showed that the starting material disappeared. The reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (15 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )azetidin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8.5 mg, Two-step yield 3.8%). MS (ESI) M/Z: 1057.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.97 (dd, J = 9.6, 4.2 Hz, 1H), 8.73 (dd, J = 12.0 1.8 Hz, 2H), 8.37 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.65-7.40 (m , 3H), 7.38 (s, 1H), 7.06 (dd, J = 8.6, 1.8 Hz, 1H), 6.70 (s, 1H), 4.95 (dd, J = 12.0, 5.2 Hz, 1H), 4.03-3.93 ( m, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 3.55 (brs, 2H), 3.13-2.65 (m, 12H), 2.49 (brs, 4H), 2.15 (s, 3H), 2.11 (s, 3H), 2.07-1.95 (m, 6H).

實施例64: 5-(4-(3-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image537
反應流程:
Figure 02_image1117
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(1-(哌啶-4-基)氮雜環丁烷)- 3-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸鹽和2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮為原料，參照實施例63的操作步驟製備得到終產物5-(4-(3-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)氮雜環丁烷-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（25.6 mg）。 MS (ESI) M/Z: 1075.5 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.12 (s, 1H), 8.85-8.80 (m, 3H), 8.45 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.73-7.70 (m, 1H), 7.56 (s, 1H), 7.46-7.44 (m, 1H), 6.86 (s, 1H), 5.13-5.08 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.55-3.40 (m, 2H), 3.00-2.80 (m, 14H), 2.60-2.20 (m, 4H), 2.10-1.95 (m, 10H), 1.80-1.70 (m, 2H). Example 64: 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)azetidin-1-yl) Piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image537
Reaction flow:
Figure 02_image1117
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(1-( Piperidin-4-yl)azetidine)-3-yl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethyl Phosphine oxide trifluoroacetate and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione as raw materials, refer to Example 63 The operation step prepares final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl) quinoline-6-yl) amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)azetidine-1 -yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (25.6 mg). MS (ESI) M/Z: 1075.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.12 (s, 1H), 8.85-8.80 (m, 3H), 8.45 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.73-7.70 (m, 1H), 7.56 (s, 1H), 7.46-7.44 (m, 1H), 6.86 (s, 1H), 5.13-5.08 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.55-3.40 (m, 2H), 3.00-2.80 (m , 14H), 2.60-2.20 (m, 4H), 2.10-1.95 (m, 10H), 1.80-1.70 (m, 2H).

實施例65: 5-(3-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image539
反應流程:
Figure 02_image1120
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（830 mg，1.2 mmol）溶於1,2二氯乙烷（35 mL）和N ,N-二甲基甲醯胺（7 mL）中，加入三乙胺（380 mg，3.8 mmol），攪拌5分鐘，然後加入4-(2-氧乙基)哌啶-1-羧酸第三丁酯（570 mg，2.5 mmol），攪拌15分鐘，加入醋酸（1.2 g），最後加入三乙醯氧基硼氫化鈉（790 mg，3.8 mmol），室溫攪拌16小時。TLC監測原料消失，向反應液加入飽和碳酸氫鈉溶液（20 mL）淬滅，乙酸乙酯（50 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/ 1~20/ 1）得到4-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基) 苯基)哌𠯤-1-基)乙基)哌啶-1-羧酸第三丁酯（600 mg，收率58%）。 MS (ESI) M/Z: 873.9 [M+H] +. 步驟2：將4-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基) 苯基)哌𠯤-1-基)乙基)哌啶-1-羧酸第三丁酯（600 mg，0.69 mmol）溶於乙酸乙酯（3 mL）中，冰浴下加入3.7M氯化氫/二氧六環溶液（3 mL），室溫攪拌16小時。TLC監測原料消失，過濾，濾餅用乙酸乙酯（3 mL）洗滌一次，乾燥得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(2-(哌啶-4-基)乙基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（560 mg，粗品）。 MS (ESI) M/Z: 773.9 [M+H] +. 後續步驟以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(2-(哌啶-4-基)乙基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽為原料，參照實施例35的製備方法得到終產物5-(3-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（36 mg）。 MS (ESI) M/Z: 1085.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.60 (s, 1H), 8.98 (dd, J= 9.2, 4.0 Hz, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.23-8.15 (m, 2H), 8.10 (s, 1H), 7.80-7.70 (m, 2H), 7.63-7.60 (m, 1H), 7.38 (s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.51 (d, J= 8.4 Hz, 1H), 4.95-4.92 (m, 1H), 4.15-4.05 (m, 2H), 3.91-3.80 (m, 5H), 3.68 (s, 3H), 3.60-2.90 (m, 9H), 2.90-2.65 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.95-1.90 (m, 2H), 1.79-1.70 (m, 2H), 1.60-1.20 (m, 5H). Example 65: 5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine-1 -yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image539
Reaction flow:
Figure 02_image1120
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (830 mg, 1.2 mmol) dissolved in 1,2 dichloroethyl Alkane (35 mL) and N,N-dimethylformamide (7 mL), added triethylamine (380 mg, 3.8 mmol), stirred for 5 minutes, then added 4-(2-oxoethyl)piper Pyridine-1-carboxylic acid tert-butyl ester (570 mg, 2.5 mmol), stirred for 15 minutes, added acetic acid (1.2 g), finally added sodium triacetyloxyborohydride (790 mg, 3.8 mmol), stirred at room temperature 16 hours. The disappearance of the starting material was monitored by TLC, and the reaction solution was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1～20/1) to obtain 4-(2-(4-(4-((5-bromo-4-((5 -(Dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl) phenyl) piperidine-1-yl) ethyl) tert-butyl piperidine-1-carboxylate (600 mg, yield 58%). MS (ESI) M/Z: 873.9 [M+H] + . Step 2: 4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 0.69 mmol) was dissolved in ethyl acetate (3 mL), and 3.7M hydrogen chloride/dioxane solution was added under ice cooling (3 mL), stirred at room temperature for 16 hours. TLC monitored the disappearance of raw materials, filtered, and the filter cake was washed once with ethyl acetate (3 mL), dried to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H -pyrazol-4-yl)-4-(4-(2-(piperidin-4-yl)ethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino) Quinolin-5-yl) dimethylphosphine oxide hydrochloride (560 mg, crude). MS (ESI) M/Z: 773.9 [M+H] + . Follow up with (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(4-(2-(piperidin-4-yl)ethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline -5-base) dimethyl phosphine oxide hydrochloride as raw material, the preparation method of referring to embodiment 35 obtains final product 5-(3-(4-(2-(4-(4-(5-bromo-4- (5-(Dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine-3- base) isoindoline-1,3-dione (36 mg). MS (ESI) M/Z: 1085.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.60 (s, 1H), 8.98 (dd, J = 9.2, 4.0 Hz, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.23-8.15 (m, 2H), 8.10 (s, 1H), 7.80-7.70 (m, 2H), 7.63-7.60 (m , 1H), 7.38 (s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.95-4.92 (m, 1H), 4.15-4.05 ( m, 2H), 3.91-3.80 (m, 5H), 3.68 (s, 3H), 3.60-2.90 (m, 9H), 2.90-2.65 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H), 1.95-1.90 (m, 2H), 1.79-1.70 (m, 2H), 1.60-1.20 (m, 5H).

實施例66: 5-(3-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image541
反應流程:
Figure 02_image1123
反應步驟： 室溫下將(6-((2-((4-(4-(2-(1-(氮雜環丁烷-3-基)哌啶-4-基)乙基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸鹽（134 mg, 約0.14 mmol）和2-(2,6-二氧哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（143 mg, 0.48 mmol）溶於DMSO（6 mL）中，加入DIEA（105 mg, 0.81 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌16小時。TLC監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅，二氯甲烷（60 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(3-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（49.7 mg，收率32%）。 MS (ESI) M/Z: 1103.5 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.11 (s, 1H), 8.84-8.81 (m, 3H), 8.45 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.63-7.56 (m, 3H), 6.92 (d, J= 7.2 Hz, 1H), 6.84 (s, 1H), 5.10-5.05 (m, 1H), 4.23 (brs, 2H), 3.96 (brs, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.20 (brs, 1H), 2.87-2.71 (m, 8H), 2.60-2.30 (m, 8H), 2.03 (s, 3H), 2.00 (s, 3H), 1.83-1.78 (m, 4H), 1.40-1.15 (m, 5H). Example 66: 5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine-1 -yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image541
Reaction flow:
Figure 02_image1123
Reaction steps: (6-((2-((4-(4-(2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl)piperone at room temperature -1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline Phenyl-5-yl) dimethylphosphine oxide trifluoroacetate (134 mg, about 0.14 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindole Phenyl-1,3-dione (143 mg, 0.48 mmol) was dissolved in DMSO (6 mL), DIEA (105 mg, 0.81 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 60°C and stirred 16 hours. TLC monitoring showed that the starting material disappeared. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) ethyl) piperidin-1-yl) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1, 3-Diketone (49.7 mg, yield 32%). MS (ESI) M/Z: 1103.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.11 (s, 1H), 8.84-8.81 (m, 3H), 8.45 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.63-7.56 (m, 3H), 6.92 (d, J = 7.2 Hz, 1H ), 6.84 (s, 1H), 5.10-5.05 (m, 1H), 4.23 (brs, 2H), 3.96 (brs, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.20 (brs, 1H), 2.87-2.71 (m, 8H), 2.60-2.30 (m, 8H), 2.03 (s, 3H), 2.00 (s, 3H), 1.83-1.78 (m, 4H), 1.40-1.15 (m, 5H).

實施例67: 5-(3-(4-((4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image543
反應流程:
Figure 02_image1126
反應步驟： 室溫下將(6-((2-((4-(4-((1-(氮雜環丁烷-3-基)哌啶-4-基)甲基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦三氟乙酸鹽（200 mg, 約0.22 mmol）和2-(2,6-二氧哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（217 mg, 0.74 mmol）溶於DMSO（5 mL）中，加入DIEA（142 mg, 1.1 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌16小時。TLC監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅，二氯甲烷（60 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(3-(4-((4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（43.5 mg，收率18%）。 MS (ESI) M/Z: 1089.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.11 (s, 1H), 8.90-8.80 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.63-7.57 (m, 3H), 6.94-6.86 (m, 2H), 5.08-5.05 (m, 1H), 4.23 (brs, 2H), 4.14-4.10 (m, 2H), 3.97 (brs, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.30-3.20 (m, 2H), 2.90-2.75 (m, 7H), 2.58-2.50 (m, 4H), 2.22 (brs, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.83-1.55 (m, 5H), 1.20-1.10 (m, 2H). Example 67: 5-(3-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)piperidin-1-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image543
Reaction flow:
Figure 02_image1126
Reaction steps: (6-((2-((4-(4-((1-(azetidin-3-yl)piperidin-4-yl)methyl)piperidine-1 -yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline- 5-yl) dimethylphosphine oxide trifluoroacetate (200 mg, about 0.22 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline- 1,3-Diketone (217 mg, 0.74 mmol) was dissolved in DMSO (5 mL), DIEA (142 mg, 1.1 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 60°C and stirred for 16 hours . TLC monitoring showed that the starting material disappeared. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl) Methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3- Diketone (43.5 mg, 18% yield). MS (ESI) M/Z: 1089.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.11 (s, 1H), 8.90-8.80 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.63-7.57 (m, 3H), 6.94-6.86 (m, 2H), 5.08 -5.05 (m, 1H), 4.23 (brs, 2H), 4.14-4.10 (m, 2H), 3.97 (brs, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.30-3.20 (m , 2H), 2.90-2.75 (m, 7H), 2.58-2.50 (m, 4H), 2.22 (brs, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.83-1.55 (m, 5H ), 1.20-1.10 (m, 2H).

實施例68: 5-(3-(4-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image545
反應流程:
Figure 02_image1129
反應步驟： 步驟1：室溫下將4-(2-溴-5-甲氧基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（1.3 g, 3.1 mmol）和1-乙基-1H-吡唑-4-基硼酸（0.57 g, 4.1 mmol）溶於二氧六環（20 mL）和水（4 mL）中, 加入碳酸鈉（0.66 g, 6.2 mmol）和二茂鐵二氯化鈀（0.23 g, 0.31 mmol)，反應液在氮氣氛圍下加熱至80℃攪拌16小時。LCMS監測反應結束，將反應液冷卻至室溫，用水（100 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 5/1~1/1）得到4-(2-(1-乙基-1H-吡唑-4-基)-5-甲氧基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（0.7 g，收率52%）。 MS (ESI) M/Z: 432.1 [M+H] +. 步驟2：室溫下將還原鐵粉（1.1 g，19.6 mmol），矽膠（2.2 g，100-200目）和氯化銨（0.65 g，36 mmol）加入到乙醇（8 mL）和水（8 mL）中，升溫至65℃攪拌0.5小時。再加入4-(2-(1-乙基-1H-吡唑-4-基)-5-甲氧基-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（1.3 g，3.0 mmol）的四氫呋喃（10 mL）溶液，反應體系在65℃繼續攪拌1.5小時。TLC監測反應結束，矽藻土過濾，濾液中加入水（10 mL）稀釋，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 10/1~1/1）得到4-(4-胺基-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-羧酸第三丁酯（1.2 g，收率99%）。 MS (ESI) M/Z: 402.4 [M+H] +. 步驟3：室溫下將4-(4-胺基-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-羧酸第三丁酯（1.1 g，2.7 mmol），(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧膦（1.2 g，2.9 mmol）和三氟乙酸（3.1 g，27.2 mmol）依次加入到正丁醇（10 mL）中，氮氣保護下升溫至98℃攪拌過夜。將反應液冷卻至室溫，減壓濃縮，加入四氫呋喃（10 mL），然後向溶液中加入三乙胺（270 mg，2.7 mmol），攪拌10分鐘，加入二碳酸二第三丁酯（0.89 g，4.0 mmol），室溫攪拌2小時。向反應液中加入水（50 mL）淬滅，乙酸乙酯（50 mL×2）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/ 1）得到4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-羧酸第三丁酯（0.9 g，收率43%）。 MS (ESI) M/Z: 777.4 [M+H] +. 步驟4：將4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-羧酸第三丁酯（900 mg，1.2 mmol）溶於二氯甲烷（10 mL）中，加入5M氯化氫/乙酸乙酯溶液（2 mL），室溫攪拌30分鐘。TLC監測原料消失，過濾，濾餅用飽和碳酸鉀溶液調節pH值到9，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到(6-((5-溴-2-((5-(1-乙基-1H-吡唑-4-基)-2-甲氧基-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（550 mg，收率70%）。 MS (ESI) M/Z: 677.4 [M+H] +. 步驟5：將(6-((5-溴-2-((5-(1-乙基-1H-吡唑-4-基)-2-甲氧基-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（900 mg，1.3 mmol）溶於DCM（7.5 mL）和MeOH（7.5 mL）中，加入4-氧代哌啶-1-羧酸第三丁酯（1.1 g，5.3 mmol），攪拌1小時，再加入氰基硼氫化鈉（500 mg，8.0 mmol），室溫攪拌16小時。TLC監測顯示原料消失，向反應液中加入水（20 mL）和乙酸乙酯（50 mL），水相再用乙酸乙酯（30 mL）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/1~25/1）得到4-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-乙基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（570 mg，收率50%）。 MS (ESI) M/Z: 860.4 [M+H] +. 步驟6：將4-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-乙基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-羧酸第三丁酯（570 mg，0.66 mmol）溶於DCM（10 mL），冰浴下加入三氟乙酸（4 mL），室溫下攪拌0.5小時，TLC監測顯示原料消失，用飽和碳酸鉀溶液調節pH值到9，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到(6-((5-溴-2-((5-(1-乙基-1H-吡唑-4-基)-2-甲氧基-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（350 mg，收率70%）。 MS (ESI) M/Z: 760.0 [M+H] +. 步驟7：將(6-((5-溴-2-((5-(1-乙基-1H-吡唑-4-基)-2-甲氧基-4-(4-(哌啶-4-基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦（350 mg, 0.46 mmol）和3-碘氮雜環丁烷-1-羧酸第三丁酯（651 mg, 2.3 mmol）溶於乙腈（30 mL）中，加入碳酸鉀（318 mg, 2.3 mmol），反應體系升溫至98℃攪拌2天。TLC監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/1~25/1）得到3-(4-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（250 mg，收率59%）。 MS (ESI) M/Z: 915.5 [M+H] +. 步驟8：將3-(4-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-羧酸第三丁酯（250 mg, 0.27 mmol）溶於二氯甲烷（10 mL）中，加入三氟乙酸（3 mL），室溫下攪拌30分鐘。TLC監測顯示反應結束，反應液減壓濃縮得到(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-5-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的三氟乙酸鹽（200 mg，收率79%）。 MS (ESI) M/Z: 814.9 [M+H] +. 步驟9：室溫下將(6-((2-((4-(4-(1-(氮雜環丁烷-3-基)哌啶-4-基)哌𠯤-1-基)-5-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物三氟乙酸鹽（200 mg, 0.22 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（204 mg, 0.73 mmol）溶於DMSO（10 mL）中，加入DIEA（160 mg, 1.2 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌16小時。TLC監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL），再用二氯甲烷（60 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(3-(4-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2-(1-乙基-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（58.7 mg，收率25%）。 MS (ESI) M/Z: 1071.8 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.10 (s, 1H), 8.84-8.80 (m, 3H), 8.46 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.67-7.45 (m, 3H), 6.85-6.75 (m, 2H), 6.70-6.60 (m, 1H), 5.09-5.04 (m, 1H), 4.11-4.05 (m, 4H), 3.85-3.75 (m, 5H), 2.90-2.80 (m, 8H), 2.70-2.50 (m, 8H), 2.03 (s, 3H), 1.99 (s, 3H), 1.91-1.80 (m, 4H), 1.45 (brs, 2H), 1.31-1.20 (m, 3H). Example 68: 5-(3-(4-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperone-1-yl)piperidin-1-yl)azacycle Butane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image545
Reaction flow:
Figure 02_image1129
Reaction steps: Step 1: tert-butyl 4-(2-bromo-5-methoxy-4-nitrophenyl)piperone-1-carboxylate (1.3 g, 3.1 mmol) and 1 -Ethyl-1H-pyrazol-4-ylboronic acid (0.57 g, 4.1 mmol) was dissolved in dioxane (20 mL) and water (4 mL), and sodium carbonate (0.66 g, 6.2 mmol) and di Ferrocene palladium dichloride (0.23 g, 0.31 mmol), the reaction solution was heated to 80°C under nitrogen atmosphere and stirred for 16 hours. After the completion of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1~1/1) to obtain 4-( tert-butyl 2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxy-4-nitrophenyl)piperone-1-carboxylate (0.7 g, yield 52% ). MS (ESI) M/Z: 432.1 [M+H] + . Step 2: Reduced iron powder (1.1 g, 19.6 mmol), silica gel (2.2 g, 100-200 mesh) and ammonium chloride (0.65 g, 36 mmol) was added to ethanol (8 mL) and water (8 mL), heated to 65°C and stirred for 0.5 hours. Then add tertiary butyl 4-(2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxy-4-nitrophenyl)piperone-1-carboxylate (1.3 g , 3.0 mmol) in tetrahydrofuran (10 mL), and the reaction system was stirred at 65°C for 1.5 hours. The completion of the reaction was monitored by TLC, filtered through diatomaceous earth, the filtrate was diluted with water (10 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1~1/1) to obtain 4-(4-amino-2-(1-ethyl-1H-pyrazole -4-yl)-5-methoxyphenyl)piperone-1-carboxylate tert-butyl ester (1.2 g, yield 99%). MS (ESI) M/Z: 402.4 [M+H] + . Step 3: 4-(4-amino-2-(1-ethyl-1H-pyrazol-4-yl)-5 -Methoxyphenyl)piperone-1-carboxylate tert-butyl ester (1.1 g, 2.7 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoline -5-yl) dimethylphosphine oxide (1.2 g, 2.9 mmol) and trifluoroacetic acid (3.1 g, 27.2 mmol) were sequentially added to n-butanol (10 mL), heated to 98°C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added tetrahydrofuran (10 mL), then added triethylamine (270 mg, 2.7 mmol) to the solution, stirred for 10 minutes, added di-tert-butyl dicarbonate (0.89 g , 4.0 mmol), stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction liquid to quench, and ethyl acetate (50 mL×2) was extracted. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=50/1) to obtain 4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) (Olin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazol-1 - Tertiary butyl carboxylate (0.9 g, 43% yield). MS (ESI) M/Z: 777.4 [M+H] + . Step 4: 4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazol-1-carboxylic acid Dissolve tributyl ester (900 mg, 1.2 mmol) in dichloromethane (10 mL), add 5M hydrogen chloride/ethyl acetate solution (2 mL), and stir at room temperature for 30 minutes. The disappearance of the raw material was monitored by TLC, filtered, the filter cake was adjusted to pH 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazole- 4-yl)-2-methoxy-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide ( 550 mg, yield 70%). MS (ESI) M/Z: 677.4 [M+H] + . Step 5: (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl) -2-methoxy-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide (900 mg, 1.3 mmol) was dissolved in DCM (7.5 mL) and MeOH (7.5 mL), added tert-butyl 4-oxopiperidine-1-carboxylate (1.1 g, 5.3 mmol), stirred for 1 hour, and then added cyanoboron Sodium hydride (500 mg, 8.0 mmol), stirred at room temperature for 16 hours. TLC monitoring showed that the raw materials disappeared, water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1~25/1) to obtain 4-(4-(4-((5-bromo-4-((5-(di Methylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-ethyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) piperidine-1-carboxylic acid tert-butyl ester (570 mg, yield 50%). MS (ESI) M/Z: 860.4 [M+H] + . Step 6: 4-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-ethyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) tert-butyl piperidine-1-carboxylate (570 mg, 0.66 mmol) was dissolved in DCM (10 mL), added trifluoroacetic acid (4 mL) under ice-cooling, stirred at room temperature for 0.5 hours, TLC monitoring showed The raw material disappeared, adjusted the pH value to 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazole- 4-yl)-2-methoxy-4-(4-(piperidin-4-yl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline- 5-yl) dimethylphosphine oxide (350 mg, yield 70%). MS (ESI) M/Z: 760.0 [M+H] + . Step 7: (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl) -2-methoxy-4-(4-(piperidin-4-yl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline-5-yl) Dimethylphosphine oxide (350 mg, 0.46 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (651 mg, 2.3 mmol) were dissolved in acetonitrile (30 mL), and potassium carbonate ( 318 mg, 2.3 mmol), the reaction system was heated to 98°C and stirred for 2 days. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1~25/1) to obtain 3-(4-(4-(4-((5-bromo-4-((5 -(Dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methyl oxyphenyl) piper-1-yl) piperidin-1-yl) azetidine-1-carboxylic acid tert-butyl ester (250 mg, yield 59%). MS (ESI) M/Z: 915.5 [M+H] + . Step 8: 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl) Quinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazol- 1-yl)piperidin-1-yl)azetidine-1-carboxylate tert-butyl ester (250 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL ), and stirred at room temperature for 30 minutes. TLC monitoring shows that the reaction is complete, and the reaction solution is concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperone-4-yl) 1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoline -5-yl)trifluoroacetic acid salt of dimethylphosphorus oxide (200 mg, yield 79%). MS (ESI) M/Z: 814.9 [M+H] + . Step 9: (6-((2-((4-(4-(1-(azetidin-3-yl )piperidin-4-yl)piper-1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-bromopyrimidine -4-yl)amino)quinolin-5-yl)dimethylphosphorus oxide trifluoroacetate (200 mg, 0.22 mmol) and 2-(2,6-dioxopiperidin-3-yl )-5-fluoroisoindoline-1,3-dione (204 mg, 0.73 mmol) was dissolved in DMSO (10 mL), added DIEA (160 mg, 1.2 mmol) and a catalytic amount of sodium iodide, and The reaction system was heated to 60°C and stirred for 16 hours. TLC monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, water (20 mL) was added, and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoline-6 -yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piper-1-yl)piper Pyridin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58.7 mg, yield 25%). MS (ESI) M/Z: 1071.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.10 (s, 1H), 8.84-8.80 (m, 3H), 8.46 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.67-7.45 (m, 3H), 6.85-6.75 (m, 2H), 6.70 -6.60 (m, 1H), 5.09-5.04 (m, 1H), 4.11-4.05 (m, 4H), 3.85-3.75 (m, 5H), 2.90-2.80 (m, 8H), 2.70-2.50 (m, 8H), 2.03 (s, 3H), 1.99 (s, 3H), 1.91-1.80 (m, 4H), 1.45 (brs, 2H), 1.31-1.20 (m, 3H).

實施例69: 5-(3-(4-(4-(4-(5-溴-4-(5-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)-2-(1-(二氟甲基)-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3- 基)異吲哚啉-1,3-二酮

Figure 02_image547
反應流程:
Figure 02_image1132
反應步驟： 以1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑為原料，參照實施例68的製備方法得到終產物5-(3-(4-(4-(4-(5-溴 -4-(5-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)-2-(1-(二氟甲基)-1H-吡唑-4-基)-5-甲氧基苯基)哌𠯤-1-基)哌啶-1-基)-2-(2,6-二氧哌啶-3- 基)異吲哚啉-1,3-二酮（33.6 mg）。 MS (ESI) M/Z: 1093.6 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 11.10 (s, 1H), 8.84-8.79 (m, 3H), 8.55 (brs, 2H), 8.31 (s, 1H), 8.20 (brs, 1H), 7.74-7.55 (m, 4H), 6.95-6.91 (m, 1H), 6.81 (s, 1H), 6.68-6.65 (m, 1H), 5.09-5.04 (m, 1H), 4.15-4.10 (m, 2H), 3.85-3.80 (m, 5H), 2.95-2.80 (m, 8H), 2.70-2.50 (m, 8H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90-1.80 (m, 4H), 1.45 (brs, 2H). Example 69: 5-(3-(4-(4-(4-(5-bromo-4-(5-(5-(dimethylphosphinoyl)quinolin-6-yl)amino) Pyrimidin-2-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-methoxyphenyl)piperidin-1-yl)piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image547
Reaction flow:
Figure 02_image1132
Reaction steps: Starting from 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole , with reference to the preparation method of Example 68 to obtain the final product 5-(3-(4-(4-(4-(5-bromo-4-(5-(5-(dimethylphosphinoyl)quinoline- 6-yl)amino)pyrimidin-2-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazol-1-yl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (33.6 mg). MS (ESI) M/Z: 1093.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 11.10 (s, 1H), 8.84-8.79 (m, 3H), 8.55 (brs, 2H) , 8.31 (s, 1H), 8.20 (brs, 1H), 7.74-7.55 (m, 4H), 6.95-6.91 (m, 1H), 6.81 (s, 1H), 6.68-6.65 (m, 1H), 5.09 -5.04 (m, 1H), 4.15-4.10 (m, 2H), 3.85-3.80 (m, 5H), 2.95-2.80 (m, 8H), 2.70-2.50 (m, 8H), 2.03 (s, 3H) , 1.99 (s, 3H), 1.90-1.80 (m, 4H), 1.45 (brs, 2H).

實施例70: 5-(3-(4-(4-(4-(4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)-5-(三氟甲基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image549
反應流程:
Figure 02_image1134
反應步驟： 以(6-((2-氯-5-(三氟甲基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物（製備參見WO2021/190417A1）為原料，參照實施例68的製備方法得到終產物5-(3-(4-(4-(4-(4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)-5-(三氟甲基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（14.1 mg）。 MS (ESI) M/Z: 1047.5 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.64 (s, 1H), 11.09 (s, 1H), 9.00 (brs, 1H), 8.84-8.81 (m, 2H), 8.51 (brs, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.65 (d, J= 8.0, 1H), 7.50 (s, 1H), 7.43 (brs, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.66 (dd, J= 8.4, 1.6Hz, 1H), 5.10-5.00 (m, 1H), 4.11 (t, J= 7.6, 2H), 3.90-3.70 (m, 8H), 2 85 (brs, 8H), 2.70-2.50 (m, 8H), 2.01 (s, 3H), 1.99 (s, 3H), 1.90-1.80 (m, 4H), 1.55-1.40 (m, 2H). Example 70: 5-(3-(4-(4-(4-(4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino)-5-(trifluoromethyl Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piperidine-1-yl) piperidine-1- Base) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image549
Reaction flow:
Figure 02_image1134
Reaction steps: (6-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphorus oxide (see WO2021/190417A1 for preparation ) as a raw material, the final product 5-(3-(4-(4-(4-(4-(4-(5-(dimethylphosphinoyl)quinolin-6-yl) was obtained with reference to the preparation method of Example 68) Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14.1 mg). MS (ESI) M/Z: 1047.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.64 (s, 1H), 11.09 (s, 1H), 9.00 (brs, 1H) , 8.84-8.81 (m, 2H), 8.51 (brs, 1H), 8.44 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 8.0, 1H), 7.50 (s, 1H), 7.43 (brs, 1H), 6.83 (s, 1H), 6.80 (s, 1H), 6.66 (dd, J = 8.4, 1.6Hz, 1H), 5.10-5.00 (m, 1H), 4.11 (t, J = 7.6, 2H), 3.90-3.70 (m, 8H), 2 85 (brs, 8H), 2.70-2.50 (m, 8H), 2.01 (s, 3H), 1.99 (s, 3H) , 1.90-1.80 (m, 4H), 1.55-1.40 (m, 2H).

實施例71: 3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image551
反應流程:
Figure 02_image1136
反應步驟： 以4-溴-3-氟苯胺為原料，參照實施例54的製備方法得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮（29.2 mg）。 MS (ESI) M/Z: 1008.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.80 (s, 1H), 10.81 (s, 1H), 9.60 (brs, 1H), 8.87-8.78 (m, 3H), 8.63 (s, 1H), 8.32 (s, 1H), 8.10 (d, J= 6.8 Hz, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.53 (brs, 1H), 7.02-6.96 (m, 1H), 6.82 (s, 1H), 6.52-6.46 (m, 2H), 4.48 (brs, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.73 (brs, 2H), 3.63-3.55 (m, 4H), 3.19-3.10 (m, 2H), 3.05-2.83 (m, 6H), 2.79-2.70 (m, 1H), 2.62-2.54 (m, 1H), 2.13-2.06 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.96-1.74 (m, 4H). Example 71: 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image551
Reaction flow:
Figure 02_image1136
Reaction steps: Using 4-bromo-3-fluoroaniline as raw material, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4 -((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyridine Azol-4-yl)phenyl)piperidine-1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (29.2 mg). MS (ESI) M/Z: 1008.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.80 (s, 1H), 10.81 (s, 1H), 9.60 (brs, 1H) , 8.87-8.78 (m, 3H), 8.63 (s, 1H), 8.32 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.53 (brs, 1H), 7.02-6.96 (m, 1H), 6.82 (s, 1H), 6.52-6.46 (m, 2H), 4.48 (brs, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.73 (brs, 2H), 3.63-3.55 (m, 4H), 3.19-3.10 (m, 2H), 3.05-2.83 (m, 6H), 2.79-2.70 (m, 1H), 2.62-2.54 ( m, 1H), 2.13-2.06 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.96-1.74 (m, 4H).

實施例72: 3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-2-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image553
反應流程:
Figure 02_image1138
反應步驟： 以4-溴-2-氟苯胺為原料，參照實施例54的製備方法得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-2-氟苯基)胺基)哌啶-2,6-二酮（26.4 mg）。 MS (ESI) M/Z: 1008.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.71 (s, 1H), 10.82 (s, 1H), 9.54 (brs, 1H), 8.86-8.81 (m, 3H), 8.46 (s, 1H), 8.30 (s, 1H), 8.09 (d, J= 6.0 Hz, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.53 (brs, 1H), 6.97-6.93 (m, 1H), 6.88-6.78 (m, 3H), 4.39-4.35 (m, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.75-3.68 (m, 2H), 3.63-3.55 (m, 4H), 3.09 (brs, 2H), 2.94-2.87 (m, 4H), 2.85-2.64 (m, 3H), 2.61-2.55 (m, 1H), 2.13-1.97 (m, 12H). Example 72: 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)-2-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image553
Reaction flow:
Figure 02_image1138
Reaction steps: Using 4-bromo-2-fluoroaniline as raw material, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4 -((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyridine Azol-4-yl)phenyl)piperidine-1-yl)-2-oxoethyl)piperidin-4-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (26.4 mg). MS (ESI) M/Z: 1008.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.71 (s, 1H), 10.82 (s, 1H), 9.54 (brs, 1H) , 8.86-8.81 (m, 3H), 8.46 (s, 1H), 8.30 (s, 1H), 8.09 (d, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.53 (brs, 1H), 6.97-6.93 (m, 1H), 6.88-6.78 (m, 3H), 4.39-4.35 (m, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.75- 3.68 (m, 2H), 3.63-3.55 (m, 4H), 3.09 (brs, 2H), 2.94-2.87 (m, 4H), 2.85-2.64 (m, 3H), 2.61-2.55 (m, 1H), 2.13-1.97 (m, 12H).

實施例73: 3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯氧基)哌啶-2,6-二酮

Figure 02_image555
反應流程:
Figure 02_image1140
反應步驟： 以4-(4-((2,6-二氧哌啶-3-基)氧代)苯基)哌啶-1-羧酸第三丁酯（製備參見WO2021/83949A1）為原料，參照實施例54的製備方法得到終產物3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯氧基)哌啶-2,6-二酮（30.8 mg）。 MS (ESI) M/Z: 991.9 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.67 (s, 1H), 10.88 (s, 1H), 8.81 (d, J= 1.6 Hz, 2H), 8.76 (d, J= 1.6 Hz, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.54 (brs, 1H), 6.91-6.81 (m, 5H), 5.02-4.99 (m, 1H), 3.79 (s, 6H), 3.74 (brs, 2H), 3.66 (brs, 2H), 3.25 (s, 2H), 3.04 (brs, 4H), 2.85 (brs, 4H), 2.68-2.64 (m, 1H), 2.60-2.56 (m, 6H), 2.19-2.13 (m, 1H), 2.11-2.05 (m, 1H), 2.03 (s, 3H), 1.99 (s, 3H). Example 73: 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino) )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2-oxoethyl Base) piperidin-4-yl) phenoxy) piperidine-2,6-dione
Figure 02_image555
Reaction flow:
Figure 02_image1140
Reaction steps: Use tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxo)phenyl)piperidine-1-carboxylate (see WO2021/83949A1 for preparation) as raw material , with reference to the preparation method of Example 54 to obtain the final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )-2-oxoethyl)piperidin-4-yl)phenoxy)piperidine-2,6-dione (30.8 mg). MS (ESI) M/Z: 991.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.67 (s, 1H), 10.88 (s, 1H), 8.81 (d, J = 1.6 Hz, 2H), 8.76 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.54 (brs, 1H), 6.91-6.81 (m, 5H), 5.02-4.99 (m, 1H), 3.79 (s, 6H), 3.74 (brs, 2H), 3.66 (brs, 2H), 3.25 (s, 2H), 3.04 (brs, 4H), 2.85 (brs, 4H), 2.68-2.64 (m, 1H), 2.60-2.56 (m, 6H), 2.19-2.13 (m, 1H), 2.11-2.05 (m, 1H), 2.03 (s, 3H), 1.99 (s, 3H).

實施例74: 3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯)硫代)哌啶-2,6-二酮

Figure 02_image557
反應流程:
Figure 02_image1142
反應步驟： 步驟1：室溫下將4-溴苯硫酚（2.0 g, 10.6 mmol）、3-溴哌啶-2,6-二酮（2.0 g，10.6 mmol）和無水碳酸鉀（4.4 g，31.8 mmol）依次加入乙腈（20 mL）中，升溫至50℃攪拌過夜。TLC監測原料消失，加入水（50 mL）稀釋，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到3-((4-溴苯基)硫代)哌啶-2,6-二酮（3.17 g，粗品），直接用於下步反應。 MS (ESI) M/Z: 300.0 [M+H] +. 步驟2：將3-((4-溴苯基)硫代)哌啶-2,6-二酮（3.17 g，粗品）、N-Boc-1,2,5,6-四氫吡啶-4-硼酸頻哪醇酯（3.3 g，10.6 mmol）、Pd(dppf)Cl 2（775 mg，1.06 mmol）和無水碳酸鉀（4.4 g，31.8 mmol）依次加入DMF（30 mL）中，氮氣置換三次，升溫至100℃攪拌過夜。TLC監測反應完畢，將反應液冷卻至室溫，加入水（50 mL）稀釋，乙酸乙酯（50 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 60/ 1）得到4-(4-((2,6-二氧代哌啶-3-基)硫代)苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（1.72 g，二步收率40%）。 MS (ESI) M/Z: 403.2 [M+H] +. 步驟3：室溫下將4-(4-((2,6-二氧代哌啶-3-基)硫代)苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（1.12 g，2.8 mmol）和10%濕鈀碳（300 mg）加入到甲醇（10 mL）中，氫氣置換三次，升溫至50℃攪拌過夜。LCMS檢測反應完全，反應液過濾，減壓濃縮，所得殘餘物用高效製備液相色譜純化得到4-(4-((2,6-二氧代哌啶-3-基)硫代)苯基)哌啶-1-羧酸第三丁酯（100 mg，收率9%）。 MS (ESI) M/Z: 405.2 [M+H] +. 後續步驟以4-(4-((2,6-二氧代哌啶-3-基)硫代)苯基)哌啶-1-羧酸第三丁酯為原料，參照實施例54的製備方法得到終產物3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)苯)硫代)哌啶-2,6-二酮（4.2 mg）。 MS (ESI) M/Z: 1007.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.62 (s, 1H), 8.96 (dd, J= 9.6, 4.0 Hz, 1H), 8.75 (d, J= 1.8 Hz, 1H), 8.71 (d, J= 1.8 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 7.68-7.59 (m, 2H), 7.57 (s, 1H), 7.53-7.35 (m, 3H), 6.64 (s, 1H), 5.36-5.34 (m, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.56-3.50 (m, 2H), 3.41-3.44 (m, 2H), 2.93-2.78 (m, 6H), 2.65-2.58 (m, 1H), 2.50-2.40 (brs, 1H), 2.38-2.29 (m, 1H), 2.24-2.16 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.03-1.99 (m, 4H), 1.66-1.61 (m, 4H). Example 74: 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino) )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2-oxoethyl Base) piperidin-4-yl) phenyl) thio) piperidine-2,6-dione
Figure 02_image557
Reaction flow:
Figure 02_image1142
Reaction steps: Step 1: Mix 4-bromothiophenol (2.0 g, 10.6 mmol), 3-bromopiperidine-2,6-dione (2.0 g, 10.6 mmol) and anhydrous potassium carbonate (4.4 g , 31.8 mmol) were sequentially added to acetonitrile (20 mL), heated to 50°C and stirred overnight. The disappearance of the raw material was monitored by TLC, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-((4-bromophenyl)thio)piperidine-2,6-dione (3.17 g, Crude product) was directly used in the next reaction. MS (ESI) M/Z: 300.0 [M+H] + . Step 2: 3-((4-bromophenyl)thio)piperidine-2,6-dione (3.17 g, crude), N -Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.3 g, 10.6 mmol), Pd(dppf)Cl 2 (775 mg, 1.06 mmol) and anhydrous potassium carbonate (4.4 g , 31.8 mmol) were sequentially added to DMF (30 mL), replaced with nitrogen three times, heated to 100°C and stirred overnight. The completion of the reaction was monitored by TLC, and the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=60/1) to obtain 4-(4-((2,6-dioxopiperidin-3-yl)thio)benzene base)-tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (1.72 g, 40% yield in two steps). MS (ESI) M/Z: 403.2 [M+H] + . Step 3: 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl) tert-butyl-3,6-dihydropyridine-1(2H)-carboxylate (1.12 g, 2.8 mmol) and 10% wet palladium on carbon (300 mg) were added to methanol (10 mL), hydrogen was replaced three times, The temperature was raised to 50°C and stirred overnight. LCMS detects that the reaction is complete, the reaction solution is filtered, concentrated under reduced pressure, and the resulting residue is purified by HPLC to obtain 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl ) tert-butyl piperidine-1-carboxylate (100 mg, yield 9%). MS (ESI) M/Z: 405.2 [M+H] + . Subsequent step with 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl)piperidine-1 -The tertiary butyl carboxylate is raw material, obtains final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-( Dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperone-1-yl)-2-oxoethyl)piperidin-4-yl)phenyl)thio)piperidine-2,6-dione (4.2 mg). MS (ESI) M/Z: 1007.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.62 (s, 1H), 8.96 (dd, J = 9.6, 4.0 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 7.68-7.59 (m, 2H), 7.57 (s, 1H), 7.53-7.35 (m, 3H), 6.64 (s, 1H), 5.36-5.34 (m, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.56 -3.50 (m, 2H), 3.41-3.44 (m, 2H), 2.93-2.78 (m, 6H), 2.65-2.58 (m, 1H), 2.50-2.40 (brs, 1H), 2.38-2.29 (m, 1H), 2.24-2.16 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.03-1.99 (m, 4H), 1.66-1.61 (m, 4H).

實施例75: 3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-2,3-二氫苯并呋喃-7-基)胺基)哌啶-2,6-二酮

Figure 02_image559
反應流程:
Figure 02_image1145
反應步驟： 以4-溴-2,3-二氫苯并呋喃-7-胺（製備參見CN106220644 A）為原料，參照實施例54的製備方法得到終產物3-(4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-2,3-二氫苯并呋喃-7-基)胺基)哌啶-2,6-二酮（22 mg）。 MS (ESI) M/Z: 1030.3 [M-H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.99-8.96 (m, 1H), 8.72 (d, J= 11.2 Hz, 2H), 8.30 (s, 1H), 8.24 (s, 1H), 8.11 (brs, 1H), 7.67-7.62 (m, 3H), 7.38 (s, 1H), 6.66 (s, 1H), 6.61 (d, J= 8.0 Hz, 1H), 6.46 (d, J= 8.4 Hz, 1H), 4.62-4.57 (m, 2H), 4.13-4.09 (m, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.67 (brs, 2H), 3.39 (brs, 2H), 3.20-3.11 (m, 4H), 2.90 (brs, 5H), 2.82-2.69 (m, 2H), 2.52-2.43 (m, 5H), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.89 (m, 5H). Example 75: 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2-oxoethyl Base) piperidin-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)piperidine-2,6-dione
Figure 02_image559
Reaction flow:
Figure 02_image1145
Reaction steps: Using 4-bromo-2,3-dihydrobenzofuran-7-amine (see CN106220644 A for preparation) as raw material, refer to the preparation method of Example 54 to obtain the final product 3-(4-(1-(2 -(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxygen-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2-oxoethyl)piperidin-4-yl)-2,3- Dihydrobenzofuran-7-yl)amino)piperidine-2,6-dione (22 mg). MS (ESI) M/Z: 1030.3 [MH] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.99-8.96 (m, 1H), 8.72 (d, J = 11.2 Hz , 2H), 8.30 (s, 1H), 8.24 (s, 1H), 8.11 (brs, 1H), 7.67-7.62 (m, 3H), 7.38 (s, 1H), 6.66 (s, 1H), 6.61 ( d, J = 8.0 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 4.62-4.57 (m, 2H), 4.13-4.09 (m, 1H), 3.90 (s, 3H), 3.75 (s , 3H), 3.67 (brs, 2H), 3.39 (brs, 2H), 3.20-3.11 (m, 4H), 2.90 (brs, 5H), 2.82-2.69 (m, 2H), 2.52-2.43 (m, 5H ), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.89 (m, 5H).

實施例76: 4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-N-(2,6-二氧代哌啶-3-基)-2-氟苯甲醯胺

Figure 02_image561
反應流程:
Figure 02_image1147
反應步驟： 步驟1：將4-溴-2-氟苯甲酸（2.0 g，9.1 mmol）、N-Boc-1,2,5,6-四氫吡啶-4-硼酸頻哪醇酯（2.8 g，9.1 mmol）、Pd(PPh 3) 4（1.1 g，0.9 mmol）和碳酸鉀（3.8 g，27.4 mmol）依次加入二氧六環/水（20 mL/5 mL）中，氮氣置換三次，升溫至100℃攪拌反應2小時。TLC監測反應完畢，將反應液冷卻至室溫，加入水（30 mL）稀釋，乙酸乙酯（30 mL×3）洗滌後，稀鹽酸調節pH值至弱酸性。有固體析出，過濾，收集濾餅，乾燥得到4-(1-(第三丁氧羰基)-1,2,3,6-四氫吡啶-4-基)-2-氟苯甲酸（2.1 g，收率72%）。 MS (ESI) M/Z: 322.1 [M+H] +. 步驟2：室溫下將4-(1-(第三丁氧羰基)-1,2,3,6-四氫吡啶-4-基)-2-氟苯甲酸（1.0 g，3.1 mmol）和10%濕鈀碳（100 mg）加入到甲醇（20 mL）中，氫氣置換三次，室溫攪拌反應2小時。TLC檢測反應完全，反應液用矽藻土過濾，濾液減壓濃縮得到4-(1-(第三丁氧羰基)哌啶-4-基)-2-氟苯甲酸（0.7 g，收率70%）。 MS (ESI) M/Z: 324.2 [M+H] +. 步驟3：室溫下將4-(1-(第三丁氧羰基)哌啶-4-基)-2-氟苯甲酸（650 mg, 2.0 mmol）溶於二氯甲烷（10 mL），N 2保護下冷卻至0℃，滴加草醯氯（0.35 mL，4.0 mmol）和DMF（0.2 mL）中，攪拌10分鐘後，升至室溫，在室溫下繼續反應1個小時。TLC監測反應結束，反應液減壓濃縮得到4-(4-(氯羰基)-3-氟苯基)哌啶-1-羧酸第三丁酯（670 mg，粗品）。 MS (ESI) M/Z: 342.2 [M+H] +. 步驟4：室溫下將3-胺基哌啶-2,6-二酮（1.0 g，8.0 mmol）和DIEA（3.5 mL，20.1 mmol）溶於二氯甲烷（20 mL），N 2保護下冷卻至0℃，滴加4-(4-(氯羰基)-3-氟苯基)哌啶-1-羧酸第三丁酯（670 mg，粗品）的四氫呋喃溶液，反應體系在0℃攪拌2個小時。TLC監測反應結束，加入水（40 mL），用二氯甲烷（30 mL×3）萃取。合併有機相，飽和食鹽水（50 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 50/ 1）得到4-(4-((2,6-二氧哌啶-3-基)氨甲醯基)-3-氟苯基)哌啶-1-羧酸第三丁酯（502 mg，二步收率58%）。 MS (ESI) M/Z: 434.2 [M+H] +. 以4-(4-((2,6-二氧哌啶-3-基)氨甲醯基)-3-氟苯基)哌啶-1-羧酸第三丁酯為原料，後續步驟參照實施例54的製備方法得到終產物4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-N-(2,6-二氧代哌啶-3-基)-2-氟苯甲醯胺（22.9 mg）。 MS (ESI) M/Z: 1036.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 9.02-8.95 (m, 1H), 8.78-8.68 (m, 2H), 8.32-8.22 (m, 3H), 8.04-8.00 (m, 1H), 7.66 (brs, 3H), 7.54-7.50 (m, 1H), 7.40 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.66 (s, 1H), 4.83-4.74 (m, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.66-3.62 (m, 2H), 3.44-3.34 (m, 2H), 3.17-3.09 (m, 2H), 2.92-2.90 (m, 4H), 2.85-2.69 (m, 3H), 2.67-2.45 (m, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 2.08-1.94 (m, 7H). Example 76: 4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper (1-yl)-2-oxoethyl)piper Pyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide
Figure 02_image561
Reaction flow:
Figure 02_image1147
Reaction steps: Step 1: Mix 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.8 g , 9.1 mmol), Pd(PPh 3 ) 4 (1.1 g, 0.9 mmol) and potassium carbonate (3.8 g, 27.4 mmol) were sequentially added into dioxane/water (20 mL/5 mL), replaced with nitrogen three times, and the temperature was raised The reaction was stirred at 100°C for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (30 mL), washed with ethyl acetate (30 mL×3), and the pH was adjusted to weak acidity with dilute hydrochloric acid. A solid was precipitated, filtered, and the filter cake was collected and dried to obtain 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (2.1 g , yield 72%). MS (ESI) M/Z: 322.1 [M+H] + . Step 2: 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4- Base)-2-fluorobenzoic acid (1.0 g, 3.1 mmol) and 10% wet palladium on carbon (100 mg) were added to methanol (20 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours. TLC detects that the reaction is complete, the reaction solution is filtered with diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 4-(1-(tertiary butoxycarbonyl)piperidin-4-yl)-2-fluorobenzoic acid (0.7 g, yield 70 %). MS (ESI) M/Z: 324.2 [M+H] + . Step 3: 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-fluorobenzoic acid (650 mg, 2.0 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C under the protection of N 2 , added dropwise in oxalyl chloride (0.35 mL, 4.0 mmol) and DMF (0.2 mL), stirred for 10 minutes, and liter to room temperature, and the reaction was continued for 1 hour at room temperature. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated under reduced pressure to obtain tert-butyl 4-(4-(chlorocarbonyl)-3-fluorophenyl)piperidine-1-carboxylate (670 mg, crude product). MS (ESI) M/Z: 342.2 [M+H] + . Step 4: Mix 3-aminopiperidine-2,6-dione (1.0 g, 8.0 mmol) and DIEA (3.5 mL, 20.1 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C under N2 protection, and added dropwise with tert-butyl 4-(4-(chlorocarbonyl)-3-fluorophenyl)piperidine-1-carboxylate (670 mg, crude product) in tetrahydrofuran, and the reaction system was stirred at 0°C for 2 hours. After the completion of the reaction was monitored by TLC, water (40 mL) was added and extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl) -3-Fluorophenyl)piperidine-1-carboxylate tert-butyl ester (502 mg, 58% yield in two steps). MS (ESI) M/Z: 434.2 [M+H] + . As 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piper Pyridine-1-carboxylic acid tert-butyl ester is used as raw material, and the subsequent steps refer to the preparation method of Example 54 to obtain the final product 4-(1-(2-(4-(4-((5-bromo-4-((5 -(Dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- Base) phenyl) piper-1-yl)-2-oxoethyl) piperidin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzene Formamide (22.9 mg). MS (ESI) M/Z: 1036.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 9.02-8.95 (m, 1H), 8.78-8.68 (m, 2H), 8.32-8.22 (m, 3H), 8.04-8.00 (m, 1H), 7.66 (brs, 3H), 7.54-7.50 (m, 1H), 7.40 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.83-4.74 (m, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.66- 3.62 (m, 2H), 3.44-3.34 (m, 2H), 3.17-3.09 (m, 2H), 2.92-2.90 (m, 4H), 2.85-2.69 (m, 3H), 2.67-2.45 (m, 3H ), 2.15 (s, 3H), 2.11 (s, 3H), 2.08-1.94 (m, 7H).

實施例77: 5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image563
反應流程:
Figure 02_image1150
反應步驟： 步驟1：將(6-((2-((4-(4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的三氟乙酸鹽（1.5 g, 1.7 mmol）和3-碘氮雜環丁烷-1-羧酸第三丁酯（2.6 g, 9.0 mmol）溶於DMF（25 mL）中，加入碳酸鉀（1.3 g, 9.0 mmol），氮氣置換3次後，反應體系升溫至75℃攪拌16小時。TLC監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。加入水（50 mL），用乙酸乙酯（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 100/1~50/1）得到3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-羧酸第三丁酯（450 mg，收率28%）。 MS (ESI) M/Z: 941.2 [M+H] +. 步驟2：將3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-羧酸第三丁酯（450 mg, 0.48 mmol）溶於乙酸乙酯（5 mL）中，冰浴下加入氯化氫的乙酸乙酯溶液（4M, 5 mL），室溫下攪拌3小時。LCMS監測顯示反應結束，減壓濃縮得到(6-((2-((4-(4-(7-(氮雜環丁烷-3-基)-7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的鹽酸鹽（450 mg，粗品）。 MS (ESI) M/Z: 841.3 [M+H] +. 步驟3：室溫下將(6-((2-((4-(4-(7-(氮雜環丁烷-3-基)-7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的鹽酸鹽（210 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（210 mg, 0.76 mmol）溶於DMF（6 mL）中，加入碳酸鉀（160 mg, 1.16 mmol）和催化量的碘化鈉，將反應體系加熱至75℃並攪拌16小時。TLC監控顯示原料消失，將反應液冷卻至室溫，加入水（30 mL），用乙酸乙酯（60 mL×2次）萃取。合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用高效製備液相色譜純化得到終產物5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（20.3 mg，二步收率8.3%）。 MS (ESI) M/Z: 1096.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.60 (s, 1H), 9.02-8.92 (m, 1H), 8.76 (d, J= 1.6 Hz, 1H), 8.72 (d, J= 1.6 Hz, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.81-7.63 (m, 3H), 7.39 (s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.53 (dd, J= 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J= 7.2 Hz, 2H), 3.92 (s, 3H), 3.87-3.80 (m, 2H), 3.67 (s, 3H), 3.58-3.45 (m, 5H), 3.40-3.25 (m, 2H), 3.20-3.12 (m, 2H), 2.88-2.66 (m, 7H), 2.30-2.20 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.80 (m, 8H). Example 77: 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image563
Reaction flow:
Figure 02_image1150
Reaction steps: Step 1: (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piper-1-yl)-2-methoxy -5-(1-Methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphorus oxide Trifluoroacetate (1.5 g, 1.7 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (2.6 g, 9.0 mmol) were dissolved in DMF (25 mL), and potassium carbonate was added (1.3 g, 9.0 mmol), and after nitrogen replacement for 3 times, the reaction system was heated to 75°C and stirred for 16 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. Add water (50 mL), and extract with ethyl acetate (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 100/1~50/1 ) to obtain 3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5]nonane-7 -yl) azetidine-1-carboxylate tert-butyl ester (450 mg, yield 28%). MS (ESI) M/Z: 941.2 [M+H] + . Step 2: 3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl )quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidine-1-carboxylic acid tert-butyl ester (450 mg, 0.48 mmol) was dissolved in ethyl acetate (5 mL ), hydrogen chloride in ethyl acetate solution (4M, 5 mL) was added under ice-cooling, and stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, and concentrated under reduced pressure to obtain (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonane- 2-yl) piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl )amino)quinolin-5-yl)dimethylphosphorus oxide hydrochloride (450 mg, crude). MS (ESI) M/Z: 841.3 [M+H] + . Step 3: (6-((2-((4-(4-(7-(azetidin-3-yl )-7-azaspiro[3.5]nonan-2-yl)piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl )amino)-5-bromopyrimidin-4-yl)amino)quinolin-5-yl)hydrochloride salt of dimethylphosphorus oxide (210 mg, crude product) and 2-(2,6-di Oxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (210 mg, 0.76 mmol) was dissolved in DMF (6 mL), potassium carbonate (160 mg, 1.16 mmol) was added and a catalytic amount of sodium iodide, the reaction system was heated to 75°C and stirred for 16 hours. TLC monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, water (30 mL) was added, and extracted with ethyl acetate (60 mL×2 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(2-(4-(4-( (5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1 -Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20.3 mg, 8.3% yield over two steps). MS (ESI) M/Z: 1096.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.60 (s, 1H), 9.02-8.92 (m, 1H), 8.76 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.81-7.63 (m, 3H), 7.39 ( s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.53 (dd, J = 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J = 7.2 Hz , 2H), 3.92 (s, 3H), 3.87-3.80 (m, 2H), 3.67 (s, 3H), 3.58-3.45 (m, 5H), 3.40-3.25 (m, 2H), 3.20-3.12 (m , 2H), 2.88-2.66 (m, 7H), 2.30-2.20 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.00-1.80 (m, 8H).

實施例78: 5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基) -6-氟異吲哚啉-1,3-二酮

Figure 02_image565
反應流程:
Figure 02_image1153
反應步驟： 室溫下將(6-((2-((4-(4-(7-(氮雜環丁烷-3-基)-7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基磷氧化物的鹽酸鹽（210 mg, 約0.24 mmol）和2-(2,6-二氧哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（210 mg, 0.71 mmol）溶於DMF（6 mL）中，加入碳酸鉀（160 mg, 1.2 mmol）和催化量的碘化鈉，將反應體系加熱至75℃並攪拌16小時。TLC監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅，二氯甲烷（60 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基) -6-氟異吲哚啉-1,3-二酮（2.1 mg，收率0.8%）。 MS (ESI) M/Z: 1116.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.60 (s, 1H), 9.00-8.97 (m, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.06 (brs, 1H), 7.81-7.73 (m, 2H), 7.40-7.30 (m, 2H), 6.84-6.82 (m, 1H), 6.71 (s, 1H), 4.92-4.89 (m, 1H), 4.25 (brs, 2H), 4.10-4.00 (m, 2H), 3.92 (s, 3H), 3.67 (s, 3H), 3.55-3.45 (m, 5H), 3.40-3.25 (m, 2H), 3.25-3.10 (m, 2H), 2.89-2.66 (m, 7H), 2.35-1.80 (m, 16H). Example 78: 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5 ]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image565
Reaction flow:
Figure 02_image1153
Reaction steps: (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl ) piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino )quinolin-5-yl)dimethylphosphorus oxide hydrochloride (210 mg, about 0.24 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-di Fluorisoindoline-1,3-dione (210 mg, 0.71 mmol) was dissolved in DMF (6 mL), potassium carbonate (160 mg, 1.2 mmol) and catalytic amount of sodium iodide were added, and the reaction system was heated to 75°C and stirred for 16 hours. TLC monitoring showed that the starting material disappeared. The reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindo Indoline-1,3-dione (2.1 mg, yield 0.8%). MS (ESI) M/Z: 1116.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.60 (s, 1H), 9.00-8.97 (m, 1H), 8.76 (s, 1H) , 8.72 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.06 (brs, 1H), 7.81-7.73 (m, 2H), 7.40-7.30 (m, 2H), 6.84-6.82 (m, 1H), 6.71 (s, 1H), 4.92-4.89 (m, 1H), 4.25 (brs, 2H), 4.10-4.00 (m, 2H), 3.92 (s, 3H), 3.67 (s, 3H ), 3.55-3.45 (m, 5H), 3.40-3.25 (m, 2H), 3.25-3.10 (m, 2H), 2.89-2.66 (m, 7H), 2.35-1.80 (m, 16H).

實施例79: 5-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image567
反應流程:
Figure 02_image1156
反應步驟： 步驟1：將3-(哌啶-4-基)丙基-1-醇（250 mg, 1.75 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟-異吲哚啉-1,3-二酮（482 mg, 1.75 mmol）溶於NMP（30 mL）和N,N-二異丙基乙胺（15 mL）中，反應體系升溫至110℃攪拌6小時。TLC監測顯示反應結束，反應液冷卻至室溫，倒入水（100 mL）中。用乙酸乙酯（100 mL×3次）萃取，合併有機相，飽和食鹽水（100 mL）洗滌兩次，然後無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 3:1）純化得到2-(2,6-氧代哌啶-3-基)-5-(4-(3-羥基丙基)哌啶-1-基)異吲哚啉-1,3-二酮（310 mg，收率44%）。 MS (ESI) M/Z: 400.2 [M+H] +. 步驟2：室溫下將2-(2,6-氧代哌啶-3-基)-5-(4-(3-羥基丙基)哌啶-1-基)異吲哚啉-1,3-二酮（300 mg, 0.75 mmol）溶於二氯甲烷（10 mL）中，加入三乙胺（114 mg, 1.1 mmol）。降溫至0℃，緩慢滴加甲磺醯氯（129 mg, 1.1 mmol），室溫下攪拌過夜。TLC監測顯示反應結束，加入飽和碳酸氫鈉水溶液（20 mL）淬滅反應。混合液用二氯甲烷（20 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌，然後無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱色譜層析法（石油醚：乙酸乙酯= 5:1）純化得到3-(1-(2-(2,6-氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基) 哌啶-4-基)丙基甲磺酸酯（270 mg，收率75%）。 MS (ESI) M/Z: 478.2 [M+H] +. 步驟3：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（200 mg, 0.29 mmol）和3-(1-(2-(2,6-氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基) 哌啶-4-基)丙基甲磺酸酯（164 mg, 0.34 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，加入DIEA（184 mg, 1.4 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（21.3 mg，收率7%）。 MS (ESI) M/Z: 1044.7 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.98 (d, J= 4.4 Hz, 1H), 8.74 (d, J= 1.6 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.53 (brs, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.76-7.54 (m, 4H), 7.38 (s, 1H), 7.05-7.03 (m, 1H), 6.74 (s, 1H), 4.95-4.85 (m, 1H), 3.97-3.90 (m, 2H), 3.90 (s, 3H), 3.70 (s, 3H), 3.08 (brs, 4H), 3.00-2.54 (m, 10H), 2.15 (s, 3H), 2.11 (s, 3H), 1.85-1.51 (m, 6H), 1.33-1.25 (m, 5H). Example 79: 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propyl) piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image567
Reaction flow:
Figure 02_image1156
Reaction steps: Step 1: Mix 3-(piperidin-4-yl)propyl-1-ol (250 mg, 1.75 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5 -Fluoro-isoindoline-1,3-dione (482 mg, 1.75 mmol) was dissolved in NMP (30 mL) and N,N-diisopropylethylamine (15 mL), and the reaction system was heated to 110 °C and stirred for 6 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (100 mL). Extract with ethyl acetate (100 mL×3 times), combine the organic phases, wash with saturated brine (100 mL) twice, then dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 2-(2,6-oxopiperidin-3-yl)-5-(4-(3-hydroxy Propyl)piperidin-1-yl)isoindoline-1,3-dione (310 mg, yield 44%). MS (ESI) M/Z: 400.2 [M+H] + . Step 2: 2-(2,6-oxopiperidin-3-yl)-5-(4-(3-hydroxypropane yl)piperidin-1-yl)isoindoline-1,3-dione (300 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (114 mg, 1.1 mmol) was added. Cool down to 0°C, slowly add methanesulfonyl chloride (129 mg, 1.1 mmol) dropwise, and stir overnight at room temperature. TLC monitoring showed that the reaction was complete, and saturated aqueous sodium bicarbonate (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3-(1-(2-(2,6-oxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)piperidin-4-yl)propyl methanesulfonate (270 mg, yield 75%). MS (ESI) M/Z: 478.2 [M+H] + . Step 3: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide hydrochloride salt (200 mg, 0.29 mmol) and 3-(1-(2-(2,6-oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine -4-yl)propyl methanesulfonate (164 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (5 mL), DIEA (184 mg, 1.4 mmol) and a catalytic amount of iodine were added NaCl, the reaction system was heated to 80°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoline-6- Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propyl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg, yield 7%). MS (ESI) M/Z: 1044.7 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.98 (d, J = 4.4 Hz, 1H), 8.74 (d , J = 1.6 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.53 (brs, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.76-7.54 (m, 4H) , 7.38 (s, 1H), 7.05-7.03 (m, 1H), 6.74 (s, 1H), 4.95-4.85 (m, 1H), 3.97-3.90 (m, 2H), 3.90 (s, 3H), 3.70 (s, 3H), 3.08 (brs, 4H), 3.00-2.54 (m, 10H), 2.15 (s, 3H), 2.11 (s, 3H), 1.85-1.51 (m, 6H), 1.33-1.25 (m , 5H).

實施例80: 5-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image569
反應流程:
Figure 02_image1159
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5,6-二氟-異吲哚啉-1,3-二酮為原料，參照實施例79的製備方法得到終產物5-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（26.4 mg）。 MS (ESI) M/Z: 1063.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.50 (s, 1H), 8.92 (d, J= 5.6 Hz, 1H), 8.67-8.64 (m, 3H), 8.22 (s, 1H), 8.13 (s, 1H), 7.60-7.55 (m, 3H), 7.39-7.30 (m, 3H), 6.67 (s, 1H), 4.87-4.85 (m, 1H), 3.82 (s, 3H), 3.64 (s, 3H), 3.59-3.56 (m, 2H), 2.96 (brs, 4H), 2.86-2.37 (m, 10H), 2.07 (s, 3H), 2.04 (s, 3H), 1.78-1.28 (m, 11H). Example 80: 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propyl) piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image569
Reaction flow:
Figure 02_image1159
Reaction steps: Using 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-isoindoline-1,3-dione as raw material, refer to the preparation method of Example 79 Obtain final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)propyl)piperidin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (26.4 mg). MS (ESI) M/Z: 1063.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.50 (s, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.67-8.64 (m, 3H), 8.22 (s, 1H), 8.13 (s, 1H), 7.60-7.55 (m, 3H), 7.39-7.30 (m, 3H), 6.67 (s, 1H), 4.87-4.85 (m , 1H), 3.82 (s, 3H), 3.64 (s, 3H), 3.59-3.56 (m, 2H), 2.96 (brs, 4H), 2.86-2.37 (m, 10H), 2.07 (s, 3H), 2.04 (s, 3H), 1.78-1.28 (m, 11H).

實施例81: 4-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image571
反應流程:
Figure 02_image1161
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-4-(4-(3-羥丙基)哌啶-1-基)異吲哚啉-1,3-二酮（製備可參考WO2020/113233 A1）為原料，參照實施例79的製備方法得到終產物4-(4-(3-(4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)丙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（27.2 mg）。 MS (ESI) M/Z: 1045.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.58 (s, 1H), 8.98 (dd, J= 9.6 Hz, 4.4 Hz, 1H), 8.74 (d, J= 2.0 Hz, 1H), 8.71 (d, J= 1.6 Hz, 1H), 8.37 (brs, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.65 (brs, 3H), 7.65-7.55 (m, 1H), 7.36 (d, J= 6.8 Hz, 2H), 7.18 (d, J= 8.4 Hz, 1H), 6.75 (s, 1H), 4.98-4.90 (m, 1H), 3.90 (s, 3H), 3.74-3.72 (m, 5H), 3.02 (brs, 4H), 2.91-2.65 (m, 6H), 2.47 (brs, 4H), 2.13 (s, 3H), 2.13 (s, 3H), 1.88-1.57 (m, 6H), 1.48- 1.35 (m, 5H). Example 81: 4-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) propyl) piperidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image571
Reaction flow:
Figure 02_image1161
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3- Diketone (preparation can refer to WO2020/113233 A1) as raw material, refer to the preparation method of Example 79 to obtain the final product 4-(4-(3-(4-(4-(5-bromo-4-(5-(di Methylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base) piper-1-yl) propyl) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (27.2 mg). MS (ESI) M/Z: 1045.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.58 (s, 1H), 8.98 (dd, J = 9.6 Hz, 4.4 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.37 (brs, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 7.65 (brs, 3H ), 7.65-7.55 (m, 1H), 7.36 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 4.98-4.90 (m, 1H) , 3.90 (s, 3H), 3.74-3.72 (m, 5H), 3.02 (brs, 4H), 2.91-2.65 (m, 6H), 2.47 (brs, 4H), 2.13 (s, 3H), 2.13 (s , 3H), 1.88-1.57 (m, 6H), 1.48- 1.35 (m, 5H).

實施例82: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image573
反應流程:
Figure 02_image1163
反應步驟： 步驟1：將2-(哌啶-4-基)乙酸（500 mg, 3.5 mmol）和2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（368 mg, 1.25 mmol）溶於NMP（30 mL）和N,N-二異丙基乙胺（15 mL）中，反應體系升溫至110℃攪拌6小時。TLC監測顯示反應結束，反應液冷卻至室溫，倒入水（100 mL）中，用稀鹽酸調節pH值至4-5，乙酸乙酯（100 mL×3次）萃取，合併有機相，飽和食鹽水（100 mL）洗滌兩次，然後無水硫酸鈉乾燥，過濾，最後減壓濃縮得到2-(1-(2-(2,6-氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-1-基)乙酸（310 mg，粗品），直接用於下一步反應。 MS (ESI) M/Z: 418.1 [M+H] +. 步驟2：室溫下將2-(1-(2-(2,6-氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-1-基)乙酸（119 mg，粗品）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（200 mg，0.29 mmol）、HATU（163 mg，0.43 mmol）和DIEA（147 mg，1.1 mmol）依次加入到二氯甲烷（5 mL）中，室溫下攪拌過夜。LCMS監測原料消失，加入水（20 mL）稀釋，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（10 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（40 mg，二步收率13%）。 MS (ESI) M/Z: 1062.5 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.77 (brs, 1H), 8.95-8.90 (m, 1H), 8.76 (d, J= 1.6 Hz, 1H), 8.72 (d, J= 1.6 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.67-7.61 (m, 3H), 7.45 (d, J= 6.8 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 6.66 (s, 1H), 4.95-4.85 (m, 1H), 3.90 (s, 3H), 3.75 (brs, 5H), 3.66-3.63 (m, 2H), 3.56 (brs, 2H), 2.89-2.65 (m, 9H), 2.35-2.30 (m, 2H), 2.15-2.11 (m, 8H), 1.95-1.92 (m, 2H), 1.47-1.44 (m, 2H). Example 82: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper (1-yl)-2-oxoethyl)piper Pyridin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image573
Reaction flow:
Figure 02_image1163
Reaction steps: Step 1: Mix 2-(piperidin-4-yl)acetic acid (500 mg, 3.5 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro Isoindoline-1,3-dione (368 mg, 1.25 mmol) was dissolved in NMP (30 mL) and N,N-diisopropylethylamine (15 mL), and the reaction system was heated to 110°C and stirred for 6 Hour. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, poured into water (100 mL), adjusted to pH 4-5 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL×3 times), combined organic phases, saturated Brine (100 mL) was washed twice, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-(1-(2-(2,6-oxopiperidin-3-yl)-6-fluoro- 1,3-Dioxoisoindolin-5-yl)piperidin-1-yl)acetic acid (310 mg, crude product) was directly used in the next reaction. MS (ESI) M/Z: 418.1 [M+H] + . Step 2: 2-(1-(2-(2,6-oxopiperidin-3-yl)-6-fluoro- 1,3-dioxoisoindolin-5-yl)piperidin-1-yl)acetic acid (119 mg, crude), (6-((5-bromo-2-((2-methoxy- 5-(1-Methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl ) Dimethylphosphine oxide hydrochloride (200 mg, 0.29 mmol), HATU (163 mg, 0.43 mmol) and DIEA (147 mg, 1.1 mmol) were sequentially added to dichloromethane (5 mL), stirred at room temperature overnight. The disappearance of the starting material was monitored by LCMS, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl) -2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (40 mg, two-step yield 13%). MS (ESI) M/Z: 1062.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.77 (brs, 1H), 8.95-8.90 (m, 1H), 8.76 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.67-7.61 (m, 3H), 7.45 ( d, J = 6.8 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 6.66 (s, 1H), 4.95-4.85 (m, 1H), 3.90 (s, 3H), 3.75 (brs, 5H ), 3.66-3.63 (m, 2H), 3.56 (brs, 2H), 2.89-2.65 (m, 9H), 2.35-2.30 (m, 2H), 2.15-2.11 (m, 8H), 1.95-1.92 (m , 2H), 1.47-1.44 (m, 2H).

實施例83: 5-(4-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)苯基)哌𠯤-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image575
反應流程:
Figure 02_image1166
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（500 mg，0.72 mmol）和三乙胺（454 mg，4.5 mmol）溶於二氯乙烷（10 mL）和DMF（2 mL）中，攪拌15分鐘後加入4-(4-甲醯基苯基)哌𠯤-1-羧酸第三丁酯（311 mg，1.1 mmol），攪拌15分鐘，再加入三乙醯氧基硼氫化鈉（216 mg，2.1 mmol），室溫攪拌過夜。TLC監測顯示原料消失，向反應液中加入水（20 mL）和乙酸乙酯（50 mL），水相再用乙酸乙酯（30 mL）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 50/1）得到4-(4-((4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)苯基)哌𠯤-1-羧酸第三丁酯（110 mg，收率16%）。 MS (ESI) M/Z: 936.8 [M+H] +. 步驟2：將4-(4-((4-(4-(5-溴-4-(5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)苯基)哌𠯤-1-羧酸第三丁酯（110 mg，0.12 mmol）溶於DCM（3 mL），冰浴下加入6 N 氯化氫/二氧六環溶液（10 mL），室溫下攪拌1小時，TLC監測顯示原料消失，減壓濃縮得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(4-(哌𠯤-1-基)苄基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦的鹽酸鹽（110 mg，粗品）。 MS (ESI) M/Z: 836.8 [M+H] +. 步驟3：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(4-(哌𠯤-1-基)苄基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（110 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（99 mg, 0.36 mmol）溶於N,N-二甲基甲醯胺（5 mL）中，加入碳酸鉀（83 mg, 0.60 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用高效製備液相色譜純化得到終產物5-(4-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)苯基)哌𠯤-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（17.9 mg，二步收率14%）。 MS (ESI) M/Z: 1092.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 8.99-8.96 (m, 1H), 8.75-8.71 (m, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 7.84 (brs, 1H), 7.71-7.69 (m, 2H), 7.45 (brs, 2H), 7.37 (s, 1H), 7.26-7.24 (m, 2H), 7.07-7.05 (m, 1H), 6.92-6.90 (m, 2H), 6.72 (s, 1H), 4.99-4.96 (m, 1H), 3.96-3.85 (m, 5H), 3.70-3.55 (m, 9H), 3.40 (brs, 6H), 3.10-2.63 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H). Example 83: 5-(4-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)methyl)phenyl)piperone -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image575
Reaction flow:
Figure 02_image1166
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, 0.72 mmol) and triethylamine (454 mg, 4.5 mmol) was dissolved in dichloroethane (10 mL) and DMF (2 mL), and after stirring for 15 minutes, tertiary butyl 4-(4-formylphenyl)piperone-1-carboxylate (311 mg, 1.1 mmol), stirred for 15 minutes, then added sodium triacetyloxyborohydride (216 mg, 2.1 mmol), stirred overnight at room temperature. TLC monitoring showed that the raw materials disappeared, water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 4-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphine Acyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) piper-1-yl)methyl)phenyl)piper-1-carboxylate tert-butyl ester (110 mg, yield 16%). MS (ESI) M/Z: 936.8 [M+H] + . Step 2: 4-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoyl) (Oline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1 -yl)methyl)phenyl)piperone-1-carboxylate tert-butyl ester (110 mg, 0.12 mmol) was dissolved in DCM (3 mL), and 6 N hydrogen chloride/dioxane solution (10 mL), stirred at room temperature for 1 hour, TLC monitoring showed that the starting material disappeared, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyridine Azol-4-yl)-4-(4-(4-(piper-1-yl)benzyl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinol (olin-5-yl) dimethylphosphine oxide hydrochloride (110 mg, crude). MS (ESI) M/Z: 836.8 [M+H] + . Step 3: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(4-(piper-1-yl)benzyl)piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino )quinolin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, crude product) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-Diketone (99 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (83 mg, 0.60 mmol) and a catalytic amount of sodium iodide were added, and The reaction system was heated to 80°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinoline) -6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl )methyl)phenyl)piperone-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17.9 mg, two-step rate of 14%). MS (ESI) M/Z: 1092.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 8.99-8.96 (m, 1H), 8.75-8.71 (m, 2H), 8.29 (s, 1H), 8.22 (s, 1H), 7.84 (brs, 1H), 7.71-7.69 (m, 2H), 7.45 (brs, 2H), 7.37 (s, 1H), 7.26-7.24 (m, 2H), 7.07-7.05 (m, 1H), 6.92-6.90 (m, 2H), 6.72 (s, 1H), 4.99-4.96 (m, 1H), 3.96-3.85 (m, 5H), 3.70 -3.55 (m, 9H), 3.40 (brs, 6H), 3.10-2.63 (m, 8H), 2.15 (s, 3H), 2.11 (s, 3H).

實施例84: 5-(3-(4-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image577
反應流程:
Figure 02_image1169
反應步驟： 步驟1：室溫下將(6-胺基-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦（487 mg, 2.1 mmol）溶於正丁醇（10 mL）中，加入5-溴-2,4-二氯吡啶（977 mg, 4.3 mmol）和N,N-二異丙基乙胺（555 mg, 4.3 mmol）。反應液在氮氣保護下加熱至100℃攪拌1小時至反應完全。將反應液冷卻至室溫並減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦（874 mg，收率98%）。 MS (ESI) M/Z: 418.0 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦（824 mg，2.0 mmol）溶於正丁醇（20 mL），加入1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（755 mg，2.0 mmol）和三氟乙酸（2.3 g， 20.0 mmol），氮氣置換2次，升溫至110℃攪拌16小時，LCMS監測反應完畢。將反應液冷卻至室溫並減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到1-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（1.05 g，收率69%）。 MS (ESI) M/Z: 765.1 [M+H] +. 步驟3：室溫下將1-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（950 mg，1.24 mmol）溶於甲醇（5 mL）和水（1 mL）中，加入氫氧化鉀（700 mg，12.4 mmol），氮氣保護下升溫至60℃攪拌1小時，LCMS監測反應結束。將反應液冷卻至室溫並減壓濃縮，加入水（30 mL），用二氯甲烷（30 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 8/1）得到(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基磷氧化物（808 mg，收率97%）。 MS (ESI) M/Z: 669.2 [M+H] +. 後續步驟以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基磷氧化物為原料，參照實施例53和61的製備方法得到終產物5-(3-(4-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（2.0 mg）。 MS (ESI) M/Z: 1063.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.60 (s, 1H), 7.98-7.95 (m, 1H), 7.85-7.77 (m, 2H), 7.71-7.66 (m, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 6.61-6.56 (m, 1H), 6.39-6.34 (m, 1H), 4.96-4.92 (m, 1H), 4.30-4.18 (m, 7H), 4.10-4.07 (m, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.78-3.75 (m, 1H), 3.57-3.41 (m, 4H), 3.33-3.28 (m, 6H), 2.90-2.74 (m, 4H), 2.64-2.52 (m, 4H), 2.35-2.20 (m, 2H), 1.90 (s, 3H), 1.86 (s, 3H). Example 84: 5-(3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b][ 1,4] Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piper-1-yl) piperidin-1-yl) azetidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1, 3-diketone
Figure 02_image577
Reaction flow:
Figure 02_image1169
Reaction steps: Step 1: (6-Amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (487 mg, 2.1 mmol) was dissolved in n-butanol (10 mL), and 5-bromo-2,4-dichloropyridine (977 mg, 4.3 mmol) and N,N-diisopropylethylamine (555 mg, 4.3 mmol) were added . The reaction solution was heated to 100°C under nitrogen protection and stirred for 1 hour until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain (6-((5-bromo-2-chloropyrimidine -4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (874 mg, yield 98%). MS (ESI) M/Z: 418.0 [M+H] + . Step 2: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-di Hydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (824 mg, 2.0 mmol) was dissolved in n-butanol (20 mL), and 1-(4-(4- Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1- Ketone (755 mg, 2.0 mmol) and trifluoroacetic acid (2.3 g, 20.0 mmol) were replaced with nitrogen twice, heated to 110°C and stirred for 16 hours. LCMS monitored the completion of the reaction. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1-(4-(4-((5-bromo -4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (1.05 g, yield 69%). MS (ESI) M/Z: 765.1 [M+H] + . Step 3: 1-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl) -2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl yl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (950 mg, 1.24 mmol) dissolved in methanol (5 mL) Potassium hydroxide (700 mg, 12.4 mmol) was added to water (1 mL), heated to 60°C under nitrogen protection and stirred for 1 hour, and the reaction was monitored by LCMS. The reaction solution was cooled to room temperature and concentrated under reduced pressure, water (30 mL) was added, and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=8/1) to obtain (6 -((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphorus oxide (808 mg, yield 97%) . MS (ESI) M/Z: 669.2 [M+H] + . Follow up with (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]two 㗁British-5-base) dimethyl phosphorus oxide is raw material, and the preparation method of referring to embodiment 53 and 61 obtains final product 5-(3-(4-(4-(4-((5-bromo-4-( (5-(Dimethylphosphinoyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)piperidin-1-yl)azetidin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.0 mg). MS (ESI) M/Z: 1063.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.60 (s, 1H), 7.98-7.95 (m, 1H), 7.85-7.77 (m, 2H), 7.71-7.66 (m, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 6.61-6.56 (m, 1H), 6.39 -6.34 (m, 1H), 4.96-4.92 (m, 1H), 4.30-4.18 (m, 7H), 4.10-4.07 (m, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.78 -3.75 (m, 1H), 3.57-3.41 (m, 4H), 3.33-3.28 (m, 6H), 2.90-2.74 (m, 4H), 2.64-2.52 (m, 4H), 2.35-2.20 (m, 2H), 1.90 (s, 3H), 1.86 (s, 3H).

實施例85: 5-(3-(4-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image579
反應流程:
Figure 02_image1172
反應步驟： 步驟1：室溫下將(2-胺基-5-環丙基苯基)二甲基氧化膦（1.0 g, 4.8 mmol）溶於正丁醇（25 mL）中，加入5-溴-2,4-二氯吡啶（2.2 g, 9.6 mmol）和N,N-二異丙基乙胺（1.85 g, 14.3 mmol）。反應液在氮氣保護下加熱至100℃攪拌16小時至反應完全。將反應液冷卻至室溫並減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/1）得到(2-((5-溴-2-氯嘧啶-4-基)胺基)-5-環丙基苯基)二甲基氧化膦（510 mg，收率27%）。 MS (ESI) M/Z: 400.0 [M+H] +. 步驟2：室溫下將(2-((5-溴-2-氯嘧啶-4-基)胺基)-5-環丙基苯基)二甲基氧化膦（510 mg，2.0 mmol）溶於正丁醇（50 mL），加入1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（489 mg，1.3 mmol）和三氟乙酸（1.45 g，12.7 mmol），氮氣置換2次，升溫至100℃攪拌16小時，LCMS監測反應完畢。將反應液冷卻至室溫，倒入石油醚中（50 mL），有固體析出，過濾，所得濾餅用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到1-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（450 mg，收率46%）。 MS (ESI) M/Z: 746.9 [M+H] +. 步驟3：室溫下將1-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（450 mg，0.60 mmol）溶於甲醇（5 mL）和水（1 mL）中，加入氫氧化鉀（338 mg，6.0 mmol），氮氣保護下升溫至60℃攪拌2小時，LCMS監測反應結束。將反應液冷卻至室溫並減壓濃縮，加入水（30 mL），用二氯甲烷（30 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-環丙基苯基)二甲基磷氧化物（260 mg，收率66%）。 MS (ESI) M/Z: 651.2 [M+H] +. 後續步驟以(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-環丙基苯基)二甲基磷氧化物為原料，參照實施例61的製備方法得到終產物5-(3-(4-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（10.0 mg）。 MS (ESI) M/Z: 1045.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.60 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.43 (d, J= 6.8 Hz, 1H), 7.36 (d, J= 7.6 Hz, 2H), 7.02- 6.98 (m, 1H), 6.79-6.75 (m, 2H), 6.55-6.53 (m 1H), 4.95-4.90 (m, 1H), 4.12 (t, J= 7.2 Hz, 2H), 4.03-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.65-3.35 (m, 4H), 3.20-3.00 (m, 6H), 2.93-2.74 (m, 3H), 2.50-2.46 (m, 2H), 2.28-2.00 (m, 8H), 1.85 (s, 3H), 1.82 (s, 3H), 1.25-1.20 (m, 1H), 0.98-0.93 (m, 2H), 0.58-0.53 (m, 2H). Example 85: 5-(3-(4-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphinoyl)phenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)piperidin-1-yl)nitrogen Heterobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image579
Reaction flow:
Figure 02_image1172
Reaction steps: Step 1: Dissolve (2-amino-5-cyclopropylphenyl) dimethylphosphine oxide (1.0 g, 4.8 mmol) in n-butanol (25 mL) at room temperature, add 5- Bromo-2,4-dichloropyridine (2.2 g, 9.6 mmol) and N,N-diisopropylethylamine (1.85 g, 14.3 mmol). The reaction solution was heated to 100°C under nitrogen protection and stirred for 16 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (2-((5-bromo-2-chloropyrimidine -4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide (510 mg, yield 27%). MS (ESI) M/Z: 400.0 [M+H] + . Step 2: (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-cyclopropyl Phenyl)dimethylphosphine oxide (510 mg, 2.0 mmol) was dissolved in n-butanol (50 mL), and 1-(4-(4-amino-5-methoxy-2-(1-methyl -1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (489 mg, 1.3 mmol) and trifluoroacetic acid (1.45 g, 12.7 mmol), replaced with nitrogen twice, heated to 100°C and stirred for 16 hours, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, poured into petroleum ether (50 mL), a solid precipitated out, filtered, and the obtained filter cake was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain 1 -(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (450 mg, Yield 46%). MS (ESI) M/Z: 746.9 [M+H] + . Step 3: 1-(4-(4-((5-bromo-4-((4-cyclopropyl-2-( Dimethylphosphinoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)-2,2,2-trifluoroethan-1-one (450 mg, 0.60 mmol) was dissolved in methanol (5 mL) and water (1 mL), and potassium hydroxide (338 mg, 6.0 mmol), heated to 60°C under nitrogen protection and stirred for 2 hours, and the reaction was monitored by LCMS. The reaction solution was cooled to room temperature and concentrated under reduced pressure, water (30 mL) was added, and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphorus oxide (260 mg, yield 66%). MS (ESI) M/Z: 651.2 [M+H] + . Follow up with (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole -4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphorus oxide as raw material, refer to The preparation method of Example 61 obtained the final product 5-(3-(4-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphinoyl)phenyl) ) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) piperidine- 1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (10.0 mg). MS (ESI) M/Z: 1045.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.60 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.43 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H) , 7.02- 6.98 (m, 1H), 6.79-6.75 (m, 2H), 6.55-6.53 (m 1H), 4.95-4.90 (m, 1H), 4.12 (t, J = 7.2 Hz, 2H), 4.03- 3.95 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.65-3.35 (m, 4H), 3.20-3.00 (m, 6H), 2.93-2.74 (m, 3H), 2.50- 2.46 (m, 2H), 2.28-2.00 (m, 8H), 1.85 (s, 3H), 1.82 (s, 3H), 1.25-1.20 (m, 1H), 0.98-0.93 (m, 2H), 0.58- 0.53 (m, 2H).

實施例86: 3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氯苯基)胺基)哌啶-2,6-二酮

Figure 02_image581
反應流程:
Figure 02_image1175
反應步驟： 以4-溴-3-氯苯胺為原料，參照實施例54的製備方法得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氯苯基)胺基)哌啶-2,6-二酮（14.4 mg）。 MS (ESI) M/Z: 1024.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.56 (s, 1H), 8.97 (dd, J= 9.2, 4.0 Hz, 1H), 8.73 (s, 1H), 8.71 (s, 1H), 8.29-8.19 (m, 3H), 7.67 (s, 1H), 7.63-7.60 (m, 2H), 7.39 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.67 (d, J= 5.6 Hz, 2H), 6.56 (dd, J= 8.0, 1.2 Hz, 1H), 4.68 (brs, 1H), 4.08-4.04 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.64 (s, 2H), 3.49 (brs, 2H), 3.21 (brs, 2H), 2.98-2.85 (m, 6H), 2.80-2.71 (m, 1H), 2.58-2.49 (m, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.01-1.81 (m, 6H). Example 86: 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)-3-chlorophenyl)amino)piperidine-2,6-dione
Figure 02_image581
Reaction flow:
Figure 02_image1175
Reaction steps: Using 4-bromo-3-chloroaniline as raw material, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4 -((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyridine Azol-4-yl)phenyl)piperidine-1-yl)-2-oxoethyl)piperidin-4-yl)-3-chlorophenyl)amino)piperidine-2,6-dione (14.4 mg). MS (ESI) M/Z: 1024.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.56 (s, 1H), 8.97 (dd, J = 9.2, 4.0 Hz, 1H), 8.73 (s, 1H), 8.71 (s, 1H), 8.29-8.19 (m, 3H), 7.67 (s, 1H), 7.63-7.60 (m, 2H), 7.39 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 5.6 Hz, 2H), 6.56 (dd, J = 8.0, 1.2 Hz, 1H), 4.68 (brs, 1H), 4.08-4.04 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.64 (s, 2H), 3.49 (brs, 2H), 3.21 (brs, 2H), 2.98-2.85 (m, 6H), 2.80-2.71 (m, 1H ), 2.58-2.49 (m, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.01-1.81 (m, 6H).

實施例87: 5-(3-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image583
反應流程:
Figure 02_image1178
反應步驟： 步驟1：將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（200 mg，0.31 mmol）溶於DMSO（5 mL）中，加入2-氧代-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（116 mg，0.48 mmol），滴加15滴醋酸，室溫攪拌1小時後，冰浴下慢慢加入三乙醯氧基硼氫化鈉（204 mg，0.96 mmol），再升溫至70℃攪拌12小時。TLC監測原料消失，向反應液加入飽和碳酸氫鈉（20 mL）淬滅，乙酸乙酯（40 mL×2）萃取。合併有機相，飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物矽膠柱層析提純（洗脫劑：二氯甲烷/甲醇= 20/ 1）得到2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（60 mg，收率36%）。 MS (ESI) M/Z: 862.4 [M+H] +. 步驟2：將2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-羧酸第三丁酯（60 mg，0.07 mmol）溶於二氯甲烷（5 mL）中，冰浴下加入三氟乙酸（2 mL），室溫攪拌1小時。TLC監測原料消失，直接減壓濃縮得到 (6-((2-((4-(4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦三氟乙酸鹽（48 mg，粗品）。 MS (ESI) M/Z: 762.3 [M+H] +. 步驟3：將(6-((2-((4-(4-(7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦三氟乙酸鹽（48 mg, 0.06 mmol）和3-碘氮雜環丁烷-1-羧酸第三丁酯（43 mg, 0.16 mmol）溶於乙腈（10 mL）中，加入碳酸鉀（32 mg, 0.23 mmol），氮氣置換3次後，反應體系升溫至100℃攪拌5天。TLC監測顯示反應結束，反應液冷卻至室溫，過濾，減壓濃縮。加入水（20 mL），用乙酸乙酯（20 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 10/1）得到3-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-羧酸第三丁酯（41 mg，收率81%）。 MS (ESI) M/Z: 917.4 [M+H] +. 步驟4：將3-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-羧酸第三丁酯（35 mg, 0.04 mmol）溶於二氯甲烷（5 mL）中，冰浴下加入三氟乙酸（2 mL），室溫下攪拌1小時。LCMS監測顯示反應結束，減壓濃縮得到(6-((2-((4-(4-(7-(氮雜環丁烷-3-基)-7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基膦氧化物的三氟乙酸鹽（27 mg，粗品）。 MS (ESI) M/Z: 817.3 [M+H] +. 步驟5：室溫下將(6-((2-((4-(4-(7-(氮雜環丁烷-3-基)-7-氮雜螺[3.5]壬烷-2-基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基膦氧化物的三氟乙酸鹽（27 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（22 mg, 0.08 mmol）溶於DMSO（3 mL）中，加入DIEA（42 mg, 0.33 mmol）和催化量的碘化鈉，將反應體系加熱至60℃並攪拌過夜。TLC監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(3-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（3.2 mg，二步收率7.8%）。 MS (ESI) M/Z: 1073.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.08 (s, 1H), 11.10 (s, 1H), 10.26 (s, 1H), 8.27 (brs, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.90-7.83 (m, 2H), 7.75 (d, J= 8.0 Hz, 1H), 7.68 (s, 1H), 6.92 (s, 1H), 6.78-6.75 (m, 2H), 6.66 (s, 1H), 5.11-5.06 (m, 1H), 4.36-4.25 (m, 5H), 3.90-3.80 (m, 8H), 3.25-3.20 (m, 4H), 3.15-3.00 (m, 3H), 2.99-2.85 (m, 6H), 2.60-2.50 (m, 2H), 2.25 (s, 3H), 2.09 (s, 3H), 2.05-2.00 (m, 4H), 1.91 (s, 3H), 1.87 (s, 3H), 1.83-1.75 (m, 4H). Example 87: 5-(3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -7-aza Spiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image583
Reaction flow:
Figure 02_image1178
Reaction steps: Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (200 mg, 0.31 mmol) was dissolved in DMSO (5 mL) , add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (116 mg, 0.48 mmol), add 15 drops of acetic acid dropwise, stir at room temperature for 1 hour, and place in ice bath Sodium triacetyloxyborohydride (204 mg, 0.96 mmol) was slowly added, and then heated to 70°C and stirred for 12 hours. The disappearance of the starting material was monitored by TLC, and the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 2-(4-(4-((5-bromo-4-((2-(dimethylphosphonic acid) Base)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene yl) piper-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (60 mg, yield 36%). MS (ESI) M/Z: 862.4 [M+H] + . Step 2: 2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3 ,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone -1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (60 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid was added under ice cooling (2 mL), stirred at room temperature for 1 hour. TLC monitors the disappearance of raw materials, and directly concentrates under reduced pressure to obtain (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperone-1-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl ) Dimethylphosphine oxide trifluoroacetate (48 mg, crude). MS (ESI) M/Z: 762.3 [M+H] + . Step 3: (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl) Piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino) -2,3-Dimethylphenyl) dimethylphosphine oxide trifluoroacetate (48 mg, 0.06 mmol) and tertiary butyl 3-iodoazetidine-1-carboxylate (43 mg, 0.16 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (32 mg, 0.23 mmol) was added, and after nitrogen replacement three times, the reaction system was heated to 100°C and stirred for 5 days. TLC monitoring showed that the reaction was complete, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. Add water (20 mL), and extract with ethyl acetate (20 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 3-(2-(4- (4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methyl Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidinine tert-butyl alkane-1-carboxylate (41 mg, yield 81%). MS (ESI) M/Z: 917.4 [M+H] + . Step 4: 3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl )-3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidine-1-carboxylic acid tert-butyl ester (35 mg, 0.04 mmol) dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added under ice-cooling, and stirred at room temperature for 1 hour. LCMS monitoring showed that the reaction was complete, and concentrated under reduced pressure to obtain (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonane- 2-yl) piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl )amino)-2,3-dimethylphenyl)dimethylphosphine oxide trifluoroacetate (27 mg, crude). MS (ESI) M/Z: 817.3 [M+H] + . Step 5: (6-((2-((4-(4-(7-(azetidin-3-yl )-7-azaspiro[3.5]nonan-2-yl)piper-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl )amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)trifluoroacetate salt of dimethylphosphine oxide (27 mg, crude) and 2-(2 ,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (22 mg, 0.08 mmol) was dissolved in DMSO (3 mL), and DIEA (42 mg, 0.33 mmol) and a catalytic amount of sodium iodide, the reaction system was heated to 60 °C and stirred overnight. TLC monitoring shows that the raw material disappears, the reaction solution is cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(2-(4-(4-((5-bromo-4-((2- (Dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-di Oxypiperidin-3-yl) isoindoline-1,3-dione (3.2 mg, 7.8% yield over two steps). MS (ESI) M/Z: 1073.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.08 (s, 1H), 11.10 (s, 1H), 10.26 (s, 1H) , 8.27 (brs, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.90-7.83 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 6.92 (s, 1H), 6.78-6.75 (m, 2H), 6.66 (s, 1H), 5.11-5.06 (m, 1H), 4.36-4.25 (m, 5H), 3.90-3.80 (m, 8H), 3.25-3.20 (m, 4H), 3.15-3.00 (m, 3H), 2.99-2.85 (m, 6H), 2.60-2.50 (m, 2H), 2.25 (s, 3H), 2.09 (s, 3H), 2.05-2.00 (m, 4H), 1.91 (s, 3H), 1.87 (s, 3H), 1.83-1.75 (m, 4H).

實施例88: 5-(3-(2-(4-(4-((5-溴-4-((4-環丙基-2-(二甲基膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image585
反應流程:
Figure 02_image1181
反應步驟： 以(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-環丙基苯基)二甲基氧化膦為原料，參照實施例87的製備方法得到終產物5-(3-(2-(4-(4-((5-溴-4-((4-環丙基-2-(二甲基膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（7.2 mg）。 MS (ESI) M/Z: 1085.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.58 (s, 1H), 8.40-8.36 (m, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.32-7.30 (m, 2H), 7.02-6.98 (m, 1H), 6.78 (brs, 2H), 6.70 (s, 1H), 6.54-6.51 (m, 1H), 4.95-4.90 (m, 1H), 4.10-4.08 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.60-3.41 (m, 5H), 3.31 (brs, 2H), 3.17-3.14 (m, 2H), 2.91-2.80 (m, 2H), 2.76-269 (m, 4H), 2.37-2.11 (m, 8H), 2.12-1.89 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.68 (brs, 4H), 0.98-0.96 (m, 2H), 0.60-0.58 (m, 2H). Example 88: 5-(3-(2-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphinoyl)phenyl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image585
Reaction flow:
Figure 02_image1181
Reaction steps: With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) -5-cyclopropylphenyl) dimethyl phosphine oxide as raw material, the preparation method of referring to Example 87 to obtain the final product 5-(3-(2 -(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azepine Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (7.2 mg). MS (ESI) M/Z: 1085.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.58 (s, 1H), 8.40-8.36 (m, 1H), 8.27 (s, 1H) , 8.20 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.32-7.30 (m, 2H), 7.02-6.98 (m, 1H ), 6.78 (brs, 2H), 6.70 (s, 1H), 6.54-6.51 (m, 1H), 4.95-4.90 (m, 1H), 4.10-4.08 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.60-3.41 (m, 5H), 3.31 (brs, 2H), 3.17-3.14 (m, 2H), 2.91-2.80 (m, 2H), 2.76-269 (m, 4H), 2.37-2.11 (m, 8H), 2.12-1.89 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.68 (brs, 4H), 0.98-0.96 (m, 2H), 0.60- 0.58 (m, 2H).

實施例89: 5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image587
反應流程:
Figure 02_image1184
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦為原料，參照實施例87的製備方法得到終產物5-(3-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-7-氮雜螺[3.5]壬烷-7-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（2.2 mg）。 MS (ESI) M/Z: 1103.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 7.99-7.95 (m, 1H), 7.89-7.80 (m, 2H), 7.70-7.65 (m, 1H), 7.62-7.55 (m, 1H), 7.52-7.48 (m, 1H), 6.87-6.79 (m, 1H), 6.73-6.68 (m, 1H), 6.63-6.57 (m, 1H), 6.42-6.34 (m, 1H), 4.98- 4.91 (m, 1H), 4.42-4.20 (m, 9H), 3.91 (s, 3H), 3.83 (s, 3H), 3.64-3.42 (m, 5H), 3.30- 3.18 (m, 5H), 3.05-2.73 (m, 7H), 2.58-2.47 (m, 4H), 2.25-1.99 (m, 4H), 1.90 (s, 3H), 1.86 (s, 3H). Example 89: 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b] [1,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base) piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxypiperidine-3- base) isoindoline-1,3-dione
Figure 02_image587
Reaction flow:
Figure 02_image1184
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino)-dihydrobenzo [b] [1,4] dioxin-5-yl) dimethylphosphine oxide as raw material, referring to Example 87 The preparation method obtains the final product 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b ][1,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piper-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxypiperidine-3 -yl) isoindoline-1,3-dione (2.2 mg). MS (ESI) M/Z: 1103.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 7.99-7.95 (m, 1H), 7.89-7.80 (m, 2H), 7.70-7.65 ( m, 1H), 7.62-7.55 (m, 1H), 7.52-7.48 (m, 1H), 6.87-6.79 (m, 1H), 6.73-6.68 (m, 1H), 6.63-6.57 (m, 1H), 6.42-6.34 (m, 1H), 4.98- 4.91 (m, 1H), 4.42-4.20 (m, 9H), 3.91 (s, 3H), 3.83 (s, 3H), 3.64-3.42 (m, 5H), 3.30- 3.18 (m, 5H), 3.05-2.73 (m, 7H), 2.58-2.47 (m, 4H), 2.25-1.99 (m, 4H), 1.90 (s, 3H), 1.86 (s, 3H).

實施例90: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image589
反應流程:
Figure 02_image1186
反應步驟： 步驟1：室溫下將(2-胺基-5-甲基苯基)二甲基氧化膦（8.1 g, 粗品，約37.6 mmol）溶於N-甲基吡咯烷酮（80 mL）中，加入5-溴-2,4-二氯吡啶（15.1 g, 66.3 mmol）和N,N-二異丙基乙胺（11.4 g, 88.4 mmol）。反應液在氮氣保護下加熱至80℃攪拌4小時至反應完全。將反應液冷卻至室溫，加入水（500 mL），用乙酸乙酯（150 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 90/1）得到(2-((5-溴-2-氯嘧啶-4-基)胺基)-5-甲基苯基)二甲基氧化膦（10.0 g，收率71%）。 MS (ESI) M/Z: 373.9 [M+H] +. 步驟2：室溫下將(2-((5-溴-2-氯嘧啶-4-基)胺基)-5-甲基苯基)二甲基氧化膦（508 mg，1.4 mmol）溶於正丁醇（15 mL），加入1-(4-(4-胺基-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（400 mg，1.0 mmol）和三氟乙酸（1.2 g， 10.4 mmol），氮氣置換2次，升溫至100℃攪拌過夜，LCMS監測反應完畢。將反應液冷卻至室溫，加入水（200 mL），用乙酸乙酯（100 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 20/1）得到1-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（519 mg，收率69%）。 MS (ESI) M/Z: 721.1 [M+H] +. 步驟3：室溫下將1-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（519 mg，0.72 mmol）溶於甲醇（10 mL）和水（2 mL）中，加入氫氧化鈉（287 mg，7.2 mmol），氮氣保護下升溫至60℃攪拌1小時，LCMS監測反應結束。將反應液冷卻至室溫，加入水（50 mL），用二氯甲烷（50 mL×3次）萃取。合併有機相，用飽和食鹽水洗滌三次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-甲基苯基)二甲基磷氧化物（442 mg，收率98%）。 MS (ESI) M/Z: 625.2 [M+H] +. 步驟4：室溫下將(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-甲基苯基)二甲基磷氧化物（50 mg, 0.08 mmol）和2-(1-(2-(2,6-氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（48 mg, 0.10 mmol）溶於乙腈（5 mL）中，加入DIEA（103 mg, 0.80 mmol）和催化量的碘化鈉，將反應體系加熱至100℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（20 mL）淬滅反應。混合液用乙酸乙酯（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經製備級薄層色譜（洗脫劑：二氯甲烷/甲醇= 10/ 1）純化得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（16.6 mg，收率20%）。 MS (ESI) M/Z: 1010.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.53 (s, 1H), 8.34 (dd, J= 8.6, 4.6 Hz, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.45 (d, J= 11.2 Hz, 1H), 7.38 (s, J= 7.2 Hz, 1H), 7.28 (s, 1H), 7.05-7.01 (m, 1H), 6.85-6.79 (m, 1H), 6.73 (s, 1H), 4.95-4.91 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.66-3.63 (m, 2H), 3.02-2.68 (m, 10H), 2.65-2.44 (m, 5H), 2.25 (s, 3H), 2.19-2.11 (m, 1H), 1.85-1.81 (m, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.58-1.35 (m, 5H). Example 90: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-4-methylphenyl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image589
Reaction flow:
Figure 02_image1186
Reaction steps: Step 1: Dissolve (2-amino-5-methylphenyl)dimethylphosphine oxide (8.1 g, crude product, about 37.6 mmol) in N-methylpyrrolidone (80 mL) at room temperature , 5-bromo-2,4-dichloropyridine (15.1 g, 66.3 mmol) and N,N-diisopropylethylamine (11.4 g, 88.4 mmol) were added. The reaction solution was heated to 80°C under nitrogen protection and stirred for 4 hours until the reaction was complete. The reaction solution was cooled to room temperature, added with water (500 mL), and extracted with ethyl acetate (150 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 90/1) to obtain (2- ((5-Bromo-2-chloropyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (10.0 g, 71% yield). MS (ESI) M/Z: 373.9 [M+H] + . Step 2: (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-methylbenzene Dimethylphosphine oxide (508 mg, 1.4 mmol) was dissolved in n-butanol (15 mL), and 1-(4-(4-amino-5-methoxy-2-(1-methyl- 1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (400 mg, 1.0 mmol) and trifluoroacetic acid (1.2 g, 10.4 mmol), replaced with nitrogen twice, heated to 100°C and stirred overnight, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, water (200 mL) was added, and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20/1) to obtain 1- (4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy Base-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)-2,2,2-trifluoroethane-1-one (519 mg, yield 69%). MS (ESI) M/Z: 721.1 [M+H] + . Step 3: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -4-methylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)-2,2,2-trifluoroethan-1-one (519 mg, 0.72 mmol) was dissolved in methanol (10 mL) and water (2 mL), and sodium hydroxide (287 mg, 7.2 mmol), heated to 60°C under nitrogen protection and stirred for 1 hour, and the reaction was monitored by LCMS. Cool the reaction solution to room temperature, add water (50 mL), and extract with dichloromethane (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphorus oxide ( 442 mg, yield 98%). MS (ESI) M/Z: 625.2 [M+H] + . Step 4: (2-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphorus oxide ( 50 mg, 0.08 mmol) and 2-(1-(2-(2,6-oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl) Piperidin-4-yl) ethyl methanesulfonate (48 mg, 0.10 mmol) was dissolved in acetonitrile (5 mL), DIEA (103 mg, 0.80 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 100°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (eluent: dichloromethane/methanol = 10/1) to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4- ((2-(Dimethylphosphinoyl)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole Phenyl-1,3-dione (16.6 mg, yield 20%). MS (ESI) M/Z: 1010.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.53 (s, 1H), 8.34 (dd, J = 8.6, 4.6 Hz, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.45 (d, J = 11.2 Hz, 1H), 7.38 (s, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.05-7.01 (m, 1H), 6.85-6.79 (m, 1H), 6.73 (s, 1H), 4.95-4.91 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.66-3.63 (m, 2H), 3.02-2.68 (m, 10H), 2.65-2.44 (m, 5H), 2.25 (s, 3H), 2.19-2.11 (m, 1H), 1.85-1.81 (m, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.58-1.35 (m, 5H).

實施例91: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image591
反應流程:
Figure 02_image1189
反應步驟： 以(6-胺基喹啉-5-基)二甲基氧化膦為原料，參照實施例90的製備方法得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（45.8 mg）。 MS (ESI) M/Z: 1047.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.38 (brs, 1H), 11.12 (s, 1H), 8.78 (s, 1H), 8.55-8.50 (m, 1H), 8.44-8.42 (m, 1H), 8.28 (brs, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.73-7.70 (m, 1H), 7.56-7.44 (m, 4H), 6.81 (s, 1H), 5.13-5.08 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.63-3.60 (m, 2H), 3.35-3.20 (m, 2H), 2.89-2.85 (m, 8H), 2.65-2.40 (m, 5H), 2.05-2.02 (m, 7H), 1.84-1.81 (m, 2H), 1.60-1.45 (m, 3H), 1.40-1.30 (m, 2H). Example 91: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine-2 - Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image591
Reaction flow:
Figure 02_image1189
Reaction steps: Using (6-aminoquinolin-5-yl) dimethylphosphine oxide as raw material, refer to the preparation method of Example 90 to obtain the final product 5-(4-(2-(4-(4-(( 5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl -1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6 -Fluoroisoindoline-1,3-dione (45.8 mg). MS (ESI) M/Z: 1047.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.38 (brs, 1H), 11.12 (s, 1H), 8.78 (s, 1H) , 8.55-8.50 (m, 1H), 8.44-8.42 (m, 1H), 8.28 (brs, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.73-7.70 (m, 1H), 7.56-7.44 (m, 4H), 6.81 (s, 1H), 5.13-5.08 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.63-3.60 (m , 2H), 3.35-3.20 (m, 2H), 2.89-2.85 (m, 8H), 2.65-2.40 (m, 5H), 2.05-2.02 (m, 7H), 1.84-1.81 (m, 2H), 1.60 -1.45 (m, 3H), 1.40-1.30 (m, 2H).

實施例92: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image593
反應流程:
Figure 02_image1192
反應步驟： 以(6-胺基-2,3-二甲基苯基)二甲基氧化膦為原料，參照實施例90的製備方法得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（32.8 mg）。 MS (ESI) M/Z: 1024.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.19 (s, 1H), 11.12 (s, 1H), 9.57 (brs, 1H), 8.45 (brs, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.88-7.85 (m, 2H), 7.75-7.72 (m, 1H), 7.66 (s, 1H), 7.48 (d, J= 7.2 Hz, 1H), 6.76 (s, 1H), 6.64 (brs, 1H), 5.14-5.10 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.65-3.23 (m, 4H), 3.01-2.83 (m, 8H), 2.66-2.40 (m, 5H), 2.25 (s, 3H), 2.10-1.95 (m, 4H), 1.91 (s, 3H), 1.88 (s, 3H), 1.83 (brs, 2H), 1.71 (brs, 2H), 1.60 (brs, 1H), 1.44-1.34 (m, 2H). Example 92: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image593
Reaction flow:
Figure 02_image1192
Reaction steps: Using (6-amino-2,3-dimethylphenyl) dimethylphosphine oxide as raw material, the final product 5-(4-(2-(4-( 4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiper Pyridin-3-yl)-6-fluoroisoindoline-1,3-dione (32.8 mg). MS (ESI) M/Z: 1024.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.19 (s, 1H), 11.12 (s, 1H), 9.57 (brs, 1H) , 8.45 (brs, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.88-7.85 (m, 2H), 7.75-7.72 (m, 1H), 7.66 (s, 1H), 7.48 (d , J = 7.2 Hz, 1H), 6.76 (s, 1H), 6.64 (brs, 1H), 5.14-5.10 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.65-3.23 ( m, 4H), 3.01-2.83 (m, 8H), 2.66-2.40 (m, 5H), 2.25 (s, 3H), 2.10-1.95 (m, 4H), 1.91 (s, 3H), 1.88 (s, 3H), 1.83 (brs, 2H), 1.71 (brs, 2H), 1.60 (brs, 1H), 1.44-1.34 (m, 2H).

實施例93: 5-(4-(2-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image595
反應流程:
Figure 02_image1195
反應步驟： 以(2-胺基-5-環丙基苯基)二甲基氧化膦為原料，參照實施例90的製備方法得到終產物5-(4-(2-(4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（37.5 mg）。 MS (ESI) M/Z: 1036.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.11 (s, 1H), 11.04 (s, 1H), 9.54 (brs, 1H), 8.46 (brs, 1H), 8.20 (s, 1H), 8.14 (brs, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.76-7.67 (m, 2H), 7.47 (d, J= 7.2 Hz, 1H), 7.24-7.20 (m, 1H), 6.76 (s, 1H), 6.45 (brs, 1H), 5.13-5.08 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.66-3.56 (m, 4H), 3.31-3.21 (m, 6H), 3.03-2.86 (m, 5H), 2.69-2.53 (m, 3H), 2.08-2.00 (m, 1H), 1.84-1.72 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.73-1.67 (m, 2H), 1.59 (brs, 1H), 1.42-1.34 (m, 2 H), 0.94-0.88 (m, 2H), 0.56-0.51 (m, 2H). Example 93: 5-(4-(2-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphinoyl)phenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)piperidine-1- Base)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image595
Reaction flow:
Figure 02_image1195
Reaction steps: Using (2-amino-5-cyclopropylphenyl) dimethylphosphine oxide as raw material, refer to the preparation method of Example 90 to obtain the final product 5-(4-(2-(4-(4- ((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- yl)-6-fluoroisoindoline-1,3-dione (37.5 mg). MS (ESI) M/Z: 1036.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.11 (s, 1H), 11.04 (s, 1H), 9.54 (brs, 1H) , 8.46 (brs, 1H), 8.20 (s, 1H), 8.14 (brs, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.76-7.67 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.24-7.20 (m, 1H), 6.76 (s, 1H), 6.45 (brs, 1H), 5.13-5.08 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.66-3.56 (m, 4H), 3.31-3.21 (m, 6H), 3.03-2.86 (m, 5H), 2.69-2.53 (m, 3H), 2.08-2.00 (m, 1H), 1.84- 1.72 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H), 1.73-1.67 (m, 2H), 1.59 (brs, 1H), 1.42-1.34 (m, 2H), 0.94-0.88 (m, 2H), 0.56-0.51 (m, 2H).

實施例94: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image597
反應流程:
Figure 02_image1198
反應步驟： 以(6-胺基-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦為原料，參照實施例90的製備方法得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（7.8 mg）。 MS (ESI) M/Z: 1054.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.63 (s, 1H), 11.10 (s, 1H), 8.12-8.08 (m, 2H), 8.02 (s, 1H), 7.94-7.87 (m, 1H), 7.80 (s, 1H), 7.72-7.68 (m, 1H), 7.58 (s, 1H), 7.45 (d, J= 7.6 Hz, 1H), 6.81 (s, 1H), 6.44-6.34 (m, 1H), 5.12-5.08 (m, 1H), 4.31-4.20 (m, 4H), 3.84 (s, 3H), 3.79 (s, 3H), 3.60-3.30 (m, 4H), 2.93-2.88 (m, 8H), 2.50-2.40 (m, 5H), 2.08-1.80 (m, 1H), 1.90-1.80 (m, 8H), 1.60-1.40 (m, 3H), 1.35-1.20 (m, 2H). Example 94: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b][ 1,4] Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piper-1-yl) ethyl) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-di ketone
Figure 02_image597
Reaction flow:
Figure 02_image1198
Reaction steps: Using (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide as raw material, refer to the preparation method of Example 90 to obtain Final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b][1, 4] Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper 𠯤-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione ( 7.8 mg). MS (ESI) M/Z: 1054.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.63 (s, 1H), 11.10 (s, 1H), 8.12-8.08 (m, 2H), 8.02 (s, 1H), 7.94-7.87 (m, 1H), 7.80 (s, 1H), 7.72-7.68 (m, 1H), 7.58 (s, 1H), 7.45 (d, J = 7.6 Hz , 1H), 6.81 (s, 1H), 6.44-6.34 (m, 1H), 5.12-5.08 (m, 1H), 4.31-4.20 (m, 4H), 3.84 (s, 3H), 3.79 (s, 3H ), 3.60-3.30 (m, 4H), 2.93-2.88 (m, 8H), 2.50-2.40 (m, 5H), 2.08-1.80 (m, 1H), 1.90-1.80 (m, 8H), 1.60-1.40 (m, 3H), 1.35-1.20 (m, 2H).

實施例95: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image599
反應流程:
Figure 02_image1200
反應步驟： 以(2-胺基-5-氟苯基)二甲基氧化膦為原料，參照實施例90的製備方法得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（32.4 mg）。 MS (ESI) M/Z: 1014.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.39 (s, 1H), 8.39-8.33 (m, 1H), 8.19 (d, J= 7.2 Hz, 2H), 8.04 (s, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.46 (d, J= 11.2 Hz, 1H), 7.38 (d, J= 7.2 Hz, 1H), 7.31 (s, 1H), 6.97-6.90 (m, 1H), 6.73 (s, 1H), 6.59 (brs, 1H), 4.95-4.91 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.66-3.63 (m, 2H), 2.98-2.63 (m, 10H), 2.56-2.42 (m, 5H), 2.16-2.11 (m, 1H), 1.86-1.82 (m, 8H), 1.58-1.40 (m, 5H). Example 95: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-4-fluorophenyl)amino)pyrimidine-2 - Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image599
Reaction flow:
Figure 02_image1200
Reaction steps: Using (2-amino-5-fluorophenyl) dimethylphosphine oxide as raw material, refer to the preparation method of Example 90 to obtain the final product 5-(4-(2-(4-(4-(( 5-bromo-4-((2-(dimethylphosphonyl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl -1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6 -Fluoroisoindoline-1,3-dione (32.4 mg). MS (ESI) M/Z: 1014.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.39 (s, 1H), 8.39-8.33 (m, 1H), 8.19 (d, J = 7.2 Hz, 2H), 8.04 (s, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H) , 7.31 (s, 1H), 6.97-6.90 (m, 1H), 6.73 (s, 1H), 6.59 (brs, 1H), 4.95-4.91 (m, 1H), 3.91 (s, 3H), 3.89 (s , 3H), 3.66-3.63 (m, 2H), 2.98-2.63 (m, 10H), 2.56-2.42 (m, 5H), 2.16-2.11 (m, 1H), 1.86-1.82 (m, 8H), 1.58 -1.40 (m, 5H).

實施例96: 3-(5-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-6-氟-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image601
反應流程:
Figure 02_image1202
反應步驟： 步驟1：室溫下將4,5-二氟-2-甲基苯甲酸甲酯（500 mg, 2.7 mmol）溶於1,2-二氯乙烷（10 mL）中，加入偶氮二異丁腈（22 mg, 0.13 mmol）。反應液在氮氣保護下加熱至80℃攪拌20小時至反應完全。將反應液冷卻至室溫，加入飽和硫代硫酸鈉水溶液（10毫升）淬滅。混合液用二氯甲烷（20 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：石油醚/乙酸乙酯= 20/ 1）純化得到2-(溴甲基)-4,5-二氟苯甲酸甲酯（741 mg，粗品）。 MS (ESI) M/Z: 265.0 [M+H] +. 步驟2：室溫下將2-(溴甲基)-4,5-二氟苯甲酸甲酯（741 mg，粗品）溶於乙腈（10 mL）中，加入3-胺基哌啶-2,6-二酮鹽酸鹽（506 mg, 3.1 mmol）和DIEA（542 mg, 4.2 mmol）。反應液在氮氣保護下加熱至80℃攪拌20小時至反應完全。將反應液冷卻至室溫，加入水（50 mL）和乙酸乙酯（50 mL）, 分液，有機相用飽和食鹽水洗滌（50 mL）一次，無水硫酸鈉乾燥，過濾，最後減壓濃縮得到3-(5,6-二氟-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（750 mg，二步收率99%）。 MS (ESI) M/Z: 281.1 [M+H] +. 步驟3：室溫下將3-(5,6-二氟-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（2.0 g，7.1 mmol）溶於DMSO（20 mL）中，加入2-(哌啶-4-基)乙醇（2.8 g，21.4 mmol）和三乙胺（2.2 g，21.4 mmol），氮氣保護下升溫至80℃攪拌20小時。TLC監測原料消失，將反應液冷卻至室溫，加入水（50 mL）稀釋，用乙酸乙酯（50 mL）萃取四次。合併有機相，用飽和食鹽水（50 mL）洗滌一次，無水硫酸鈉乾燥，過濾，減壓濃縮，所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 50/ 1）純化得到3-(6-氟-5-(4-(2-羥乙基)哌啶-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（0.9 g，收率33%）。 MS (ESI) M/Z: 389.6 [M+H] +. 步驟4：將3-(6-氟-5-(4-(2-羥乙基)哌啶-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（500 mg，1.3 mmol）和三乙胺（261 mg，2.6 mmol）溶於二氯甲烷（20 mL）中，冰浴下滴加甲磺醯氯（220 mg，1.9 mmol），室溫攪拌2小時。TLC監測原料消失，加入水（50 mL）淬滅，用二氯甲烷（50 mL）萃取三次。合併有機相，用飽和食鹽水（50 mL）洗滌一次，無水硫酸鈉乾燥，過濾，減壓濃縮，所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 50/ 1）純化得到2-(1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1-氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（89 mg，收率15%）。 MS (ESI) M/Z: 468.2 [M+H] +. 步驟5：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦鹽酸鹽（126 mg, 0.18 mmol）和2-(1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1-氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（89 mg, 0.19 mmol）溶於乙腈（10 mL）中，加入DIEA（74 mg, 0.57 mmol）和催化量的碘化鈉，將反應體系加熱至80℃並攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（50 mL）淬滅反應。混合液用二氯甲烷（50 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物3-(5-(4-(2-(4-(4-(5-溴-4-(5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-6-氟-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（23.2 mg，收率12%）。 MS (ESI) M/Z: 1034.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.73 (s, 1H), 12.72 (s, 1H), 8.86 (s, 1H), 8.79 (s, 1H), 8.65-8.64 (m, 1H), 8.05-8.02 (m, 2H), 7.75 (s, 1H), 7.65-7.62 (m, 1H), 7.52-7.50 (m, 2H), 6.75 (s,1H), 5.18-5.14 (m, 1H), 4.48-4.35 (m, 2H), 3.85 (s, 6H), 3.66-3.60 (m, 6H), 3.35-2.80 (m, 9H), 2.40-2.20 (m, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10-1.50 (m, 7H). Example 96: 3-(5-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinolin-6-yl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine-1 -yl)-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione
Figure 02_image601
Reaction flow:
Figure 02_image1202
Reaction steps: Step 1: Dissolve methyl 4,5-difluoro-2-methylbenzoate (500 mg, 2.7 mmol) in 1,2-dichloroethane (10 mL) at room temperature, add Azodiisobutyronitrile (22 mg, 0.13 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 20 hours until the reaction was complete. The reaction solution was cooled to room temperature, and quenched by adding saturated aqueous sodium thiosulfate (10 mL). The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to give methyl 2-(bromomethyl)-4,5-difluorobenzoate (741 mg, crude product) . MS (ESI) M/Z: 265.0 [M+H] + . Step 2: Methyl 2-(bromomethyl)-4,5-difluorobenzoate (741 mg, crude) was dissolved in acetonitrile at room temperature (10 mL), 3-aminopiperidine-2,6-dione hydrochloride (506 mg, 3.1 mmol) and DIEA (542 mg, 4.2 mmol) were added. The reaction solution was heated to 80°C under nitrogen protection and stirred for 20 hours until the reaction was complete. Cool the reaction solution to room temperature, add water (50 mL) and ethyl acetate (50 mL), separate the layers, wash the organic phase with saturated brine (50 mL) once, dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure 3-(5,6-difluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (750 mg, 99% yield in two steps) was obtained. MS (ESI) M/Z: 281.1 [M+H] + . Step 3: 3-(5,6-Difluoro-1-oxoisoindolin-2-yl)piperidine-2 ,6-Diketone (2.0 g, 7.1 mmol) was dissolved in DMSO (20 mL), and 2-(piperidin-4-yl)ethanol (2.8 g, 21.4 mmol) and triethylamine (2.2 g, 21.4 mmol) were added ), heated to 80°C under nitrogen protection and stirred for 20 hours. The disappearance of the raw material was monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted four times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 50/1) 3-(6-fluoro-5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione was obtained (0.9 g, yield 33%). MS (ESI) M/Z: 389.6 [M+H] + . Step 4: Add 3-(6-fluoro-5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxy (isoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.3 mmol) and triethylamine (261 mg, 2.6 mmol) were dissolved in dichloromethane (20 mL), ice-bathed Add methanesulfonyl chloride (220 mg, 1.9 mmol) dropwise and stir at room temperature for 2 hours. The disappearance of the starting material was monitored by TLC, quenched by adding water (50 mL), and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 50/1) 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-4-yl)ethyl Methanesulfonate (89 mg, yield 15%). MS (ESI) M/Z: 468.2 [M+H] + . Step 5: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide hydrochloride salt (126 mg, 0.18 mmol) and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl) Piperidin-4-yl) ethyl methanesulfonate (89 mg, 0.19 mmol) was dissolved in acetonitrile (10 mL), DIEA (74 mg, 0.57 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-(5-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphinoyl)quinoline) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (23.2 mg, yield 12%). MS (ESI) M/Z: 1034.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.73 (s, 1H), 12.72 (s, 1H), 8.86 (s, 1H), 8.79 (s, 1H), 8.65-8.64 (m, 1H), 8.05-8.02 (m, 2H), 7.75 (s, 1H), 7.65-7.62 (m, 1H), 7.52-7.50 (m, 2H), 6.75 (s,1H), 5.18-5.14 (m, 1H), 4.48-4.35 (m, 2H), 3.85 (s, 6H), 3.66-3.60 (m, 6H), 3.35-2.80 (m, 9H), 2.40 -2.20 (m, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10-1.50 (m, 7H).

實施例97: 3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image603
反應流程:
Figure 02_image1204
反應步驟： 室溫下將2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)-2-氟苯基)哌啶-1-基)乙酸鹽酸鹽（50 mg，約0.13 mmol）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（78 mg，0.12 mmol）、HATU（91 mg，0.24 mmol）和DIEA（78 mg，0.60 mmol）依次加入到DMF（3 mL）中，升溫至35℃攪拌30分鐘。LCMS監測原料消失，加入水（30 mL）稀釋，乙酸乙酯（30 mL×3）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮（21.6 mg，收率18%）。 MS (ESI) M/Z: 982.2 [M-H] +. 1H NMR (400 MHz, CDCl 3/CD 3OD): δ 8.18 (s, 1H), 8.14 (s, 1H), 8.10-8.06 (m, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 6.92 (t, J= 8.0 Hz, 1H), 6.80 (d, J= 7.2 Hz, 1H), 6.68 (s, 1H), 6.44-6.39 (m, 2H), 4.13-4.09 (m, 1H), 3.88 (s, 6H), 3.84-3.66 (m, 4H), 3.57 (brs, 2H), 3.45-3.39 (m, 3H), 2.93-2.80 (m, 7H), 2.48-2.38 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.94-1.76 (m, 6H). Example 97: 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethyl Phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)- 2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image603
Reaction flow:
Figure 02_image1204
Reaction steps: 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetate at room temperature salt (50 mg, about 0.13 mmol), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4- (Piperyl-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (78 mg, 0.12 mmol), HATU (91 mg, 0.24 mmol) and DIEA (78 mg, 0.60 mmol) were sequentially added to DMF (3 mL), heated to 35°C and stirred for 30 minutes. The disappearance of the starting material was monitored by LCMS, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl )-3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperidine-1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (21.6 mg, yield 18% ). MS (ESI) M/Z: 982.2 [MH] + . 1 H NMR (400 MHz, CDCl 3 /CD 3 OD): δ 8.18 (s, 1H), 8.14 (s, 1H), 8.10-8.06 (m, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 6.44- 6.39 (m, 2H), 4.13-4.09 (m, 1H), 3.88 (s, 6H), 3.84-3.66 (m, 4H), 3.57 (brs, 2H), 3.45-3.39 (m, 3H), 2.93- 2.80 (m, 7H), 2.48-2.38 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.94-1.76 (m, 6H).

實施例98: 3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image605
反應流程:
Figure 02_image1206
反應步驟： 室溫下將2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)-2-氟苯基)哌啶-1-基)乙酸鹽酸鹽（35 mg，0.09 mmol）、(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-甲基苯基)二甲基氧化膦（63 mg，0.10 mmol）、HATU（54 mg，0.14 mmol）和DIEA（37 mg，0.29 mmol）依次加入到DMF（2 mL）中，室溫攪拌2小時。LCMS監測原料消失，加入水（20 mL）稀釋，有固體析出，過濾，濾餅經製備級薄層色譜（洗脫劑：二氯甲烷/甲醇= 10/ 1）純化得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮（18.7 mg，收率21%）。 MS (ESI) M/Z: 970.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.55 (s, 1H), 8.34 (dd, J= 8.4, 4.4 Hz, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.31 (s, 1H), 7.07-7.02 (m, 2H), 6.84-6.81 (m, 1H), 6.65 (s, 1H), 6.41 (dd, J= 8.2, 2.2 Hz, 1H), 6.33 (dd, J= 12.4, 2.4 Hz, 1H), 4.71-4.70 (m, 1H), 4.06-4.01 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.74-3.70 (m, 4H), 3.27-3.22 (brs, 2H), 3.03-2.99 (m, 2H), 2.91-2.86 (m, 5H), 2.80-2.71 (m, 2H), 2.56-2.51 (m, 1H), 2.26 (s, 3H), 2.30-2.10 (m, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.95-1.75 (m, 5H). Example 98: 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-4-methylphenyl) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2-oxo Ethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image605
Reaction flow:
Figure 02_image1206
Reaction steps: 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetate at room temperature salt (35 mg, 0.09 mmol), (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( Piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (63 mg, 0.10 mmol), HATU (54 mg, 0.14 mmol ) and DIEA (37 mg, 0.29 mmol) were sequentially added to DMF (2 mL), and stirred at room temperature for 2 hours. LCMS monitored the disappearance of raw materials, added water (20 mL) to dilute, solids precipitated, filtered, and the filter cake was purified by preparative thin-layer chromatography (eluent: dichloromethane/methanol = 10/1) to obtain the final product 3-(( 4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-methylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2-oxoethyl)piperidine-4 -yl)-3-fluorophenyl)amino)piperidine-2,6-dione (18.7 mg, yield 21%). MS (ESI) M/Z: 970.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.55 (s, 1H), 8.34 (dd, J = 8.4, 4.4 Hz, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.31 (s, 1H), 7.07-7.02 (m, 2H), 6.84-6.81 (m, 1H), 6.65 (s, 1H), 6.41 (dd, J = 8.2, 2.2 Hz, 1H), 6.33 (dd, J = 12.4, 2.4 Hz, 1H), 4.71-4.70 (m, 1H), 4.06-4.01 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.74-3.70 (m, 4H), 3.27-3.22 (brs, 2H), 3.03-2.99 (m, 2H), 2.91-2.86 (m, 5H), 2.80-2.71 (m, 2H), 2.56-2.51 (m, 1H), 2.26 (s, 3H), 2.30-2.10 (m, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.95-1.75 (m, 5H).

實施例99: 3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image607
反應流程:
Figure 02_image1208
反應步驟： 室溫下將2-(4-(4-((2,6-二氧代哌啶-3-基)胺基)-2-氟苯基)哌啶-1-基)乙酸鹽酸鹽（56 mg，0.14 mmol）、(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-氟苯基)二甲基氧化膦（75 mg，0.12 mmol）、HATU（68 mg，0.18 mmol）和DIEA（31 mg，0.24 mmol）依次加入到DMF（3 mL）中，室溫攪拌1小時。LCMS監測原料消失，加入水（20 mL）稀釋，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-((4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)胺基)哌啶-2,6-二酮（22.3 mg，收率19%）。 MS (ESI) M/Z: 974.1 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 10.78 (d, J= 3.2 Hz, 2H), 8.30 (brs, 1H), 8.21 (d, J= 3.2 Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.43-7.35 (m, 1H), 6.96 (t, J= 8.6 Hz, 1H), 6.79 (s, 1H), 6.68 (brs, 1H), 6.44 (s, 1H), 6.40 (s, 1H), 5.99 (d, J= 7.6 Hz, 1H), 4.33-4.26 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.74-3.71 (m, 2H), 3.63 (brs, 2H), 3.19 (s, 2H), 2.95-2.87 (m, 4H), 2.81-2.50 (m, 5H), 2.14-2.05 (m, 3H), 1.93-1.82 (m, 1H), 1.79 (s, 3H), 1.76 (s, 3H), 1.65 (brs, 4H). Example 99: 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphino)-4-fluorophenyl))amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image607
Reaction flow:
Figure 02_image1208
Reaction steps: 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetate at room temperature salt (56 mg, 0.14 mmol), (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( Piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (75 mg, 0.12 mmol), HATU (68 mg, 0.18 mmol) and DIEA (31 mg, 0.24 mmol) were sequentially added to DMF (3 mL), and stirred at room temperature for 1 hour. The disappearance of the starting material was monitored by LCMS, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl )-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-4- 1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (22.3 mg, yield 19%). MS (ESI) M/Z: 974.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.78 (d, J = 3.2 Hz, 2H), 8.30 (brs, 1H), 8.21 (d, J = 3.2 Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.43-7.35 (m, 1H), 6.96 ( t, J = 8.6 Hz, 1H), 6.79 (s, 1H), 6.68 (brs, 1H), 6.44 (s, 1H), 6.40 (s, 1H), 5.99 (d, J = 7.6 Hz, 1H), 4.33-4.26 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.74-3.71 (m, 2H), 3.63 (brs, 2H), 3.19 (s, 2H), 2.95-2.87 ( m, 4H), 2.81-2.50 (m, 5H), 2.14-2.05 (m, 3H), 1.93-1.82 (m, 1H), 1.79 (s, 3H), 1.76 (s, 3H), 1.65 (brs, 4H).

實施例100: 5-(3-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)喹啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image609
反應流程:
Figure 02_image1211
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹啉-5-基)二甲基氧化膦和4-甲醯基哌啶-1-羧酸第三丁酯為原料，參照實施例49和35的操作步驟製備得到終產物5-(3-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)喹啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（14.9 mg）。 MS (ESI) M/Z: 1069.9 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.37 (s, 1H), 11.08 (s, 1H), 8.78 (d, J= 3.6 Hz, 1H), 8.58-8.52 (m, 1H), 8.44 (d, J= 9.6 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.60-7.49 (m, 3H), 6.81 (brs, 2H), 6.67-6.65 (m, 1H), 5.10-5.04 (m, 1H), 4.66 (brs, 8H), 4.12 (brs, 2H), 3.85-3.75 (m, 8H), 2.87 (brs, 7H), 2.20 (brs, 3H), 2.10-1.96 (m, 8H), 1.90-1.70 (m, 4H). Example 100: 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)piperidin-1-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image609
Reaction flow:
Figure 02_image1211
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) quinoline-5-yl) dimethyl phosphine oxide and tertiary butyl 4-formylpiperidine-1-carboxylate as raw materials, refer to implementation The operation steps of example 49 and 35 are prepared to obtain final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphinoyl) quinoline-6- Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl )piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14.9 mg) . MS (ESI) M/Z: 1069.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.37 (s, 1H), 11.08 (s, 1H), 8.78 (d, J = 3.6 Hz, 1H), 8.58-8.52 (m, 1H), 8.44 (d, J = 9.6 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.83 ( s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60-7.49 (m, 3H), 6.81 (brs, 2H), 6.67-6.65 (m, 1H), 5.10-5.04 (m, 1H) , 4.66 (brs, 8H), 4.12 (brs, 2H), 3.85-3.75 (m, 8H), 2.87 (brs, 7H), 2.20 (brs, 3H), 2.10-1.96 (m, 8H), 1.90-1.70 (m, 4H).

實施例101: 5-(3-(4-((4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image611
反應流程:
Figure 02_image1214
反應步驟： 以(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-環丙基苯基)二甲基氧化膦和4-甲醯基哌啶-1-羧酸第三丁酯為原料，參照實施例49和35的操作步驟製備得到終產物5-(3-(4-((4-(4-((5-溴-4-((4-環丙基-2-(二甲膦醯基)苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（17.2 mg）。 MS (ESI) M/Z: 1059.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.51 (s, 1H), 8.32-8.29 (m, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.88 (brs, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.26 (s, 1H), 6.95-6.90 (m, 1H), 6.72-6.64 (m, 3H), 6.47 (d, J= 8.8 Hz, 1H), 4.8-4.84 (m, 1H), 4.08-4.01 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.67-3.26 (m, 5H), 3.10-3.03 (m, 2H), 2.92-2.64 (m, 10H), 2.09-2.03 (m, 2H), 2.01-1.92 (m, 5H), 1.78 (s, 3H), 1.75 (s, 3H), 1.50-1.25 (m, 3H), 0.90-0.88 (m, 2H), 0.53-0.49 (m, 2H). Example 101: 5-(3-(4-((4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphinoyl)phenyl)amino) Pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)piperidine-1 -yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image611
Reaction flow:
Figure 02_image1214
Reaction steps: With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) -5-cyclopropylphenyl) dimethyl phosphine oxide and tertiary butyl 4-formylpiperidine-1-carboxylate as raw materials, With reference to the operating steps of Examples 49 and 35, the final product 5-(3-(4-((4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphine Acyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1- Base) methyl) piperidin-1-yl) azetidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (17.2 mg). MS (ESI) M/Z: 1059.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.51 (s, 1H), 8.32-8.29 (m, 1H), 8.20 (s, 1H) , 8.13 (s, 1H), 7.88 (brs, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 6.95-6.90 (m, 1H), 6.72-6.64 (m, 3H ), 6.47 (d, J = 8.8 Hz, 1H), 4.8-4.84 (m, 1H), 4.08-4.01 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.67-3.26 ( m, 5H), 3.10-3.03 (m, 2H), 2.92-2.64 (m, 10H), 2.09-2.03 (m, 2H), 2.01-1.92 (m, 5H), 1.78 (s, 3H), 1.75 ( s, 3H), 1.50-1.25 (m, 3H), 0.90-0.88 (m, 2H), 0.53-0.49 (m, 2H).

實施例102: 5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image613
反應流程:
Figure 02_image1217
反應步驟： 步驟1：室溫下將哌啶-4-羧酸乙酯（8.9 g, 56.6 mmol）和N-第三丁氧羰基-3-氮雜環丁酮（9.7 g, 56.6 mmol）溶於四氫呋喃（180 mL）中，冰浴下緩慢加入三乙醯氧基硼氫化鈉（36.0 g, 169.8 mmol)。反應體系在室溫下攪拌16小時，LC-MS顯示反應結束。向反應液中緩慢加入飽和碳酸氫鈉水溶液（300 mL）淬滅，混合液用乙酸乙酯（100 mL × 3次）萃取。合併有機相，用飽和食鹽水（200 mL）洗滌，無水硫酸鈉乾燥並過濾。濾液減壓濃縮，所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇 = 30/1）純化得到1-(1-(第三丁氧羰基)氮雜環丁-3-基)哌啶-4-羧酸乙酯（16.0 g，收率90%）。 MS (ESI) M/Z: 313.2 [M+H] +. 步驟2：氮氣保護下將四氫呋喃（170 mL）冷卻至0℃，慢慢加入氫化鋁鋰（2.9 g, 76.8 mmol），攪拌10分鐘後，緩慢滴加1-(1-(第三丁氧羰基)氮雜環丁-3-基)哌啶-4-羧酸乙酯（16.0 g, 51.3 mmol）的四氫呋喃（30 mL）溶液，反應體系在0℃下攪拌1小時。TLC顯示反應結束，反應液在0℃下經十水合硫酸鈉淬滅並過濾。濾液減壓濃縮得到3-(4-(羥甲基)哌啶-1-基)氮雜環丁-1-羧酸第三丁酯（10.5 g，收率76%）。 MS (ESI) M/Z: 271.2 [M+H] +. 步驟3：室溫下將3-(4-(羥甲基)哌啶-1-基)氮雜環丁-1-羧酸第三丁酯（10.5 g, 38.9 mmol）和咪唑（5.5 g, 81.2 mmol）溶於二氯甲烷（200 mL）中，冰浴並下緩慢加入第三丁基二苯基氯矽烷（15.2 g, 55.4 mmol），反應體系在室溫下攪拌16小時。LC-MS顯示反應結束，向反應液中加入水（300 mL），用乙酸乙酯（100 mL × 3次）萃取。合併有機相，用飽和食鹽水（100 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：石油醚/乙酸乙酯 = 3/1）純化得到3-(4-((第三丁基二苯基矽氧基)甲基)哌啶-1-基)氮雜環丁-1-羧酸第三丁酯（17.2 g，收率87%）。 MS (ESI) M/Z: 509.3 [M+H] +. 步驟4：室溫下將3-(4-((第三丁基二苯基矽氧基)甲基)哌啶-1-基)氮雜環丁-1-羧酸第三丁酯（17.2 g, 33.8 mmol）溶於二氯甲烷（200 mL）中，冰浴下慢慢加入三氟乙酸（25.9 mL, 338 mmol）。反應體系在室溫下攪拌5小時，LC-MS顯示反應結束。反應液減壓濃縮後加入飽和碳酸氫鈉水溶液（400 mL）中和，再用二氯甲烷（150 mL × 3次）萃取。合併有機相，用飽和食鹽水（200 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/四氫呋喃 = 10/1）純化得到1-(氮雜環丁-3-基)-4-((第三丁基二苯基矽氧基)甲基)哌啶（13.2 g，收率96%）。 MS (ESI) M/Z: 409.3 [M+H] +. 步驟5：室溫下將1-(氮雜環丁-3-基)-4-((第三丁基二苯基矽氧基)甲基)哌啶（2.0 g, 4.9 mmol）和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮（1.35 g, 4.9 mmol）溶於二甲基亞碸（20 mL）中，加入N,N-二異丙基乙胺（6.3 g, 49.0 mmol）。反應體系升溫至140℃攪拌30分鐘。LC-MS顯示原料消失，將反應液冷卻至室溫，加水（50 mL）稀釋，用乙酸乙酯（50 mL × 3次）萃取。合併有機相，用飽和食鹽水（50 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：石油醚/乙酸乙酯= 1/1）純化得到5-(3-(4-((第三丁基二苯基矽氧基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（1.5 g，收率46%）。 MS (ESI) M/Z: 665.3 [M+H] +. 步驟6：將5-(3-(4-((第三丁基二苯基矽氧基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（1.3 g, 1.95 mmol）溶於四氫呋喃（15 mL）中，冰浴下加入四丁基氟化銨的四氫呋喃溶液（1 M, 3.9 mL, 3.9 mmol）。反應體系室溫下攪拌2小時。LC-MS顯示原料消失，往反應液中加水（20 mL）稀釋，用乙酸乙酯（20 mL × 3次）萃取。合併有機相，用飽和食鹽水（20 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 30/1）純化得到2-(2,6-二氧代哌啶-3-基)-5-(3-(4-(羥甲基)哌啶-1-基)氮雜環丁-1-基)異吲哚啉-1,3-二酮（630 mg，收率76%）。 MS (ESI) M/Z: 427.1 [M+H] +. 步驟7：氮氣保護下將草醯氯（66 mg, 0.52 mmol）溶於乾燥二氯甲烷（3 mL）中，冷卻至-78℃，滴加二甲基亞碸（81 mg, 1.04 mmol），攪拌10分鐘後，再滴加2-(2,6-二氧代哌啶-3-基)-5-(3-(4-(羥甲基)哌啶-1-基)氮雜環丁-1-基)異吲哚啉-1,3-二酮（200 mg, 0.47 mmol）的乾燥二氯甲烷（2 mL）溶液。反應體系在-78℃繼續攪拌1小時，然後滴加三乙胺（238 mg, 2.35 mmol）並攪拌10分鐘。LC-MS顯示原料消失，反應液自然升溫至室溫，加水（10 mL）稀釋，用二氯甲烷（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 40/1）純化得到1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁-3-基)哌啶-4-甲醛（80 mg，收率40%）。 MS (ESI) M/Z: 425.0 [M+H] +. 步驟8：將1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁-3-基)哌啶-4-甲醛（40 mg, 0.094 mmol）和(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-氟苯基)二甲基氧化膦（59 mg, 0.094 mmol）溶於四氫呋喃/N,N-二甲基甲醯胺（2.7 mL/0.3 mL）中，冰浴下加入三乙醯氧基硼氫化鈉（60 mg, 0.28 mmol）。反應體系在室溫下攪拌2小時。LC-MS顯示原料消失，反應液加水（10 mL）淬滅，用二氯甲烷（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（36.5 mg，收率37%）。 MS (ESI) M/Z: 1037.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.37 (s, 1H), 8.37-8.30 (m, 1H), 8.23-8.17 (m, 2H), 8.10 (s, 1H), 7.73 (s, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 6.98-6.90 (m, 1H), 6.78 (d, J= 2.0 Hz, 1H), 6.71 (s, 1H), 6.58 (brs, 1H), 6.53 (dd, J= 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J= 7.4 Hz, 2H), 3.91-3.88 (m, 8H), 3.39-3.31 (m, 1H), 2.94-2.70 (m, 9H), 2.57 (brs, 4H), 2.32-2.30 (m, 2H), 2.15-2.10 (m, 1H), 1.94-1.82 (m, 10H), 1.64-1.60 (brs, 1H), 1.34-1.24 (m, 2H). Example 102: 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-fluorophenyl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)piperidin-1-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image613
Reaction flow:
Figure 02_image1217
Reaction steps: Step 1: Dissolve ethyl piperidine-4-carboxylate (8.9 g, 56.6 mmol) and N-tert-butoxycarbonyl-3-azetidinone (9.7 g, 56.6 mmol) at room temperature In tetrahydrofuran (180 mL), slowly add sodium triacetyloxyborohydride (36.0 g, 169.8 mmol) under ice cooling. The reaction system was stirred at room temperature for 16 hours, and LC-MS showed that the reaction was complete. Slowly add saturated aqueous sodium bicarbonate (300 mL) to the reaction solution to quench, and the mixture is extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 30/1) to obtain 1-(1-(tertiary butoxycarbonyl)azetidin-3-yl ) ethyl piperidine-4-carboxylate (16.0 g, yield 90%). MS (ESI) M/Z: 313.2 [M+H] + . Step 2: Cool tetrahydrofuran (170 mL) to 0°C under nitrogen protection, slowly add lithium aluminum hydride (2.9 g, 76.8 mmol), and stir for 10 minutes Afterwards, a solution of ethyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidine-4-carboxylate (16.0 g, 51.3 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, The reaction system was stirred at 0°C for 1 hour. TLC showed that the reaction was complete, and the reaction solution was quenched with sodium sulfate decahydrate at 0°C and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(4-(hydroxymethyl)piperidin-1-yl)azetidin-1-carboxylate (10.5 g, yield 76%). MS (ESI) M/Z: 271.2 [M+H] + . Step 3: 3-(4-(Hydroxymethyl)piperidin-1-yl)azetidine-1-carboxylic acid at room temperature Tributyl ester (10.5 g, 38.9 mmol) and imidazole (5.5 g, 81.2 mmol) were dissolved in dichloromethane (200 mL), and tertiary butyldiphenylchlorosilane (15.2 g, 55.4 mmol), the reaction system was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete, water (300 mL) was added to the reaction solution, and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1) to obtain 3-(4-((tert-butyldiphenylsilyloxy)methyl)piperidine- 1-yl) azetidine-1-carboxylate tert-butyl ester (17.2 g, yield 87%). MS (ESI) M/Z: 509.3 [M+H] + . Step 4: 3-(4-((tert-butyldiphenylsilyloxy)methyl)piperidin-1-yl ) Tert-butyl azetidine-1-carboxylate (17.2 g, 33.8 mmol) was dissolved in dichloromethane (200 mL), and trifluoroacetic acid (25.9 mL, 338 mmol) was slowly added under ice cooling. The reaction system was stirred at room temperature for 5 hours, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, neutralized by adding saturated aqueous sodium bicarbonate (400 mL), and extracted with dichloromethane (150 mL × 3 times). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/tetrahydrofuran = 10/1) to obtain 1-(azetidin-3-yl)-4-((tert-butyldiphenylsilane Oxy)methyl)piperidine (13.2 g, yield 96%). MS (ESI) M/Z: 409.3 [M+H] + . Step 5: 1-(azetidin-3-yl)-4-((tert-butyldiphenylsilyloxy )methyl)piperidine (2.0 g, 4.9 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.35 g, 4.9 mmol) was dissolved in dimethylsulfoxide (20 mL), and N,N-diisopropylethylamine (6.3 g, 49.0 mmol) was added. The reaction system was heated to 140°C and stirred for 30 minutes. LC-MS showed that the starting material disappeared, and the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3 times). The organic phases were combined, washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain 5-(3-(4-((tert-butyldiphenylsilyloxy)methyl) Piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.5 g, rate of 46%). MS (ESI) M/Z: 665.3 [M+H] + . Step 6: Add 5-(3-(4-((tert-butyldiphenylsilyloxy)methyl)piperidin-1-yl )azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.3 g, 1.95 mmol) dissolved in THF ( 15 mL), a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 3.9 mL, 3.9 mmol) was added under ice cooling. The reaction system was stirred at room temperature for 2 hours. LC-MS showed that the starting material disappeared, and the reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 30/1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4 -(Hydroxymethyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (630 mg, yield 76%). MS (ESI) M/Z: 427.1 [M+H] + . Step 7: Dissolve oxalyl chloride (66 mg, 0.52 mmol) in dry dichloromethane (3 mL) under nitrogen and cool to -78°C , dropwise added dimethylsulfene (81 mg, 1.04 mmol), stirred for 10 minutes, then added dropwise 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4- (Hydroxymethyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (200 mg, 0.47 mmol) in dry dichloromethane (2 mL). The reaction system was stirred at -78°C for 1 hour, then triethylamine (238 mg, 2.35 mmol) was added dropwise and stirred for 10 minutes. LC-MS showed that the starting material disappeared, and the reaction solution was naturally warmed to room temperature, diluted with water (10 mL), and extracted with dichloromethane (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 40/1) to obtain 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidine-4-carbaldehyde (80 mg, yield 40%). MS (ESI) M/Z: 425.0 [M+H] + . Step 8: Add 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo (2-((5-bromo-2-((2-methoxy Base-5-(1-methyl-1H-pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorobenzene Dimethylphosphine oxide (59 mg, 0.094 mmol) was dissolved in tetrahydrofuran/N,N-dimethylformamide (2.7 mL/0.3 mL), and sodium triacetyloxyborohydride ( 60 mg, 0.28 mmol). The reaction system was stirred at room temperature for 2 hours. LC-MS showed that the starting material disappeared, and the reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-4- Fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol-1-yl) Methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36.5 mg, yield 37%). MS (ESI) M/Z: 1037.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.37 (s, 1H), 8.37-8.30 (m, 1H), 8.23-8.17 (m, 2H), 8.10 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 6.98-6.90 (m, 1H ), 6.78 (d, J = 2.0 Hz, 1H), 6.71 (s, 1H), 6.58 (brs, 1H), 6.53 (dd, J = 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H) , 4.10 (t, J = 7.4 Hz, 2H), 3.91-3.88 (m, 8H), 3.39-3.31 (m, 1H), 2.94-2.70 (m, 9H), 2.57 (brs, 4H), 2.32-2.30 (m, 2H), 2.15-2.10 (m, 1H), 1.94-1.82 (m, 10H), 1.64-1.60 (brs, 1H), 1.34-1.24 (m, 2H).

實施例103: 5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image615
反應流程:
Figure 02_image1220
反應步驟： 將1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁-3-基)哌啶-4-甲醛（47 mg, 0.11 mmol）和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（60 mg, 0.094 mmol）溶於四氫呋喃/N,N-二甲基甲醯胺（2.5 mL/0.5 mL）中，冰浴下加入三乙醯氧基硼氫化鈉（60 mg, 0.28 mmol）。反應體系在室溫下攪拌2小時。LC-MS顯示原料消失，反應液加水（10 mL）淬滅，用二氯甲烷（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（37.1 mg，收率31%）。 MS (ESI) M/Z: 1047.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.77 (s, 1H), 8.23 (s, 1H), 8.17-8.13 (m, 2H), 8.04 (brs, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.24 (s, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 2.4 Hz, 1H), 6.71 (s, 1H), 6.52 (dd, J= 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J= 7.6 Hz, 2H), 3.91-3.86 (m, 8H), 3.37-3.31 (m, 1H), 2.92-2.68 (m, 9H), 2.55 (brs, 4H), 2.30-2.28 (m, 5H), 2.13 (s, 4H), 2.00 (s, 3H), 1.97 (s, 3H), 1.93-1.83 (m, 4H), 1.60 (brs, 1H), 1.33-1.23 (m, 2H). Example 103: 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylphenyl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl) piperidine -1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image615
Reaction flow:
Figure 02_image1220
Reaction steps: 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azetidin-3 -yl)piperidine-4-carbaldehyde (47 mg, 0.11 mmol) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (60 mg, 0.094 mmol) was dissolved in tetrahydrofuran/N,N-dimethylformamide (2.5 mL/0.5 mL), and sodium triacetyloxyborohydride (60 mg, 0.28 mmol) was added under ice cooling. The reaction system was stirred at room temperature for 2 hours. LC-MS showed that the starting material disappeared, and the reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3, 4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol- 1-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Diketone (37.1 mg, yield 31%). MS (ESI) M/Z: 1047.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.77 (s, 1H), 8.23 (s, 1H), 8.17-8.13 (m, 2H) , 8.04 (brs, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.71 (s, 1H), 6.52 (dd, J = 8.4, 2.0 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J = 7.6 Hz, 2H), 3.91-3.86 (m, 8H), 3.37-3.31 (m, 1H), 2.92-2.68 (m, 9H), 2.55 (brs, 4H), 2.30-2.28 (m, 5H), 2.13 (s, 4H), 2.00 (s, 3H), 1.97 (s, 3H), 1.93-1.83 (m, 4H), 1.60 (brs, 1H), 1.33-1.23 (m, 2H).

實施例104: 5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-4-甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image617
反應流程:
Figure 02_image1223
反應步驟： 將1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁-3-基)哌啶-4-甲醛（40 mg, 0.094 mmol）和(2-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-5-甲基苯基)二甲基氧化膦（59 mg, 0.094 mmol）溶於四氫呋喃/N,N-二甲基甲醯胺（2.7 mL/0.3 mL）中，冰浴下加入三乙醯氧基硼氫化鈉（60 mg, 0.28 mmol）。反應體系在室溫下攪拌2小時。LC-MS顯示原料消失，反應液加水（10 mL）淬滅，用二氯甲烷（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(3-(4-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（34.5 mg，收率36%）。 MS (ESI) M/Z: 1033.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 10.51 (s, 1H), 8.34 (dd, J= 8.6, 4.6 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J= 14.4 Hz, 1H), 6.82-6.77 (m, 2H), 6.72 (s, 1H), 6.52 (dd, J= 8.2, 2.2 Hz, 1H), 4.95-4.90 (m, 1H), 4.10 (t, J= 7.4 Hz, 2H), 3.91-3.86 (m, 8H), 3.37-3.31 (m, 1H), 2.93-2.70 (m, 9H), 2.56 (brs, 4H), 2.29 (d, J= 6.4 Hz, 2H), 2.25 (s, 3H), 2.15-2.10 (m, 1H), 1.94-1.81 (m, 10H), 1.60 (brs, 1H), 1.33-1.24 (m, 2H). Example 104: 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-methylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)methyl)piperidine-1- Base) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image617
Reaction flow:
Figure 02_image1223
Reaction steps: 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azetidin-3 -yl)piperidine-4-carbaldehyde (40 mg, 0.094 mmol) and (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (59 mg, 0.094 mmol) In tetrahydrofuran/N,N-dimethylformamide (2.7 mL/0.3 mL), add sodium triacetyloxyborohydride (60 mg, 0.28 mmol) under ice-cooling. The reaction system was stirred at room temperature for 2 hours. LC-MS showed that the starting material disappeared, and the reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3, 4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazol- 1-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Diketone (34.5 mg, 36% yield). MS (ESI) M/Z: 1033.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 10.51 (s, 1H), 8.34 (dd, J = 8.6, 4.6 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 14.4 Hz, 1H), 6.82-6.77 (m, 2H), 6.72 (s, 1H), 6.52 (dd, J = 8.2, 2.2 Hz, 1H), 4.95-4.90 (m , 1H), 4.10 (t, J = 7.4 Hz, 2H), 3.91-3.86 (m, 8H), 3.37-3.31 (m, 1H), 2.93-2.70 (m, 9H), 2.56 (brs, 4H), 2.29 (d, J = 6.4 Hz, 2H), 2.25 (s, 3H), 2.15-2.10 (m, 1H), 1.94-1.81 (m, 10H), 1.60 (brs, 1H), 1.33-1.24 (m, 2H).

實施例105: 5-((R)-3-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image619
反應流程:
Figure 02_image1226
反應步驟： 步驟1: 室溫下將 (S)-3-(2-羥乙基)吡咯啉-1-羧酸第三丁酯（200 mg, 0.93 mmol）溶於二氯甲烷（2 mL）中，冰浴下加入氯化氫/1,4-二氧六環溶液（4 M, 1 mL, 4 mmol）。反應體系在室溫下攪拌1小時，LC-MS顯示反應結束。反應液減壓濃縮，加入飽和碳酸氫鈉水溶液（5 mL），用二氯甲烷（5 mL × 3次）萃取。合併有機相，用飽和食鹽水（5 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到(S)-2-(吡咯啉-3-基)乙-1-醇（110 mg, 粗品），直接用於下一步反應。 MS (ESI) M/Z: 116.2 [M+H +]. 步驟2：室溫下將(S)-2-(吡咯啉-3-基)乙-1-醇（110 mg, 粗品）和2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮（281 mg, 0.96 mmol）溶於二甲基亞碸（2 mL）中，加入N,N-二異丙基乙胺（1.3 g, 10.0 mmol）。反應體系升溫至140℃攪拌30分鐘。LC-MS顯示原料消失，將反應液冷卻至室溫，加水（10 mL）稀釋，用乙酸乙酯（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 20/1）純化得到2-(2,6-二氧代哌啶-3-基)-5-氟-6-((S)-3-(2-羥乙基)吡咯啉-1-基)異吲哚啉-1,3-二酮（307 mg，收率85%）。 MS (ESI) M/Z: 390.1 [M+H] +. 步驟3：室溫下將2-(2,6-二氧代哌啶-3-基)-5-氟-6-((S)-3-(2-羥乙基)吡咯啉-1-基)異吲哚啉-1,3-二酮（100 mg, 0.26 mmol）溶於二氯甲烷（4 mL）中，冰浴下加入三乙胺（78 mg, 0.77 mmol）和甲基磺醯氯（44 mg, 0.39 mmol）。反應體系在冰浴下攪拌1小時。LC-MS顯示原料消失，加入飽和碳酸氫鈉水溶液（8 mL）和水（5 mL）稀釋，用二氯甲烷（20 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：石油醚/乙酸乙酯= 1/2）純化得到2-((3S)-1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)吡咯啉-3-基)乙基甲磺酸酯（78 mg，收率65%）。 MS (ESI) M/Z: 468.1 [M+H] +. 步驟4：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（107 mg, 0.17 mmol）和2-((3S)-1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)吡咯啉-3-基)乙基甲磺酸酯（78 mg, 0.17 mmol）溶於乙腈（5 mL）中，加入DIEA（216 mg, 1.7 mmol）和催化量的碘化鈉，將反應體系加熱至85℃攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入飽和碳酸氫鈉水溶液（10 mL）淬滅反應。混合液用二氯甲烷/無水甲醇=10/1（33 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經製備級薄層色譜（洗脫劑：二氯甲烷/甲醇= 10/1）純化得到終產物5-((R)-3-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（52.2 mg，收率31%）。 MS (ESI) M/Z: 1010.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.79 (s, 1H), 8.25 (s, 1H), 8.17-8.14 (m, 2H), 7.99 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.38 (d, J= 12.4 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J= 7.6 Hz, 1H), 6.87-6.83 (m, 1H), 6.71 (s, 1H), 4.94-4.89 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.76-3.72 (m, 1H), 3.65-3.58 (m, 2H), 3.28-3.22 (m, 1H), 2.99-2.65 (m, 8H), 2.61-2.45 (m, 5H), 2.37-2.29 (m, 4H), 2.23-2.11 (m, 5H), 2.00 (s, 3H), 1.97 (s, 3H), 1.72-1.56 (m, 3H). Example 105: 5-((R)-3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl )pyrroline-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image619
Reaction flow:
Figure 02_image1226
Reaction steps: Step 1: Dissolve tert-butyl (S)-3-(2-hydroxyethyl)pyrroline-1-carboxylate (200 mg, 0.93 mmol) in dichloromethane (2 mL) at room temperature , add hydrogen chloride/1,4-dioxane solution (4 M, 1 mL, 4 mmol) under ice-cooling. The reaction system was stirred at room temperature for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, added with saturated aqueous sodium bicarbonate (5 mL), and extracted with dichloromethane (5 mL × 3 times). The organic phases were combined, washed with saturated brine (5 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-2-(pyrrolin-3-yl)ethan-1-ol (110 mg , crude product) was directly used in the next reaction. MS (ESI) M/Z: 116.2 [M+H + ]. Step 2: Mix (S)-2-(pyrrolin-3-yl)ethan-1-ol (110 mg, crude) and 2 -(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (281 mg, 0.96 mmol) was dissolved in dimethylsulfoxide (2 mL), N,N-diisopropylethylamine (1.3 g, 10.0 mmol) was added. The reaction system was heated to 140°C and stirred for 30 minutes. LC-MS showed that the starting material disappeared, and the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20/1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-( (S)-3-(2-Hydroxyethyl)pyrrolin-1-yl)isoindoline-1,3-dione (307 mg, yield 85%). MS (ESI) M/Z: 390.1 [M+H] + . Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((S )-3-(2-hydroxyethyl)pyrroline-1-yl)isoindoline-1,3-dione (100 mg, 0.26 mmol) was dissolved in dichloromethane (4 mL), under ice-cooling Triethylamine (78 mg, 0.77 mmol) and methylsulfonyl chloride (44 mg, 0.39 mmol) were added. The reaction system was stirred under ice bath for 1 hour. LC-MS showed that the starting material disappeared, and diluted with saturated aqueous sodium bicarbonate (8 mL) and water (5 mL), extracted with dichloromethane (20 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/2) to obtain 2-((3S)-1-(2-(2,6-dioxopiperidine-3 -yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolin-3-yl)ethyl methanesulfonate (78 mg, yield 65%). MS (ESI) M/Z: 468.1 [M+H] + . Step 4: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethyloxidation Phosphine (107 mg, 0.17 mmol) and 2-((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol Indolin-5-yl)pyrrolin-3-yl)ethyl methanesulfonate (78 mg, 0.17 mmol) was dissolved in acetonitrile (5 mL), DIEA (216 mg, 1.7 mmol) and a catalytic amount of iodine were added NaCl, the reaction system was heated to 85°C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane/anhydrous methanol=10/1 (33 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (eluent: dichloromethane/methanol = 10/1) to obtain the final product 5-((R)-3-(2-(4-(4-((5- Bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)pyrrolin-1-yl)-2-(2,6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1,3-dione (52.2 mg, yield 31%). MS (ESI) M/Z: 1010.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.79 (s, 1H), 8.25 (s, 1H), 8.17-8.14 (m, 2H) , 7.99 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.38 (d, J = 12.4 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.87-6.83 (m, 1H), 6.71 (s, 1H), 4.94-4.89 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.76-3.72 (m, 1H) , 3.65-3.58 (m, 2H), 3.28-3.22 (m, 1H), 2.99-2.65 (m, 8H), 2.61-2.45 (m, 5H), 2.37-2.29 (m, 4H), 2.23-2.11 ( m, 5H), 2.00 (s, 3H), 1.97 (s, 3H), 1.72-1.56 (m, 3H).

實施例106: 5-((S)-3-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image621
反應流程:
Figure 02_image1229
反應步驟： 以(R)-3-(2-羥乙基)吡咯啉-1-羧酸第三丁酯為原料，參照實施例105的操作步驟製備得到終產物5-((S)-3-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（23.6 mg）。 MS (ESI) M/Z: 1010.1 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.92 (s, 1H), 11.08 (s, 1H), 8.11 (s, 1H), 7.99 (s, 2H), 7.90-7.88 (m, 1H), 7.79 (s, 1H), 7.61-7.57 (m, 2H), 7.06 (d, J= 7.6 Hz, 1H), 6.79 (s, 1H), 6.69 (brs, 1H), 5.08-5.04 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76-3.71 (m, 1H), 3.66-3.56 (m, 2H), 3.27-3.21 (m, 1H), 2.92-2.84 (m, 5H), 2.68-2.56 (m, 5H), 2.50-2.43 (m, 3H), 2.34-2.21 (m, 4H), 2.17-1.99 (m, 5H), 1.88 (s, 3H), 1.85 (s, 3H), 1.66-1.61 (m, 3H). Example 106: 5-((S)-3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl )pyrroline-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image621
Reaction flow:
Figure 02_image1229
Reaction steps: The final product 5-((S)-3 -(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amine Base)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)pyrroline-1-yl)-2-( 2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (23.6 mg). MS (ESI) M/Z: 1010.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.92 (s, 1H), 11.08 (s, 1H), 8.11 (s, 1H) , 7.99 (s, 2H), 7.90-7.88 (m, 1H), 7.79 (s, 1H), 7.61-7.57 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H ), 6.69 (brs, 1H), 5.08-5.04 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.76-3.71 (m, 1H), 3.66-3.56 (m, 2H), 3.27-3.21 (m, 1H), 2.92-2.84 (m, 5H), 2.68-2.56 (m, 5H), 2.50-2.43 (m, 3H), 2.34-2.21 (m, 4H), 2.17-1.99 (m , 5H), 1.88 (s, 3H), 1.85 (s, 3H), 1.66-1.61 (m, 3H).

實施例107: 5-(3-((R)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image623
反應流程:
Figure 02_image1231
反應步驟： 步驟1：室溫下將 (S)-3-(羥甲基)吡咯啉-1-羧酸第三丁酯（500 mg, 2.5 mmol）溶於二氯甲烷（8 mL）中，冰浴下加入DIEA（641 mg, 5.0 mmol）和甲基磺醯氯（427 mg, 3.7 mmol）。反應體系在室溫下攪拌1小時。LC-MS顯示原料消失，加入水（20 mL）稀釋，用二氯甲烷（20 mL × 3次）萃取。合併有機相，用飽和食鹽水（20 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：石油醚/乙酸乙酯= 5/1）純化得到 (S)-3-((甲磺醯氧基)甲基)吡咯啉-1-羧酸第三丁酯（540 mg，收率78%）。 MS (ESI) M/Z: 280.1 [M+H] +. 步驟2：室溫下將(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（200 mg, 0.31 mmol）和(S)-3-((甲磺醯氧基)甲基)吡咯啉-1-羧酸第三丁酯（131 mg, 0.47 mmol）溶於DMSO（8 mL）中，加入DIEA（121 mg, 0.94 mmol）和催化量的碘化鈉，將反應體系加熱至100℃攪拌過夜。LCMS監控顯示原料消失，將反應液冷卻至室溫，加入水（40 mL）淬滅反應。混合液用乙酸乙酯（40 mL×3次）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經矽膠柱層析（洗脫劑：二氯甲烷/甲醇= 30/1）純化得到 (R)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-羧酸第三丁酯（140 mg，收率55%）。 MS (ESI) M/Z: 822.3 [M+H] +. 步驟3: 室溫下將(R)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-羧酸第三丁酯（140 mg, 0.17 mmol）溶於二氯甲烷（6 mL）中，冰浴下加入氯化氫/1,4-二氧六環溶液（4 M, 3 mL, 12 mmol）。反應體系在室溫下攪拌1小時，LC-MS顯示反應結束。反應液減壓濃縮得到(S)-(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(吡咯啉-3-基甲基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦鹽酸鹽（140 mg, 粗品），直接用於下一步反應。 MS (ESI) M/Z: 722.3 [M+H +]. 後續步驟以(S)-(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-(吡咯啉-3-基甲基)哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦鹽酸鹽為原料，參照實施例35的製備方法得到終產物5-(3-((R)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（6.6 mg）。 MS (ESI) M/Z: 1033.4 [M+H] +. 1H NMR (400 MHz, CDCl 3/CD 3OD): δ 8.08-7.88 (m, 4H), 7.64 (d, J= 1.8 Hz, 1H), 7.53-7.58 (m, 3H), 6.74-6.66 (m, 3H), 6.54-6.45 (m, 1H), 4.90-4.80 (m, 1H), 4.09-4.07 (m, 2H), 3.88-3.92 (m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 3.25-2.88 (m, 5H), 2.75-2.63 (m, 6H), 2.60-2.40 (m, 4H), 2.26 (s, 3H), 2.13-2.10 (m, 2H), 2.04 (s, 3H), 1.93 (s, 3H), 1.89 (s, 3H), 1.60-1.46 (m, 3H). Example 107: 5-(3-((R)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethyl Phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl Base) pyrroline-1-yl) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image623
Reaction flow:
Figure 02_image1231
Reaction steps: Step 1: Dissolve (S)-3-(hydroxymethyl)pyrroline-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) in dichloromethane (8 mL) at room temperature, DIEA (641 mg, 5.0 mmol) and methylsulfonyl chloride (427 mg, 3.7 mmol) were added under ice cooling. The reaction system was stirred at room temperature for 1 hour. LC-MS showed that the starting material disappeared, and it was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain (S)-3-((methylsulfonyloxy)methyl)pyrroline-1-carboxylic acid Tertiary butyl ester (540 mg, yield 78%). MS (ESI) M/Z: 280.1 [M+H] + . Step 2: (6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazol-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethyloxidation Phosphine (200 mg, 0.31 mmol) and (S)-3-((methylsulfonyloxy)methyl)pyrroline-1-carboxylic acid tert-butyl ester (131 mg, 0.47 mmol) were dissolved in DMSO (8 mL ), DIEA (121 mg, 0.94 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 100 °C and stirred overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, and water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 30/1) to obtain (R)-3-((4-(4-((5-bromo-4-((2- (Dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piper-1-yl)methyl)pyrroline-1-carboxylic acid tert-butyl ester (140 mg, yield 55%). MS (ESI) M/Z: 822.3 [M+H] + . Step 3: (R)-3-((4-(4-((5-bromo-4-((2-(di Methylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- Base) phenyl) piper-1-yl) methyl) pyrroline-1-carboxylic acid tert-butyl ester (140 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL), and hydrogen chloride/ 1,4-Dioxane solution (4 M, 3 mL, 12 mmol). The reaction system was stirred at room temperature for 1 hour, and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain (S)-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(pyrrolin-3-ylmethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide Hydrochloride (140 mg, crude product) was directly used in the next reaction. MS (ESI) M/Z: 722.3 [M+H + ]. Follow up with (S)-(6-((5-bromo-2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(4-(pyrroline-3-ylmethyl)piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2, 3-Dimethylphenyl) dimethylphosphine oxide hydrochloride was used as a raw material, and the final product 5-(3-((R)-3-((4-(4-(( 5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-( 1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)methyl)pyrroline-1-yl)azetidin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione (6.6 mg). MS (ESI) M/Z: 1033.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 /CD 3 OD): δ 8.08-7.88 (m, 4H), 7.64 (d, J = 1.8 Hz, 1H), 7.53-7.58 (m, 3H), 6.74-6.66 (m, 3H), 6.54-6.45 (m, 1H), 4.90-4.80 (m, 1H), 4.09-4.07 (m, 2H), 3.88- 3.92 (m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 3.25-2.88 (m, 5H), 2.75-2.63 (m, 6H), 2.60-2.40 (m, 4H), 2.26 ( s, 3H), 2.13-2.10 (m, 2H), 2.04 (s, 3H), 1.93 (s, 3H), 1.89 (s, 3H), 1.60-1.46 (m, 3H).

實施例108: 5-(3-((S)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image625
反應流程:
Figure 02_image1233
反應步驟： 以(R)-3-(羥甲基)吡咯啉-1-羧酸第三丁酯為原料，參照實施例107的製備方法得到終產物5-(3-((S)-3-((4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)吡咯啉-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（12.9 mg）。 MS (ESI) M/Z: 1033.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.74 (s, 1H), 8.19-8.07 (m, 4H), 7.76 (s, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.45 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 6.46 (d, J= 8.0 Hz, 1H), 4.87-4.83 (m, 1H), 4.04 (t, J= 6.8 Hz, 2H), 3.94-3.88 (m, 2H), 3.80 (s, 6H), 3.50 (brs, 2H), 3.22- 3.06 (m, 3H), 2.85-2.53 (m, 12H), 2.23 (s, 3H), 2.18-2.13 (m, 2H), 2.10 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H), 1.60-1.46 (m, 3H). Example 108: 5-(3-((S)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethyl Phenyl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) methyl Base) pyrroline-1-yl) azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image625
Reaction flow:
Figure 02_image1233
Reaction steps: Using tert-butyl (R)-3-(hydroxymethyl)pyrroline-1-carboxylate as raw material, refer to the preparation method of Example 107 to obtain the final product 5-(3-((S)-3 -((4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)methyl)pyrroline-1-yl)azetidin-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.9 mg). MS (ESI) M/Z: 1033.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.74 (s, 1H), 8.19-8.07 (m, 4H), 7.76 (s, 1H) , 7.57 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.87-4.83 (m, 1H), 4.04 (t, J = 6.8 Hz, 2H), 3.94-3.88 (m, 2H), 3.80 (s, 6H), 3.50 (brs, 2H), 3.22- 3.06 (m, 3H), 2.85-2.53 (m, 12H), 2.23 (s, 3H), 2.18-2.13 (m, 2H), 2.10 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H ), 1.60-1.46 (m, 3H).

實施例109: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-甲基哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image627
反應流程:
Figure 02_image1235
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮和2-(4-甲基哌啶-4-基)乙烷-1-醇（製備可參考文獻Collection of Czechoslovak Chemical Communications, 1953, vol. 18, p. 818,821）為原料，參照實施例55的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-甲基哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（7 mg）。 MS (ESI) M/Z: 1038.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.78 (s, 1H), 8.24 (s, 1H), 8.17-8.14 (m, 2H), 8.00 (brs, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.46 (d, J= 11.2 Hz, 1H), 7.40 (d, J= 7.2 Hz, 1H), 7.24 (s, 1H), 6.89-6.82 (m, 1H), 6.70 (s, 1H), 4.95-4.91 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.37-3.30 (m, 2H), 3.22-3.15 (m, 2H), 3.00 (brs, 4H), 2.93-2.68 (m, 6H), 2.63-2.53 (m, 3H), 2.30 (s, 3H), 2.18-2.11 (m, 4H), 2.00 (s, 3H), 1.97 (s, 3H), 1.60-1.45 (m, 6H), 1.05 (s, 3H). Example 109: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)-4- Methylpiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image627
Reaction flow:
Figure 02_image1235
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-methylpiperidine- 4-yl)ethan-1-ol (preparation can refer to the literature Collection of Czechoslovak Chemical Communications, 1953, vol. 18, p. 818,821) as a raw material, and the final product 5-(4- (2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)-4-methylpiperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (7 mg). MS (ESI) M/Z: 1038.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.78 (s, 1H), 8.24 (s, 1H), 8.17-8.14 (m, 2H) , 8.00 (brs, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.46 (d, J = 11.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 6.89-6.82 (m, 1H), 6.70 (s, 1H), 4.95-4.91 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.37-3.30 (m, 2H) , 3.22-3.15 (m, 2H), 3.00 (brs, 4H), 2.93-2.68 (m, 6H), 2.63-2.53 (m, 3H), 2.30 (s, 3H), 2.18-2.11 (m, 4H) , 2.00 (s, 3H), 1.97 (s, 3H), 1.60-1.45 (m, 6H), 1.05 (s, 3H).

實施例110: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image629
反應流程:
Figure 02_image1237
反應步驟： 步驟1：氮氣保護下將四氫呋喃（10 mL）冷卻至0℃，慢慢加入氫化鋁鋰（176 mg, 4.6 mmol），攪拌10分鐘後，緩慢滴加4-(2-乙氧基-2-氧代乙基)-4-氟哌啶-1-羧酸苄酯（1.0 g, 3.1 mmol）的四氫呋喃（2 mL）溶液，反應體系在0℃下攪拌0.5小時。LCMS顯示反應結束，冰浴下向反應液中加入乙酸乙酯（20 mL）稀釋，再依次加水（0.5 mL）、10%氫氧化鈉水溶液（0.4 mL）和水（0.5 mL）。混合物過濾，濾液經無水硫酸鈉乾燥後減壓濃縮得到4-氟-4-(2-羥乙基)哌啶-1-羧酸苄酯（800 mg，粗品）。 MS (ESI) M/Z: 282.0 [M+H] +. 步驟2：室溫下將4-氟-4-(2-羥乙基)哌啶-1-羧酸苄酯（800 mg，粗品）溶於甲醇（10 mL）中，加入10%濕鈀碳(240 mg)。反應體系在氫氣球氛圍下攪拌過夜。LCMS顯示反應結束，反應液減壓濃縮得到2-(4-氟哌啶-4-基)乙烷-1-醇（520 mg，粗品）。 MS (ESI) M/Z: 148.1 [M+H] +. 後續步驟以2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮和2-(4-氟哌啶-4-基)乙烷-1-醇為原料，參照實施例55的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（41.1 mg）。 MS (ESI) M/Z: 1042.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.92 (s, 1H), 11.10 (s, 1H), 8.11 (s, 1H), 7.99 (s, 2H), 7.89 (dd, J= 7.8, 3.4 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J= 11.6 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J= 7.6 Hz, 1H), 6.77 (s, 1H), 6.71 (brs, 1H), 5.13-5.08 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.51-3.47 (m, 2H), 3.33-3.29 (m, 1H), 3.19-3.12 (m, 2H), 2.93-2.80 (m, 5H), 2.68-2.53 (m, 7H), 2.22 (s, 3H), 2.07-2.00 (m, 4H), 1.96-1.81 (m, 12H). Example 110: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)-4- Haloperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image629
Reaction flow:
Figure 02_image1237
Reaction steps: Step 1: Cool tetrahydrofuran (10 mL) to 0°C under nitrogen protection, slowly add lithium aluminum hydride (176 mg, 4.6 mmol), and after stirring for 10 minutes, slowly add 4-(2-ethoxy Benzyl-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (1.0 g, 3.1 mmol) was dissolved in tetrahydrofuran (2 mL), and the reaction system was stirred at 0°C for 0.5 hours. LCMS showed that the reaction was complete. Ethyl acetate (20 mL) was added to the reaction solution under ice cooling to dilute, and then water (0.5 mL), 10% aqueous sodium hydroxide solution (0.4 mL) and water (0.5 mL) were added in sequence. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain benzyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (800 mg, crude product). MS (ESI) M/Z: 282.0 [M+H] + . Step 2: Benzyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (800 mg, crude ) was dissolved in methanol (10 mL), and 10% wet palladium on carbon (240 mg) was added. The reaction system was stirred overnight under a hydrogen balloon atmosphere. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain 2-(4-fluoropiperidin-4-yl)ethan-1-ol (520 mg, crude product). MS (ESI) M/Z: 148.1 [M+H] + . Subsequent step with 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1, 3-diketone and 2-(4-fluoropiperidin-4-yl)ethan-1-ol are raw materials, and the final product 5-(4-(2-(4-( 4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)-4-fluoropiperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (41.1 mg). MS (ESI) M/Z: 1042.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.92 (s, 1H), 11.10 (s, 1H), 8.11 (s, 1H) , 7.99 (s, 2H), 7.89 (dd, J = 7.8, 3.4 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 11.6 Hz, 1H), 7.58 (s, 1H), 7.51 ( d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.71 (brs, 1H), 5.13-5.08 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.51-3.47 (m, 2H), 3.33-3.29 (m, 1H), 3.19-3.12 (m, 2H), 2.93-2.80 (m, 5H), 2.68-2.53 (m, 7H), 2.22 (s, 3H), 2.07 -2.00 (m, 4H), 1.96-1.81 (m, 12H).

實施例111: 3-(4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)哌啶-2,6-二酮

Figure 02_image631
反應流程:
Figure 02_image1240
反應步驟： 室溫下將2-(1-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)-4-羥基哌啶-4-基)乙酸鹽酸鹽（50 mg，0.14 mmol，製備參照專利WO2021/127561A1）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（88 mg，0.14 mmol）、HATU（80 mg，0.21 mmol）和DIEA（35 mg，0.27 mmol）依次加入到DMF（3 mL）中，室溫攪拌1小時。LCMS監測原料消失，加入水（10 mL）稀釋，乙酸乙酯（10 mL×3）萃取。合併有機相，飽和食鹽水（10 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-(4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)哌啶-2,6-二酮（68.8 mg，收率50%）。 MS (ESI) M/Z: 985.1 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.91 (s, 1H), 10.81 (s, 1H), 8.11 (d, J= 7.6 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J= 5.2 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.02-6.93 (m, 3H), 6.78 (s, 1H), 6.70 (brs, 1H), 4.94 (s, 1H), 3.86 (s, 3H), 3.79 (brs, 4H), 3.70 (brs, 4H), 3.10-2.98 (m, 4H), 2.83 (brs, 4H), 2.69-2.57 (m, 4H), 2.23-2.15 (m, 4H), 2.08 (s, 3H), 2.03-1.97 (m, 1H), 1.89 (s, 3H), 1.85 (s, 3H), 1.83-1.68 (m, 4H). Example 111: 3-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl)-2 -Oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione
Figure 02_image631
Reaction flow:
Figure 02_image1240
Reaction steps: 2-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate Salt (50 mg, 0.14 mmol, refer to patent WO2021/127561A1 for preparation), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (88 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol) and DIEA (35 mg, 0.27 mmol) were sequentially added to DMF (3 mL), and stirred at room temperature for 1 hour. LCMS monitored the disappearance of the starting material, added water (10 mL) to dilute, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (68.8 mg, yield 50% ). MS (ESI) M/Z: 985.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 10.81 (s, 1H), 8.11 (d, J = 7.6 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.02-6.93 (m, 3H), 6.78 ( s, 1H), 6.70 (brs, 1H), 4.94 (s, 1H), 3.86 (s, 3H), 3.79 (brs, 4H), 3.70 (brs, 4H), 3.10-2.98 (m, 4H), 2.83 (brs, 4H), 2.69-2.57 (m, 4H), 2.23-2.15 (m, 4H), 2.08 (s, 3H), 2.03-1.97 (m, 1H), 1.89 (s, 3H), 1.85 (s , 3H), 1.83-1.68 (m, 4H).

實施例112: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image633
反應流程:
Figure 02_image1242
反應步驟： 步驟1：將1,4-二氯-2-氟-5-硝基苯（11.5 g, 55.0 mmol）和哌𠯤-1-羧酸第三丁酯 （12.2 g, 65.6 mmol）溶於乙腈（300 mL）中，加入碳酸鉀（15.1 g, 109 mmol），升溫至70℃攪拌過夜。反應液冷卻至室溫，減壓濃縮除去大部分溶劑，加入乙酸乙酯（300 mL）稀釋，再用飽和食鹽水（200 mL×3）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 20/1）得到4-(2,5-二氯-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（18.6 g，收率90%）。 MS (ESI) M/Z: 376.0 [M+H] +. 步驟2：室溫下向4-(2,5-二氯-4-硝基苯基)哌𠯤-1-羧酸第三丁酯（15.6 g, 41.6 mmol）的二氯甲烷（50 mL）溶液中加入氯化氫二氧六環溶液（50 mL, 4M）。室溫下攪拌3小時後減壓濃縮得到1-(2,5-二氯-4-硝基苯基)哌𠯤鹽酸鹽（10.1 g，粗品）。 MS (ESI) M/Z: 276.1 [M+H] +. 步驟3：室溫下將1-(2,5-二氯-4-硝基苯基)哌𠯤鹽酸鹽（10.1 g，粗品）和DMAP（8.9 g，73.2 mmol）加入到二氯甲烷（150 mL）中，攪拌5分鐘，再加入三氟乙酸酐（11.5 g，54.9 mmol），室溫攪拌反應1小時。將反應液倒入冰水（150 mL）中，用二氯甲烷（100 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 20/1）得到1-(4-(2,5-二氯-4-硝基苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（9.1 g，二步收率59%）。 MS (ESI) M/Z: 372.0 [M+H] +. 步驟4：室溫下將1-(4-(2,5-二氯-4-硝基苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（9.1 g，24.5 mmol）溶於甲醇（100 mL）和水（20 mL）中，依次加入和原料等重的氯化銨和鐵粉，升溫至70℃攪拌2小時。LCMS檢測反應完全，反應液冷卻至室溫，過濾，濾液減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 5/1）得到1-(4-(4-胺基-2,5-二氯苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（4.2 g，收率50%）。 MS (ESI) M/Z: 342.1 [M+H] +. 步驟5：室溫下將1-(4-(4-胺基-2,5-二氯苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（176 mg，0.52 mmol），(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧膦（200 mg，0.52 mmol）和三氟乙酸（582 mg，5.1 mmol）依次加入到正丁醇（10 mL）中，氮氣保護下升溫至110℃攪拌過夜。LCMS檢測反應完全，將反應液冷卻至室溫，加水（50 mL）稀釋後用乙酸乙酯（50 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇= 25/1）得到1-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（84 mg，收率24%）。 MS (ESI) M/Z: 693.1 [M+H] +. 步驟6：室溫下將1-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)-2,2,2-三氟乙烷-1-酮（84 mg，0.12 mmol）和氫氧化鉀（34 mg，0.60 mmol）加入到甲醇（8 mL）和水（2 mL）中，升溫至60℃攪拌反應1小時。LCMS監測反應完畢，將反應液冷卻至室溫，加入冰水（20 mL）稀釋，再用乙酸乙酯（20 mL×3次）萃取。合併有機相，用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物經製備級薄層色譜純化（洗脫劑：二氯甲烷/甲醇= 15/1）得到(6-((5-溴-2-((2,5-二氯-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯)二甲基氧化膦（23 mg，收率32%）。 MS (ESI) M/Z: 597.1 [M+H] +. 步驟7：室溫下將(6-((5-溴-2-((2,5-二氯-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯)二甲基氧化膦（23 mg, 0.039 mmol）和2-(1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代異吲哚啉-5-基)哌啶-4-基)乙基甲磺酸酯（19 mg, 0.040 mmol）溶於乙腈（3 mL）中，加入DIEA（15 mg, 0.12 mmol）和催化量的碘化鈉，將反應體系加熱至85℃並攪拌15小時。LCMS監控顯示原料消失，將反應液冷卻至室溫，用高效製備液相色譜純化得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（6.5 mg，收率17%）。 MS (ESI) M/Z: 982.1 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.61 (s, 1H), 8.01 (d, J= 5.6 Hz, 2H), 7.88-7.85 (m, 2H), 7.47 (d, J= 10.8 Hz, 1H), 7.38 (d, J= 7.2 Hz, 1H), 7.14-7.11 (m, 2H), 4.96-4.91 (m, 1H), 3.76-3.64 (m, 4H), 3.44-3.31 (m, 4H), 3.19-3.15 (m, 2H), 3.09-3.04 (m, 2H), 2.88-2.81 (m, 4H), 2.78-2.69 (m, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 2.16-2.12 (m, 1H), 2.00 (s, 3H), 1.97(s, 3H), 1.86-1.81 (m, 3H), 167-1.59 (m, 1H), 1.54-1.45 (m, 2H). Example 112: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amine Base) pyrimidin-2-yl) amino)-2,5-dichlorophenyl) piper-1-yl) ethyl) piperidin-1-yl)-2-(2,6-dioxopiper Pyridin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image633
Reaction flow:
Figure 02_image1242
Reaction steps: Step 1: Dissolve 1,4-dichloro-2-fluoro-5-nitrobenzene (11.5 g, 55.0 mmol) and tert-butyl piper-1-carboxylate (12.2 g, 65.6 mmol) Add potassium carbonate (15.1 g, 109 mmol) to acetonitrile (300 mL), heat up to 70°C and stir overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (300 mL), washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and finally decompressed concentrate. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain 4-(2,5-dichloro-4-nitrophenyl)piperone-1-carboxylic acid Tertiary butyl ester (18.6 g, yield 90%). MS (ESI) M/Z: 376.0 [M+H] + . Step 2: Add 4-(2,5-dichloro-4-nitrophenyl)piperone-1-carboxylic acid to tert-butyl To a solution of the ester (15.6 g, 41.6 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride in dioxane (50 mL, 4M). After stirring at room temperature for 3 hours, it was concentrated under reduced pressure to obtain 1-(2,5-dichloro-4-nitrophenyl)piperone hydrochloride (10.1 g, crude product). MS (ESI) M/Z: 276.1 [M+H] + . Step 3: 1-(2,5-dichloro-4-nitrophenyl)piperone hydrochloride (10.1 g, crude ) and DMAP (8.9 g, 73.2 mmol) were added to dichloromethane (150 mL), stirred for 5 minutes, then added trifluoroacetic anhydride (11.5 g, 54.9 mmol), and stirred at room temperature for 1 hour. The reaction solution was poured into ice water (150 mL), and extracted with dichloromethane (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain 1-(4-(2,5-dichloro-4-nitrophenyl)piperone-1 -yl)-2,2,2-trifluoroethane-1-one (9.1 g, 59% yield in two steps). MS (ESI) M/Z: 372.0 [M+H] + . Step 4: Add 1-(4-(2,5-dichloro-4-nitrophenyl)piperone-1-yl) at room temperature -2,2,2-Trifluoroethane-1-one (9.1 g, 24.5 mmol) was dissolved in methanol (100 mL) and water (20 mL), and ammonium chloride and iron powder of the same weight as the raw materials were added sequentially , heated to 70°C and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain 1-(4-(4-amino-2,5-dichlorophenyl)piperone-1 -yl)-2,2,2-trifluoroethane-1-one (4.2 g, yield 50%). MS (ESI) M/Z: 342.1 [M+H] + . Step 5: 1-(4-(4-Amino-2,5-dichlorophenyl)piperone-1-yl) -2,2,2-Trifluoroethane-1-one (176 mg, 0.52 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-di Methylphenyl)dimethylphosphine oxide (200 mg, 0.52 mmol) and trifluoroacetic acid (582 mg, 5.1 mmol) were sequentially added to n-butanol (10 mL), heated to 110°C under nitrogen protection and stirred overnight. LCMS detected that the reaction was complete, and the reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=25/1) to obtain 1-(4-(4-((5-bromo-4-((2-(dimethylphosphine Acyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piper-1-yl)-2,2,2- Trifluoroethane-1-one (84 mg, 24% yield). MS (ESI) M/Z: 693.1 [M+H] + . Step 6: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) )-3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piper-1-yl)-2,2,2-trifluoro Ethan-1-one (84 mg, 0.12 mmol) and potassium hydroxide (34 mg, 0.60 mmol) were added to methanol (8 mL) and water (2 mL), heated to 60°C and stirred for 1 hour. The completion of the reaction was monitored by LCMS, and the reaction solution was cooled to room temperature, diluted with ice water (20 mL), and extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (eluent: dichloromethane/methanol = 15/1) to give (6-((5-bromo-2-((2,5-dichloro-4-(piper 𠯤-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (23 mg, yield 32%). MS (ESI) M/Z: 597.1 [M+H] + . Step 7: (6-((5-bromo-2-((2,5-dichloro-4-(piperone 𠯤-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (23 mg, 0.039 mmol) and 2-(1-(2-( 2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)ethyl methanesulfonate (19 mg, 0.040 mmol) was dissolved in acetonitrile (3 mL), DIEA (15 mg, 0.12 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 85°C and stirred for 15 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-((2- (Dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piper-1-yl)ethyl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (6.5 mg, yield 17%) . MS (ESI) M/Z: 982.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.61 (s, 1H), 8.01 (d, J = 5.6 Hz, 2H), 7.88-7.85 (m, 2H), 7.47 (d, J = 10.8 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.14-7.11 (m, 2H), 4.96-4.91 (m, 1H), 3.76- 3.64 (m, 4H), 3.44-3.31 (m, 4H), 3.19-3.15 (m, 2H), 3.09-3.04 (m, 2H), 2.88-2.81 (m, 4H), 2.78-2.69 (m, 2H ), 2.30 (s, 3H), 2.24 (s, 3H), 2.16-2.12 (m, 1H), 2.00 (s, 3H), 1.97(s, 3H), 1.86-1.81 (m, 3H), 167- 1.59 (m, 1H), 1.54-1.45 (m, 2H).

實施例113: 5-(4-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image635
反應流程:
Figure 02_image1244
反應步驟： 以(6-((5-溴-2-氯嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例112的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（20 mg）。 MS (ESI) M/Z: 1006.0 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.66 (s, 1H), 8.93 (dd, J= 9.6, 4.0 Hz, 1H), 8.78 (d, J= 2.0 Hz, 1H), 8.73 (d, J= 1.6 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.21 (d, J= 9.2 Hz, 1H), 8.08 (brs, 1H), 7.45 (d, J= 11.2 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 7.30 (s, 1H), 7.09 (s, 1H), 4.95-4.91 (m, 1H), 3.65 (d, J= 12.4 Hz, 2H), 3.10 (brs, 4H), 2.93-2.69 (m, 8H), 2.60-2.56 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.84 (brs, 4H), 1.62-1.45 (m, 5H). Example 113: 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine -2-yl)amino)-2,5-dichlorophenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3 -yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image635
Reaction flow:
Figure 02_image1244
Reaction steps: Using (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide as raw material, it was prepared by referring to the operation steps of Example 112 Final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidine-2 -yl)amino)-2,5-dichlorophenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl )-6-fluoroisoindoline-1,3-dione (20 mg). MS (ESI) M/Z: 1006.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.66 (s, 1H), 8.93 (dd, J = 9.6, 4.0 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.08 (brs, 1H), 7.45 (d, J = 11.2 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.30 (s, 1H), 7.09 (s, 1H), 4.95-4.91 (m, 1H), 3.65 (d, J = 12.4 Hz, 2H), 3.10 (brs, 4H), 2.93-2.69 (m, 8H), 2.60-2.56 (m, 2H), 2.16 (s, 3H), 2.12 (s , 3H), 1.84 (brs, 4H), 1.62-1.45 (m, 5H).

實施例114: 1-(6-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-3,3-二氟哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮

Figure 02_image637
反應流程:
Figure 02_image1247
反應步驟： 以2-(4-(3-(2,4-二氧代四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-3,3-二氟哌啶-1-基)乙酸三氟乙酸鹽（製備參見專利WO2021/127561A1）和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦為原料，參照實施例111的操作步驟製備得到終產物1-(6-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-3,3-二氟哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（46 mg）。 MS (ESI) M/Z: 1042.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 11.94 (s, 1H), 8.21 (s, 1H), 8.15-8.12 (m, 2H), 7.77 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.63 (d, J= 8.8 Hz, 1H), 7.29 (s, 1H), 7.11 (d, J= 8.4 Hz, 1H), 6.83 (d, J= 7.6 Hz, 1H), 6.66 (s, 1H), 4.09 (t, J= 6.8 Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.76-3.67 (m, 3H), 3.47-3.34 (m, 2H), 3.27-3.22 (m, 1H), 3.13-3.03 (m, 2H), 2.95-2.87 (m, 7H), 2.73-2.63 (m, 1H), 2.55-2.50 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.72 (brs, 2H). Example 114: 1-(6-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl)-2 -Oxoethyl)-3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure 02_image637
Reaction flow:
Figure 02_image1247
Reaction steps: With 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3 -Difluoropiperidin-1-yl)acetic acid trifluoroacetate (preparation see patent WO2021/127561A1) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl -1H-pyrazol-4-yl)-4-(piperyl-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethyl Phosphine oxide was used as a raw material, and the final product 1-(6-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphine Acyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl) piper-1-yl)-2-oxoethyl)-3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine -2,4(1H,3H)-dione (46 mg). MS (ESI) M/Z: 1042.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 11.94 (s, 1H), 8.21 (s, 1H), 8.15-8.12 (m, 2H) , 7.77 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 4.09 (t, J = 6.8 Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.85 ( s, 3H), 3.76-3.67 (m, 3H), 3.47-3.34 (m, 2H), 3.27-3.22 (m, 1H), 3.13-3.03 (m, 2H), 2.95-2.87 (m, 7H), 2.73-2.63 (m, 1H), 2.55-2.50 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.72 (brs, 2H).

實施例115: 1-(6-(1-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮

Figure 02_image639
反應流程:
Figure 02_image1249
反應步驟： 以2-(4-(3-(2,4-二氧代四氫嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)哌啶-1-基)乙酸三氟乙酸鹽（製備參見專利WO2021/127561A1）和 (6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例111的操作步驟製備得到終產物1-(6-(1-(2-(4-(4-((5-溴-4-((5-(二甲基膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氫嘧啶-2,4(1H,3H)-二酮（14.8 mg）。 MS (ESI) M/Z: 1029.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.59 (s, 1H), 9.03-8.93 (m, 1H), 8.72 (d, J= 12.6 Hz, 2H), 8.30 (s, 1H), 8.25 (s, 1H), 7.74-7.57 (m, 5H), 7.40 (d, J= 0.9 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.67 (s, 1H), 4.10-4.07 (m, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 3.75-3.71 (m, 6H), 3.35-3.25 (m, 2H), 3.09-3.05 (m, 2H), 2.91-2.84 (m, 4H), 2.72-2.62 (m, 1H), 2.40-2.27 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.93-1.84 (m, 7H). Example 115: 1-(6-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) -2-oxo Ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure 02_image639
Reaction flow:
Figure 02_image1249
Reaction steps: With 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1 -yl)acetic acid trifluoroacetate (preparation see patent WO2021/127561A1) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide as raw material, referring to Example 111 The operation steps prepare the final product 1-(6-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl) quinoline-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)-2- Oxoethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (14.8 mg). MS (ESI) M/Z: 1029.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.59 (s, 1H), 9.03-8.93 (m, 1H), 8.72 (d, J = 12.6 Hz, 2H), 8.30 (s, 1H), 8.25 (s, 1H), 7.74-7.57 (m, 5H), 7.40 (d, J = 0.9 Hz, 1H), 7.15 (s, 1H), 7.05 ( d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 4.10-4.07 (m, 2H), 3.98 (s, 3H), 3.89 (s, 3H), 3.75-3.71 (m, 6H), 3.35 -3.25 (m, 2H), 3.09-3.05 (m, 2H), 2.91-2.84 (m, 4H), 2.72-2.62 (m, 1H), 2.40-2.27 (m, 2H), 2.15 (s, 3H) , 2.11 (s, 3H), 1.93-1.84 (m, 7H).

實施例116: 3-(5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮

Figure 02_image641
反應流程:
Figure 02_image1251
反應步驟： 以3-(5-(4-(2-羥乙基)哌啶-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（製備參見專利US2020/339572A1）和 (6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例55的操作步驟製備得到終產物3-(5-(4-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-1-氧代異吲哚啉-2-基)哌啶-2,6-二酮（7.1 mg）。 MS (ESI) M/Z: 1016.1 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 12.68 (s, 1H), 10.96 (s, 1H), 8.85-8.81 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.52-7.45 (m, 3H), 7.10-7.00 (m, 2H), 6.83 (s, 1H), 5.07-5.04 (m, 1H), 4.34-4.22 (m, 2H), 3.90-3.87 (m, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 2.90-2.75 (m, 8H), 2.70-2.40 (m, 6H), 2.03-1.90 (m, 8H), 1.80-1.70 (m, 2H), 1.55-1.40 (m, 5H). Example 116: 3-(5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphonyl)quinolin-6-yl)amino )pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)piperidine- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
Figure 02_image641
Reaction flow:
Figure 02_image1251
Reaction steps: With 3-(5-(4-(2-hydroxyethyl) piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( Preparation see patent US2020/339572A1) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperone -1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoline-5-yl) dimethylphosphine oxide as raw material, the final product 3-( 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-1-yl)ethyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (7.1 mg). MS (ESI) M/Z: 1016.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.68 (s, 1H), 10.96 (s, 1H), 8.85-8.81 (m, 3H), 8.43 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.52-7.45 (m, 3H), 7.10-7.00 (m, 2H), 6.83 (s, 1H), 5.07-5.04 (m, 1H), 4.34-4.22 (m, 2H), 3.90-3.87 (m, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 2.90-2.75 (m, 8H), 2.70-2.40 (m, 6H), 2.03-1.90 (m, 8H), 1.80-1.70 (m, 2H), 1.55-1.40 (m, 5H).

實施例117: 3-((4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)胺基)哌啶-2,6-二酮

Figure 02_image643
反應流程:
Figure 02_image1253
反應步驟： 室溫下將2-(1-(4-((2,6-二氧代哌啶-3-基)胺基)-2-氟苯基)-4-羥基哌啶-4-基)乙酸鹽酸鹽（80 mg，0.19 mmol，製備參照專利WO2021/127561A1）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（183 mg，0.22 mmol）、HATU（123 mg，0.32 mmol）和DIEA（105 mg，0.81 mmol）依次加入到DMF（5 mL）中，室溫攪拌3小時。LCMS監測原料消失，反應液倒入水（20 mL）中，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（10 mL）洗滌二次，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-((4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)胺基)哌啶-2,6-二酮（95 mg，收率49%）。 MS (ESI) M/Z: 1000.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.98 (s, 1H), 10.86 (s, 1H), 8.18 (d, J= 2.0 Hz, 2H), 8.09 (s, 1H), 7.95 (d, J= 4.0 Hz, 1H), 7.83 (s, 1H), 7.69 (brs, 1H), 6.92-6.90 (m, 1H), 6.85 (s, 1H), 6.80-6.70 (m, 1H), 6.58-6.54 (m, 1H), 6.49-6.46 (m, 1H), 5.87-5.83 (m, 1H), 4.95 (s, 1H), 4.40-4.28 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.77-3.70 (m, 4H), 2.90-2.75 (m, 9H), 2.63-2.56 (m, 3H), 2.29 (s, 3H), 2.14-2.05 (m, 5H), 1.95 (s, 3H), 1.92 (s, 3H), 1.85-1.65 (m, 4H). Example 117: 3-((4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethyl Phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)- 2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
Figure 02_image643
Reaction flow:
Figure 02_image1253
Reaction steps: 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidine-4- base) acetic acid hydrochloride (80 mg, 0.19 mmol, refer to patent WO2021/127561A1 for preparation), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H- Pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide ( 183 mg, 0.22 mmol), HATU (123 mg, 0.32 mmol) and DIEA (105 mg, 0.81 mmol) were sequentially added to DMF (5 mL), and stirred at room temperature for 3 hours. The disappearance of raw materials was monitored by LCMS, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl )-3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperidine-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (95 mg, Yield 49%). MS (ESI) M/Z: 1000.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.98 (s, 1H), 10.86 (s, 1H), 8.18 (d, J = 2.0 Hz, 2H), 8.09 (s, 1H), 7.95 (d, J = 4.0 Hz, 1H), 7.83 (s, 1H), 7.69 (brs, 1H), 6.92-6.90 (m, 1H), 6.85 ( s, 1H), 6.80-6.70 (m, 1H), 6.58-6.54 (m, 1H), 6.49-6.46 (m, 1H), 5.87-5.83 (m, 1H), 4.95 (s, 1H), 4.40- 4.28 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.77-3.70 (m, 4H), 2.90-2.75 (m, 9H), 2.63-2.56 (m, 3H), 2.29 ( s, 3H), 2.14-2.05 (m, 5H), 1.95 (s, 3H), 1.92 (s, 3H), 1.85-1.65 (m, 4H).

實施例118: 1-(4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)二氫嘧啶-2,4(1H,3H)-二酮

Figure 02_image645
反應流程:
Figure 02_image1255
反應步驟： 室溫下將2-(1-(4-(2,4-二氧代四氫嘧啶-1(2H)-基)-2-氟苯基)-4-羥基哌啶-4-基)乙酸（150 mg，0.41 mmol，製備參照專利WO2021/127561A1）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（277 mg，0.43 mmol）、HATU（187 mg，0.49 mmol）和DIEA（159 mg，1.23 mmol）依次加入到DMF（5 mL）中，室溫攪拌3小時。LCMS監測原料消失，反應液倒入水（20 mL）中，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（10 mL）洗滌二次，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物1-(4-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)-4-羥基哌啶-1-基)-3-氟苯基)二氫嘧啶-2,4(1H,3H)-二酮（55.8 mg，收率14%）。 MS (ESI) M/Z: 986.5 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.92 (s, 1H), 10.38 (s, 1H), 8.12 (d, J= 2.0 Hz, 2H), 8.03 (s, 1H), 7.88 (d, J= 4.0 Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.18-7.14 (m, 1H), 7.07-7.05 (m, 2H), 6.78 (s, 1H), 6.76 (brs, 1H), 4.96 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.75-3.65 (m, 6H), 3.10-2.95 (m, 4H), 2.83-2.80 (m, 4H), 2.68 (t, J= 6.8 Hz, 2H), 2.58 (brs, 2H), 2.23 (s, 3H), 2.08 (s, 3H), 1.89 (s, 3H), 1.85 (s, 3H), 1.80-1.69 (m, 4H). Example 118: 1-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl)-2 -Oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
Figure 02_image645
Reaction flow:
Figure 02_image1255
Reaction steps: 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)-4-hydroxypiperidine-4- base) acetic acid (150 mg, 0.41 mmol, refer to patent WO2021/127561A1 for preparation), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole- 4-yl)-4-(piperone-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (277 mg, 0.43 mmol), HATU (187 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were sequentially added to DMF (5 mL), and stirred at room temperature for 3 hours. The disappearance of raw materials was monitored by LCMS, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 1-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (55.8 mg, yield 14%). MS (ESI) M/Z: 986.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.92 (s, 1H), 10.38 (s, 1H), 8.12 (d, J = 2.0 Hz, 2H), 8.03 (s, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.18-7.14 (m, 1H), 7.07- 7.05 (m, 2H), 6.78 (s, 1H), 6.76 (brs, 1H), 4.96 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.75-3.65 (m, 6H) , 3.10-2.95 (m, 4H), 2.83-2.80 (m, 4H), 2.68 (t, J = 6.8 Hz, 2H), 2.58 (brs, 2H), 2.23 (s, 3H), 2.08 (s, 3H ), 1.89 (s, 3H), 1.85 (s, 3H), 1.80-1.69 (m, 4H).

實施例119: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image647
反應流程:
Figure 02_image1257
反應步驟： 以(2-((5-溴-2-氯嘧啶-4-基)胺基)苯基)二甲基氧化膦為原料，參照實施例112的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)苯基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（三氟乙酸鹽，26.2 mg）。 MS (ESI) M/Z: 953.9 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 13.00 (s, 1H), 11.64 (s, 1H), 11.32 (brs, 1H), 8.14-8.10 (m, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.63 (s, 1H), 7.47 (d, J= 10.8 Hz, 1H), 7.38 (d, J= 7.6 Hz, 1H), 7.30-7.21 (m, 3H), 7.16 (s, 1H), 4.96-4.91 (m, 1H), 3.78 (d, J= 11.6 Hz, 2H), 3.65 (d, J= 12.8 Hz, 2H), 3.47 (d, J= 11.6 Hz, 2H), 3.45 (t, J= 11.8 Hz, 2H), 3.22-3.17 (m, 2H), 3.13-3.07 (m, 2H), 2.94-2.72 (m, 5H), 2.18-2.11 (m, 1H), 1.89-1.83 (m, 10H), 1.65-1.61 (m, 1H), 1.55-1.43 (m, 2H). Example 119: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl) Amino)-2,5-dichlorophenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6 -Fluoroisoindoline-1,3-dione
Figure 02_image647
Reaction flow:
Figure 02_image1257
Reaction steps: The final product 5-( 4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)phenyl)amino)pyrimidin-2-yl)amino)-2,5 -Dichlorophenyl)piper-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Diketone (trifluoroacetate, 26.2 mg). MS (ESI) M/Z: 953.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 13.00 (s, 1H), 11.64 (s, 1H), 11.32 (brs, 1H), 8.14 -8.10 (m, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.63 (s, 1H), 7.47 (d, J = 10.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30-7.21 (m, 3H), 7.16 (s, 1H), 4.96-4.91 (m, 1H), 3.78 (d, J = 11.6 Hz, 2H), 3.65 (d, J = 12.8 Hz, 2H ), 3.47 (d, J = 11.6 Hz, 2H), 3.45 (t, J = 11.8 Hz, 2H), 3.22-3.17 (m, 2H), 3.13-3.07 (m, 2H), 2.94-2.72 (m, 5H), 2.18-2.11 (m, 1H), 1.89-1.83 (m, 10H), 1.65-1.61 (m, 1H), 1.55-1.43 (m, 2H).

實施例120: 5-(4-(2-(4-(2,5-二氯-4-((5-氯-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image649
反應流程:
Figure 02_image1259
反應步驟： 以(6-((2,5-二氯嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦為原料，參照實施例116的操作步驟製備得到終產物5-(4-(2-(4-(2,5-二氯-4-((5-氯-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（35 mg）。 MS (ESI) M/Z: 938.3 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.03 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 2H), 8.07 (s, 1H), 7.46 (d, J= 10.8 Hz, 1H), 7.38 (d, J= 8.0 Hz, 2H), 7.25 (s, 1H), 7.07 (s, 1H), 4.95-4.91 (m, 1H), 3.65 (d, J= 12.0 Hz, 2H), 3.10 (brs, 4H), 2.89-2.80 (m, 8H), 2.64-2.61 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.16-2.12 (m, 2H), 2.01 (s, 3H), 1.97 (s, 3H), 1.86 (d, J= 11.6 Hz, 2H), 1.63-1.55 (m, 3H), 1.50-1.42 (m, 2H). Example 120: 5-(4-(2-(4-(2,5-dichloro-4-((5-chloro-4-((2-(dimethylphosphinoyl)-3,4- Dimethylphenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiper Pyridin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image649
Reaction flow:
Figure 02_image1259
Reaction steps: Using (6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dimethylphenyl) dimethylphosphine oxide as raw material, refer to the operation steps of Example 116 The final product 5-(4-(2-(4-(2,5-dichloro-4-((5-chloro-4-((2-(dimethylphosphinoyl)-3,4- Dimethylphenyl)amino)pyrimidin-2-yl)amino)phenyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiper Pyridine-3-yl)-6-fluoroisoindoline-1,3-dione (35 mg). MS (ESI) M/Z: 938.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.03 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 2H) , 8.07 (s, 1H), 7.46 (d, J = 10.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.07 (s, 1H), 4.95-4.91 ( m, 1H), 3.65 (d, J = 12.0 Hz, 2H), 3.10 (brs, 4H), 2.89-2.80 (m, 8H), 2.64-2.61 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.16-2.12 (m, 2H), 2.01 (s, 3H), 1.97 (s, 3H), 1.86 (d, J = 11.6 Hz, 2H), 1.63-1.55 (m, 3H), 1.50-1.42 (m, 2H).

實施例121: 3-(4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)哌啶-2,6-二酮

Figure 02_image651
反應流程:
Figure 02_image1262
反應步驟： 步驟1：室溫下將6-苄基-2-(苄氧基)-3-溴吡啶（826 mg, 2.3 mmol）和 4-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代環戊硼烷-2-基)苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（900 mg, 2.2 mmol，製備參考專利WO2014/6554A1）溶於二氧六環（20 mL）和水（4 mL）中, 加入磷酸鉀（946 mg, 4.4 mmol）和二茂鐵二氯化鈀（162 mg, 0.21 mmol)，反應體系在氮氣氛圍下加熱至100℃攪拌3小時。LCMS監測反應結束，將反應液冷卻至室溫，用水（30 mL）稀釋後用乙酸乙酯（20 mL×3次）萃取。合併有機相，用飽和食鹽水（20 mL）洗滌二次，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：石油醚/乙酸乙酯= 50/1~5/1）得到4-(4-(2,6-二(苄氧基)吡啶-3-基)-2-氟苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（527 mg，收率42%）。 MS (ESI) M/Z: 567.3 [M+H] +. 步驟2：室溫下將4-(4-(2,6-二(苄氧基)吡啶-3-基)-2-氟苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯（400 mg, 0.71 mmol）溶於甲醇/乙酸乙酯（5 mL/5 mL）中，加入10%濕鈀碳(40 mg)。反應體系在氫氣球氛圍下攪拌15小時。LCMS顯示反應結束，反應液用矽藻土過濾，濾液減壓濃縮得到4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-羧酸第三丁酯（258 mg，收率94%）。 MS (ESI) M/Z: 391.2 [M+H] +. 步驟3：將4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-羧酸第三丁酯（110 mg， 0.28 mmol）和5M HCl/dioxane（3 mL）加入到DCM（5 mL）中，室溫下攪拌2小時。LCMS監測反應完成。反應液減壓濃縮得到3-(3-氟-4-(哌啶-4-基)苯基)哌啶-2,6-二酮鹽酸鹽（87 mg，粗品）。 MS (ESI) M/Z: 291.1 [M+H] +. 步驟4：室溫下將3-(3-氟-4-(哌啶-4-基)苯基)哌啶-2,6-二酮鹽酸鹽（87 mg，粗品）、DIEA（194 mg，1.5 mmol）和2-溴乙酸第三丁酯（59 mg，0.3 mmol）依次加入到DMSO（2 mL）中，升溫至50℃攪拌3小時。LCMS監測原料消失，加入水（20 mL）稀釋，乙酸乙酯（20 mL×3）萃取。合併有機相，飽和食鹽水（30 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用製備級TLC板純化（洗脫劑：乙酸乙酯）得到2-(4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-基)乙酸第三丁酯（78 mg，二步收率69%）。 MS (ESI) M/Z: 405.2 [M+H] +. 步驟5：將2-(4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-基)乙酸第三丁酯（47 mg，0.12 mmol）和三氟乙酸（1 mL）加入到DCM（2 mL）中，室溫下攪拌1小時。LCMS監測反應完成。反應液減壓濃縮得到2-(4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-基)乙酸三氟乙酸鹽（47 mg，粗品）。 MS (ESI) M/Z: 349.2 [M+H] +. 步驟6：室溫下將2-(4-(4-(2,6-二氧代哌啶-3-基)-2-氟苯基)哌啶-1-基)乙酸三氟乙酸鹽（47 mg，粗品）、(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦（72 mg，0.11 mmol）、HATU（86 mg，0.23 mmol）和DIEA（72 mg，0.56 mmol）依次加入到DMF（2 mL）中，室溫攪拌1小時。LCMS監測原料消失，加入水（10 mL）稀釋，乙酸乙酯（10 mL×3）萃取。合併有機相，飽和食鹽水（10 mL）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘留物經高效製備液相色譜純化得到終產物3-(4-(1-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)-2-氧代乙基)哌啶-4-基)-3-氟苯基)哌啶-2,6-二酮（13.5 mg，二步收率13%）。 MS (ESI) M/Z: 969.2 [M+H] +. 1H NMR (400 MHz, CDCl 3): δ 12.90 (s, 1H), 10.43 (brs, 1H), 8.26 (s, 1H), 7.92 (s, 2H), 7.82-7.61 (m, 2H), 7.51 (d, J= 12.4 Hz, 1H), 7.11-6.79 (m, 2H), 6.63 (brs, 2H), 4.31-4.19 (m, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 3.78-3.69 (m, 4H), 3.60-3.46 (m, 4H), 3.23-3.13 (m, 2H), 3.02-2.84 (m, 3H), 2.69-2.77 (m, 2H), 2.40-2.24 (m, 6H), 2.11 (s, 3H), 2.04-1.80 (m, 10H). Example 121: 3-(4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl)-2 -Oxoethyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2,6-dione
Figure 02_image651
Reaction flow:
Figure 02_image1262
Reaction steps: Step 1: Mix 6-benzyl-2-(benzyloxy)-3-bromopyridine (826 mg, 2.3 mmol) and 4-(2-fluoro-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (900 mg, 2.2 mmol, preparation reference patent WO2014/6554A1) was dissolved in dioxane (20 mL) and water (4 mL), and potassium phosphate (946 mg, 4.4 mmol) and ferrocene palladium dichloride (162 mg, 0.21 mmol), the reaction system was heated to 100°C under nitrogen atmosphere and stirred for 3 hours. After the completion of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1~5/1) to obtain 4-(4-(2,6-bis(benzyloxy)pyridine-3- yl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (527 mg, yield 42%). MS (ESI) M/Z: 567.3 [M+H] + . Step 2: 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorobenzene tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.71 mmol) was dissolved in methanol/ethyl acetate (5 mL/5 mL), and 10% wet palladium was added Carbon (40 mg). The reaction system was stirred for 15 hours under a hydrogen balloon atmosphere. LCMS showed that the reaction was complete, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-1- Tertiary butyl carboxylate (258 mg, yield 94%). MS (ESI) M/Z: 391.2 [M+H] + . Step 3: Add 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine- Tert-butyl 1-carboxylate (110 mg, 0.28 mmol) and 5M HCl/dioxane (3 mL) were added to DCM (5 mL), stirred at room temperature for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (87 mg, crude product). MS (ESI) M/Z: 291.1 [M+H] + . Step 4: 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6- Diketone hydrochloride (87 mg, crude product), DIEA (194 mg, 1.5 mmol) and tertiary butyl 2-bromoacetate (59 mg, 0.3 mmol) were successively added to DMSO (2 mL) and heated to 50°C Stir for 3 hours. The disappearance of the starting material was monitored by LCMS, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a preparative TLC plate (eluent: ethyl acetate) to give 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piper Pyridin-1-yl) tert-butyl acetate (78 mg, 69% yield in two steps). MS (ESI) M/Z: 405.2 [M+H] + . Step 5: Addition of 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl) Piperidin-1-yl)-tert-butyl acetate (47 mg, 0.12 mmol) and trifluoroacetic acid (1 mL) were added to DCM (2 mL) and stirred at room temperature for 1 hour. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-1-yl)acetic acid trifluoroacetate (47 mg, crude). MS (ESI) M/Z: 349.2 [M+H] + . Step 6: 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluoro Phenyl)piperidin-1-yl)acetic acid trifluoroacetate (47 mg, crude), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H -pyrazol-4-yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (72 mg, 0.11 mmol), HATU (86 mg, 0.23 mmol) and DIEA (72 mg, 0.56 mmol) were sequentially added to DMF (2 mL), and stirred at room temperature for 1 hour. LCMS monitored the disappearance of the starting material, added water (10 mL) to dilute, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piper-1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2,6-dione (13.5 mg, 13% yield in two steps). MS (ESI) M/Z: 969.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 12.90 (s, 1H), 10.43 (brs, 1H), 8.26 (s, 1H), 7.92 (s, 2H), 7.82-7.61 (m, 2H), 7.51 (d, J = 12.4 Hz, 1H), 7.11-6.79 (m, 2H), 6.63 (brs, 2H), 4.31-4.19 (m, 2H ), 3.96 (s, 3H), 3.83 (s, 3H), 3.78-3.69 (m, 4H), 3.60-3.46 (m, 4H), 3.23-3.13 (m, 2H), 3.02-2.84 (m, 3H ), 2.69-2.77 (m, 2H), 2.40-2.24 (m, 6H), 2.11 (s, 3H), 2.04-1.80 (m, 10H).

實施例122: 5-((R)-3-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image653
反應流程:
Figure 02_image1265
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5-氟-6-((S)-3-(2-羥乙基)吡咯啉-1-基)異吲哚啉-1,3-二酮和(6-((5-溴-2-((2,5-二氯-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)喹㗁啉-5-基)二甲基氧化膦為原料，參照實施例105的操作步驟製備得到終產物5-((R)-3-(2-(4-(4-((5-溴-4-((5-(二甲膦醯基)喹㗁啉-6-基)胺基)嘧啶-2-基)胺基)-2,5-二氯苯基)哌𠯤-1-基)乙基)吡咯啉-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（10.2 mg）。 MS (ESI) M/Z: 992.1 [M+H] +. 1H NMR (400 MHz, CDCl 3/D 2O): δ 8.93 (dd, J= 9.4 Hz, 3.8 HZ, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.21 (d, J= 9.2 Hz, 1H), 7.39 (d, J= 12.4 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J= 7.6 Hz, 1H), 4.94-4.89 (m, 1H), 3.78-3.60 (m, 3H), 3.29-3.23 (m, 1H), 3.14-3.01 (m, 4H), 2.93-2.67 (m, 7H), 2.63 (brs, 2H), 2.40-2.25 (m, 1H), 2.50-2.12 (m, 8H), 1.75-1.62 (m, 3H). Example 122: 5-((R)-3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amine Base) pyrimidin-2-yl) amino) -2,5-dichlorophenyl) piper-1-yl) ethyl) pyrroline-1-yl) -2-(2,6-dioxopiper Pyridin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image653
Reaction flow:
Figure 02_image1265
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((S)-3-(2-hydroxyethyl)pyrroline-1-yl)iso Indoline-1,3-dione and (6-((5-bromo-2-((2,5-dichloro-4-(piper-1-yl)phenyl)amino)pyrimidine-4 -yl) amino) quinoline-5-yl) dimethylphosphine oxide as raw material, the final product 5-((R)-3-(2-(4-(4 -((5-bromo-4-((5-(dimethylphosphinoyl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl) Piper-1-yl)ethyl)pyrrolin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (10.2 mg). MS (ESI) M/Z: 992.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 /D 2 O): δ 8.93 (dd, J = 9.4 Hz, 3.8 HZ, 1H), 8.78 (s , 1H), 8.73 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 12.4 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.94-4.89 (m, 1H), 3.78-3.60 (m, 3H), 3.29-3.23 (m, 1H), 3.14-3.01 (m , 4H), 2.93-2.67 (m, 7H), 2.63 (brs, 2H), 2.40-2.25 (m, 1H), 2.50-2.12 (m, 8H), 1.75-1.62 (m, 3H).

實施例123: 5-(3-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image655
反應流程:
Figure 02_image1268
反應步驟： 以(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦為原料，參照實施例65的製備方法得到終產物5-(3-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)異吲哚啉-1,3-二酮（78 mg）。 MS (ESI) M/Z: 1061.5 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.93 (s, 1H), 11.10 (s, 1H), 8.12 (s, 1H), 8.04-8.00 (m, 2H), 7.90-7.85 (m, 1H), 7.81 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.50 (s, 1H), 6.79-6.76 (m, 2H), 6.66-6.63 (m, 2H), 5.09-5.04 (m, 1H), 4.18-4.12 (m, 2H), 3.84-3.80 (m, 8H), 3.40-3.20 (m, 5H), 2.90-2.84 (m, 8H), 2.70-2.50 (m, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 8H), 1.73-1.60 (m, 2H), 1.50-1.10 (m, 5H). Example 123: 5-(3-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl )piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure 02_image655
Reaction flow:
Figure 02_image1268
Reaction steps: With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(pipera-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) -2,3-dimethylphenyl) dimethylphosphine oxide as raw material, the final product 5-(3- (4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-3,4-dimethylphenyl)amino)pyrimidine-2- Base) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl) piperidin-1-yl) nitrogen Heterobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (78 mg). MS (ESI) M/Z: 1061.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.93 (s, 1H), 11.10 (s, 1H), 8.12 (s, 1H) , 8.04-8.00 (m, 2H), 7.90-7.85 (m, 1H), 7.81 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 6.79-6.76 (m , 2H), 6.66-6.63 (m, 2H), 5.09-5.04 (m, 1H), 4.18-4.12 (m, 2H), 3.84-3.80 (m, 8H), 3.40-3.20 (m, 5H), 2.90 -2.84 (m, 8H), 2.70-2.50 (m, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 8H), 1.73 -1.60 (m, 2H), 1.50-1.10 (m, 5H).

實施例124: 5-(3-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image657
反應流程:
Figure 02_image1271
反應步驟： 以(6-((2-((4-(4-(2-(1-(氮雜環丁烷-3-基)哌啶-4-基)乙基)哌𠯤-1-基)-2-甲氧基-5-(1-甲基-1H-吡唑-4-基)苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二甲基苯基)二甲基氧化膦為原料，參照實施例66的製備方法得到終產物5-(3-(4-(2-(4-(4-((5-溴-4-((2-(二甲基膦醯基)-3,4-二甲基苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)哌啶-1-基)氮雜環丁烷-1-基)-2-(2,6-二氧哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（47 mg）。 MS (ESI) M/Z: 1079.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.93 (s, 1H), 11.12 (s, 1H), 8.12 (d, J= 2.4 Hz, 1H), 8.05-8.02 (m, 2H), 7.79-7.88 (m, 1H), 7.83 (s, 1H), 7.64-7.61 (m, 2H), 6.94-6.92 (m, 1H), 6.77-6.60 (m, 2H), 5.10-5.05 (m, 1H), 4.24 (brs, 2H), 3.97 (brs, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.55-3.45 (m, 1H), 3.40-3.10 (m, 2H), 3.00-2.80 (m, 6H), 2.60-2.30 (m, 7H), 2.20 (s, 3H), 2.10 (s, 3H), 2.10-2.04 (m, 1H), 1.89-1.85 (m, 8H), 1.75-1.60 (m, 2H) , 1.40-1.10 (m, 5H). Example 124: 5-(3-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-3,4-dimethylbenzene Base) amino) pyrimidin-2-yl) amino) -5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) phenyl) piper-1-yl) ethyl )piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image657
Reaction flow:
Figure 02_image1271
Reaction steps: With (6-((2-((4-(4-(2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl)piperone-1- Base)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3- Dimethylphenyl) dimethylphosphine oxide is a raw material, and the final product 5-(3-(4-(2-(4-(4-((5-bromo-4-( (2-(Dimethylphosphinoyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H -pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione (47 mg). MS (ESI) M/Z: 1079.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.93 (s, 1H), 11.12 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.05-8.02 (m, 2H), 7.79-7.88 (m, 1H), 7.83 (s, 1H), 7.64-7.61 (m, 2H), 6.94-6.92 (m, 1H), 6.77 -6.60 (m, 2H), 5.10-5.05 (m, 1H), 4.24 (brs, 2H), 3.97 (brs, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.55-3.45 (m , 1H), 3.40-3.10 (m, 2H), 3.00-2.80 (m, 6H), 2.60-2.30 (m, 7H), 2.20 (s, 3H), 2.10 (s, 3H), 2.10-2.04 (m , 1H), 1.89-1.85 (m, 8H), 1.75-1.60 (m, 2H) , 1.40-1.10 (m, 5H).

實施例125: 5-(3-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮

Figure 02_image659
反應流程:
Figure 02_image1274
反應步驟： 將1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代異吲哚啉-5-基)氮雜環丁-3-基)哌啶-4-甲醛（30 mg, 0.07 mmol）和(6-((5-溴-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(哌𠯤-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二㗁英-5-基)二甲基氧化膦（40 mg, 0.06 mmol）溶於四氫呋喃/N,N-二甲基甲醯胺（2.5 mL/0.5 mL）中，冰浴下加入三乙醯氧基硼氫化鈉（32 mg, 0.18 mmol）。反應體系在室溫下攪拌2小時。LC-MS顯示原料消失，反應液加水（10 mL）淬滅，用二氯甲烷（10 mL × 3次）萃取。合併有機相，用飽和食鹽水（10 mL × 3次）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物經高效製備液相色譜純化得到終產物5-(3-(4-((4-(4-((5-溴-4-((5-(二甲膦醯基)-2,3-二氫苯并[b][1,4]二㗁英-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)甲基)哌啶-1-基)氮雜環丁-1-基)-2-(2,6-二氧代哌啶-3-基)異吲哚啉-1,3-二酮（三氟乙酸鹽，28.7 mg，收率40%）。 MS (ESI) M/Z: 1077.4 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.93 (brs, 1H), 11.10 (s, 1H), 10.52 (brs, 1H), 9.68 (brs, 1H), 8.60 (brs, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.87 (brs, 2H), 7.75 (d, J= 8.0 Hz, 1H), 7.66 (s, 1H), 6.91 (s, 1H), 6.80-6.72 (m, 2H), 5.11-5.06 (m, 1H), 4.50-4.15 (m, 12H), 3.87 (s, 3H), 3.83 (s, 3H), 3.66-3.50 (m, 4H), 3.33-3.21 (m, 3H), 3.07-3.01 (m, 2H), 2.94-2.81 (m, 3H), 2.68-2.54 (m, 2H), 2.18-1.93 (m, 4H), 1.82 (s, 3H), 1.78 (s, 3H), 1.54-1.37 (m, 2H). Example 125: 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2,3-dihydrobenzo[b] [1,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base) piper-1-yl) methyl) piperidin-1-yl) azetidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindoline -1,3-dione
Figure 02_image659
Reaction flow:
Figure 02_image1274
Reaction steps: 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azetidin-3 -yl)piperidine-4-carbaldehyde (30 mg, 0.07 mmol) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4 -yl)-4-(piper-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin- 5-yl) dimethylphosphine oxide (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran/N,N-dimethylformamide (2.5 mL/0.5 mL), added triacetyloxy borohydrogenate under ice-cooling Sodium (32 mg, 0.18 mmol). The reaction system was stirred at room temperature for 2 hours. LC-MS showed that the starting material disappeared, and the reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL × 3 times). The organic phases were combined, washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphinoyl)-2, 3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H -pyrazol-4-yl)phenyl)piperone-1-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (trifluoroacetate, 28.7 mg, yield 40%). MS (ESI) M/Z: 1077.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.93 (brs, 1H), 11.10 (s, 1H), 10.52 (brs, 1H) , 9.68 (brs, 1H), 8.60 (brs, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.87 (brs, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.66 ( s, 1H), 6.91 (s, 1H), 6.80-6.72 (m, 2H), 5.11-5.06 (m, 1H), 4.50-4.15 (m, 12H), 3.87 (s, 3H), 3.83 (s, 3H), 3.66-3.50 (m, 4H), 3.33-3.21 (m, 3H), 3.07-3.01 (m, 2H), 2.94-2.81 (m, 3H), 2.68-2.54 (m, 2H), 2.18- 1.93 (m, 4H), 1.82 (s, 3H), 1.78 (s, 3H), 1.54-1.37 (m, 2H).

實施例126: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-甲基哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image661
反應流程:
Figure 02_image1276
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮和2-(4-甲基哌啶-4-基)乙烷-1-醇（製備可參考文獻Collection of Czechoslovak Chemical Communications, 1953, vol. 18, p. 818,821）為原料，參照實施例55的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-甲基哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（三氟乙酸鹽, 30.8 mg）。 MS (ESI) M/Z: 1028.3 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.11 (s, 1H), 10.94 (s, 1H), 9.55 (brs, 1H), 8.50 (s, 1H), 8.27 (brs, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.73 (d, J= 11.6 Hz, 1H), 7.65 (s, 1H), 7.50-7.39 (m, 2H), 6.76 (s, 1H), 6.65 (brs, 1H), 5.13-5.09 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.61 (d, J= 10.4 Hz, 2H), 3.40-3.10 (m, 6H), 2.98-2.84 (m, 3H), 2.62-2.50 (m, 6H), 2.09-1.98 (m, 1H), 1.84-1.68 (m, 8H), 1.64-1.51 (m, 4H), 1.04 (s, 3H). Example 126: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-fluorophenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piper-1-yl)ethyl)-4-methylpiperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image661
Reaction flow:
Figure 02_image1276
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-methylpiperidine- 4-yl)ethan-1-ol (preparation can refer to the literature Collection of Czechoslovak Chemical Communications, 1953, vol. 18, p. 818,821) as a raw material, and the final product 5-(4- (2-(4-(4-((5-bromo-4-((2-(dimethylphosphonyl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)-4-methylpiperidin-1-yl)-2-( 2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (trifluoroacetate, 30.8 mg). MS (ESI) M/Z: 1028.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.11 (s, 1H), 10.94 (s, 1H), 9.55 (brs, 1H) , 8.50 (s, 1H), 8.27 (brs, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.73 (d, J = 11.6 Hz, 1H), 7.65 ( s, 1H), 7.50-7.39 (m, 2H), 6.76 (s, 1H), 6.65 (brs, 1H), 5.13-5.09 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H) , 3.61 (d, J = 10.4 Hz, 2H), 3.40-3.10 (m, 6H), 2.98-2.84 (m, 3H), 2.62-2.50 (m, 6H), 2.09-1.98 (m, 1H), 1.84 -1.68 (m, 8H), 1.64-1.51 (m, 4H), 1.04 (s, 3H).

實施例127: 5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮

Figure 02_image663
反應流程:
Figure 02_image1278
反應步驟： 以2-(2,6-二氧代哌啶-3-基)-5,6-二氟異吲哚啉-1,3-二酮和2-(4-氟哌啶-4-基)乙烷-1-醇為原料，參照實施例55的操作步驟製備得到終產物5-(4-(2-(4-(4-((5-溴-4-((2-(二甲膦醯基)-4-氟苯基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-(1-甲基-1H-吡唑-4-基)苯基)哌𠯤-1-基)乙基)-4-氟哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟異吲哚啉-1,3-二酮（28.9 mg）。 MS (ESI) M/Z: 1032.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6): δ 11.11 (s, 1H), 10.80 (s, 1H), 8.34 (brs, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.75 (d, J= 11.2 Hz, 1H), 7.62 (s, 1H), 7.52 (d, J= 7.2 Hz, 1H), 7.44-7.37 (m, 1H), 6.78 (s, 1H), 6.69 (brs, 1H), 5.13-5.09 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.53-3.49 (m, 3H), 3.19-3.10 (m, 3H), 3.01-2.79 (m, 6H), 2.72-2.50 (m, 4H), 2.09-1.84 (m, 7H), 1.80-1.76 (m, 7H). Example 127: 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphinoyl)-4-fluorophenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperone-1-yl)ethyl)-4-fluoropiperidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione
Figure 02_image663
Reaction flow:
Figure 02_image1278
Reaction steps: With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-fluoropiperidine-4 -yl)ethan-1-ol as raw material, the final product 5-(4-(2-(4-(4-((5-bromo-4-((2-( Dimethylphosphinoyl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene Base) piper-1-yl) ethyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Diketone (28.9 mg). MS (ESI) M/Z: 1032.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.11 (s, 1H), 10.80 (s, 1H), 8.34 (brs, 1H) , 8.30 (s, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 11.2 Hz, 1H), 7.62 (s, 1H), 7.52 ( d, J = 7.2 Hz, 1H), 7.44-7.37 (m, 1H), 6.78 (s, 1H), 6.69 (brs, 1H), 5.13-5.09 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.53-3.49 (m, 3H), 3.19-3.10 (m, 3H), 3.01-2.79 (m, 6H), 2.72-2.50 (m, 4H), 2.09-1.84 (m, 7H) , 1.80-1.76 (m, 7H).

二、生物活性實驗2. Bioactivity experiment

測試例1：評價本發明化合物對穩定表達三突變表皮生長因子受體的Ba/F3細胞株的抑制增殖作用 本實驗採用熒光法測定細胞內ATP含量來檢測化合物對穩定表達三突變表皮生長因子受體（EGFR triple mutants）細胞株的抑制增殖作用，並得出化合物對三突變表皮生長因子受體（EGFR triple mutants）細胞株抑制增殖的半數抑制濃度 IC50。 實驗材料 RPMI-1640培養基，胎牛血清（FBS），100X Pen/Strep，GlutaMAX-I Supplement購自GIBCO公司。Cell Titer-Glo發光法細胞活力檢測試劑購自Promega 公司。 1. 實驗方法 1)將穩定轉染的Ba/F3（DEL19/T790M/C797S和L858R/T790M/C797S）細胞用細胞計數儀計數，按照每孔 3000個細胞的密度將細胞接種於 96 孔培養板，每孔 100 μL。置於培養箱（37 ℃，5%CO 2）中孵育過夜。 2)Day 0：使用 D300e (TECAN) 向培養板細胞中加入 500 nL梯度稀釋的待測化合物 (起始濃度為30 μM，10個濃度，1:3比例稀釋)， DMSO終濃度為 0.5%，將培養板置於細胞培養箱中孵育72小時（37 ℃，5%CO 2）。空白對照加入每孔 500 nL的 DMSO。 3)Day 3：每孔加入 100 μL Cell Titer-Glo 試劑，500 rpm震盪2分鐘，1000 rpm離心1分鐘，室溫避光靜置孵育10 分鐘穩定發光訊號。 4)Envision 酶標儀（PerkinElmer）檢測發光訊號。 5)使用GraphPad Prism 6 軟件進行數據分析，計算化合物的IC50。 經測定，本發明化合物對Ba/F3 Del19/T790M/C797S EGFR 三突變細胞系和 Ba/F3 L858R/T790M/C797S EGFR 三突變細胞系的細胞增殖有著很好的抑制作用，其IC 50值一般低於1 μM；部分本發明化合物的IC 50值低於0.5 μM，更為優異的本發明化合物的IC 50值低於0.1 μM，甚至低於0.015 μM。本發明部分化合物對三突變表皮生長因子受體的Ba/F3細胞株的抑制結果見表1。 表1 實施例 Del19/T790M/C797S IC 50(nM) L858R/T790M/C797S IC 50(nM) 實施例 Del19/T790M/C797S IC 50(nM) L858R/T790M/C797S IC 50(nM) 1 AB AC 63 AA AA 2 B B 64 AA AA 4 AA AB 65 AA AA 5 AC B 66 AA AB 6 A B 67 AA AA 7 B B 68 AA AA 8 AC B 69 AA AA 9 B B 70 AA AA 10 B B 71 AA AA 11 AB AB 72 AA AA 12 AA AA 73 AB AA 13 AB N.D. 74 AC AC 14 AA AA 75 AA AA 15 AC N.D. 76 AA AA 16 AA N.D. 77 AA AA 17 AA AA 78 AA AA 18 AA AA 79 AA AB 19 AA AA 80 AA AA 20 AA AA 81 AA AA 21 AA AA 82 AB AB 22 AB AB 83 AA AA 23 B B 84 AA AA 24 AB AB 85 AA AB 25 AA AA 86 AA AA 26 AA AB 87 AA AB 27 AA AA 88 AA AB 28 AB AB 89 AA AA 29 AB AC 90 AB AB 30 AA AA 91 AA AB 31 AA AA 92 AB AB 32 AA AA 93 AB AB 33 AA AA 94 AB AB 34 AA AB 95 AA AB 35 AA AA 96 AA AA 36 AA AB 97 AA AA 37 AA AA 98 AA AA 38 AA AB 99 AA AB 39 AA AA 100 AA AA 40 AA AC 101 AA AA 41 AA AA 102 AA AA 42 AA AA 103 AA AA 43 AA AB 104 AA AA 44 AA AA 105 AA AA 45 AA AA 106 AB AC 46 AA AB 107 AA AA 47 AA AA 108 AA AA 48 AA AA 109 AB AB 49 AA AA 110 AA AB 50 AA AA 111 AA AA 51 AA AA 114 AA AA 52 AA AA 115 AA AA 53 AA AA 116 AA AA 54 AA AA 117 AA AA 55 AA AA 118 AA AB 56 AA AA 121 AB AA 57 AA AA 123 AA AB 58 AA AA 124 AB AB 59 AA AA 125 AA AA 60 AA AB 126 AB AB 61 AA AA 127 AB AB 62 AC AA          各個數值代表以下範圍： A: ＜100 nM； 100 nM≤B＜500 nM； 500 nM≤C＜1000 nM；1000 nM≤C＜2500 nM；E≥2500 nM；其中，＜100 nM 的化合物又可以細分為AA: ＜15 nM；15 nM≤AB＜50 nM； 50 nM≤AC＜100 nM； N.D.代表未測定。 測試例2：EGFR PROTAC ELISA實驗 1. 實驗材料 HCC827細胞培養基（RPMI-1640培養基，10%胎牛血清（FBS），100X Pen/Strep，GlutaMAX-I Supplement）均購自GIBCO公司。10×RIPA 購自CST公司，蛋白酶抑制劑購自Roche公司。EGFR抗體及羊抗兔二抗來自Abcam公司，EGFR蛋白購自SignalChem公司。牛血清白蛋白（BSA），TMB溶液及Tween-20來自Sigma公司。20×PBS及ELISA終止液購自生工生物。ELISA包被板購自Thermo公司。 2. 實驗方法 1)將HCC827細胞用細胞計數儀計數（85%以上活細胞才可用於後續實驗），按照每孔 40000個細胞的密度將細胞接種於 96 孔培養板，每孔 100 μL。置於培養箱（37 ℃，5%CO2）中孵育過夜。 2)Day 1：使用 D300e (TECAN) 向培養板細胞中加入梯度稀釋的待測化合物(起始濃度為1μM，9個濃度，1:3比例稀釋，3複孔)， DMSO終濃度為 0.5%，空白對照加入每孔 500 nL的 DMSO。將培養板置於細胞培養箱中孵育8小時（37 ℃，5%CO 2），加入PBS洗細胞一次，每孔加入100μL含蛋白酶抑制劑的RIPA裂解液，放-80℃保存。 3)Day 2：每孔取10μL細胞裂解液，用PBS補齊到100μL，轉移到ELISA包被板中，EGFR蛋白作為標準品，稀釋後以最高濃度10ng/mL，7個濃度，1：2比例稀釋，加入ELISA包被板中。將包被板放入4℃孵育過夜。 4)Day 3：每孔加入300μL洗滌緩衝液（含0.05% tween-20的PBS）洗滌 4 次。後加入200μL封閉緩衝液(1%BSA)，在室溫下孵育1小時。加入300μL洗滌緩衝液洗滌4次後，加入100μL一抗（1:2000 稀釋在封閉緩衝液中），並在室溫下孵育2小時。繼續300μL洗滌緩衝液洗滌4次後，加入100μL二抗（1:1000 稀釋在封閉緩衝液），室溫下孵育1小時。300μL洗滌緩衝液洗滌4次後，每孔加入 100μL TMB溶液，避光在室溫下孵育 5-10 分鐘，每孔加入50μL終止液，震盪混勻後用酶標儀讀取450nm處吸光值。 5)計算：以EGFR已知蛋白濃度做標準曲線，線性擬合，計算出對應樣品孔的EGFR蛋白含量，以空白對照為參考，計算加藥後的EGFR降解率。 EGFR%=(處理組細胞EGFR蛋白水平/對照組細胞EGFR蛋白水平) ×100% 用Prism軟件，4參數法擬合曲線 Y=Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) 計算出藥物降解EGFR蛋白的DC 50。 從表2實驗結果可以看出，本發明化合物能夠顯著的誘導EGFR蛋白的降解，優選地，本發明部分化合物的DC 50小於50 nM，更優選地，部分化合物的DC 50小於10 nM。 表2 實施例 DC 50(nM) 1 B ， 4 A ， 19 A ， 22 A ， 24 B ， 32 A ， 28 A ， 35 A ， 36 A ， 49 A ， 54 A ， 55 B ， 57 A ， 66 A ， 75 A ， 92 B ， 94 B ， 98 A ， 99 A ， 100 A ， 114 A ， 115 A ， 各個數值代表以下範圍：A ，: ＜10 nM；B ，: 10-50 nM； 本文已經詳細地描述了本發明，其中也公開了其具體實施例方式，對本發明所屬技術領域具有通常知識者而言，在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。 Test Example 1: Evaluation of the inhibitory effect of the compound of the present invention on the Ba/F3 cell line stably expressing the three-mutant EGFR. The anti-proliferation effect of the EGFR triple mutants cell line, and the half inhibitory concentration IC50 of the compound on the proliferation of the triple mutant epidermal growth factor receptor (EGFR triple mutants) cell line was obtained. Experimental materials RPMI-1640 medium, fetal bovine serum (FBS), 100X Pen/Strep, and GlutaMAX-I Supplement were purchased from GIBCO. Cell Titer-Glo luminescent cell viability detection reagent was purchased from Promega Company. 1. Experimental method 1) Count the stably transfected Ba/F3 (DEL19/T790M/C797S and L858R/T790M/C797S) cells with a cell counter, and inoculate the cells in a 96-well culture plate at a density of 3000 cells per well , 100 μL per well. Place in an incubator (37°C, 5% CO 2 ) and incubate overnight. 2) Day 0: Use D300e (TECAN) to add 500 nL of the compound to be tested in a gradient dilution (initial concentration of 30 μM, 10 concentrations, 1:3 ratio dilution) to the culture plate cells, the final concentration of DMSO is 0.5%, Place the culture plate in a cell culture incubator and incubate for 72 hours (37°C, 5% CO 2 ). For the blank control, 500 nL of DMSO was added to each well. 3) Day 3: Add 100 μL Cell Titer-Glo reagent to each well, shake at 500 rpm for 2 minutes, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature in the dark for 10 minutes to stabilize the luminescent signal. 4) Envision microplate reader (PerkinElmer) detects the luminescent signal. 5) Use GraphPad Prism 6 software for data analysis and calculate the IC50 of the compound. It has been determined that the compound of the present invention has a good inhibitory effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR triple mutation cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutation cell line, and its IC 50 value is generally low at 1 μM; the IC 50 values of some compounds of the present invention are lower than 0.5 μM, and the IC 50 values of more excellent compounds of the present invention are lower than 0.1 μM, even lower than 0.015 μM. See Table 1 for the inhibitory results of some compounds of the present invention on the Ba/F3 cell line with triple mutant EGFR. Table 1 Example Del19/T790M/C797S IC 50 (nM) L858R/T790M/C797S IC 50 (nM) Example Del19/T790M/C797S IC 50 (nM) L858R/T790M/C797S IC 50 (nM) 1 AB AC 63 AAA AAA 2 B B 64 AAA AAA 4 AAA AB 65 AAA AAA 5 AC B 66 AAA AB 6 A B 67 AAA AAA 7 B B 68 AAA AAA 8 AC B 69 AAA AAA 9 B B 70 AAA AAA 10 B B 71 AAA AAA 11 AB AB 72 AAA AAA 12 AAA AAA 73 AB AAA 13 AB ND 74 AC AC 14 AAA AAA 75 AAA AAA 15 AC ND 76 AAA AAA 16 AAA ND 77 AAA AAA 17 AAA AAA 78 AAA AAA 18 AAA AAA 79 AAA AB 19 AAA AAA 80 AAA AAA 20 AAA AAA 81 AAA AAA twenty one AAA AAA 82 AB AB twenty two AB AB 83 AAA AAA twenty three B B 84 AAA AAA twenty four AB AB 85 AAA AB 25 AAA AAA 86 AAA AAA 26 AAA AB 87 AAA AB 27 AAA AAA 88 AAA AB 28 AB AB 89 AAA AAA 29 AB AC 90 AB AB 30 AAA AAA 91 AAA AB 31 AAA AAA 92 AB AB 32 AAA AAA 93 AB AB 33 AAA AAA 94 AB AB 34 AAA AB 95 AAA AB 35 AAA AAA 96 AAA AAA 36 AAA AB 97 AAA AAA 37 AAA AAA 98 AAA AAA 38 AAA AB 99 AAA AB 39 AAA AAA 100 AAA AAA 40 AAA AC 101 AAA AAA 41 AAA AAA 102 AAA AAA 42 AAA AAA 103 AAA AAA 43 AAA AB 104 AAA AAA 44 AAA AAA 105 AAA AAA 45 AAA AAA 106 AB AC 46 AAA AB 107 AAA AAA 47 AAA AAA 108 AAA AAA 48 AAA AAA 109 AB AB 49 AAA AAA 110 AAA AB 50 AAA AAA 111 AAA AAA 51 AAA AAA 114 AAA AAA 52 AAA AAA 115 AAA AAA 53 AAA AAA 116 AAA AAA 54 AAA AAA 117 AAA AAA 55 AAA AAA 118 AAA AB 56 AAA AAA 121 AB AAA 57 AAA AAA 123 AAA AB 58 AAA AAA 124 AB AB 59 AAA AAA 125 AAA AAA 60 AAA AB 126 AB AB 61 AAA AAA 127 AB AB 62 AC AAA Each value represents the following range: A: <100 nM; 100 nM≤B<500 nM; 500 nM≤C<1000 nM; 1000 nM≤C<2500 nM; Subdivided into AA: <15 nM; 15 nM≤AB<50 nM; 50 nM≤AC<100 nM; ND means not determined. Test Example 2: EGFR PROTAC ELISA experiment 1. Experimental materials HCC827 cell culture medium (RPMI-1640 medium, 10% fetal bovine serum (FBS), 100X Pen/Strep, GlutaMAX-I Supplement) were purchased from GIBCO. 10×RIPA was purchased from CST Company, and protease inhibitors were purchased from Roche Company. EGFR antibody and goat anti-rabbit secondary antibody were from Abcam, and EGFR protein was purchased from SignalChem. Bovine serum albumin (BSA), TMB solution and Tween-20 were from Sigma. 20×PBS and ELISA stop solution were purchased from Sangon Biotech. ELISA coated plates were purchased from Thermo Company. 2. Experimental method 1) Count HCC827 cells with a cell counter (more than 85% viable cells can be used for subsequent experiments), and seed the cells in a 96-well culture plate at a density of 40,000 cells per well, 100 μL per well. Incubate overnight in an incubator (37°C, 5% CO2). 2) Day 1: Use D300e (TECAN) to add serial dilutions of the compound to be tested (initial concentration is 1 μM, 9 concentrations, 1:3 ratio dilution, 3 duplicate wells), and the final concentration of DMSO is 0.5% , the blank control was added 500 nL of DMSO per well. Place the culture plate in a cell incubator and incubate for 8 hours (37 °C, 5% CO 2 ), add PBS to wash the cells once, add 100 μL of RIPA lysate containing protease inhibitors to each well, and store at -80 °C. 3) Day 2: Take 10 μL of cell lysate from each well, make up to 100 μL with PBS, transfer to an ELISA-coated plate, use EGFR protein as a standard, and dilute it with the highest concentration of 10 ng/mL, 7 concentrations, 1:2 Dilute proportionally and add to the ELISA coated plate. Incubate the coated plate overnight at 4°C. 4) Day 3: Add 300 μL of washing buffer (PBS containing 0.05% tween-20) to each well and wash 4 times. Then add 200 μL of blocking buffer (1% BSA) and incubate at room temperature for 1 hour. After washing 4 times with 300 μL wash buffer, add 100 μL primary antibody (diluted 1:2000 in blocking buffer) and incubate at room temperature for 2 hours. After continuing to wash 4 times with 300 μL wash buffer, add 100 μL secondary antibody (diluted 1:1000 in blocking buffer) and incubate at room temperature for 1 hour. After washing 4 times with 300 μL of washing buffer, add 100 μL of TMB solution to each well, incubate at room temperature for 5-10 minutes in the dark, add 50 μL of stop solution to each well, shake and mix well, and read the absorbance at 450 nm with a microplate reader. 5) Calculation: The known protein concentration of EGFR was used as a standard curve, and the linear fitting was used to calculate the EGFR protein content of the corresponding sample wells. Using the blank control as a reference, the EGFR degradation rate after drug addition was calculated. EGFR%=(EGFR protein level in treatment group cells/EGFR protein level in control group cells) × 100% Using Prism software, 4-parameter method fitting curve Y=Bottom + (Top-Bottom)/(1+10^((LogIC50- X)*HillSlope)) Calculate the DC 50 of drug degradation EGFR protein. It can be seen from the experimental results in Table 2 that the compounds of the present invention can significantly induce the degradation of EGFR protein. Preferably, the DC 50 of some compounds of the present invention is less than 50 nM, more preferably, the DC 50 of some compounds is less than 10 nM. Table 2 Example DC 50 (nM) 1 B , 4 A , 19 A , twenty two A , twenty four B , 32 A , 28 A , 35 A , 36 A , 49 A , 54 A , 55 B , 57 A , 66 A , 75 A , 92 B , 94 B , 98 A , 99 A , 100 A , 114 A , 115 A , Each numerical value represents the following range: A , : <10 nM; B , : 10-50 nM; The present invention has been described in detail herein, and its specific embodiments are also disclosed, and those with ordinary knowledge in the technical field of the present invention will appreciate In other words, it will be apparent that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention.

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Claims (54)

一種雙功能化合物，具有下式：
Figure 03_image1280
或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物， 其中， R 1選自
Figure 03_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)-(3-7元雜環烷基)-、6-14元螺雜環基、6-14元橋雜環基、6-14元并雜環基； R 2選自C 6-10芳基、5-12元雜芳基、5-6元雜環烯基，其中所述C 6-10芳基、5-12元雜芳基，5-6元雜環烯基各自獨立任選地被一個或多個R 10基團所取代； R 3選自H、鹵素、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、C 1-4鹵代烷氧基； M選自N或者CR 11； R 4選自H、鹵素、-CN、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基； R 5選自-C(=O)NR bR c、-S(=O) 2R b、-P(=O)R bR c、-P(=O)R bNR cR d、-P(=O)R bOR c、-P(=O)OR bOR c、-P(=S)R bR c、-P(=S)R bNR cR d、-P(=S)R bOR c、-P(=S)OR bOR c、-S(=O) 2NR bR c、-NR cS(=O) 2R b、或-NR bC(O)R c； R 6、R 7、R 8各自獨立地選自H、C 1-4烷基、鹵素、C 3-6環烷基； 或者，R 6、R 7和與其連接的原子一起環化成C 4-6環烷基、4-7元雜環烷基、5-7元雜芳基； 或者R 7、R 8和與其連接的原子一起環化成C 4-6環烷基、4-7元雜環烷基、5-7元雜芳基； R 9任意地選自H、鹵素、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、-C 0-4烷基-NR aR b； R 10選自H、鹵素、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基磺醯基； R 11選自H、鹵素、C 1-4烷基； R a選自H、C 1-4烷基； R b、R c、R d各自獨立地選自H、C 1-4烷基、C 3-6環烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 A bifunctional compound having the formula:
Figure 03_image1280
Or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope labeled derivative, wherein, R 1 is selected from
Figure 03_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 Yuan Heterocyclyl; R 2 is selected from C 6-10 aryl, 5-12 member heteroaryl, 5-6 member heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 member heteroaryl The 5-6 membered heterocycloalkenyl groups are each independently and optionally substituted by one or more R 10 groups; R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; M is selected from N or CR 11 ; R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3 -6 cycloalkyl; R 5 is selected from -C(=O)NR b R c , -S(=O) 2 R b , -P(=O)R b R c , -P(=O)R b NR c R d , -P(=O)R b OR c , -P(=O)OR b OR c , -P(=S)R b R c , -P(=S)R b NR c R d , -P(=S)R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C(O)R c ; R 6 , R 7 , and R 8 are each independently selected from H, C 1-4 alkyl, halogen, and C 3-6 cycloalkyl; or, R 6 , R 7 , and The atoms of R 7 and R 8 are cyclized together into C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl; or R 7 , R 8 and the atoms connected to them are cyclized together into C 4-6 cycloalkane radical, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl; R 9 is arbitrarily selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy , C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ; R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl Sulfonyl; R 11 is selected from H, halogen, C 1-4 alkyl; R a is selected from H, C 1-4 alkyl; R b , R c , R d are each independently selected from H, C 1-4 4 alkyl, C 3-6 cycloalkyl; Linker is a group covalently bonded with R 1 group in targeting ligand and degradant; Degradant is a group capable of binding with ubiquitin ligase. 如請求項1所述的雙功能化合物，其中，式（I）化合物中， R 1選自
Figure 03_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)- (3-7元雜環烷基)-、6-14元螺雜環基、6-14元橋雜環基、6-14元并雜環基； R 2選自C 6-10芳基、5-12元雜芳基、5-6元雜環烯基，其中所述C 6-10芳基、5-12元雜芳基，5-6元雜環烯基各自獨立任選地被一個或多個R 10基團所取代； R 3選自H、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、C 1-4鹵代烷氧基； M選自N或者CR 11； R 4選自H、鹵素、-CN、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基； R 5選自-C(=O)NR bR c、-S(=O) 2R b、-P(=O)R bR c、-P(=O)R bNR cR d、-P(=O)R bOR c、-P(=O)OR bOR c、-P(=S)R bR c、-P(=S)R bNR cR d、-P(=S)R bOR c、-P(=S)OR bOR c、-S(=O) 2NR bR c、-NR cS(=O) 2R b、或-NR bC(O)R c； R 6、R 7、R 8各自獨立地選自H、C 1-4烷基； 或者，R 6與R 7和與其連接的原子一起環化成C 4-6環烷基、5-7元雜芳基； 或者R 7與R 8和與其連接的原子一起環化成C 4-6環烷基、5-7元雜芳基； R 9任意地選自H、鹵素、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4鹵代烷基、-C 0-4烷基-NR aR b； R 10選自H、鹵素、C 1-4烷基、C 1-4鹵代烷基、C 3-6環烷基磺醯基； R 11選自H、鹵素、C 1-4烷基； R a選自H、C 1-4烷基； R b、R c、R d各自獨立地選自H、C 1-4烷基、C 3-6環烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 The bifunctional compound as described in Claim 1, wherein, in the compound of formula (I), R 1 is selected from
Figure 03_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 Yuan Heterocyclyl; R 2 is selected from C 6-10 aryl, 5-12 member heteroaryl, 5-6 member heterocycloalkenyl, wherein said C 6-10 aryl, 5-12 member heteroaryl The 5-6 membered heterocycloalkenyl groups are each independently optionally substituted by one or more R 10 groups; R 3 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 1 -4 haloalkyl, C 1-4 haloalkoxy; M is selected from N or CR 11 ; R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 Cycloalkyl; R 5 is selected from -C(=O)NR b R c , -S(=O) 2 R b , -P(=O)R b R c , -P(=O)R b NR c R d , -P(=O)R b OR c , -P(=O)OR b OR c , -P(=S)R b R c , -P(=S)R b NR c R d , - P(=S)R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C (O) R c ; R 6 , R 7 , and R 8 are each independently selected from H, C 1-4 alkyl; or, R 6 and R 7 and the atoms connected to it are cyclized into C 4-6 cycloalkyl , 5-7 membered heteroaryl; or R 7 and R 8 and the atoms connected to it are cyclized together to form C 4-6 cycloalkyl, 5-7 membered heteroaryl; R 9 is arbitrarily selected from H, halogen, - OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ; R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl; R 11 is selected from H, halogen, C 1-4 alkyl; R a is selected from H, C 1-4 alkane R b , R c , R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl; the linker is covalent with the R 1 group and degron in the targeting ligand Groups that bind; degrons are groups that are capable of binding to ubiquitin ligases. 如請求項1所述的雙功能化合物，其中，式（I）化合物中， R 1選自
Figure 03_image009
或任選地被一個或多個R 9基團所取代的A； A選自3-7元雜環烷基、3-7元雜環烷基-O-、3-7元雜環烷基-NR a-、-(3-7元雜環烷基)-(3-7元雜環烷基)-、6-14元螺雜環基、6-14元并雜環基； R 2選自5-6元雜芳基，其中所述5-6元雜芳基任選地被一個或多個R 10基團所取代； R 3選自C 1-4烷氧基； M選自CR 11； R 4選自H、鹵素、C 1-4烷基； R 5選自-P(=O)R bR c、-NR cS(=O) 2R b； R 6、R 7、R 8各自獨立的選自H、C 1-4烷基； 或者，R 6、R 7和與其連接的原子一起環化成5-7元雜芳基； R 9任意地選自H、鹵素、-OH、-NH 2、C 1-4烷基； R 10選自H、C 1-4烷基； R 11選自H、鹵素； R a選自H、C 1-4烷基； R b、R c各自獨立的選自H、C 1-4烷基； 接頭是與靶向配體中R 1基團和降解決定子共價結合的基團； 降解決定子是能夠與泛素連接酶結合的基團。 The bifunctional compound as described in Claim 1, wherein, in the compound of formula (I), R 1 is selected from
Figure 03_image009
Or A optionally substituted by one or more R9 groups; A is selected from 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl -NR a -, -(3-7 membered heterocycloalkyl)-(3-7 membered heterocyclyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered heterocyclyl; R 2 optional From 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted by one or more R 10 groups; R 3 is selected from C 1-4 alkoxy; M is selected from CR 11 ; R 4 is selected from H, halogen, C 1-4 alkyl; R 5 is selected from -P(=O)R b R c , -NR c S(=O) 2 R b ; R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl; or, R 6 , R 7 and the atoms connected to them are cyclized together to form a 5-7 membered heteroaryl; R 9 is arbitrarily selected from H, halogen, - OH, -NH 2 , C 1-4 alkyl; R 10 is selected from H, C 1-4 alkyl; R 11 is selected from H, halogen; R a is selected from H, C 1-4 alkyl; R b , R c are each independently selected from H, C 1-4 alkyl; the linker is a group that is covalently bonded to the R 1 group and the degradant in the targeting ligand; the degradant is capable of combining with ubiquitin ligase group. 如請求項1-3任一項所述的雙功能化合物，M選自CH。The bifunctional compound according to any one of claims 1-3, M is selected from CH. 如請求項1-4任一項所述的雙功能化合物，其中R 1選自
Figure 03_image1282
。 The bifunctional compound as described in any one of claim items 1-4 , wherein R is selected from
Figure 03_image1282
. 如請求項1-4任一項所述的雙功能化合物，其中A選自
Figure 03_image011
、
Figure 03_image013
、
Figure 03_image015
、
Figure 03_image017
、
Figure 03_image1288
、
Figure 03_image021
Figure 03_image023
、
Figure 03_image025
、
Figure 03_image027
、
Figure 03_image029
；R a如請求項1-4任一項所定義。 The bifunctional compound as described in any one of claim items 1-4, wherein A is selected from
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image1288
,
Figure 03_image021
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; R a is as defined in any one of claims 1-4. 如請求項6所述的雙功能化合物，其中A選自
Figure 03_image011
。 The bifunctional compound as described in claim item 6, wherein A is selected from
Figure 03_image011
. 如請求項1-7任一項所述的雙功能化合物，其中R 2選自
Figure 03_image040
。 The bifunctional compound as described in any one of claim items 1-7, wherein R is selected from
Figure 03_image040
. 如請求項1-7任一項所述的雙功能化合物，其中環R 2選自
Figure 03_image042
、
Figure 03_image044
。 The bifunctional compound as described in any one of claim items 1-7, wherein ring R 2 is selected from
Figure 03_image042
,
Figure 03_image044
. 如請求項1-9任一項所述的雙功能化合物，其中R 3選自甲氧基。 The bifunctional compound as described in any one of claims 1-9, wherein R 3 is selected from methoxy. 如請求項1-9任一項所述的雙功能化合物，其中R 3選自H、甲基。 The bifunctional compound as described in any one of claims 1-9, wherein R 3 is selected from H, methyl. 如請求項1-11任一項所述的雙功能化合物，其中R 4選自F、Cl、Br、甲基或三氟甲基。 The bifunctional compound as described in any one of claims 1-11, wherein R 4 is selected from F, Cl, Br, methyl or trifluoromethyl. 如請求項12所述的雙功能化合物，其中R 4選自Br。 The bifunctional compound as claimed in claim 12, wherein R 4 is selected from Br. 如請求項1-13任一項所述的雙功能化合物，其中R 5選自
Figure 03_image046
、
Figure 03_image048
。 The bifunctional compound as described in any one of claim items 1-13, wherein R is selected from
Figure 03_image046
,
Figure 03_image048
. 如請求項14所述的雙功能化合物，其中R 5選自
Figure 03_image046
。 The bifunctional compound as described in claim item 14 , wherein R is selected from
Figure 03_image046
. 如請求項1-15任一項所述的雙功能化合物，其中R 6、R 7、R 8選自H。 The bifunctional compound according to any one of claims 1-15, wherein R 6 , R 7 , R 8 are selected from H. 如請求項1-15任一項所述的雙功能化合物，其中R 6、R 7、R 8各自獨立地選自CH 3、環丙基、氟。 The bifunctional compound according to any one of claims 1-15, wherein R 6 , R 7 , and R 8 are each independently selected from CH 3 , cyclopropyl, and fluorine. 如請求項1-15任一項所述的雙功能化合物，其中R 6、R 7和與其連接的原子一起環化成吡𠯤環、吡啶環。 The bifunctional compound as described in any one of claims 1-15, wherein R 6 , R 7 and the atoms connected to them are cyclized together to form a pyridine ring or a pyridine ring. 如請求項1-18任一項所述的雙功能化合物，其中所述接頭具有式LA：
Figure 03_image130
或其立體異構體， 其中，p 1選自0-6的整數；p 2選自0-6的整數；p 3選自0-6的整數； U為鍵，或者選自C=O、O、NH或NR 12； 每個Q獨立地選自鍵、CH 2、O、S、NH或NR 12； W為鍵，或者選自C=O、O、NH、NR 12、C≡C； 其中所述R 12選自C 1-4烷基； 所述接頭通過U基團與靶向配體TL中的R 1共價結合，W基團與降解決定子共價結合。 The bifunctional compound as claimed in any one of items 1-18, wherein the linker has the formula LA:
Figure 03_image130
or its stereoisomer, wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6; U is a bond, or selected from C=O, O, NH or NR 12 ; each Q is independently selected from a bond, CH 2 , O, S, NH or NR 12 ; W is a bond, or selected from C=O, O, NH, NR 12 , C≡C; Wherein the R 12 is selected from C 1-4 alkyl; the linker is covalently bonded to the R 1 in the targeting ligand TL through the U group, and the W group is covalently bonded to the degradant. 如請求項19所述的雙功能化合物，其中，所述TL-LA選自：
Figure 03_image132
，
Figure 03_image134
，
Figure 03_image136
，
Figure 03_image138
，
Figure 03_image140
，
Figure 03_image142
，
Figure 03_image144
，
Figure 03_image146
，
Figure 03_image148
，
Figure 03_image150
Figure 03_image152
； 其中，p 1選自0-6的整數；p 2選自0-6的整數；p 3選自0-6的整數。 The bifunctional compound as claimed in item 19, wherein the TL-LA is selected from:
Figure 03_image132
,
Figure 03_image134
,
Figure 03_image136
,
Figure 03_image138
,
Figure 03_image140
,
Figure 03_image142
,
Figure 03_image144
,
Figure 03_image146
,
Figure 03_image148
,
Figure 03_image150
Figure 03_image152
; Wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6. 如請求項20所述的雙功能化合物，其中，所述TL-LA選自：
Figure 03_image154
、
Figure 03_image156
、
Figure 03_image158
、
Figure 03_image160
、
Figure 03_image162
、
Figure 03_image164
、
Figure 03_image166
、
Figure 03_image168
、
Figure 03_image170
、
Figure 03_image172
、
Figure 03_image174
、
Figure 03_image176
、
Figure 03_image178
、
Figure 03_image180
、
Figure 03_image182
、
Figure 03_image184
、
Figure 03_image186
、
Figure 03_image188
、
Figure 03_image190
、
Figure 03_image192
、
Figure 03_image194
、
Figure 03_image196
、
Figure 03_image198
、
Figure 03_image200
、
Figure 03_image202
、
Figure 03_image204
。 The bifunctional compound as claimed in item 20, wherein the TL-LA is selected from:
Figure 03_image154
,
Figure 03_image156
,
Figure 03_image158
,
Figure 03_image160
,
Figure 03_image162
,
Figure 03_image164
,
Figure 03_image166
,
Figure 03_image168
,
Figure 03_image170
,
Figure 03_image172
,
Figure 03_image174
,
Figure 03_image176
,
Figure 03_image178
,
Figure 03_image180
,
Figure 03_image182
,
Figure 03_image184
,
Figure 03_image186
,
Figure 03_image188
,
Figure 03_image190
,
Figure 03_image192
,
Figure 03_image194
,
Figure 03_image196
,
Figure 03_image198
,
Figure 03_image200
,
Figure 03_image202
,
Figure 03_image204
. 如請求項20所述的雙功能化合物，其中，所述TL-LA選自：
Figure 03_image206
、
Figure 03_image208
、
Figure 03_image210
、
Figure 03_image212
、
Figure 03_image214
、
Figure 03_image216
、
Figure 03_image218
、
Figure 03_image220
、
Figure 03_image222
、
Figure 03_image1335
。 The bifunctional compound as claimed in item 20, wherein the TL-LA is selected from:
Figure 03_image206
,
Figure 03_image208
,
Figure 03_image210
,
Figure 03_image212
,
Figure 03_image214
,
Figure 03_image216
,
Figure 03_image218
,
Figure 03_image220
,
Figure 03_image222
,
Figure 03_image1335
. 如請求項1-18任一項所述的雙功能化合物，其中，所述接頭具有式LB：
Figure 03_image1336
或其立體異構體， 其中，p 1選自0-6的整數；p 2選自0-6的整數；p 3選自0-6的整數，p 4選自0-6的整數；p 5選自0-6的整數； U為鍵，或者選自C=O、O、NH或NR 13； 每個Q獨立地選自鍵、CH 2、O、S、NH或NR 13；； W為鍵，或者選自C=O、O、NH、NR 13、C≡C； 其中所述R 13選自C 1-4烷基； 每個Z 1獨立地選自不存在、苯基、C 3-6元環烷基、3-6元雜環烷基、5-6元雜芳基，其中所述苯基、C 3-6元環烷基、3-6元雜環烷基、5-6元雜芳基各自獨立任選地被一個或多個R 14基團所取代，R 14選自鹵素、C 1-4烷基、羥基； 或每個Z 1各自獨立地選自7-11元氮雜螺環，其中所述7-11元氮雜螺環任選地被一個或多個R 14基團所取代；R 14選自鹵素、C 1-4烷基、羥基； 所述接頭通過U基團與靶向配體中的R 1共價結合，W基團與降解決定子共價結合。 The bifunctional compound according to any one of claims 1-18, wherein the linker has the formula LB:
Figure 03_image1336
or its stereoisomer, wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6, and p 4 is selected from an integer of 0-6; p 5 is an integer selected from 0-6; U is a bond, or is selected from C=O, O, NH or NR 13 ; each Q is independently selected from a bond, CH 2 , O, S, NH or NR 13 ; W is a bond, or selected from C=O, O, NH, NR 13 , C≡C; wherein said R 13 is selected from C 1-4 alkyl; each Z 1 is independently selected from nonexistent, phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 Each -6 membered heteroaryl is independently optionally substituted by one or more R 14 groups, R 14 is selected from halogen, C 1-4 alkyl, hydroxyl; or each Z 1 is independently selected from 7- 11-membered azaspiro ring, wherein the 7-11-membered azaspiro ring is optionally substituted by one or more R 14 groups; R 14 is selected from halogen, C 1-4 alkyl, hydroxyl; the The linker is covalently bound to R1 in the targeting ligand through the U group, and the W group is covalently bound to the degron. 如請求項23所述的雙功能化合物，其中所述接頭LB選自：
Figure 03_image228
，
Figure 03_image230
其中，p 1、p 2、p 3、p 4、U、W、Z 1如請求項23所定義。 The bifunctional compound as claimed in item 23, wherein the linker LB is selected from:
Figure 03_image228
,
Figure 03_image230
Wherein, p 1 , p 2 , p 3 , p 4 , U, W, and Z 1 are as defined in claim 23. 如請求項24所述的雙功能化合物，其中，TL-LB選自：
Figure 03_image232
、
Figure 03_image234
、
Figure 03_image236
、
Figure 03_image238
、
Figure 03_image240
、
Figure 03_image242
、
Figure 03_image244
； 其中，p 1、p 2、p 3、p 4、Z 1如請求項24所定義。 The bifunctional compound as claimed in item 24, wherein TL-LB is selected from:
Figure 03_image232
,
Figure 03_image234
,
Figure 03_image236
,
Figure 03_image238
,
Figure 03_image240
,
Figure 03_image242
,
Figure 03_image244
; Wherein, p 1 , p 2 , p 3 , p 4 , and Z 1 are as defined in claim item 24. 如請求項25所述的雙功能化合物，其中，所述TL-LB選自：
Figure 03_image246
、
Figure 03_image248
、
Figure 03_image250
、
Figure 03_image252
、
Figure 03_image254
、
Figure 03_image256
、
Figure 03_image258
、
Figure 03_image260
、
Figure 03_image262
、
Figure 03_image264
、
Figure 03_image300
、
Figure 03_image304
、
Figure 03_image306
。 The bifunctional compound as claimed in item 25, wherein the TL-LB is selected from:
Figure 03_image246
,
Figure 03_image248
,
Figure 03_image250
,
Figure 03_image252
,
Figure 03_image254
,
Figure 03_image256
,
Figure 03_image258
,
Figure 03_image260
,
Figure 03_image262
,
Figure 03_image264
,
Figure 03_image300
,
Figure 03_image304
,
Figure 03_image306
. 如請求項24所述的雙功能化合物，其中，所述TL-LB選自：
Figure 03_image1351
、
Figure 03_image1353
、
Figure 03_image1355
、
Figure 03_image1357
。 The bifunctional compound as claimed in item 24, wherein the TL-LB is selected from:
Figure 03_image1351
,
Figure 03_image1353
,
Figure 03_image1355
,
Figure 03_image1357
. 如請求項24所述的雙功能化合物，其中，所述TL-LB選自：
Figure 03_image274
、
Figure 03_image276
、
Figure 03_image278
、
Figure 03_image280
、
Figure 03_image282
、
Figure 03_image284
、
Figure 03_image286
、
Figure 03_image288
、
Figure 03_image290
、
Figure 03_image292
、
Figure 03_image294
、
Figure 03_image296
、
Figure 03_image302
、
Figure 03_image308
、
Figure 03_image310
、
Figure 03_image312
、
Figure 03_image314
、
Figure 03_image316
、
Figure 03_image318
、
Figure 03_image320
、
Figure 03_image322
。 The bifunctional compound as claimed in item 24, wherein the TL-LB is selected from:
Figure 03_image274
,
Figure 03_image276
,
Figure 03_image278
,
Figure 03_image280
,
Figure 03_image282
,
Figure 03_image284
,
Figure 03_image286
,
Figure 03_image288
,
Figure 03_image290
,
Figure 03_image292
,
Figure 03_image294
,
Figure 03_image296
,
Figure 03_image302
,
Figure 03_image308
,
Figure 03_image310
,
Figure 03_image312
,
Figure 03_image314
,
Figure 03_image316
,
Figure 03_image318
,
Figure 03_image320
,
Figure 03_image322
. 如請求項1-28任一項所述的雙功能化合物，其中所述的降解決定子具有式D1：
Figure 03_image324
或其立體異構體， 其中，每個R 15任意獨立地選自C 1-4烷基； R 16選自H、氘； 每個R 17任意獨立地選自鹵素、C 1-4烷基、C 1-4烷氧基、羥基； Z 2選自CH 2或者C=O； Y為鍵、O或者NH，其通過共價鍵與接頭相連； m選自0-3的整數； n選自0-4的整數。 The bifunctional compound as described in any one of claims 1-28, wherein the degron has the formula D1:
Figure 03_image324
or its stereoisomer, wherein, each R 15 is independently selected from C 1-4 alkyl; R 16 is selected from H, deuterium; each R 17 is independently selected from halogen, C 1-4 alkyl , C 1-4 alkoxy, hydroxyl; Z 2 is selected from CH 2 or C=O; Y is a bond, O or NH, which is connected to the linker through a covalent bond; m is selected from an integer of 0-3; n is selected An integer from 0-4. 如請求項29所述的雙功能化合物，所述的降解決定子D1中的Z 2選自C=O。 The bifunctional compound as claimed in item 29, Z 2 in the degron D1 is selected from C=O. 如請求項29所述的雙功能化合物，所述的降解決定子D1中Y選自鍵或者NH。The bifunctional compound as claimed in item 29, Y in the degron D1 is selected from a bond or NH. 如請求項29所述的雙功能化合物，所述的降解決定子D1選自：
Figure 03_image326
、
Figure 03_image328
、
Figure 03_image330
、
Figure 03_image332
、
Figure 03_image1372
、
Figure 03_image336
、
Figure 03_image338
、
Figure 03_image340
。 The bifunctional compound as claimed in item 29, the degradon D1 is selected from:
Figure 03_image326
,
Figure 03_image328
,
Figure 03_image330
,
Figure 03_image332
,
Figure 03_image1372
,
Figure 03_image336
,
Figure 03_image338
,
Figure 03_image340
. 如請求項1-28任一項所述的雙功能化合物，其中，所述的降解決定子具有式D2：
Figure 03_image342
或其立體異構體， 其中，每個R 15 ，任意獨立地選自C 1-4烷基； R 16 ，選自H、氘； 每個R 17 ，任意獨立地選自鹵素、C 1-4烷基、C 1-4烷氧基； Y ，為鍵、O或者NH，其通過共價鍵與接頭相連； m選自0-3的整數； n選自0-4的整數。 The bifunctional compound as described in any one of claims 1-28, wherein the degron has the formula D2:
Figure 03_image342
or its stereoisomers, wherein , each R 15 is independently selected from C 1-4 alkyl; R 16 is selected from H , deuterium; each R 17 is independently selected from halogen, C 1- 4 alkyl, C 1-4 alkoxy; Y , is a bond, O or NH, which is connected to the linker through a covalent bond; m is selected from an integer of 0-3; n is selected from an integer of 0-4. 如請求項33所述的雙功能化合物，其中，所述的降解決定子D2選自：
Figure 03_image344
。 The bifunctional compound as claimed in item 33, wherein the degron D2 is selected from:
Figure 03_image344
. 如請求項1-28任一項所述的雙功能化合物，其中所述的降解決定子具有式D3：
Figure 03_image1377
或其立體異構體， 其中，R 18選自H、C 1-4烷基； 每個R 19任意獨立地選自C 1-4烷基； R 20選自H、C 1-4烷基； q選自0-4的整數。 The bifunctional compound as described in any one of claims 1-28, wherein the degron has the formula D3:
Figure 03_image1377
or its stereoisomer, wherein, R 18 is selected from H, C 1-4 alkyl; each R 19 is independently selected from C 1-4 alkyl; R 20 is selected from H, C 1-4 alkyl ; q is an integer selected from 0-4. 如請求項35所述的雙功能化合物，其中，所述的降解決定子D3中的R 18是甲基。 The bifunctional compound as claimed in item 35, wherein R 18 in the degron D3 is a methyl group. 如請求項35所述的雙功能化合物，其中，所述的降解決定子D3中的R 20是甲基。 The bifunctional compound as claimed in item 35, wherein R 20 in the degron D3 is a methyl group. 如請求項35所述的雙功能化合物，所述的降解決定子D3選自：
Figure 03_image348
，
Figure 03_image350
，
Figure 03_image352
。 As the bifunctional compound as described in claim item 35, the degradon D3 is selected from:
Figure 03_image348
,
Figure 03_image350
,
Figure 03_image352
. 如請求項1-28任一項所述的雙功能化合物，其中，所述的降解決定子具有式D4：
Figure 03_image362
或其立體異構體， Y為鍵、或者NH，其通過共價鍵與接頭相連。 The bifunctional compound as described in any one of claims 1-28, wherein the degron has the formula D4:
Figure 03_image362
or its stereoisomer, Y is a bond, or NH, which is connected to the linker through a covalent bond. 如請求項39所述的雙功能化合物，其中，所述的降解決定子D4選自：
Figure 03_image1380
。 The bifunctional compound as claimed in item 39, wherein the degron D4 is selected from:
Figure 03_image1380
. 如請求項1-28任一項所述的雙功能化合物，其中，所述的降解決定子具有式D5，
Figure 03_image366
其中，M選自NH、O或者S； V為鍵、NH或者O，其通過共價鍵與接頭相連； R 21選自鹵素； S選自0、1、2或3。 The bifunctional compound as described in any one of claims 1-28, wherein the degron has the formula D5,
Figure 03_image366
Wherein, M is selected from NH, O or S; V is a bond, NH or O, which is connected to the linker through a covalent bond; R 21 is selected from halogen; S is selected from 0, 1, 2 or 3. 如請求項41所述的雙功能化合物，其中，所述的降解決定子D5選自：
Figure 03_image1382
、
Figure 03_image368
、
Figure 03_image372
、
Figure 03_image374
、
Figure 03_image376
、
Figure 03_image378
、
Figure 03_image380
。 The bifunctional compound as claimed in item 41, wherein the degradon D5 is selected from:
Figure 03_image1382
,
Figure 03_image368
,
Figure 03_image372
,
Figure 03_image374
,
Figure 03_image376
,
Figure 03_image378
,
Figure 03_image380
. 如請求項1-28任一項所述的雙功能化合物，其中，所述的降解決定子選自：
Figure 03_image382
、
Figure 03_image384
。 The bifunctional compound as described in any one of claims 1-28, wherein the degradant is selected from:
Figure 03_image382
,
Figure 03_image384
. 如請求項1-43任一項所述的雙功能化合物，其中，所述的靶向配體（TL）選自：
Figure 03_image1388
、
Figure 03_image052
、
Figure 03_image054
、
Figure 03_image1392
、
Figure 03_image058
、
Figure 03_image060
、
Figure 03_image062
、
Figure 03_image064
、
Figure 03_image1397
、
Figure 03_image1399
Figure 03_image110
； 所述靶向配體通過
Figure 03_image070
與所述接頭共價結合。 The bifunctional compound according to any one of claims 1-43, wherein the targeting ligand (TL) is selected from:
Figure 03_image1388
,
Figure 03_image052
,
Figure 03_image054
,
Figure 03_image1392
,
Figure 03_image058
,
Figure 03_image060
,
Figure 03_image062
,
Figure 03_image064
,
Figure 03_image1397
,
Figure 03_image1399
Figure 03_image110
; The targeting ligand is passed
Figure 03_image070
Covalently bound to the linker. 如請求項1-43任一項所述的雙功能化合物，其中，所述的靶向配體（TL）選自：
Figure 03_image072
、
Figure 03_image084
、
Figure 03_image086
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image108
、
Figure 03_image110
、
Figure 03_image112
、
Figure 03_image114
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image120
、
Figure 03_image122
、
Figure 03_image124
、
Figure 03_image126
和
Figure 03_image128
。 The bifunctional compound according to any one of claims 1-43, wherein the targeting ligand (TL) is selected from:
Figure 03_image072
,
Figure 03_image084
,
Figure 03_image086
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image108
,
Figure 03_image110
,
Figure 03_image112
,
Figure 03_image114
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image120
,
Figure 03_image122
,
Figure 03_image124
,
Figure 03_image126
with
Figure 03_image128
. 如請求項1-45任一項所述的雙功能化合物，其選自：
Figure 03_image1407
，
Figure 03_image1409
，
Figure 03_image1411
，
Figure 03_image1413
； 其中，A、M、R 2、R 3、R 4、R 5、R 6、R 7、R 8、Y、R 20、R 15、n、接頭、降解決定子如請求項1-45任一項所定義。 The bifunctional compound as described in any one of claim items 1-45, which is selected from:
Figure 03_image1407
,
Figure 03_image1409
,
Figure 03_image1411
,
Figure 03_image1413
; Wherein, A, M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y, R 20 , R 15 , n, linker, degradant such as any of claim items 1-45 defined by one. 如請求項46所述的雙功能化合物，其選自：
Figure 03_image1415
，
Figure 03_image1417
，
Figure 03_image1419
，
Figure 03_image1421
； R 2、R 3、R 4、R 5、R 6、R 7、R 8、Y、R 20、R 15、n、M、接頭與降解決定子如請求項46所定義。 The bifunctional compound as claimed in item 46, which is selected from:
Figure 03_image1415
,
Figure 03_image1417
,
Figure 03_image1419
,
Figure 03_image1421
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y, R 20 , R 15 , n, M, linkers and degrons are as defined in Claim 46. 如請求項47所述的雙功能化合物，其選自：
Figure 03_image1423
，
Figure 03_image1425
，
Figure 03_image1427
、
Figure 03_image1429
； 其中，R 6、R 7、R 15、Y、n、接頭與降解決定子如請求項47所定義。 The bifunctional compound as claimed in item 47, which is selected from:
Figure 03_image1423
,
Figure 03_image1425
,
Figure 03_image1427
,
Figure 03_image1429
; Wherein, R 6 , R 7 , R 15 , Y, n, linker and degron are as defined in claim item 47. 如請求項48所述的雙功能化合物，其選自：
Figure 03_image1431
，
Figure 03_image1433
，
Figure 03_image1435
； 其中，接頭、Y、R 20、R 15、n、如請求項48所定義。 The bifunctional compound as described in claim 48, which is selected from:
Figure 03_image1431
,
Figure 03_image1433
,
Figure 03_image1435
; Wherein, linker, Y, R 20 , R 15 , n, are as defined in claim item 48. 一種雙功能化合物或其立體異構體、互變異構體或藥學上可接受的鹽、前藥、水合物、溶劑合物、同位素標記衍生物，其選自：
Figure 03_image416
Figure 03_image418
Figure 03_image420
Figure 03_image422
Figure 03_image424
Figure 03_image426
Figure 03_image1442
Figure 03_image428
Figure 03_image1444
‘
Figure 03_image430
Figure 03_image432
Figure 03_image434
Figure 03_image436
Figure 03_image438
Figure 03_image440
Figure 03_image442
Figure 03_image444
Figure 03_image446
Figure 03_image448
Figure 03_image450
Figure 03_image452
Figure 03_image454
Figure 03_image456
Figure 03_image458
Figure 03_image460
Figure 03_image462
Figure 03_image464
Figure 03_image466
Figure 03_image468
Figure 03_image470
Figure 03_image472
Figure 03_image474
Figure 03_image476
Figure 03_image478
Figure 03_image480
Figure 03_image482
Figure 03_image484
Figure 03_image486
Figure 03_image488
Figure 03_image490
Figure 03_image492
Figure 03_image494
Figure 03_image496
Figure 03_image498
Figure 03_image500
Figure 03_image502
Figure 03_image504
Figure 03_image506
Figure 03_image508
Figure 03_image510
Figure 03_image1071
Figure 03_image1075
Figure 03_image1079
Figure 03_image513
Figure 03_image515
Figure 03_image517
Figure 03_image519
Figure 03_image521
Figure 03_image523
Figure 03_image525
Figure 03_image527
Figure 03_image529
、
Figure 03_image531
Figure 03_image533
Figure 03_image535
Figure 03_image537
Figure 03_image539
Figure 03_image541
Figure 03_image543
Figure 03_image545
Figure 03_image547
Figure 03_image549
Figure 03_image551
Figure 03_image553
Figure 03_image555
Figure 03_image557
Figure 03_image559
Figure 03_image561
Figure 03_image563
Figure 03_image565
Figure 03_image567
Figure 03_image569
Figure 03_image571
Figure 03_image573
Figure 03_image575
Figure 03_image577
Figure 03_image579
Figure 03_image581
Figure 03_image583
Figure 03_image585
Figure 03_image587
Figure 03_image589
Figure 03_image591
Figure 03_image593
Figure 03_image595
Figure 03_image597
Figure 03_image599
Figure 03_image601
Figure 03_image603
Figure 03_image605
Figure 03_image607
Figure 03_image609
Figure 03_image611
Figure 03_image613
Figure 03_image615
Figure 03_image617
Figure 03_image619
Figure 03_image621
Figure 03_image623
Figure 03_image625
Figure 03_image627
Figure 03_image629
Figure 03_image631
Figure 03_image633
Figure 03_image635
Figure 03_image637
Figure 03_image639
Figure 03_image641
Figure 03_image643
Figure 03_image645
Figure 03_image647
Figure 03_image649
Figure 03_image651
Figure 03_image653
Figure 03_image655
Figure 03_image657
Figure 03_image659
Figure 03_image661
Figure 03_image663
Figure 03_image665
Figure 03_image667
Figure 03_image669
Figure 03_image671
Figure 03_image673
Figure 03_image675
Figure 03_image677
Figure 03_image679
Figure 03_image681
Figure 03_image683
Figure 03_image685
Figure 03_image687
Figure 03_image689
Figure 03_image691
Figure 03_image693
Figure 03_image695
Figure 03_image697
Figure 03_image699
Figure 03_image701
Figure 03_image703
Figure 03_image705
Figure 03_image707
Figure 03_image709
Figure 03_image711
Figure 03_image713
Figure 03_image715
Figure 03_image717
Figure 03_image719
Figure 03_image721
Figure 03_image723
Figure 03_image725
Figure 03_image727
Figure 03_image729
Figure 03_image731
Figure 03_image733
Figure 03_image735
Figure 03_image737
Figure 03_image739
Figure 03_image741
Figure 03_image743
Figure 03_image745
Figure 03_image747
Figure 03_image749
Figure 03_image751
Figure 03_image753
Figure 03_image755
Figure 03_image757
Figure 03_image759
Figure 03_image761
Figure 03_image1522
Figure 03_image1524
Figure 03_image767
Figure 03_image769
Figure 03_image763
Figure 03_image771
Figure 03_image773
Figure 03_image775
Figure 03_image777
Figure 03_image779
Figure 03_image781
。 A bifunctional compound or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotope-labeled derivative thereof, selected from the group consisting of:
Figure 03_image416
Figure 03_image418
Figure 03_image420
Figure 03_image422
Figure 03_image424
Figure 03_image426
Figure 03_image1442
Figure 03_image428
Figure 03_image1444
'
Figure 03_image430
Figure 03_image432
Figure 03_image434
Figure 03_image436
Figure 03_image438
Figure 03_image440
Figure 03_image442
Figure 03_image444
Figure 03_image446
Figure 03_image448
Figure 03_image450
Figure 03_image452
Figure 03_image454
Figure 03_image456
Figure 03_image458
Figure 03_image460
Figure 03_image462
Figure 03_image464
Figure 03_image466
Figure 03_image468
Figure 03_image470
Figure 03_image472
Figure 03_image474
Figure 03_image476
Figure 03_image478
Figure 03_image480
Figure 03_image482
Figure 03_image484
Figure 03_image486
Figure 03_image488
Figure 03_image490
Figure 03_image492
Figure 03_image494
Figure 03_image496
Figure 03_image498
Figure 03_image500
Figure 03_image502
Figure 03_image504
Figure 03_image506
Figure 03_image508
Figure 03_image510
Figure 03_image1071
Figure 03_image1075
Figure 03_image1079
Figure 03_image513
Figure 03_image515
Figure 03_image517
Figure 03_image519
Figure 03_image521
Figure 03_image523
Figure 03_image525
Figure 03_image527
Figure 03_image529
,
Figure 03_image531
Figure 03_image533
Figure 03_image535
Figure 03_image537
Figure 03_image539
Figure 03_image541
Figure 03_image543
Figure 03_image545
Figure 03_image547
Figure 03_image549
Figure 03_image551
Figure 03_image553
Figure 03_image555
Figure 03_image557
Figure 03_image559
Figure 03_image561
Figure 03_image563
Figure 03_image565
Figure 03_image567
Figure 03_image569
Figure 03_image571
Figure 03_image573
Figure 03_image575
Figure 03_image577
Figure 03_image579
Figure 03_image581
Figure 03_image583
Figure 03_image585
Figure 03_image587
Figure 03_image589
Figure 03_image591
Figure 03_image593
Figure 03_image595
Figure 03_image597
Figure 03_image599
Figure 03_image601
Figure 03_image603
Figure 03_image605
Figure 03_image607
Figure 03_image609
Figure 03_image611
Figure 03_image613
Figure 03_image615
Figure 03_image617
Figure 03_image619
Figure 03_image621
Figure 03_image623
Figure 03_image625
Figure 03_image627
Figure 03_image629
Figure 03_image631
Figure 03_image633
Figure 03_image635
Figure 03_image637
Figure 03_image639
Figure 03_image641
Figure 03_image643
Figure 03_image645
Figure 03_image647
Figure 03_image649
Figure 03_image651
Figure 03_image653
Figure 03_image655
Figure 03_image657
Figure 03_image659
Figure 03_image661
Figure 03_image663
Figure 03_image665
Figure 03_image667
Figure 03_image669
Figure 03_image671
Figure 03_image673
Figure 03_image675
Figure 03_image677
Figure 03_image679
Figure 03_image681
Figure 03_image683
Figure 03_image685
Figure 03_image687
Figure 03_image689
Figure 03_image691
Figure 03_image693
Figure 03_image695
Figure 03_image697
Figure 03_image699
Figure 03_image701
Figure 03_image703
Figure 03_image705
Figure 03_image707
Figure 03_image709
Figure 03_image711
Figure 03_image713
Figure 03_image715
Figure 03_image717
Figure 03_image719
Figure 03_image721
Figure 03_image723
Figure 03_image725
Figure 03_image727
Figure 03_image729
Figure 03_image731
Figure 03_image733
Figure 03_image735
Figure 03_image737
Figure 03_image739
Figure 03_image741
Figure 03_image743
Figure 03_image745
Figure 03_image747
Figure 03_image749
Figure 03_image751
Figure 03_image753
Figure 03_image755
Figure 03_image757
Figure 03_image759
Figure 03_image761
Figure 03_image1522
Figure 03_image1524
Figure 03_image767
Figure 03_image769
Figure 03_image763
Figure 03_image771
Figure 03_image773
Figure 03_image775
Figure 03_image777
Figure 03_image779
Figure 03_image781
. 一種藥物組合物，其包含請求項1-50任一項所述的雙功能化合物，以及藥學上可接受的載體。A pharmaceutical composition, comprising the bifunctional compound described in any one of claims 1-50, and a pharmaceutically acceptable carrier. 如請求項1-50任一項所述的雙功能化合物或請求項51所述的藥物組合物在製備治療EGFR介導的癌症藥物中的應用。Use of the bifunctional compound described in any one of claim items 1-50 or the pharmaceutical composition described in claim item 51 in the preparation of a drug for treating EGFR-mediated cancer. 如請求項52所述的應用，其中，所述癌症選自淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宮頸癌、***癌、結腸直腸癌、乳腺癌、胰腺癌、膠質瘤、膠質母細胞瘤，黑色素瘤、白血病、胃癌、子宮內膜癌、肺癌、肝細胞癌、胃腸道間質瘤(GIST)、急性髓細胞白血病(AML)、膽管癌、腎癌、甲狀腺癌、間變性大細胞淋巴瘤、間皮瘤、多發性骨髓瘤、黑色素瘤。The application according to claim 52, wherein the cancer is selected from lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioma Cell tumor, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic Cellular lymphoma, mesothelioma, multiple myeloma, melanoma. 如請求項1-50任一項所述的雙功能化合物，其製備方法包括以下步驟： 靶向配體與接頭連接後，再與降解決定子連接得到：
Figure 03_image1531
； 或者，接頭與降解決定子連接後，再與靶向配體連接得到：
Figure 03_image1533
； 其中，靶向配體，接頭，降解決定子如請求項1-50任一項所述。 The preparation method of the bifunctional compound as described in any one of claim items 1-50 comprises the following steps: After the targeting ligand is connected to the linker, it is then connected to the degradant to obtain:
Figure 03_image1531
; or, after the linker is connected to the degron, it is connected to the targeting ligand to obtain:
Figure 03_image1533
; Wherein, the targeting ligand, linker, and degron are as described in any one of claim items 1-50.
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