TW202233617A - Pyridopyrimidinone compounds - Google Patents

Pyridopyrimidinone compounds Download PDF

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TW202233617A
TW202233617A TW110147594A TW110147594A TW202233617A TW 202233617 A TW202233617 A TW 202233617A TW 110147594 A TW110147594 A TW 110147594A TW 110147594 A TW110147594 A TW 110147594A TW 202233617 A TW202233617 A TW 202233617A
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徐招兵
胡利紅
照中 丁
曙輝 陳
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大陸商正大天晴藥業集團股份有限公司
大陸商南京明德新藥研發有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

A kind of pyridopyrimidinone compounds, specifically relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, and application of the compound of formula (I) and the pharmaceutically acceptable salt thereof in preparation of a medicine for treatment of related diseases.

Description

吡啶並嘧啶酮類化合物pyridopyrimidinones

本申請涉及一類吡啶並嘧啶酮類化合物，具體涉及式（I）化合物及其藥學上可接受的鹽，以及式（I）化合物及其藥學上可接受的鹽在製備治療相關疾病的藥物中的應用。The present application relates to a class of pyridopyrimidinone compounds, in particular to compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the preparation of medicines for the treatment of related diseases application.

本申請主張如下優先權： CN202011508100.7，申請日2020年12月18日； CN202110560291.X，申請日2021年5月21日； CN202111522022.0，申請日2021年12月13日。 This application claims the following priority: CN202011508100.7, application date December 18, 2020; CN202110560291.X, application date May 21, 2021; CN202111522022.0, application date December 13, 2021.

RAS基因是第一個在人類腫瘤中被鑑定出來的致癌基因，RAS蛋白可以與鳥嘌呤三核苷酸磷酸（GTP）或鳥嘌呤二核苷酸磷酸（GDP）結合，RAS蛋白的活性狀態對細胞的生長、分化、細胞骨架、蛋白質運輸和分泌等都具有影響，其活性是通過與GTP或GDP的結合進行調節：當RAS蛋白與GDP結合時，它處於休眠狀態，也就是“失活”狀態；當有上游特定的細胞生長因子刺激時，RAS蛋白被誘導交換GDP，與GTP結合，此時稱為“活化”狀態。與GTP結合的RAS蛋白能夠活化下游的蛋白，進行信號傳遞。RAS蛋白自身具有弱的水解GTP水解活性，能夠水解GTP到GDP。這樣就可以實現從活化狀態到失活狀態的轉化。在這個水解過程中，還需要GAP（GTPase activating proteins, GTP水解酶活化蛋白）參與。它能與RAS蛋白作用，大大促進其水解GTP到GDP的能力。RAS蛋白的突變將影響其與GAP的作用，也就影響了其水解GTP到GDP的能力，使其一直處於活化狀態。活化的RAS蛋白持續的給予下游蛋白生長信號，最終導致細胞不停的生長和分化，最終產生腫瘤。RAS基因家族成員眾多，其中與各種癌症密切相關的亞家族主要有克爾斯滕大鼠肉瘤病毒致癌基因同源物（KRAS）、哈維大鼠肉瘤病毒致癌同源物（HRAS）和神經母細胞瘤大鼠肉瘤病毒致癌基因同源物（NRAS）。人們發現大約30%的人類腫瘤中都攜帶某些突變的RAS基因，其中以KRAS突變最為顯著，占到所有RAS突變中的86%。KRAS突變經常與靶向治療的抵抗和癌症患者的預後不良有關。據統計，約13%的非小細胞肺癌(NSCLC)和1%-3%的結直腸癌和其他癌症會發生KRAS p.G12C突變。The RAS gene is the first oncogene identified in human tumors. The RAS protein can bind to either guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP). Cell growth, differentiation, cytoskeleton, protein transport and secretion all have effects, and its activity is regulated by binding to GTP or GDP: when the RAS protein is bound to GDP, it is dormant, that is, "inactive" state; when stimulated by upstream specific cell growth factors, RAS protein is induced to exchange GDP and bind to GTP, which is called the "activated" state. The RAS protein bound to GTP can activate downstream proteins for signal transmission. The RAS protein itself has weak hydrolysis GTP hydrolysis activity and can hydrolyze GTP to GDP. In this way, the transition from the activated state to the deactivated state can be achieved. In this hydrolysis process, GAP (GTPase activating proteins, GTP hydrolase activating proteins) is also required. It can interact with RAS protein, greatly promoting its ability to hydrolyze GTP to GDP. Mutation of the RAS protein will affect its interaction with GAP, which also affects its ability to hydrolyze GTP to GDP, making it always active. Activated RAS proteins continue to give downstream proteins growth signals, which eventually lead to continuous cell growth and differentiation, and ultimately produce tumors. There are many members of the RAS gene family, among which subfamilies closely related to various cancers mainly include Kirsten rat sarcoma virus oncogene homolog (KRAS), Harvey rat sarcoma virus oncogene homolog (HRAS) and neuroblastoma Neoplastic rat sarcoma virus oncogene homolog (NRAS). It has been found that about 30% of human tumors carry some mutated RAS gene, among which KRAS mutation is the most significant, accounting for 86% of all RAS mutations. KRAS mutations are frequently associated with resistance to targeted therapy and poor prognosis in cancer patients. According to statistics, KRAS p.G12C mutation occurs in about 13% of non-small cell lung cancer (NSCLC) and 1%-3% of colorectal cancer and other cancers.

KRAS G12C突變蛋白作為一個前沿熱門靶點，近幾年有多款產品進入臨床研究階段，但是仍沒有被批准的選擇性KRAS G12C小分子抑制劑。近年來，Araxes Pharma公司申請了數篇針對KRAS G12C抑制劑的專利，例如WO2016164675和WO2016168540。Araxes Pharma公司開發的ARS-3248目前處在臨床一期。Amgen公司自2018年以來有多篇關於KRAS G12C抑制劑的專利公開：WO2018119183，WO2018217651，WO2019051291，WO2019213516，WO2020050890等。MIRATI公司則開發的KRAS G12C抑制劑MRTX849已邁入二期臨床。AMG 510是臨床進展最快的選擇性小分子KRAS G12C抑制劑，AMG 510有望成為治療轉移性非小細胞肺癌（NSCLC）新的選擇，並與其他抗腫瘤藥物聯用以產生更好的療效。美國食品和藥物管理局（FDA）已授予靶向抗癌藥AMG 510突破性藥物資格（BTD）和實時腫瘤學審查資格（RTOR），用於治療經FDA批准的檢測方法證實存在KRAS G12C突變的局部晚期或NSCLC患者。

Figure 02_image003
KRAS G12C mutant protein is a cutting-edge hot target. In recent years, many products have entered the clinical research stage, but there is still no approved selective KRAS G12C small molecule inhibitor. In recent years, Araxes Pharma has applied for several patents for KRAS G12C inhibitors, such as WO2016164675 and WO2016168540. ARS-3248, developed by Araxes Pharma, is currently in Phase I clinical trials. Amgen has published several patents on KRAS G12C inhibitors since 2018: WO2018119183, WO2018217651, WO2019051291, WO2019213516, WO2020050890, etc. The KRAS G12C inhibitor MRTX849 developed by MIRATI has entered Phase II clinical trials. AMG 510 is a selective small molecule KRAS G12C inhibitor with the fastest clinical progress. AMG 510 is expected to become a new option for the treatment of metastatic non-small cell lung cancer (NSCLC), and can be used in combination with other anti-tumor drugs to produce better efficacy. The U.S. Food and Drug Administration (FDA) has granted targeted cancer drug AMG 510 Breakthrough Drug Designation (BTD) and Real-Time Oncology Review Designation (RTOR) for the treatment of patients with a KRAS G12C mutation confirmed by an FDA-approved test. Patients with locally advanced or NSCLC.
Figure 02_image003

本申請提供式（I）化合物或其藥學上可接受的鹽，

Figure 02_image001
其中， X選自CR 13和N； Q和Y分別獨立地選自CH和N； R 1選自H、F、Cl、Br、I、C 1-3烷基，所述C 1-3烷基任選被1、2或3個鹵素取代； R 2、R 3、R 4、R 5和R 6分別獨立地選自H、F、Cl、Br、I、OH、C 1-3烷基、NH 2和-NH-C 1-3烷基，所述C 1-3烷基任選被1、2或3個鹵素取代； R 7、R 8、R 9和R 10分別獨立地選自H和CH 3； R 11選自H和F； R 12和R 13分別獨立地選自H、C 1-6烷基、環丙基和C 1-3烷氧基。 The application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure 02_image001
Wherein, X is selected from CR 13 and N; Q and Y are independently selected from CH and N; R 1 is selected from H, F, Cl, Br, I, C 1-3 alkyl, the C 1-3 alkane The group is optionally substituted with 1, 2 or 3 halogens; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, C 1-3 alkyl , NH 2 and -NH-C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 halogens; R 7 , R 8 , R 9 and R 10 are each independently selected from H and CH 3 ; R 11 is selected from H and F; R 12 and R 13 are each independently selected from H, C 1-6 alkyl, cyclopropyl and C 1-3 alkoxy.

在本申請的一些方案中，上述X選自CR 13，其他變量如本申請所定義。 In some aspects of the present application, the above X is selected from CR 13 , and other variables are as defined herein.

在本申請的一些方案中，上述Y選自N，其他變量如本申請所定義。In some aspects of the present application, the above Y is selected from N, and other variables are as defined herein.

在本申請的一些方案中，上述Q選自CH，其他變量如本申請所定義。In some aspects of the present application, the above Q is selected from CH, and other variables are as defined herein.

在本申請的一些方案中，上述R 1選自H、F、Cl、Br、I、CH 3，所述CH 3任選被1、2或3個鹵素取代，其他變量如本申請所定義。 In some aspects of the present application, the above R 1 is selected from H, F, Cl, Br, I, CH 3 optionally substituted with 1, 2 or 3 halogens, and other variables are as defined herein.

在本申請的一些方案中，上述R 1選自H、F和CF 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 1 is selected from H, F and CF 3 , and other variables are as defined herein.

在本申請的一些方案中，上述R 1選自CF 3，其他變量如本申請所定義。 In some aspects of this application, the above R 1 is selected from CF 3 , and other variables are as defined in this application.

在本申請的一些方案中，上述R 2、R 3、R 4、R 5和R 6分別獨立地選自H、F、Cl、Br、I、OH、CF 3、CH 3、NH 2和-NHCH 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, CF 3 , CH 3 , NH 2 and - NHCH3 , other variables are as defined herein.

在本申請的一些方案中，上述R 2、R 3、R 4、R 5和R 6分別獨立地選自H、F、Cl、Br、CF 3、CH 3、NH 2和-NHCH 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CF 3 , CH 3 , NH 2 and -NHCH 3 , other Variables are as defined in this application.

在本申請的一些方案中，上述R 2選自H、F、NH 2和-NHCH 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 2 is selected from H, F, NH 2 and -NHCH 3 , and other variables are as defined herein.

在本申請的一些方案中，上述R 3選自H、F和Cl，其他變量如本申請所定義。 In some aspects of this application, the above R3 is selected from H, F and Cl, and other variables are as defined in this application.

在本申請的一些方案中，上述R 4選自H和F，其他變量如本申請所定義。 In some aspects of this application, the above R4 is selected from H and F, and other variables are as defined in this application.

在本申請的一些方案中，上述R 5選自H、F、Cl和CH 3，其他變量如本申請所定義。 In some aspects of this application, the above R5 is selected from H, F, Cl and CH3 , and other variables are as defined in this application.

在本申請的一些方案中，上述R 6選自H、F和CF 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 6 is selected from H, F and CF 3 , and other variables are as defined herein.

在本申請的一些方案中，上述R 7選自H，其他變量如本申請所定義。 In some aspects of the present application, the above R7 is selected from H, and other variables are as defined herein.

在本申請的一些方案中，上述R 10選自H，其他變量如本申請所定義。 In some aspects of the present application, the above R 10 is selected from H, and other variables are as defined herein.

在本申請的一些方案中，上述R 11選自H，其他變量如本申請所定義。 In some aspects of this application, the above R 11 is selected from H, and other variables are as defined in this application.

在本申請的一些方案中，上述R 12選自

Figure 02_image005
，其他變量如本申請所定義。 In some aspects of the present application, the above R 12 is selected from
Figure 02_image005
, and other variables are as defined in this application.

在本申請的一些方案中，上述R 13選自CH 3和OCH 3，其他變量如本申請所定義。 In some aspects of the present application, the above R 13 is selected from CH 3 and OCH 3 , and other variables are as defined herein.

在本申請的一些方案中，上述X選自CR 13，Y選自N，Q選自CH，其他變量如本申請所定義。 In some aspects of the present application, the aforementioned X is selected from CR 13 , Y is selected from N, Q is selected from CH, and other variables are as defined herein.

在本申請的一些方案中，上述X選自CR 13，Y選自N，Q選自CH，R 2選自F，R 6選自F，其他變量如本申請所定義。 In some aspects of the present application, the above X is selected from CR 13 , Y is selected from N, Q is selected from CH, R 2 is selected from F, R 6 is selected from F, and other variables are as defined herein.

在本申請的一些方案中，上述X選自CR 13，Y選自N，Q選自CH，R 12選自

Figure 02_image005
，R 13選自CH 3，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned X is selected from CR 13 , Y is selected from N, Q is selected from CH, and R 12 is selected from
Figure 02_image005
, R 13 is selected from CH 3 , and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image007
選自
Figure 02_image009
、
Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
和
Figure 02_image017
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image007
selected from
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
and
Figure 02_image017
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image007
選自
Figure 02_image015
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image007
selected from
Figure 02_image015
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image007
選自
Figure 02_image019
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image007
selected from
Figure 02_image019
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image021
選自
Figure 02_image023
、
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image061
和
Figure 02_image063
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image021
selected from
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
,
Figure 02_image057
,
Figure 02_image059
,
Figure 02_image061
and
Figure 02_image063
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image021
選自
Figure 02_image023
、
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image047
、
Figure 02_image055
和
Figure 02_image063
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image021
selected from
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image047
,
Figure 02_image055
and
Figure 02_image063
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image021
選自
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image047
和
Figure 02_image063
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image021
selected from
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image047
and
Figure 02_image063
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image021
選自
Figure 02_image047
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image021
selected from
Figure 02_image047
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image067
選自
Figure 02_image069
、
Figure 02_image071
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image067
selected from
Figure 02_image069
,
Figure 02_image071
, and other variables are as defined in this application.

在本申請的一些方案中，上述結構單元

Figure 02_image067
選自
Figure 02_image069
，其他變量如本申請所定義。 In some aspects of the present application, the above-mentioned structural unit
Figure 02_image067
selected from
Figure 02_image069
, and other variables are as defined in this application.

在本申請的一些方案中，上述化合物選自

Figure 02_image074
， 其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和R 13如本申請所定義。 In some aspects of the present application, the above-mentioned compounds are selected from
Figure 02_image074
, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined herein.

在本申請的一些方案中，上述化合物選自

Figure 02_image076
， 其中，R 1、R 3、R 4、R 5、R 7、R 8、R 9、R 10、R 11、R 12和R 13如本申請所定義。 In some aspects of the present application, the above-mentioned compounds are selected from
Figure 02_image076
, wherein R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined herein.

在本申請的一些方案中，上述化合物選自

Figure 02_image078
， 其中，R 2、R 3、R 4、R 5、R 6、R 8、和R 9如本申請所定義。 In some aspects of the present application, the above-mentioned compounds are selected from
Figure 02_image078
, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are as defined herein.

在本申請的一些方案中，上述化合物選自

Figure 02_image080
， 其中，R 2、R 3、R 4、R 5、R 6、R 8、和R 9如本申請所定義。 In some aspects of the present application, the above-mentioned compounds are selected from
Figure 02_image080
, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are as defined herein.

在本申請的一些方案中，上述化合物不選自下列化合物：

Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
。 In some aspects of the application, the above-mentioned compounds are not selected from the following compounds:
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
.

本申請還提供化合物或其藥學上可接受的鹽，其選自

Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
、
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
和
Figure 02_image190
。 The application also provides compounds, or pharmaceutically acceptable salts thereof, selected from
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
,
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
and
Figure 02_image190
.

在本申請的一些方案中，上述化合物或其藥學上可接受的鹽，其選自

Figure 02_image192
、
Figure 02_image194
、
Figure 02_image196
、
Figure 02_image198
、
Figure 02_image200
、
Figure 02_image202
、
Figure 02_image204
、
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
、
Figure 02_image226
、
Figure 02_image228
、
Figure 02_image230
、
Figure 02_image232
、
Figure 02_image234
、
Figure 02_image236
、
Figure 02_image238
、
Figure 02_image240
、
Figure 02_image242
、
Figure 02_image244
、
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
、
Figure 02_image264
、
Figure 02_image266
、
Figure 02_image268
、
Figure 02_image270
、
Figure 02_image272
、
Figure 02_image274
、
Figure 02_image276
、
Figure 02_image278
、
Figure 02_image280
、
Figure 02_image282
、
Figure 02_image284
、
Figure 02_image286
、
Figure 02_image288
、
Figure 02_image290
、
Figure 02_image292
、
Figure 02_image294
、
Figure 02_image296
、
Figure 02_image298
、
Figure 02_image300
、
Figure 02_image302
、
Figure 02_image304
、
Figure 02_image306
、
Figure 02_image308
、
Figure 02_image310
、
Figure 02_image312
、
Figure 02_image314
、
Figure 02_image316
、
Figure 02_image318
、
Figure 02_image320
、
Figure 02_image322
、
Figure 02_image324
、
Figure 02_image326
、
Figure 02_image328
、
Figure 02_image330
、
Figure 02_image332
、
Figure 02_image334
、
Figure 02_image336
、
Figure 02_image338
、
Figure 02_image340
、
Figure 02_image342
、
Figure 02_image344
、
Figure 02_image346
、
Figure 02_image348
、
Figure 02_image350
、
Figure 02_image352
、
Figure 02_image354
、
Figure 02_image356
、
Figure 02_image358
、
Figure 02_image360
、
Figure 02_image362
、
Figure 02_image364
、
Figure 02_image366
、
Figure 02_image368
、
Figure 02_image370
、
Figure 02_image372
、
Figure 02_image374
、
Figure 02_image376
、
Figure 02_image378
、
Figure 02_image380
、
Figure 02_image382
、
Figure 02_image384
、
Figure 02_image386
、
Figure 02_image388
、
Figure 02_image390
、
Figure 02_image392
和
Figure 02_image394
。 In some aspects of the application, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
Figure 02_image192
,
Figure 02_image194
,
Figure 02_image196
,
Figure 02_image198
,
Figure 02_image200
,
Figure 02_image202
,
Figure 02_image204
,
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
,
Figure 02_image226
,
Figure 02_image228
,
Figure 02_image230
,
Figure 02_image232
,
Figure 02_image234
,
Figure 02_image236
,
Figure 02_image238
,
Figure 02_image240
,
Figure 02_image242
,
Figure 02_image244
,
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
,
Figure 02_image264
,
Figure 02_image266
,
Figure 02_image268
,
Figure 02_image270
,
Figure 02_image272
,
Figure 02_image274
,
Figure 02_image276
,
Figure 02_image278
,
Figure 02_image280
,
Figure 02_image282
,
Figure 02_image284
,
Figure 02_image286
,
Figure 02_image288
,
Figure 02_image290
,
Figure 02_image292
,
Figure 02_image294
,
Figure 02_image296
,
Figure 02_image298
,
Figure 02_image300
,
Figure 02_image302
,
Figure 02_image304
,
Figure 02_image306
,
Figure 02_image308
,
Figure 02_image310
,
Figure 02_image312
,
Figure 02_image314
,
Figure 02_image316
,
Figure 02_image318
,
Figure 02_image320
,
Figure 02_image322
,
Figure 02_image324
,
Figure 02_image326
,
Figure 02_image328
,
Figure 02_image330
,
Figure 02_image332
,
Figure 02_image334
,
Figure 02_image336
,
Figure 02_image338
,
Figure 02_image340
,
Figure 02_image342
,
Figure 02_image344
,
Figure 02_image346
,
Figure 02_image348
,
Figure 02_image350
,
Figure 02_image352
,
Figure 02_image354
,
Figure 02_image356
,
Figure 02_image358
,
Figure 02_image360
,
Figure 02_image362
,
Figure 02_image364
,
Figure 02_image366
,
Figure 02_image368
,
Figure 02_image370
,
Figure 02_image372
,
Figure 02_image374
,
Figure 02_image376
,
Figure 02_image378
,
Figure 02_image380
,
Figure 02_image382
,
Figure 02_image384
,
Figure 02_image386
,
Figure 02_image388
,
Figure 02_image390
,
Figure 02_image392
and
Figure 02_image394
.

本申請還有一些方案是由上述各變量任意組合而來。There are also some solutions in the present application which are obtained by any combination of the above variables.

本申請還提供上述化合物或其藥學上可接受的鹽在製備KRAS G12C突變蛋白抑制劑的應用。The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a KRAS G12C mutein inhibitor.

本申請還提供上述化合物或其藥學上可接受的鹽在製備治療非小細胞肺癌藥物中的應用。The present application also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.

技術效果technical effect

本申請化合物是優效的KRAS G12C突變蛋白抑制劑。本申請化合物對於KRAS G12C突變型細胞NCI-H358顯示了較高的細胞抗增殖活性，同時對於野生型的A375細胞抗增殖活性較弱，體現了高的選擇性。The compounds of the present application are potent KRAS G12C mutein inhibitors. The compounds of the present application show high cell anti-proliferation activity on KRAS G12C mutant cells NCI-H358, and at the same time have weak anti-proliferative activity on wild-type A375 cells, showing high selectivity.

定義和說明Definition and Explanation

除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

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

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

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

除非另有規定，術語“有效量”或“治療有效量”是指無毒的但能達到預期效果的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本發明所屬技術領域具通常知識者根據常規試驗確定。Unless otherwise specified, the term "effective amount" or "therapeutically effective amount" refers to an amount that is nontoxic but achieves the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by one of ordinary skill in the art to which the present invention belongs based on routine experiments.

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

除非另有說明，術語“對映異構體”或者“旋光異構體”是指互為鏡像關係的立體異構體。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

除非另有說明，術語“順反異構體”或者“幾何異構體”系由因雙鍵或者成環碳原子單鍵不能自由旋轉而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.

除非另有說明，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。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.

除非另有說明，“(+)”表示右旋，“(-) ”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

除非另有說明，用楔形實線鍵（

Figure 02_image396
）和楔形虛線鍵（
Figure 02_image398
）表示一個立體中心的絕對構型，用直形實線鍵（
Figure 02_image400
）和直形虛線鍵（
Figure 02_image402
）表示立體中心的相對構型，用波浪線（
Figure 02_image404
）表示楔形實線鍵（
Figure 02_image396
）或楔形虛線鍵（
Figure 02_image398
），或用波浪線（
Figure 02_image404
）表示直形實線鍵（
Figure 02_image400
）或直形虛線鍵（
Figure 02_image402
）。 Unless otherwise specified, use the solid wedge key (
Figure 02_image396
) and the dashed wedge key (
Figure 02_image398
) represents the absolute configuration of a stereocenter, using straight solid-line bonds (
Figure 02_image400
) and straight dashed keys (
Figure 02_image402
) represents the relative configuration of the stereocenter, with a wavy line (
Figure 02_image404
) represents a solid wedge key (
Figure 02_image396
) or the dashed wedge key (
Figure 02_image398
), or use a wavy line (
Figure 02_image404
) indicates a straight solid key (
Figure 02_image400
) or a straight dashed key (
Figure 02_image402
).

除非另有說明，術語“互變異構體”或“互變異構體形式”是指在室溫下，不同官能團異構體處於動態平衡，並能很快的相互轉化。若互變異構體是可能的 (如在溶液中)，則可以達到互變異構體的化學平衡。例如，質子互變異構體 (proton tautomer) (也稱質子轉移互變異構體 (prototropic tautomer)) 包括通過質子遷移來進行的互相轉化，如酮-烯醇異構化和亞胺-烯胺異構化。價鍵異構體 (valence tautomer) 包括一些成鍵電子的重組來進行的相互轉化。其中酮-烯醇互變異構化的具體實例是戊烷-2,4-二酮與4-羥基戊-3-烯-2-酮兩個互變異構體之間的互變。Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerizations and imine-enamine isoforms structured. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

除非另有說明，術語“富含一種異構體”、“異構體富集”、“富含一種對映體”或者“對映體富集”指其中一種異構體或對映體的含量小於100%，並且，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%。Unless otherwise specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or enantiomers The content is less than 100%, and 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 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%.

除非另有說明，術語“異構體過量”或“對映體過量”指兩種異構體或兩種對映體相對百分數之間的差值。例如，其中一種異構體或對映體的含量為90%，另一種異構體或對映體的含量為10%，則異構體或對映體過量（ee值）為80%。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

可以通過的手性合成或手性試劑或者其他常規技術製備光學活性的( R)-和( S)-異構體以及 D和 L異構體。如果想得到本申請某化合物的一種對映體，可以通過不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。或者，當分子中含有鹼性官能團（如氨基）或酸性官能團（如羧基）時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後通過本領域所公知的常規方法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是通過使用色譜法完成的，所述色譜法採用手性固定相，並任選地與化學衍生法相結合（例如由胺生成氨基甲酸鹽）。 Optically active ( R )- and ( S )-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure Enantiomers are required. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).

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

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

術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代，可以包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為氧（即=O）時，意味著兩個氫原子被取代。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted.

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

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

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

Figure 02_image407
）、直形虛線鍵（
Figure 02_image409
）、或波浪線（
Figure 02_image411
）表示。例如-OCH 3中的直形實線鍵表示通過該基團中的氧原子與其他基團相連；
Figure 02_image413
中的直形虛線鍵表示通過該基團中的氮原子的兩端與其他基團相連；
Figure 02_image415
中的波浪線表示通過該苯基基團中的1和2位碳原子與其他基團相連；
Figure 02_image417
表示該哌啶基上的任意可連接位點可以通過1個化學鍵與其他基團相連，至少包括
Figure 02_image419
、
Figure 02_image421
、
Figure 02_image423
、
Figure 02_image425
這4種連接方式，即使-N-上畫出了H原子，但是
Figure 02_image417
仍包括
Figure 02_image419
這種連接方式的基團，只是在連接1個化學鍵時，該位點的H會對應減少1個變成相應的一價哌啶基。 Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not positioned and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond to which the site is attached to other groups can be represented by straight solid-line bonds (
Figure 02_image407
), straight dashed key (
Figure 02_image409
), or a wavy line (
Figure 02_image411
)express. For example, a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
Figure 02_image413
The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
Figure 02_image415
The wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
Figure 02_image417
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure 02_image419
,
Figure 02_image421
,
Figure 02_image423
,
Figure 02_image425
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure 02_image417
still includes
Figure 02_image419
The group in this connection method is only that when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.

除非另有規定，術語“C 1-6烷基”用於表示直鏈或支鏈的由1至6個碳原子組成的飽和碳氫基團。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一價（如甲基）、二價（如亞甲基）或者多價（如次甲基）。C 1-6烷基的實例包括但不限於甲基 (Me)、乙基 (Et)、丙基 (包括 n-丙基和異丙基)、丁基 (包括 n-丁基，異丁基， s-丁基和 t-丁基)、戊基 (包括 n-戊基，異戊基和新戊基)、己基等。 Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine). Examples of C1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl , s -butyl and t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and the like.

除非另有規定，術語“C 1-3烷基”用於表示直鏈或支鏈的由1至3個碳原子組成的飽和碳氫基團。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一價（如甲基）、二價（如亞甲基）或者多價（如次甲基）。C 1-3烷基的實例包括但不限於甲基 (Me)、乙基 (Et)、丙基 (包括 n-丙基和異丙基) 等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), and the like.

除非另有規定，術語“C 1-3烷氧基”表示通過一個氧原子連接到分子的其餘部分的那些包含1至3個碳原子的烷基基團。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基 (包括正丙氧基和異丙氧基)等。 Unless otherwise specified, the term " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

除非另有規定，術語“鹵代素”或“鹵素”本身或作為另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

本申請的化合物可以通過本發明所屬技術領域具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申請的實施例。The compounds of the present application can be prepared by various synthetic methods well known to those of ordinary skill in the art to which the present invention belongs, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art. Equivalent alternatives well known to persons, and preferred embodiments include but are not limited to the examples of the present application.

本申請的化合物可以通過本發明所屬技術領域具通常知識者所熟知的常規方法來確認結構，如果本申請涉及化合物的絕對構型，則該絕對構型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（SXRD），把培養出的單晶用Bruker D8 venture衍射儀收集衍射強度數據，光源為CuKα輻射，掃描方式：φ/ω 掃描，收集相關數據後，進一步採用直接法(Shelxs97)解析晶體結構，便可以確證絕對構型。The structure of the compound of the present application can be confirmed by conventional methods well known to those with ordinary knowledge in the technical field to which the present invention belongs. If the present application relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, scanning mode: φ/ω scanning, after collecting relevant data, the direct method is further adopted. (Shelxs97) analysis of the crystal structure, the absolute configuration can be confirmed.

本申請所使用的溶劑可經市售獲得。The solvent used in this application is commercially available.

本申請採用下述縮略詞：aq代表水； eq代表當量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚； DMF 代表N，N-二甲基甲醯胺；DMAc代表N，N-二甲基乙醯胺；PyBrOP代表三吡咯烷基溴化鏻六氟磷酸鹽；DMSO代表二甲亞碸；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一種胺保護基團；BOC代表第三丁氧羰基，是一種胺保護基團；Pd 2dba 3代表三(二亞苄基丙酮)二鈀，NaH代表氫化鈉，SiO 2代表矽膠，HOAc代表乙酸； r.t.代表室溫；O/ N代表過夜；THF代表四氫呋喃；Boc 2O代表二-第三丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二異丙基乙基胺； TsOH代表對甲苯磺酸；NCS代表1-氯吡咯烷-2,5-二酮。 The following abbreviations are used in this application: aq stands for water; eq stands for equivalent, equivalent; CDI stands for carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMAc for N,N-dimethylacetamide; PyBrOP for tripyrrolidinophosphonium bromide hexafluorophosphate; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; MeOH for methanol; CBz for Benzyloxycarbonyl, is an amine protecting group; BOC stands for third butoxycarbonyl, is an amine protecting group; Pd 2 dba 3 stands for tris(dibenzylideneacetone)dipalladium, NaH stands for sodium hydride, SiO 2 stands for Silica gel, HOAc for acetic acid; rt for room temperature; O/N for overnight; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine ; TsOH stands for p-toluenesulfonic acid; NCS stands for 1-chloropyrrolidine-2,5-dione.

下面通過實施例對本申請進行詳細描述，但並不意味著對本申請任何不利限制。本申請的化合物可以通過本發明所屬技術領域具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申請的實施例。對本領域的技術人員而言，在不脫離本申請精神和範圍的情況下針對本申請具體實施方式進行各種變化和改進將是顯而易見的。The present application will be described in detail below through the examples, but it does not mean any unfavorable limitation to the present application. The compounds of the present application can be prepared by various synthetic methods well known to those of ordinary skill in the art to which the present invention belongs, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art. Equivalent alternatives well known to persons, and preferred embodiments include but are not limited to the examples of the present application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

中間體A的合成

Figure 02_image427
第一步： 向化合物A-1(5克)的三級-丁醇（50毫升）溶液中加入化合物A-2(5克)，碳酸銫(10.27克)和BrettPhos Pd G3(1.43克)，反應體系用氮氣置換3次，在氮氣保護下，反應液在105攝氏度反應36小時。反應液墊矽藻土過濾，濾餅用乙酸乙酯（50毫升*3）淋洗，濾液減壓濃縮得到殘留物，殘留物經柱層析純化(SiO 2，洗脫劑：石油醚：乙酸乙酯 = 10：1 ~ 2：1)得到化合物A-3。LCMS (ESI) m/z: 451.1 (m+1) +。 第二步： 在0-10攝氏度下，向化合物A-3 (14.75克，92.2% 純度)的二氯甲烷（150毫升）溶液中加入N-溴代琥珀醯亞胺(5.37克)，反應液在0-10攝氏度下反應0.5小時。反應液在0-10攝氏度下用飽和亞硫酸鈉溶液（40毫升）淬滅，然後靜置分層，有機相用飽和食鹽水（40毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物A-4。LCMS (ESI) m/z: 531.0 (m+1) +。 第三步： 向化合物A-4 (16克)的乙醇（160毫升）和水（40毫升）的混合溶液中加入鐵粉(8.44克)和氯化銨(8.09克)，反應液在80攝氏度下反應2小時。反應液冷卻至25攝氏度，然後墊矽藻土過濾，濾餅用甲醇（50毫升*3）淋洗，濾液減壓濃縮得到殘留物，殘留物用水（50毫升）和乙酸乙酯（150毫升）稀釋，有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物A-5。LCMS (ESI) m/z: 501.0(m+1) +。 第四步： 向化合物A-5 (15克)的N，N-二甲基甲醯胺（150毫升）溶液中加入鋅粉(0.96克)，氰化鋅(2.76克)，DPPF (3.33克)，Pd 2(dba) 3(2.75克)和溴化鋅(338.27毫克)，然後將反應體系置換氮氣三次，在氮氣保護下，反應液在120攝氏度反應14小時。將反應液墊矽藻土過濾，濾餅用乙酸乙酯（50毫升*4）洗滌，濾液用水（600毫升）稀釋，然後靜置分層，有機相用飽和食鹽水（100毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經柱層析純化(SiO 2，洗脫劑：石油醚：乙酸乙酯 = 3：1)得到化合物A-6。LCMS (ESI) m/z: 446.0(m+1) +。 第五步： 在0-10攝氏度下，向化合物A-6 (10.8克)的二甲基亞碸（108毫升）和水（27毫升）混合溶液中加入氫氧化鈉(969.82毫克)和過氧化氫 (28.01克，質量百分比：30%)，反應液在0-10攝氏度反應0.5小時，升溫至25攝氏度反應1小時。反應液用飽和亞硫酸鈉溶液（500毫升）淬滅，用乙酸乙酯（100毫升*2）萃取，合併有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物用柱層析純化(SiO 2，洗脫劑：石油醚：乙酸乙酯 = 1：1~1：2)得到化合物A-7。LCMS (ESI) m/z: 464.1(m+1) +。 第六步： 在0-10攝氏度下，向化合物A-7 (8克)的無水四氫呋喃（80毫升）溶液中加入羰基二咪唑(5.60克)和氫化鈉(2.07克，質量百分比：60%)，反應液在25攝氏度反應2小時。將反應液加入到1莫耳/升的鹽酸（80毫升）中，然後用飽和碳酸氫鈉溶液調節水相pH值到8，靜置分層，水相用乙酸乙酯（50毫升）萃取，有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到中間體A。LCMS (ESI) m/z: 490.1(m+1) +。 Synthesis of Intermediate A
Figure 02_image427
Step 1: To a solution of compound A-1 (5 g) in tertiary-butanol (50 mL) was added compound A-2 (5 g), cesium carbonate (10.27 g) and BrettPhos Pd G3 (1.43 g), The reaction system was replaced with nitrogen three times, and under nitrogen protection, the reaction solution was reacted at 105 degrees Celsius for 36 hours. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (50 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO 2 , eluent: petroleum ether: acetic acid) Ethyl ester = 10:1 ~ 2:1) to obtain compound A-3. LCMS (ESI) m/z: 451.1 (m+1) + . The second step: N-bromosuccinimide (5.37 g) was added to a solution of compound A-3 (14.75 g, 92.2% purity) in dichloromethane (150 ml) at 0-10 degrees Celsius. The reaction solution React at 0-10 degrees Celsius for 0.5 hours. The reaction solution was quenched with saturated sodium sulfite solution (40 mL) at 0-10 degrees Celsius, and then allowed to stand for layers. The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A. -4. LCMS (ESI) m/z: 531.0 (m+1) + . The third step: Iron powder (8.44 g) and ammonium chloride (8.09 g) were added to a mixed solution of compound A-4 (16 g) in ethanol (160 ml) and water (40 ml), and the reaction solution was heated at 80 degrees Celsius The reaction was continued for 2 hours. The reaction solution was cooled to 25°C, then filtered through celite, the filter cake was rinsed with methanol (50 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, the residue was water (50 mL) and ethyl acetate (150 mL) After dilution, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound A-5. LCMS (ESI) m/z: 501.0(m+1) + . Step 4: To a solution of compound A-5 (15 g) in N,N-dimethylformamide (150 ml) was added zinc powder (0.96 g), zinc cyanide (2.76 g), DPPF (3.33 g) ), Pd 2 (dba) 3 (2.75 g) and zinc bromide (338.27 mg), then the reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 120 degrees Celsius for 14 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (50 ml*4), the filtrate was diluted with water (600 ml), then left to stand for layers, the organic phase was washed with saturated brine (100 ml), and anhydrous It was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound A-6. LCMS (ESI) m/z: 446.0(m+1) + . Step 5: To a mixed solution of compound A-6 (10.8 g) in dimethyl sulfoxide (108 ml) and water (27 ml) at 0-10 degrees Celsius was added sodium hydroxide (969.82 mg) and peroxide Hydrogen (28.01 g, mass percentage: 30%), the reaction solution was reacted at 0-10 degrees Celsius for 0.5 hours, and then heated to 25 degrees Celsius for 1 hour. The reaction solution was quenched with saturated sodium sulfite solution (500 mL), extracted with ethyl acetate (100 mL*2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , eluent: petroleum ether: ethyl acetate=1:1~1:2) to obtain compound A-7. LCMS (ESI) m/z: 464.1(m+1) + . The sixth step: Add carbonyldiimidazole (5.60 g) and sodium hydride (2.07 g, mass percentage: 60%) to a solution of compound A-7 (8 g) in anhydrous tetrahydrofuran (80 ml) at 0-10 degrees Celsius , the reaction solution was reacted at 25 degrees Celsius for 2 hours. The reaction solution was added to 1 mol/L hydrochloric acid (80 mL), then the pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, the layers were allowed to stand, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate A. LCMS (ESI) m/z: 490.1(m+1) + .

實施例1

Figure 02_image429
第一步： 向中間體A（400毫克）的N,N-二甲基甲醯胺（3毫升）溶液中加入DIEA（184.39毫克），PyBrOP（997.63毫克）和化合物1-1（664.29毫克），反應液在50攝氏度下反應10小時。將反應液減壓濃縮得到殘餘物，殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 250*50mm*15μm；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：34%-64%，10分鐘）純化，得到化合物1-2。LCMS (ESI) m/z: 658.2.(M+1) +。 第二步： 向化合物1-2（300毫克）的乙腈（3毫升）溶液中加入對甲苯磺酸（60.43毫克）和N-氯代丁二醯亞胺（93.72毫克），在氮氣保護下，反應液在60攝氏度下反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（15毫升），在0攝氏度攪拌10分鐘。再用飽和的碳酸氫鈉水溶液將反應體系pH值調節為8，最後用乙酸乙酯（30毫升*3）萃取，合併有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到化合物1-3。LCMS (ESI) m/z: 728.1 (M+3) +。 第三步： 向化合物1-3（310毫克）的二氯甲烷（4.5毫升）溶液中加入三氟乙酸（2.31克），反應液在25攝氏度下反應20分鐘。將反應液直接減壓濃縮得到化合物1-4的三氟乙酸鹽，粗品直接用於下一步反應。LCMS (ESI) m/z: 626.0 (M+1) +。 第四步： 向化合物1-4（400毫克）的四氫呋喃（5毫升）和水（2毫升）混合溶液中，依次加入碳酸鉀（194.09毫克）和化合物1-5（63.55毫克），反應液在20攝氏度下反應10分鐘。反應液用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（10毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 150*25mm*10μm；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：乙腈，32%-62%，10分鐘）純化，得到化合物1. 化合物1用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度: 二氧化碳臨界流體50%-50%，2.5分鐘；40分鐘）分離純化得到化合物1A和化合物1B。 化合物1A和化合物1B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物1A的保留時間為0.867min，e.e.值為100%；化合物1B的保留時間為1.760min，e.e.值為100%。化合物1A (保留時間=0.867 min)： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.46 (br d, J= 4.89 Hz, 1H), 7.40 (d, J= 7.15 Hz, 1H), 6.97-7.19 (m, 2H), 6.62 (dd, J= 16.75, 10.48 Hz, 1H), 6.29-6.50 (m, 1H), 5.83 (dd, J= 10.48, 1.44 Hz, 1H), 4.06-4.32 (m, 2H), 3.94 (br s, 8H), 2.57-2.78 (m, 1H), 2.12 (s, 3H), 1.22 (br d, J= 6.65 Hz, 3H), 1.13 (br d, J= 6.65 Hz, 3H)；LCMS (ESI) m/z: 680.1(M+1) +。 化合物1B(保留時間=1.760 min)： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.49 (d, J= 4.89 Hz, 1H), 7.41 (d, J= 7.15 Hz, 1H), 7.11 (br d, J= 4.39 Hz, 1H), 7.05 (s, 1H), 6.63 (dd, J= 16.75, 10.35 Hz, 1H), 6.37-6.47 (m, 1H), 5.84 (d, J= 11.54 Hz, 1H), 4.06-4.29 (m, 2H), 3.74-4.05 (m, 8H), 2.72-2.95 (m, 1H), 2.12 (s, 3H), 1.28 (br d, J= 6.40 Hz, 3H), 1.20 (br d, J= 6.53 Hz, 3H)；LCMS (ESI) m/z: 680.2(M+1) +。 Example 1
Figure 02_image429
Step 1: To a solution of Intermediate A (400 mg) in N,N-dimethylformamide (3 mL) was added DIEA (184.39 mg), PyBrOP (997.63 mg) and compound 1-1 (664.29 mg) , the reaction solution was reacted at 50 degrees Celsius for 10 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was subjected to preparative HPLC (column type: Phenomenex luna C18 250*50mm*15μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 34%-64%, 10 min) to obtain compound 1-2. LCMS (ESI) m/z: 658.2.(M+1) + . Step 2: To a solution of compound 1-2 (300 mg) in acetonitrile (3 mL) was added p-toluenesulfonic acid (60.43 mg) and N-chlorosuccinimide (93.72 mg), under nitrogen protection, The reaction solution was reacted at 60 degrees Celsius for 1 hour. A saturated aqueous sodium sulfite solution (15 ml) was added to the reaction solution, and the mixture was stirred at 0°C for 10 minutes. The pH of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 1-3. LCMS (ESI) m/z: 728.1 (M+3) + . The third step: Trifluoroacetic acid (2.31 g) was added to a solution of compound 1-3 (310 mg) in dichloromethane (4.5 ml), and the reaction solution was reacted at 25 degrees Celsius for 20 minutes. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 1-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 626.0 (M+1) + . The fourth step: To a mixed solution of compound 1-4 (400 mg) in tetrahydrofuran (5 mL) and water (2 mL), potassium carbonate (194.09 mg) and compound 1-5 (63.55 mg) were added in sequence, and the reaction solution was The reaction was carried out at 20 degrees Celsius for 10 minutes. The reaction solution was extracted with ethyl acetate (10 mL*2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative HPLC (column type: Phenomenex). luna C18 150*25mm*10μm; mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: acetonitrile, 32%-62%, 10 minutes) purification to give compound 1. Compound 1 was purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 40 minutes) separation and purification to obtain compound 1A and compound 1B. Compound 1A and compound 1B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 1A is 0.867min, and the ee value is 100%; the retention time of compound 1B is 1.760min, and the ee value is 100%. Compound 1A (retention time = 0.867 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.46 (br d, J = 4.89 Hz, 1H), 7.40 (d, J = 7.15 Hz, 1H), 6.97-7.19 (m, 2H), 6.62 (dd, J = 16.75, 10.48 Hz, 1H), 6.29-6.50 (m, 1H), 5.83 (dd, J = 10.48, 1.44 Hz, 1H), 4.06-4.32 (m, 2H) ), 3.94 (br s, 8H), 2.57-2.78 (m, 1H), 2.12 (s, 3H), 1.22 (br d, J = 6.65 Hz, 3H), 1.13 (br d, J = 6.65 Hz, 3H ); LCMS (ESI) m/z: 680.1(M+1) + . Compound 1B (retention time = 1.760 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.49 (d, J = 4.89 Hz, 1H), 7.41 (d, J = 7.15 Hz, 1H), 7.11 (br d , J = 4.39 Hz, 1H), 7.05 (s, 1H), 6.63 (dd, J = 16.75, 10.35 Hz, 1H), 6.37-6.47 (m, 1H), 5.84 (d, J = 11.54 Hz, 1H) , 4.06-4.29 (m, 2H), 3.74-4.05 (m, 8H), 2.72-2.95 (m, 1H), 2.12 (s, 3H), 1.28 (br d, J = 6.40 Hz, 3H), 1.20 ( br d, J = 6.53 Hz, 3H); LCMS (ESI) m/z: 680.2(M+1) + .

實施例2

Figure 02_image431
第一步： 向中間體A（150毫克）的四氫呋喃（3毫升）溶液中加入DIEA（79.22毫克），PyBrOP（429毫克）和化合物2-1（307毫克），反應液在70攝氏度下反應10小時。將反應混合物減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18（250*50mm*15μm）；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：35%-65%，10分鐘）分離純化得到化合物2-2。LCMS (ESI) m/z: 672.3.(M+1) +。 第二步： 將化合物2-2（50毫克）的乙腈（3毫升）溶液冷卻到0攝氏度，在0攝氏度下將對甲苯磺酸（12.82毫克）和NCS（19.88毫克）加入到反應液中，在氮氣保護下，反應液在60攝氏度下反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（2毫升），在0攝氏度下攪拌10分鐘。再用飽和的碳酸氫鈉水溶液將反應體系pH值調節為8，最後用乙酸乙酯（10毫升*3）萃取三次，有機相用無水硫酸鈉乾燥後過濾，濾液得到化合物2-3。LCMS (ESI) m/z: 740.2 (M+1) +。 第三步： 向化合物2-3（50毫克）的二氯甲烷（0.9毫升）溶液中加入三氟乙酸（462毫克），反應液在25攝氏度下反應0.5小時。將反應液直接減壓濃縮得到化合物2-4的三氟乙酸鹽，粗品直接用於下一步反應。LCMS (ESI) m/z: 640.4 (M+1) +。 第四步： 將化合物2-4（130毫克，三氟乙酸鹽）溶解在四氫呋喃（3毫升）和水（1毫升）混合溶液中，依次加入碳酸鉀（62.06毫克）和化合物1-5（20.32毫克），反應液在25攝氏度下反應10分鐘。反應液用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（10毫升）洗滌一次，無水硫酸鈉乾燥，過濾，減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 150*25mm*10μm；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：29%-59%，10分鐘）純化，得到的化合物2。 化合物2用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度: 二氧化碳臨界流體45%-45%，2.0分鐘；40分鐘）分離純化得到化合物2A和化合物2B。 化合物2A和化合物2B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物2A的保留時間為0.702min，e.e.值為100%；化合物2B的保留時間為1.158min，e.e.值為100%。 化合物2A (保留時間=0.702min)：LCMS (ESI) m/z: 694.2 (M+1) +。 化合物2B (保留時間=1.158min)：LCMS (ESI) m/z: 694.2 (M+1) +。 Example 2
Figure 02_image431
The first step: DIEA (79.22 mg), PyBrOP (429 mg) and compound 2-1 (307 mg) were added to a solution of intermediate A (150 mg) in tetrahydrofuran (3 ml), and the reaction solution was reacted at 70 degrees Celsius for 10 Hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative HPLC (column type: Phenomenex luna C18 (250*50mm*15μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 35%-65% , 10 minutes) separation and purification to obtain compound 2-2. LCMS (ESI) m/z: 672.3.(M+1) + . Step 2: A solution of compound 2-2 (50 mg) in acetonitrile (3 mL) was cooled to 0 degrees Celsius, p-toluenesulfonic acid (12.82 mg) and NCS (19.88 mg) were added to the reaction solution at 0 degrees Celsius, Under nitrogen protection, the reaction solution was reacted at 60 degrees Celsius for 1 hour. A saturated aqueous sodium sulfite solution (2 ml) was added to the reaction solution, followed by stirring at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and finally extracted three times with ethyl acetate (10 ml*3). The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate obtained compound 2-3. LCMS (ESI) m/z: 740.2 (M+1) + . The third step: Trifluoroacetic acid (462 mg) was added to a solution of compound 2-3 (50 mg) in dichloromethane (0.9 ml), and the reaction solution was reacted at 25 degrees Celsius for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 2-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) + . The fourth step: Compound 2-4 (130 mg, trifluoroacetate) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), potassium carbonate (62.06 mg) and compound 1-5 (20.32 mg) were added sequentially mg), the reaction solution was reacted at 25°C for 10 minutes. The reaction solution was extracted with ethyl acetate (10 mL*2), the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 29%-59%, 10 minutes) purification to obtain compound 2. Compound 2 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.0 minutes; 40 minutes) Compound 2A and Compound 2B. Compound 2A and compound 2B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the retention time of compound 2A is 0.702min, and the ee value is 100%; the retention time of compound 2B is 1.158min, and the ee value is 100%. Compound 2A (retention time=0.702 min): LCMS (ESI) m/z: 694.2 (M+1) + . Compound 2B (retention time=1.158 min): LCMS (ESI) m/z: 694.2 (M+1) + .

實施例3

Figure 02_image433
第一步： 向中間體A（150毫克）的四氫呋喃（5毫升）溶液中加入DIPEA（79.22毫克），PyBrOP（429毫克）和化合物3-1（328毫克），反應液在70攝氏度下反應10小時。反應混合物減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenexluna C18 250*50mm*15μm；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：35%-65%，10分鐘）純化，得到化合物3-2。LCMS (ESI) m/z: 686.3.(M+1) +。 第二步： 將化合物3-2（70毫克）的乙腈（3毫升）溶液冷卻到0攝氏度，在0攝氏度下將對甲苯磺酸（17.58毫克）和NCS（27.26毫克）加入到反應液中，在氮氣保護下，反應液在60攝氏度下反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（2毫升），在0攝氏度下攪拌10分鐘。再用飽和的碳酸氫鈉水溶液將反應體系pH值調節為8，用乙酸乙酯（20毫升*3）萃取，有機相用無水硫酸鈉乾燥後過濾，濾液得到化合物3-3。LCMS (ESI) m/z: 754.4 (M+1) +。 第三步： 向化合物3-3（80毫克）的二氯甲烷（1.2毫升）溶液中加入三氟乙酸（690.90毫克），反應液在25攝氏度下反應0.5小時。將反應液直接減壓濃縮得到化合物3-4的三氟乙酸鹽，粗品直接用於下一步反應。LCMS (ESI) m/z: 654.4 (M+1) +。 第四步： 向化合物3-4（180毫克）的四氫呋喃（4毫升）和水（1毫升）混合溶液中依次加入碳酸鉀（84.57毫克）和化合物1-5（27.69毫克），反應液在20攝氏度下反應10分鐘。反應液用乙酸乙酯（10毫升*2）萃取兩次，有機相用飽和食鹽水（10毫升）洗滌一次，無水硫酸鈉乾燥，過濾，減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 150*25mm*10μm；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：31%-64%，10分鐘）純化，得到化合物3。 化合物3用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度: 二氧化碳臨界流體45%-45%，2.3分鐘；40分鐘）分離純化得到化合物3A和化合物3B。 化合物3A和化合物3B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物3A的保留時間為2.104min，e.e.值為100%；化合物3B的保留時間為2.654min，e.e.值為100%。 化合物3A(保留時間=2.104min)： 1H NMR (400 MHz, DMSO- d 6) δ 8.32 (d, J= 4.77 Hz, 1H), 7.66 (d, J= 7.46 Hz, 1H), 7.04-7.18 (m, 2H), 6.82 (ddd, J= 16.60, 12.68, 10.58 Hz, 1H), 6.11-6.28 (m, 3H), 5.67-5.81 (m, 1H), 4.48-4.81 (m, 2H), 3.71-4.22 (m, 4H), 2.62-2.75 (m, 1H), 2.03 (d, J= 3.42 Hz, 3H), 1.28-1.37 (m, 3H), 1.15-1.27 (m, 3H), 1.03 (br d, J= 6.60 Hz, 3H), 0.93 (d, J= 6.60 Hz, 3H)；LCMS (ESI) m/z: 708.2 (M+1) +。 化合物3B(保留時間=2.654min)： 1H NMR (400 MHz, DMSO- d 6) δ 8.31 (d, J= 4.77 Hz, 1H), 7.68 (d, J= 7.58 Hz, 1H), 7.04-7.14 (m, 2H), 6.84 (dt, J= 16.60, 10.84 Hz, 1H), 6.13-6.28 (m, 3H), 5.68-5.81 (m, 1H), 4.45-4.83 (m, 2H), 3.44-4.16 (m, 4H), 2.82 (dq, J= 13.36, 6.63 Hz, 1H), 1.95 (s, 3H), 1.31-1.37 (m, 3H), 1.17-1.26 (m, 3H), 1.03 (br d, J= 6.60 Hz, 6H)；LCMS (ESI) m/z: 708.3 (M+1) +。 Example 3
Figure 02_image433
The first step: DIPEA (79.22 mg), PyBrOP (429 mg) and compound 3-1 (328 mg) were added to a solution of intermediate A (150 mg) in tetrahydrofuran (5 ml), and the reaction solution was reacted at 70 degrees Celsius for 10 Hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was passed through preparative HPLC (column type: Phenomenexluna C18 250*50mm*15μm; mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 35%-65% in 10 minutes) Purification gave compound 3-2. LCMS (ESI) m/z: 686.3.(M+1) + . Step 2: A solution of compound 3-2 (70 mg) in acetonitrile (3 mL) was cooled to 0 degrees Celsius, p-toluenesulfonic acid (17.58 mg) and NCS (27.26 mg) were added to the reaction solution at 0 degrees Celsius, Under nitrogen protection, the reaction solution was reacted at 60 degrees Celsius for 1 hour. A saturated aqueous sodium sulfite solution (2 ml) was added to the reaction solution, followed by stirring at 0°C for 10 minutes. The pH value of the reaction system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 ml*3), the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate obtained compound 3-3. LCMS (ESI) m/z: 754.4 (M+1) + . The third step: Trifluoroacetic acid (690.90 mg) was added to a solution of compound 3-3 (80 mg) in dichloromethane (1.2 ml), and the reaction solution was reacted at 25 degrees Celsius for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 654.4 (M+1) + . The fourth step: To a mixed solution of compound 3-4 (180 mg) in tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (84.57 mg) and compound 1-5 (27.69 mg) were added successively, and the reaction solution was heated at 20 The reaction was carried out at degrees Celsius for 10 minutes. The reaction solution was extracted twice with ethyl acetate (10 mL*2), the organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to preparative HPLC (column Model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 31%-64%, 10 minutes) Purification to give compound 3. Compound 3 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45%, 2.3 minutes; 40 minutes) Compound 3A and Compound 3B. Compound 3A and compound 3B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 5%-40%] obtained: the retention time of compound 3A was 2.104 min, and the ee value was 100%; the retention time of compound 3B was 2.654 min, and the ee value was 100%. Compound 3A (retention time = 2.104 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32 (d, J = 4.77 Hz, 1H), 7.66 (d, J = 7.46 Hz, 1H), 7.04-7.18 (m, 2H), 6.82 (ddd, J = 16.60, 12.68, 10.58 Hz, 1H), 6.11-6.28 (m, 3H), 5.67-5.81 (m, 1H), 4.48-4.81 (m, 2H), 3.71 -4.22 (m, 4H), 2.62-2.75 (m, 1H), 2.03 (d, J = 3.42 Hz, 3H), 1.28-1.37 (m, 3H), 1.15-1.27 (m, 3H), 1.03 (br d, J = 6.60 Hz, 3H), 0.93 (d, J = 6.60 Hz, 3H); LCMS (ESI) m/z: 708.2 (M+1) + . Compound 3B (retention time = 2.654 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 4.77 Hz, 1H), 7.68 (d, J = 7.58 Hz, 1H), 7.04-7.14 (m, 2H), 6.84 (dt, J = 16.60, 10.84 Hz, 1H), 6.13-6.28 (m, 3H), 5.68-5.81 (m, 1H), 4.45-4.83 (m, 2H), 3.44-4.16 (m, 4H), 2.82 (dq, J = 13.36, 6.63 Hz, 1H), 1.95 (s, 3H), 1.31-1.37 (m, 3H), 1.17-1.26 (m, 3H), 1.03 (br d, J = 6.60 Hz, 6H); LCMS (ESI) m/z: 708.3 (M+1) + .

實施例4

Figure 02_image435
第一步： 向中間體A（200毫克）的乙腈（4毫升）溶液中加入N-氯代丁二醯亞胺（109.14毫克）和一水合甲苯磺酸（105.55毫克）。反應液在60攝氏度下反應2小時，反應液後處理加入飽和亞硫酸鈉水（5毫升）溶液淬滅，乙酸乙酯（10毫升）萃取，有機相濃縮得到化合物4-1。LCMS (ESI) m/z: 558.3(M+1) +。 第二步： 向化合物4-1（280毫克）的四氫呋喃（5毫升）溶液中加入化合物4-2（537.38毫克）及PyBROP（935.18毫克），N,N-二異丙基乙胺（129.63毫克）。反應液在60攝氏度下反應12小時，反應濃縮液得到化合物4-3。LCMS (ESI) m/z: 754.5(M+1) +。 第三步： 向化合物4-3（80毫克）的二氯甲烷（3毫升）溶液中加入三氟乙酸（10.88毫克）。反應液在25攝氏度下反應1小時，反應濃縮液得到化合物4-4。LCMS (ESI) m/z: 654.3(M+1) +。 第四步： 向化合物4-4（375毫克）的四氫呋喃：水=3:1（4毫升:1毫升）溶液中加入碳酸鉀（395.95毫克）及化合物1-5（25.93毫克）。反應液在0攝氏度下反應半小時，反應液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Unisil 3-100 C18 Ultra （150*50mm*3 μm），流動相：水（0.225%甲酸）-乙腈，梯度：40%-60%，10分鐘]純化，得到化合物4。 化合物4通過製備SFC(柱型號： DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流動相：甲醇（0.1%氨水）；梯度：二氧化碳臨界流體35%-35%，2.2分鐘；40分鐘）分離純化得到化合物4A和化合物4B。 化合物4A和化合物4B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇+乙腈（0.05%二乙胺）；梯度（B%）：40%甲醇+乙腈（0.05%二乙胺）]得到：化合物4A的保留時間為0.552min，e.e.值為100%；化合物4B的保留時間為0.807min，e.e.值為100%。 化合物4A(保留時間=0.552分鐘)： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.24-8.40 (m, 1H), 7.66 (d, J= 7.58 Hz, 1H), 7.29 (s, 1H), 7.09 (d, J= 4.77 Hz, 1H), 6.82 (dd, J= 16.57, 10.45 Hz, 1H), 6.14-6.23 (m, 3H), 5.68-5.84 (m, 1H), 4.52-4.74 (m, 2H), 4.28 (br d, J= 13.82 Hz, 1H), 4.12 (br d, J= 14.18 Hz, 1H), 3.46-3.57 (m, 2H), 3.44-3.59 (m, 1H), 2.08 (s, 3H), 1.37 (br dd, J= 11.74, 7.09 Hz, 6H), 1.01 (d, J= 6.60 Hz, 3H), 0.91 (d, J= 6.72 Hz, 3H)。LCMS (ESI) m/z: 708.3(M+1) +。 化合物4B(保留時間=0.807分鐘)： 1H NMR (400 MHz, DMSO- d 6) δ 8.31 (d, J= 5.01 Hz, 1H), 7.60-7.74 (m, 1H), 7.27 (s, 1H), 7.07 (d, J= 5.14 Hz, 1H), 6.72-6.90 (m, 1H), 6.11-6.27 (m, 3H), 5.71-5.81 (m, 1H), 4.51-4.74 (m, 2H), 4.06-4.28 (m, 2H), 3.48-3.58 (m, 2H), 2.92 (br d, J= 6.72 Hz, 1H), 1.89 (s, 3H), 1.33-1.44 (m, 6H), 0.98-1.10 (m, 6 H)。 LCMS (ESI) m/z: 708.3(M+1) +。 Example 4
Figure 02_image435
First step: To a solution of Intermediate A (200 mg) in acetonitrile (4 ml) was added N-chlorosuccinimide (109.14 mg) and toluenesulfonic acid monohydrate (105.55 mg). The reaction solution was reacted at 60 degrees Celsius for 2 hours, the reaction solution was post-treated by adding saturated aqueous sodium sulfite (5 mL) solution to quench, extracted with ethyl acetate (10 mL), and the organic phase was concentrated to obtain compound 4-1. LCMS (ESI) m/z: 558.3(M+1) + . Step 2: To a solution of compound 4-1 (280 mg) in tetrahydrofuran (5 mL) were added compound 4-2 (537.38 mg) and PyBROP (935.18 mg), N,N-diisopropylethylamine (129.63 mg) ). The reaction solution was reacted at 60 degrees Celsius for 12 hours, and the reaction concentrate obtained compound 4-3. LCMS (ESI) m/z: 754.5(M+1) + . Third step: To a solution of compound 4-3 (80 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (10.88 mg). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction concentrate obtained compound 4-4. LCMS (ESI) m/z: 654.3(M+1) + . Fourth step: To a solution of compound 4-4 (375 mg) in tetrahydrofuran:water=3:1 (4 mL:1 mL), potassium carbonate (395.95 mg) and compound 1-5 (25.93 mg) were added. The reaction solution was reacted at 0 degrees Celsius for half an hour, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Unisil 3-100 C18 Ultra (150*50mm*3 μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 40%-60%, 10 minutes] to give Compound 4. Compound 4 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 35%-35%, 2.2 minutes; 40 minutes) Compound 4A and Compound 4B. Compound 4A and compound 4B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol + acetonitrile (0.05% diethylamine) in phase B; gradient ( B%): 40% methanol + acetonitrile (0.05% diethylamine)] to obtain: compound 4A has a retention time of 0.552 min and an ee value of 100%; compound 4B has a retention time of 0.807 min and an ee value of 100%. Compound 4A (RT=0.552 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.24-8.40 (m, 1H), 7.66 (d, J = 7.58 Hz, 1H), 7.29 (s, 1H) , 7.09 (d, J = 4.77 Hz, 1H), 6.82 (dd, J = 16.57, 10.45 Hz, 1H), 6.14-6.23 (m, 3H), 5.68-5.84 (m, 1H), 4.52-4.74 (m , 2H), 4.28 (br d, J = 13.82 Hz, 1H), 4.12 (br d, J = 14.18 Hz, 1H), 3.46-3.57 (m, 2H), 3.44-3.59 (m, 1H), 2.08 ( s, 3H), 1.37 (br dd, J = 11.74, 7.09 Hz, 6H), 1.01 (d, J = 6.60 Hz, 3H), 0.91 (d, J = 6.72 Hz, 3H). LCMS (ESI) m/z: 708.3(M+1) + . Compound 4B (RT=0.807 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 5.01 Hz, 1H), 7.60-7.74 (m, 1H), 7.27 (s, 1H) , 7.07 (d, J = 5.14 Hz, 1H), 6.72-6.90 (m, 1H), 6.11-6.27 (m, 3H), 5.71-5.81 (m, 1H), 4.51-4.74 (m, 2H), 4.06 -4.28 (m, 2H), 3.48-3.58 (m, 2H), 2.92 (br d, J = 6.72 Hz, 1H), 1.89 (s, 3H), 1.33-1.44 (m, 6H), 0.98-1.10 ( m, 6H). LCMS (ESI) m/z: 708.3(M+1) + .

實施例5

Figure 02_image437
第一步： 向中間體A（500毫克）的四氫呋喃（10毫升）溶液中加入DIPEA（263.65毫克），PyBrOP（1.90克）和化合物5-1（1.63克），該反應在70攝氏度反應15小時。將反應混合物減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex Synergi Max-RP （250*50mm*10 μm）；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：36%-66%，18分鐘）純化，得到化合物5-2。LCMS (ESI) m/z: 672.5(M+1) +。 第二步： 向化合物5-2（200毫克）的乙腈（6毫升）溶液中依次加入對甲苯磺酸（76.91毫克）和N-氯代丁二醯亞胺（79.52毫克），在氮氣保護下，混合物在60攝氏度反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（20毫升），用乙酸乙酯（20毫升*2）萃取，有機相用無水硫酸鈉乾燥後過濾，濾液減壓濃縮得到化合物5-3。LCMS (ESI) m/z: 740.3 (M+1) +。 第三步： 向化合物5-3（200毫克）的二氯甲烷（1毫升）溶液中加入三氟乙酸（924毫克），在氮氣保護下，反應體系在10攝氏度反應0.5小時。反應液直接減壓濃縮得到化合物5-4，粗品直接用於下一步反應。LCMS (ESI) m/z: 640.4 (M+1) +。 第四步： 將化合物5-4（250毫克）溶解在四氫呋喃（4毫升）和水（1毫升）混合溶液中，依次加入碳酸鉀（119.35毫克）和化合物1-5（26.05毫克），該反應在10攝氏度反應30分鐘。向反應混合物中加入飽和的碳酸氫鈉水溶液（15毫升），用乙酸乙酯（10毫升*3）萃取，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 （150*25mm*10μm）；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：28%-58%，2分鐘）純化，得到化合物5。 化合物5用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度: 二氧化碳臨界流體40%-40%，2.6分鐘；40分鐘）分離純化得到化合物5A和化合物5B。 化合物5A和化合物5B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物5A的保留時間為0.785min，e.e.值為99.30%；化合物5B的保留時間為1.090min，e.e.值為98.98%。 化合物5A (保留時間=0.785min)：LCMS (ESI) m/z: 694.1 (M+1) +。 化合物5B (保留時間=1.090min)：LCMS (ESI) m/z: 694.1 (M+1) +。 Example 5
Figure 02_image437
Step 1: To a solution of Intermediate A (500 mg) in tetrahydrofuran (10 mL) was added DIPEA (263.65 mg), PyBrOP (1.90 g) and compound 5-1 (1.63 g), and the reaction was carried out at 70 degrees Celsius for 15 hours . The reaction mixture was concentrated under reduced pressure and the resulting residue was passed through preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50mm*10 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 36% -66%, 18 min) purification to give compound 5-2. LCMS (ESI) m/z: 672.5(M+1) + . Step 2: To a solution of compound 5-2 (200 mg) in acetonitrile (6 mL) was added p-toluenesulfonic acid (76.91 mg) and N-chlorosuccinimide (79.52 mg) sequentially, under nitrogen protection , the mixture was reacted at 60 degrees Celsius for 1 hour. Saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-3. LCMS (ESI) m/z: 740.3 (M+1) + . The third step: Trifluoroacetic acid (924 mg) was added to a solution of compound 5-3 (200 mg) in dichloromethane (1 ml), and the reaction system was reacted at 10 degrees Celsius for 0.5 hour under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to obtain compound 5-4, and the crude product was directly used in the next reaction. LCMS (ESI) m/z: 640.4 (M+1) + . The fourth step: Compound 5-4 (250 mg) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (1 mL), potassium carbonate (119.35 mg) and compound 1-5 (26.05 mg) were added in sequence, and the reaction React at 10 degrees Celsius for 30 minutes. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the obtained residue was purified by preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 28%-58%, 2 minutes), Compound 5 is obtained. Compound 5 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 40%-40%, 2.6 minutes; 40 minutes) Compound 5A and Compound 5B. Compound 5A and compound 5B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: phase A was supercritical carbon dioxide, phase B was methanol (0.05% diethylamine); gradient (B% ): 40%-40%] obtained: the retention time of compound 5A is 0.785min, and the ee value is 99.30%; the retention time of compound 5B is 1.090min, and the ee value is 98.98%. Compound 5A (retention time=0.785 min): LCMS (ESI) m/z: 694.1 (M+1) + . Compound 5B (retention time=1.090 min): LCMS (ESI) m/z: 694.1 (M+1) + .

實施例6

Figure 02_image439
Figure 02_image441
第一步: 向化合物6-1 (18.45克)中加入180毫升N，N-二甲基甲醯胺和化合物6-2(18.56克)，然後在0-10攝氏度下分批加入氫化鈉(6.36克，質量百分比：60%)，加畢，反應液在0-10攝氏度下反應1小時。反應液在0-10攝氏度用飽和氯化銨溶液（200毫升）淬滅，然後加水（600毫升）和乙酸乙酯（400毫升）稀釋，水相用乙酸乙酯（400毫升）萃取一次，合併有機相用水（200毫升）和飽和食鹽水（200毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物通過柱層析純化(SiO 2，洗脫液：石油醚：乙酸乙酯 = 3:1 ~ 1:1)得到化合物6-3。LCMS (ESI) m/z: 313.0(m+1) +。 第二步: 向化合物6-3 (4.25克)的1,4-二氧六環（42.5毫升）溶液中加入化合物6-4(2.45克)，碳酸銫(8.85克)，Pd 2(dba) 3(1.24克)和Xantphos(1.57克)，反應體系用氮氣置換3次，氮氣保護下，反應液在100攝氏度反應12個小時。將反應液墊矽藻土過濾，濾餅每次用乙酸乙酯（30毫升*3）淋洗，濾液減壓濃縮得到殘留物，殘留物通過柱層析純化(SiO 2，洗脫液：石油醚：乙酸乙酯 = 3：1 ~ 1：1)得到化合物6-5。LCMS (ESI) m/z: 383.2(m+1) +。 第三步: 在0-10攝氏度下，向化合物6-5 (8.3克)的四氫呋喃（160毫升）溶液中，加入N-溴代琥珀醯亞胺(3.86克)，反應液在25攝氏度反應1個小時。將反應液用飽和亞硫酸鈉溶液（40毫升）淬滅，然後靜置分層，水相用乙酸乙酯（20毫升）萃取，合併有機相用飽和食鹽水（40毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經柱層析純化(洗脫劑：石油醚：乙酸乙酯 = 3：1)得到化合物6-6。LCMS (ESI) m/z: 463.0(m+3) +。 第四步: 向化合物6-6 (6.7克)的乙醇（90毫升）和水（30毫升）溶液中加入鐵粉(4.06克)和氯化銨(3.88克，反應液在80攝氏度下反應2個小時。將反應液墊矽藻土過濾，濾餅用乙酸乙酯（30毫升*3）洗滌，濾液減壓濃縮得到殘留物，殘留物用水（20毫升）和乙酸乙酯（100毫升）稀釋，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經柱層析純化(洗脫劑：石油醚：乙酸乙酯 = 2：1到1：1)得到化合物6-7。LCMS (ESI) m/z: 433.3(m+3) +。 第五步: 向化合物6-7(5.3克)中加入N，N-二甲基甲醯胺（50毫升），然後加入鋅粉(0.4克)，氰化鋅(1.16克)，DPPF (1.36克)，Pd 2(dba) 3(1.13克)和溴化鋅(138.37毫克)，然後將反應體系置換氮氣三次，在氮氣保護下，反應液在120攝氏度下反應12個小時。將反應液墊矽藻土過濾，濾餅用乙酸乙酯（30毫升*3）淋洗，濾液用水（200毫升）稀釋，然後靜置分層，水相用乙酸乙酯（50毫升）洗滌2次，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經柱層析純化(洗脫劑：石油醚：乙酸乙酯 = 2：1到 1：2)得到化合物6-8。LCMS (ESI) m/z: 378.4(m+1) +。 第六步: 向化合物6-8(4.3克)中加入濃硫酸（43毫升， w%=98%），反應液在60攝氏度下反應5個小時。將反應液緩慢加入到冰水（200毫升）中，然後將67克氫氧化鈉固體溶于200毫升水中，在0-10攝氏度，加入到上述混合物中，再用飽和碳酸氫鈉溶液調節混合液的pH值到8，將混合液墊矽藻土過濾，濾餅用乙酸乙酯（50毫升*3）淋洗，濾液靜置分層，水相用乙酸乙酯（50毫升）萃取，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物。將上述矽藻土濾餅每次用甲醇（50毫升）淋洗3次，濾液減壓濃縮得到化合物6-9。LCMS (ESI) m/z: 396.2(m+1) +。 第七步: 向化合物6-9 (2.07克)的N，N-二甲基甲醯胺（40毫升）溶液中加入羰基二咪唑(2.55克)和氫化鈉(628.12毫克，質量百分比：60%)，反應液在25攝氏度下反應0.5個小時。將4毫升濃鹽酸用200毫升水稀釋，將反應液緩慢加入到上述酸性溶液中，然後用飽和碳酸氫鈉溶液調節水相pH到8，靜置分層，水相用乙酸乙酯（100毫升*2）萃取，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物6-10。LCMS (ESI) m/z: 422.2(m+1) +。 第八步: 向化合物6-10 (1.62克，3.84毫莫耳，1當量)的乙腈（32毫升）溶液中加入N-氯代琥珀醯亞胺(1.03克，7.69毫莫耳，2當量)和對甲苯磺酸(1.32克，7.69毫莫耳，2當量)，反應液在60攝氏度下反應2小時。反應液冷卻至25°C，然後加入飽和亞硫酸鈉（10毫升）水溶液淬滅反應，然後將反應液減壓濃縮得到殘留物，殘留物用飽和碳酸氫鈉溶液（40毫升）和乙酸乙酯（40毫升）稀釋，水相用乙酸乙酯（40毫升）萃取，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經製備HPLC純化[柱型號: Phenomenex luna C18 150*40 mm* 15 μm；流動相：[水(0.225%甲酸)–乙腈]；梯度：20%-50%，10分鐘]得到化合物6-11。LCMS (ESI) m/z: 490.1(m+1) +。 第九步: 向化合物6-11 (490毫克)的N，N-二甲基乙醯胺（10毫升）溶液中加入化合物2-1 (1.60克)和PyBrOP (1.86克)，反應液在75攝氏度反應12小時，將反應液加到水（40毫升）中，然後用乙酸乙酯（20毫升*2）萃取，合併有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經製備HPLC純化[柱型號: Phenomenex luna C18 (250*70 mm，10 μm)；流動相：[水(0.225% 甲酸)–乙腈]；梯度：30%-60%，20分鐘]得到化合物6-12。LCMS (ESI) m/z: 672.4(m+1) +。 第十步: 向化合物6-12（450毫克）的二氯甲烷（4.5毫升）溶液中加入三氟乙酸（2.31克），反應液在25攝氏度反應半個小時。將反應液減壓濃縮得到殘留物，然後將殘留物用飽和碳酸氫鈉溶液（10毫升）和乙酸乙酯（10毫升）稀釋，水相用乙酸乙酯（5毫升）萃取，合併有機相用飽和食鹽水（5毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物6-13的三氟乙酸鹽。LCMS (ESI) m/z: 572.2(m+1) +。 第十一步: 向化合物6-13 (179毫克)的四氫呋喃（6毫升）和水（2毫升）溶液中加入碳酸鉀(86.43毫克)和化合物1-5 (28.30毫克)，反應液在25攝氏度反應0.5小時。將反應液減壓濃縮得到殘留物，然後將殘留物用飽和食鹽水（10毫升）和乙酸乙酯（20毫升）稀釋，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經製備HPLC [柱型號：Phenomenex Synergi C18 (150*25 mm* 10 μm)；流動相：[水(0.225%甲酸) –乙腈]；梯度：15%-45%，10分鐘]純化，得到的化合物6。 將化合物6通過製備SFC（柱型號：DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體45%-45%，45分鐘，50分鐘]分離得到化合物6A和6AM。 將6AM再通過製備SFC（柱型號：Daicel ChiralPak IG (250*30 mm，10 μm)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，4.8分鐘，45分鐘）分離純化得到化合物6B和6BM。 將6BM再通過製備SFC（柱型號：Daicel ChiralPak IG (250*30 mm，10 μm)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，4.8分鐘，45分鐘）分離純化得到化合物6C和化合物6D。 化合物6A經SFC檢測[柱型號：Chiralpak IJ-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物6A的保留時間為2.494min，e.e.值為96.34%。 化合物6B經SFC檢測[柱型號：Cellucoat 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物6B的保留時間為1.066min。 化合物6C和化合物6D經SFC檢測[柱型號：Chiralpak OJ-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物6C的保留時間為1.368min，e.e.值為100%；化合物6D的保留時間為1.492min，e.e.值為100%。 化合物6A（保留時間=2.494 min）： 1H NMR (400 MHz，CHLOROFORM- d) δ 8.47 (d， J= 4.9 Hz，1H)，7.39 (d， J= 7.1 Hz，1H)，7.04 (d， J= 4.8 Hz，1H)，6.89 (br d， J= 7.0 Hz，1H)，6.62 (br s，1H)，6.52-6.32 (m，2H)，5.82 (br d， J= 10.9 Hz，1H)，5.11-4.45 (m，2H)，4.43-4.12 (m，1H)，3.93-3.42 (m，3H)，3.31-2.86 (m，1H)，2.83-2.60 (m，1H)，2.15 (br s，3H)，1.44 (br s，3H)，1.24-1.10 (m，6H)；LCMS (ESI) m/z: 626.2 (M+1) +。 化合物6B（保留時間=1.606 min）： LCMS (ESI) m/z: 626.2 (M+1) +。 化合物6C（保留時間=1.368 min）： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.47 (d， J= 4.9 Hz，1H)，7.39 (d， J= 7.2 Hz，1H)，7.04 (d， J= 4.9 Hz，1H)，6.90 (d， J= 7.5 Hz，1H)，6.75-6.53 (m，1H)，6.52-6.34 (m，2H)，5.82 (dd， J= 1.7，10.4 Hz，1H)，5.05-4.15 (m，3H)，3.94-3.38 (m，3H)，3.32-2.95 (m，1H)，2.80-2.54 (m，1H)，2.16 (s，3H)，1.54-1.36 (m，3H)，1.24-1.08 (m，6H)；LCMS (ESI) m/z: 626.3 (M+1) +。 化合物6D（保留時間=1.492 min）： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.47 (d， J= 4.9 Hz，1H)，7.39 (d， J= 7.1 Hz，1H)，7.04 (d， J= 4.9 Hz，1H)，6.89 (s，1H)，6.75-6.53 (m，1H)，6.51-6.28 (m，2H)，5.82 (dd， J= 1.5，10.5 Hz，1H)，5.17-4.47 (m，2H)，4.43-4.12 (m，1H)，3.97-3.37 (m，3H)，3.34-2.92 (m，1H)，2.89-2.60 (m，1H)，2.11 (s，3H)，1.44 (br s，3H)，1.29-1.13 (m，6H)；LCMS (ESI) m/z: 626.2 (M+1) +。 Example 6
Figure 02_image439
Figure 02_image441
Step 1: To compound 6-1 (18.45 g) was added 180 ml of N,N-dimethylformamide and compound 6-2 (18.56 g), then sodium hydride ( 6.36 g, mass percentage: 60%), after the addition, the reaction solution was reacted at 0-10 degrees Celsius for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (200 mL) at 0-10°C, then diluted with water (600 mL) and ethyl acetate (400 mL). The aqueous phase was extracted once with ethyl acetate (400 mL), and the combined The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , eluent: petroleum ether: acetic acid) ethyl ester = 3:1 ~ 1:1) to obtain compound 6-3. LCMS (ESI) m/z: 313.0(m+1) + . Step 2: To a solution of compound 6-3 (4.25 g) in 1,4-dioxane (42.5 mL) was added compound 6-4 (2.45 g), cesium carbonate (8.85 g), Pd 2 (dba) 3 (1.24 g) and Xantphos (1.57 g), the reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 100 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3) each time, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (SiO 2 , eluent: petroleum ether: ethyl acetate = 3: 1 ~ 1: 1) to obtain compound 6-5. LCMS (ESI) m/z: 383.2(m+1) + . The third step: N-bromosuccinimide (3.86 g) was added to a solution of compound 6-5 (8.3 g) in tetrahydrofuran (160 ml) at 0-10 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius for 1 Hours. The reaction solution was quenched with saturated sodium sulfite solution (40 mL), then allowed to stand for layers, the aqueous phase was extracted with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound 6-6. LCMS (ESI) m/z: 463.0(m+3) + . Step 4: To a solution of compound 6-6 (6.7 g) in ethanol (90 ml) and water (30 ml), iron powder (4.06 g) and ammonium chloride (3.88 g) were added, and the reaction solution was reacted at 80 degrees Celsius for 2 The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (30 mL*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was diluted with water (20 mL) and ethyl acetate (100 mL). , the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 to 1:1) Compound 6-7 was obtained. LCMS (ESI) m/z: 433.3(m+3) + . Fifth step: N,N-dimethylformamide was added to compound 6-7 (5.3 g). amine (50 ml), then zinc powder (0.4 g), zinc cyanide (1.16 g), DPPF (1.36 g), Pd 2 (dba) 3 (1.13 g) and zinc bromide (138.37 mg) were added, then the The reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 120 degrees Celsius for 12 hours under the protection of nitrogen. ml), and then allowed to stand to separate the layers. The aqueous phase was washed twice with ethyl acetate (50 ml), the combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. , the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1 to 1:2) to give compound 6-8. LCMS (ESI) m/z: 378.4 (m+1) + . Step 6: Concentrated sulfuric acid (43 ml, w%=98%) was added to compound 6-8 (4.3 g), and the reaction solution was reacted at 60 degrees Celsius for 5 hours. The reaction solution was slowly added to ice water (200 ml) ), then dissolve 67 g of solid sodium hydroxide in 200 ml of water, add it to the above mixture at 0-10 degrees Celsius, and then adjust the pH of the mixture to 8 with saturated sodium bicarbonate solution, and put the mixture into a silicon The filter cake was rinsed with ethyl acetate (50 mL*3), the filtrate was left to stand for layers, the aqueous phase was extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the residue. The above-mentioned diatomaceous earth filter cake is rinsed 3 times with methanol (50 ml) each time, and the filtrate is concentrated under reduced pressure to obtain compound 6-9. LCMS (ESI) m/ z: 396.2(m+1) + . Seventh step: To a solution of compound 6-9 (2.07 g) in N,N-dimethylformamide (40 mL) was added carbonyldiimidazole (2.55 g) and hydrogenated Sodium (628.12 mg, mass percentage: 60%), the reaction solution was reacted at 25 degrees Celsius for 0.5 hours. 4 ml of concentrated hydrochloric acid was mixed with 200 ml of Diluted with water, the reaction solution was slowly added to the above acidic solution, then the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, the layers were left to stand, the aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined. Washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-10. LCMS (ESI) m/z: 422.2(m+1) + . Step 8: To a solution of compound 6-10 (1.62 g, 3.84 mmol, 1 equiv) in acetonitrile (32 mL) was added N-chlorosuccinimide (1.03 g, 7.69 mmol, 2 equiv) and p-toluenesulfonic acid (1.32 g, 7.69 mmol, 2 equiv), and the reaction solution was reacted at 60 degrees Celsius for 2 hours. The reaction solution was cooled to 25°C, then a saturated aqueous solution of sodium sulfite (10 mL) was added to quench the reaction, and then the reaction solution was concentrated under reduced pressure to obtain a residue, which was treated with saturated sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL). mL), the aqueous phase was extracted with ethyl acetate (40 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC [ Column type: Phenomenex luna C18 150*40 mm* 15 μm; mobile phase: [water (0.225% formic acid) – acetonitrile]; gradient: 20%-50%, 10 minutes] to give compound 6-11. LCMS (ESI) m/z: 490.1(m+1) + . Step 9: Compound 2-1 (1.60 g) and PyBrOP (1.86 g) were added to a solution of compound 6-11 (490 mg) in N,N-dimethylacetamide (10 mL), and the reaction solution was heated at 75 The reaction was carried out at degrees Celsius for 12 hours. The reaction solution was added to water (40 mL), then extracted with ethyl acetate (20 mL*2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave a residue, which was purified by preparative HPLC [column size: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (0.225% formic acid)–acetonitrile]; gradient: 30%-60 %, 20 min] to obtain compound 6-12. LCMS (ESI) m/z: 672.4(m+1) + . The tenth step: Trifluoroacetic acid (2.31 g) was added to a solution of compound 6-12 (450 mg) in dichloromethane (4.5 ml), and the reaction solution was reacted at 25 degrees Celsius for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL), the aqueous phase was extracted with ethyl acetate (5 mL), and the organic phases were combined with Washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 6-13. LCMS (ESI) m/z: 572.2(m+1) + . Step 11: To a solution of compound 6-13 (179 mg) in tetrahydrofuran (6 mL) and water (2 mL) were added potassium carbonate (86.43 mg) and compound 1-5 (28.30 mg), the reaction solution was at 25°C The reaction was carried out for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with saturated brine (10 mL) and ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The product was purified by preparative HPLC [column type: Phenomenex Synergi C18 (150*25 mm*10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 15%-45%, 10 minutes], the obtained Compound 6. Compound 6 was prepared by preparative SFC (column type: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 45 minutes, 50 minutes ] Compounds 6A and 6AM were obtained by separation. 6AM was then passed through preparative SFC (column type: Daicel ChiralPak IG (250*30 mm, 10 μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40 %, 4.8 minutes, 45 minutes) to separate and purify compounds 6B and 6BM. The 6BM was then passed through preparative SFC (column type: Daicel ChiralPak IG (250*30 mm, 10 μm), mobile phase: ethanol (0.1% ammonia water), gradient : carbon dioxide critical fluid 40%-40%, 4.8 minutes, 45 minutes) separation and purification to obtain compound 6C and compound 6D. Compound 6A was detected by SFC [column model: Chiralpak IJ-3 50 × 4.6 mm ID, 3 μm; mobile phase: A The phase is supercritical carbon dioxide, and the phase B is ethanol (0.05% diethylamine); gradient (B%): 5%-40%] to obtain: the retention time of compound 6A is 2.494min, and the ee value is 96.34%. SFC detection [column type: Cellucoat 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient (B%): 5%-40%] obtained : The retention time of compound 6B is 1.066min. The compound 6C and compound 6D are detected by SFC [column type: Chiralpak OJ-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05 μm in phase B) % diethylamine); gradient (B%): 5%-40%] obtained: compound 6C has a retention time of 1.368 min and an ee value of 100%; compound 6D has a retention time of 1.492 min and an ee value of 100%. Compound 6A (retention time = 2.494 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.47 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 6.89 (br d, J = 7.0 Hz, 1H), 6.62 (br s, 1H), 6.52-6.32 (m, 2H), 5.82 (br d, J = 10.9 Hz, 1H) , 5.11-4.45 (m, 2H), 4.43-4.12 ( m, 1H), 3.93-3.42 (m, 3H), 3.31-2.86 (m, 1H), 2.83-2.60 (m, 1H), 2.15 (br s, 3H), 1.44 (br s, 3H), 1.24- 1.10 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) + . Compound 6B (retention time = 1.606 min): LCMS (ESI) m/z: 626.2 (M+1) + . Compound 6C (retention time = 1.368 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.47 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.75-6.53 (m, 1H), 6.52-6.34 (m, 2H), 5.82 (dd, J = 1.7, 10.4 Hz, 1H) ), 5.05-4.15 (m, 3H), 3.94-3.38 (m, 3H), 3.32-2.95 (m, 1H), 2.80-2.54 (m, 1H), 2.16 (s, 3H), 1.54-1.36 (m , 3H), 1.24-1.08 (m, 6H); LCMS (ESI) m/z: 626.3 (M+1) + . Compound 6D (retention time = 1.492 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.47 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 7.1 Hz, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.89 (s, 1H), 6.75-6.53 (m, 1H), 6.51-6.28 (m, 2H), 5.82 (dd, J = 1.5, 10.5 Hz, 1H), 5.17-4.47 (m, 2H), 4.43-4.12 (m, 1H), 3.97-3.37 (m, 3H), 3.34-2.92 (m, 1H), 2.89-2.60 (m, 1H), 2.11 (s, 3H), 1.44 (br s, 3H), 1.29-1.13 (m, 6H); LCMS (ESI) m/z: 626.2 (M+1) + .

實施例7

Figure 02_image443
第一步： 在0-10攝氏度下，向化合物7-1 （8克）的二氯甲烷（80毫升）溶液中滴加化合物7-2（8.01克），加畢，反應液25攝氏度下反應12小時。LCMS檢測原料剩餘，然後補加化合物7-2（3.34克）到反應體系中，在25攝氏度下反應12小時。反應液減壓濃縮得到殘留物，殘留物用二氯甲烷（50毫升）和飽和碳酸氫鈉水溶液（100毫升）稀釋，靜置分層，水相用二氯甲烷（50毫升）萃取，合併有機相用飽和食鹽水（40毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-3。LCMS (ESI) m/z: 264.3 (m+1) +。 第二步： 向化合物7-3 （14克）的乙腈（140毫升）溶液中加入碳酸銫（17.30克），然後在0-10攝氏度加入化合物7-4（9.11克），反應液在25攝氏度反應1小時。將反應液墊矽藻土過濾，濾餅每次用乙酸乙酯（30毫升*3）淋洗，然後將濾液減壓濃縮得到化合物7-5。LCMS (ESI) m/z: 385.8 (m+1) +。 第三步： 向化合物7-5（28克）的三氟乙醇（140毫升）溶液中加入三乙胺（14.69克），反應液在80攝氏度反應12小時。將反應液減壓濃縮得到殘留物，然後將殘留物用乙酸乙酯（150毫升）和水（100毫升）稀釋，用1莫耳/升的鹽酸水溶液調節水相pH值到1，然後靜置分層，水相用乙酸乙酯（50毫升）萃取，合併有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-6。LCMS (ESI) m/z: 354.0 (m+1) +。 第四步： 向化合物7-6（18.3克）的第三丁醇（183毫升）溶液中加入4A分子篩（18.3克）和三乙胺（10.47克），然後在80攝氏度攪拌2小時。將DPPA（15.99克, 98% 純度）加入到反應體系中，反應液在80攝氏度反應1小時。將反應液過濾濾餅每次用乙酸乙酯（50毫升*3）洗滌，濾液減壓濃縮得到殘留物，殘留物用10%檸檬酸溶液（150毫升）和乙酸乙酯（150毫升）稀釋，水相用乙酸乙酯（100毫升）萃取，合併有機相用飽和食鹽水（50升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-7。LCMS (ESI) m/z: 369.2(m+1-56) +。 第五步： 向化合物7-7（28克）的甲醇（140毫升）溶液中加入鹽酸甲醇溶液（4 莫耳/升，140.00毫升），反應液在40攝氏度反應2小時。將反應液減壓濃縮得到殘留物，將殘留物用飽和碳酸氫鈉溶液（200毫升）和乙酸乙酯（200毫升）稀釋，有機相用飽和食鹽水（100毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物通過柱層析純化（SiO 2, 石油醚：乙酸乙酯 = 4:1）得到化合物7-8。LCMS (ESI) m/z: 325.0 (m+1) +。 第六步： 向化合物7-8 （4.35克）的三級-丁醇（45毫升）溶液中加入化合物A-2（4.30克）, 碳酸銫（8.73克）和BrettPhos Pd（1.21克），反應體系用氮氣置換3次，並在氮氣保護下，在100攝氏度反應12小時。將反應液墊矽藻土過濾，濾餅每次用乙酸乙酯（50毫升*3）洗滌，濾液減壓濃縮得到殘留物，殘留物經柱層析純化（SiO 2, 石油醚/乙酸乙酯=10:1 ~ 5:1）得到化合物7-9。LCMS (ESI) m/z: 458.3 (m+1) +。 第七步： 在0-10攝氏度下，向化合物7-9（4.52克）的二氯甲烷（45毫升）溶液中，加入N-溴代丁二醯亞胺（1.76克），反應液在0-10攝氏度反應1小時，將反應液用飽和亞硫酸鈉溶液（20毫升）淬滅，然後靜置分層，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-10。LCMS (ESI) m/z: 538.2 (m+3) +。 第八步： 向化合物7-10（4.83克）的N,N-二甲基甲醯胺（50 毫升）溶液中加入鋅粉（0.33克），氰化鋅（0.86克），DPPF(997.78 毫克)，Pd 2(dba) 3（824.06毫克）和溴化鋅（101.33毫克），然後將反應體系置換氮氣三次，在氮氣保護下，反應液在120攝氏度反應12小時。將反應液墊矽藻土過濾，濾餅用乙酸乙酯（30毫升*3）洗滌，濾液用水（250毫升）稀釋，然後靜置分層，水相用乙酸乙酯（50毫升*2）洗滌，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物經柱層析純化（洗脫劑： 石油醚：乙酸乙酯 = 5:1 到 3:1）得到化合物7-11。LCMS (ESI) m/z: 483.2 (m+1) +。 第九步： 向化合物7-11（2.48克）中加入濃硫酸（25毫升），反應液在60攝氏度下反應12小時，將反應液緩慢加入到冰水（80毫升）中，然後將氫氧化鈉固體（32克）溶於（100毫升）水中，然後在0-10攝氏度加入到上述混合物中，再用碳酸氫鈉固體調節混合液的pH到8，將混合液墊矽藻土過濾，濾餅用乙酸乙酯（50毫升*2）洗滌，濾液靜置分層，水相用乙酸乙酯（50毫升）萃取，合併有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-12。LCMS (ESI) m/z: 501.2 (m+1) +。 第十步： 向化合物7-12（1.9克）的無水四氫呋喃（40毫升）溶液中加入羰基二咪唑（1.85克）和 氫化鈉 （455.23毫克，質量百分比：60%），反應液在25攝氏度下反應1小時，將濃鹽酸（2毫升）用水（40毫升）稀釋，將反應液緩慢加入到上述酸性溶液中，然後用飽和碳酸氫鈉溶液（40毫升）中和，靜置分層，水相用乙酸乙酯（40毫升）萃取，合併有機相用飽和食鹽水（40毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-13。LCMS (ESI) m/z: 527.2 (m+1) +。 第十一步： 向化合物7-13（500 毫克）的四氫呋喃（5毫升）溶液中加入化合物1-1（1.77克）和PyBrOP（2.21克），反應液在60攝氏度下反應12小時，將反應液過濾，濾餅用乙酸乙酯（5毫升*3）洗滌，濾液減壓濃縮得到殘留物，殘留物經製備HPLC [柱型號: Phenomenex luna c18 250 mm*100 mm*10 μm; 流動相: [水(0.225%甲酸)–乙腈]；梯度: 40%-60%，20分鐘]純化得到化合物7-14。LCMS (ESI) m/z: 695.3 (m+1) +。 第十二步： 向化合物7-14（1.65克）的二氯甲烷（15毫升）溶液中加入三氟乙酸（7.70克），反應液在25攝氏度下反應半小時，將反應液減壓濃縮得到殘留物，然後將殘留物用飽和碳酸氫鈉溶液（20毫升）和乙酸乙酯（40毫升）稀釋，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物7-15的三氟乙酸鹽。LCMS (ESI) m/z: 595.1 (m+1) +。 第十三步： 在0-10攝氏度下，向化合物7-15（1.47克）的四氫呋喃（14毫升）和水（4毫升）溶液中加入碳酸鉀（341.47 毫克），然後將化合物1-5溶于無水四氫呋喃（2毫升）中再加入到上述反應液中，反應體系在25°C反應半個小時。將反應液減壓濃縮得到殘留物，然後將殘留物用飽和食鹽水（20毫升）和乙酸乙酯（40毫升）稀釋，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，殘留物通過製備HPLC [柱型號: Phenomenex luna C18 （150*40 mm* 15 μm）；流動相: [水 (0.225% 甲酸) –乙腈]；乙腈%: 25%-55%, 10分鐘]純化，得到化合物7。LCMS (ESI) m/z: 649.4 (m+1) +。 Example 7
Figure 02_image443
The first step: Compound 7-2 (8.01 g) was added dropwise to a solution of compound 7-1 (8 g) in dichloromethane (80 mL) at 0-10 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius after the addition was completed. 12 hours. The remaining raw materials were detected by LCMS, and then compound 7-2 (3.34 g) was added to the reaction system, and the reaction was carried out at 25 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (100 mL), and the layers were allowed to stand. The aqueous phase was extracted with dichloromethane (50 mL), and the organic The phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-3. LCMS (ESI) m/z: 264.3 (m+1) + . Step 2: To a solution of compound 7-3 (14 g) in acetonitrile (140 ml) was added cesium carbonate (17.30 g), then compound 7-4 (9.11 g) was added at 0-10 degrees Celsius, and the reaction solution was at 25 degrees Celsius React for 1 hour. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3) each time, and then the filtrate was concentrated under reduced pressure to obtain compound 7-5. LCMS (ESI) m/z: 385.8 (m+1) + . The third step: Triethylamine (14.69 g) was added to a solution of compound 7-5 (28 g) in trifluoroethanol (140 ml), and the reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with ethyl acetate (150 mL) and water (100 mL), and the pH of the aqueous phase was adjusted to 1 with 1 mol/L aqueous hydrochloric acid solution, and then allowed to stand. The layers were separated, the aqueous phase was extracted with ethyl acetate (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-6. LCMS (ESI) m/z: 354.0 (m+1) + . Step 4: To a solution of compound 7-6 (18.3 g) in tertiary butanol (183 ml) were added 4A molecular sieves (18.3 g) and triethylamine (10.47 g), followed by stirring at 80 degrees Celsius for 2 hours. DPPA (15.99 g, 98% purity) was added to the reaction system, and the reaction solution was reacted at 80 degrees Celsius for 1 hour. The filter cake of the reaction solution was washed with ethyl acetate (50 mL*3) each time, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with 10% citric acid solution (150 mL) and ethyl acetate (150 mL), The aqueous phase was extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (50 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-7. LCMS (ESI) m/z: 369.2(m+1-56) + . The fifth step: To the methanol (140 mL) solution of compound 7-7 (28 g) was added hydrochloric acid methanol solution (4 mol/L, 140.00 mL), and the reaction solution was reacted at 40 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a residue, which was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=4:1) to give compound 7-8. LCMS (ESI) m/z: 325.0 (m+1) + . The sixth step: Compound A-2 (4.30 g), cesium carbonate (8.73 g) and BrettPhos Pd (1.21 g) were added to a solution of compound 7-8 (4.35 g) in tertiary-butanol (45 ml) to react The system was replaced with nitrogen three times and reacted at 100 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, and the filter cake was washed with ethyl acetate (50 mL*3) each time. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate). =10:1 ~ 5:1) to obtain compound 7-9. LCMS (ESI) m/z: 458.3 (m+1) + . The seventh step: at 0-10 degrees Celsius, to a solution of compound 7-9 (4.52 g) in dichloromethane (45 ml) was added N-bromosuccinimide (1.76 g), the reaction solution was at 0 -10 degrees Celsius for 1 hour, the reaction solution was quenched with saturated sodium sulfite solution (20 mL), then left to stand for layers, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compounds 7-10. LCMS (ESI) m/z: 538.2 (m+3) + . Step 8: To a solution of compound 7-10 (4.83 g) in N,N-dimethylformamide (50 ml) was added zinc powder (0.33 g), zinc cyanide (0.86 g), DPPF (997.78 mg) ), Pd 2 (dba) 3 (824.06 mg) and zinc bromide (101.33 mg), then the reaction system was replaced with nitrogen three times, and the reaction solution was reacted at 120 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate (30 mL*3), the filtrate was diluted with water (250 mL), then left to stand for separation, and the aqueous phase was washed with ethyl acetate (50 mL*2). , the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1) to obtain compound 7-11. LCMS (ESI) m/z: 483.2 (m+1) + . The ninth step: Concentrated sulfuric acid (25 ml) was added to compound 7-11 (2.48 g), the reaction solution was reacted at 60 degrees Celsius for 12 hours, the reaction solution was slowly added to ice water (80 ml), and then hydrogenated The sodium solid (32 g) was dissolved in (100 ml) water, and then added to the above mixture at 0-10 degrees Celsius. The pH of the mixture was adjusted to 8 with sodium bicarbonate solid, and the mixture was filtered through a pad of celite. The cake was washed with ethyl acetate (50 mL*2), the filtrate was left to stand for layers, the aqueous phase was extracted with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. , concentrated under reduced pressure to obtain compound 7-12. LCMS (ESI) m/z: 501.2 (m+1) + . The tenth step: To a solution of compound 7-12 (1.9 g) in anhydrous tetrahydrofuran (40 ml), carbonyldiimidazole (1.85 g) and sodium hydride (455.23 mg, mass percentage: 60%) were added, and the reaction solution was heated at 25 degrees Celsius. The reaction was carried out for 1 hour, concentrated hydrochloric acid (2 ml) was diluted with water (40 ml), the reaction solution was slowly added to the above acidic solution, then neutralized with saturated sodium bicarbonate solution (40 ml), and the layers were left to stand. Extracted with ethyl acetate (40 mL), the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-13. LCMS (ESI) m/z: 527.2 (m+1) + . The eleventh step: Compound 1-1 (1.77 g) and PyBrOP (2.21 g) were added to a solution of compound 7-13 (500 mg) in tetrahydrofuran (5 ml), and the reaction solution was reacted at 60 degrees Celsius for 12 hours. The liquid was filtered, the filter cake was washed with ethyl acetate (5 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was subjected to preparative HPLC [Column type: Phenomenex luna c18 250 mm*100 mm*10 μm; Mobile phase: [ Water (0.225% formic acid)-acetonitrile]; gradient: 40%-60%, 20 min] purification gave compound 7-14. LCMS (ESI) m/z: 695.3 (m+1) + . The twelfth step: Trifluoroacetic acid (7.70 g) was added to a solution of compound 7-14 (1.65 g) in dichloromethane (15 ml), the reaction solution was reacted at 25 degrees Celsius for half an hour, and the reaction solution was concentrated under reduced pressure to obtain The residue was then diluted with saturated sodium bicarbonate solution (20 mL) and ethyl acetate (40 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The trifluoroacetate salt of compounds 7-15. LCMS (ESI) m/z: 595.1 (m+1) + . Thirteenth step: Potassium carbonate (341.47 mg) was added to a solution of compound 7-15 (1.47 g) in tetrahydrofuran (14 mL) and water (4 mL) at 0-10 degrees Celsius, followed by dissolving compound 1-5. In anhydrous tetrahydrofuran (2 ml), it was added to the above reaction solution, and the reaction system was reacted at 25 ° C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then diluted with saturated brine (20 mL) and ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The compound was purified by preparative HPLC [column type: Phenomenex luna C18 (150*40 mm*15 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 25%-55%, 10 minutes] to give Compound 7. LCMS (ESI) m/z: 649.4 (m+1) + .

實施例8

Figure 02_image445
第一步： 零下78攝氏度下，向化合物8-1(7.0克)的四氫呋喃（70毫升）溶液中加入正丁基鋰（2.5莫耳/升，15.3毫升），反應液在零下78攝氏度下攪拌1小時，然後將反應液倒入乾冰中，反應液用1莫耳/升的鹽酸酸化，然後用乙酸乙酯（150毫升*2）萃取，所得有機相經飽和食鹽水(150毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-2。粗品直接用於下一步。 第二步： 室溫下向化合物8-2 (8.5克)的第三丁醇（90毫升）溶液中加入4A分子篩（10.0克）和三乙胺(7.58克)，反應液在80攝氏度條件下攪拌1小時，然後加入疊氮磷酸二苯酯（10.82克），反應液在80攝氏度條件下攪拌11小時，反應液過濾，濾餅用乙酸乙酯（200毫升*3）洗滌，濾液濃縮得殘餘物。殘餘物用乙酸乙酯(250毫升)稀釋，經10%檸檬酸(200毫升*2)、飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-3。粗品直接用於下一步。 第三步： 室溫下將化合物8-3（11.0克）溶於鹽酸乙酸乙酯（4.0莫耳/升，110.0毫升）中，反應液在室溫條件下攪拌0.5小時，反應液濃縮得中間體8-4。粗品直接用於下一步。 第四步： 室溫下將化合物8-4 (9.0克，鹽酸鹽)和化合物8-5（6.29克）溶於二氯甲烷（90毫升）中，反應液在室溫條件下攪拌12小時，反應液濃縮得化合物8-6。粗品直接用於下一步。LCMS (ESI) m/z: 298.0(M+1) +。 第五步： 室溫下將化合物8-6 (10.0克)，化合物8-7（5.92克）和碳酸銫(10.93.克)溶於乙腈（120毫升）中，反應液在室溫條件下攪拌1小時，反應液倒入水（250毫升）中，然後用乙酸乙酯（250毫升*3）萃取，所得有機相經飽和食鹽水（250毫升）洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-8。粗品直接用於下一步。LCMS (ESI) m/z: 420.0(M+1) +。 第六步： 室溫下將化合物8-8 (14.0克)和三乙胺（6.74克）溶於三氟乙醇（140毫升）中，反應液在80攝氏度下攪拌12小時，反應液用1莫耳/升的鹽酸（250毫升）酸化，然後用乙酸乙酯（250毫升*2）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-9。粗品直接用於下一步。LCMS (ESI) m/z: 388.0(M+1) +。 第七步： 室溫下向化合物8-9 (13.0克)的第三丁醇（130毫升）溶液中加入4Å分子篩（13.0克）和三乙胺(6.78克)，反應液在80攝氏度攪拌1小時，然後加入疊氮磷酸二苯酯（9.68克），反應液在80攝氏度攪拌11小時，反應液過濾，濾餅用乙酸乙酯（250毫升*3）洗滌，濾液濃縮得殘餘物。殘餘物用乙酸乙酯(250毫升)稀釋，經10%檸檬酸(250毫升*2)、飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-10。產物無需純化直接用於下一步。LCMS (ESI) m/z: 403.1(M+1-56) +。 第八步： 室溫下將化合物8-10（15.0克）溶於鹽酸乙酸乙酯（4.0莫耳/升，100.0毫升）中，反應液在室溫條件下攪拌0.5小時，反應液濃縮得殘餘物，殘餘物經反相色譜柱分離（柱型號:Welch Ultimate XB_C18 （20-40μm; 120 A）， 流動相:[水(0.05%甲酸)-乙腈]; 梯度: 15-70%，30分鐘;70%，30分鐘）得化合物8-11。 1H NMR (400 MHz, DMSO- d 6 ) δ 8.47-8.37 (m, 1H), 7.05-6.97 (m, 1H), 6.59-6.50 (m, 1H), 6.46-6.25 (m, 2H)。LCMS (ESI) m/z: 359.0(M+1) +。 第九步： 室溫下向化合物8-11 (2.5克)的三級-丁醇（30毫升）溶液中加入化合物A-2(2.24克)，BrettPhos Pd G3(631.13毫克)和碳酸銫(4.54克)，反應液在105攝氏度，氮氣保護條件下反應3小時，反應液過濾，濾餅用乙酸乙酯（150毫升*3）洗滌，濾液濃縮得殘餘物，殘餘物經反相色譜柱分離（柱型號: Welch Ultimate XB_C18 20-40μm; 120 A; 流動相: [水(0.0 5%甲酸)-乙腈]; 梯度: 60%，10分鐘）得化合物8-12。LCMS (ESI) m/z: 492.1(M+1) +。 第十步： 在0攝氏度下，向化合物8-12(1.9克)的二氯甲烷（20毫升）溶液中加入N-溴代丁二醯亞胺（686.96毫克），反應液在0攝氏度條件下攪拌0.5小時，反應液在0攝氏度下用飽和亞硫酸鈉（20毫升）淬滅，經飽和食鹽水(20毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得殘餘物，向殘餘物中加入甲醇（10毫升），室溫攪拌0.5小時，混合物過濾，濾餅乾燥得到化合物8-13。LCMS (ESI) m/z: 572.0(M+3) +。 第十一步： 室溫下向化合物8-13(0.8克)的N,N-二甲基甲醯胺（5毫升）溶液中加入鋅粉(54.95毫克)，氰化鋅(131.58毫克)，溴化鋅(15.77毫克)，1,1’-雙(二苯基膦)二茂鐵(155.30毫克)和三(二亞苄基丙酮)二鈀(128.26毫克)，反應液在120攝氏度，氮氣保護條件下攪拌2小時，反應液過濾，濾餅用乙酸乙酯（150毫升*3）洗滌，濾液濃縮得殘餘物，向殘餘物中加入甲醇（10毫升），室溫攪拌0.5小時，混合物過濾，濾餅乾燥得到化合物8-14。LCMS (ESI) m/z: 517.3(M+1) +。 第十二步： 室溫下將化合物8-14（0.6克）溶於濃硫酸（12.0毫升）中，反應液在60攝氏度下攪拌4小時，反應液緩慢滴加到2莫耳/升的氫氧化鈉（250毫升）水溶液中，然後用乙酸乙酯（250毫升*2）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-15。產物無需純化直接用於下一步。LCMS (ESI) m/z: 535.3(M+1) +。 第十三步： 室溫下向化合物8-15 (0.5克)的四氫呋喃（25毫升）溶液中加入氫化鈉（186.80毫克，質量百分比：60%）和1,1-羰基二咪唑(454.37毫克)，反應液在室溫條件下攪拌0.5小時反應液倒入飽和氯化銨（150毫升）水溶液中淬滅，然後用乙酸乙酯（150毫升*3）萃取，所得有機相經飽和食鹽水(150毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得殘餘物，向殘餘物中加入甲醇（5毫升），室溫攪拌0.5小時，混合物過濾，濾餅乾燥得到化合物8-16。LCMS (ESI) m/z: 561.3(M+1) +。 第十四步： 室溫下向化合物8-16 (0.3克)和化合物1-1(497.74毫克)的四氫呋喃（10毫升）溶液中加入N,N-二異丙基乙胺（345.39毫克）和三吡咯烷基溴化鏻六氟磷酸鹽(1.25克)，反應液在80攝氏度下攪拌24小時，反應液倒入水（150毫升）中，然後用乙酸乙酯（150毫升*3）萃取，所得有機相經飽和食鹽水(150毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得化合物8-17。產物無需純化直接用於下一步。LCMS (ESI) m/z: 729.4(M+1) +。 第十五步： 室溫下向化合物8-17(0.3克) 的二氯甲烷（9毫升）溶液中加入三氟乙酸（13.86克），反應液在室溫條件下攪拌0.5小時，反應液濃縮得化合物8-18的三氟乙酸鹽。產物無需純化直接用於下一步。LCMS (ESI) m/z: 629.4(M+1) +。 第十六步： 在0攝氏度下，向化合物8-18(0.2克)的四氫呋喃（10毫升）和水（2毫升）溶液中加入碳酸鉀（219.58毫克），然後加入化合物1-5(28.76毫克)，反應液在0攝氏度下攪拌0.5小時，反應液倒入水（50毫升）中，然後用乙酸乙酯（50毫升*3）萃取，所得有機相經飽和食鹽水(50毫升)洗滌後用無水硫酸鈉乾燥，減壓濃縮得殘餘物，殘餘物經製備色譜柱分離（柱型號:Phenomenex Gemini-NX C18 （75*30mm*3μm），流動相:[水(0.225%甲酸)-乙腈]; 乙腈%: 32%-62%，7分鐘）純化，得到的化合物8。 化合物8再通過製備SFC（柱型號:DAICEL CHIRALCEL OD(250mm*30mm,10um;流動相:[甲醇(0.1%氨水)]; 梯度：二氧化碳臨界流體: 30%-30%，3.3分鐘,50分鐘）後都經製備色譜柱分離（柱型:Phenomenex Gemini-NX C18 75*30mm*3μm;流動相:[水(0.225%甲酸)-乙腈]; 乙腈%: 32%-62%，7分鐘）得化合物8A和化合物8B。 化合物8A（保留時間=1.688 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.51-8.37 (m, 1H), 8.37-8.30 (m, 1H), 7.41-7.28 (m, 1H), 7.16-7.05 (m, 1H), 6.92-6.77 (m, 1H), 6.28-6.12 (m, 1H), 5.83-5.69 (m, 1H), 4.02-3.66 (m, 9H), 2.02-1.96 (m, 3H), 1.07-1.04 (m, 3H), 1.01-0.95 (m, 3H)。LCMS (ESI) m/z: 683.4(M+1) +。 化合物8B（保留時間=1.808 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.49-8.38 (m, 1H), 8.36-8.31 (m, 1H), 7.42-7.28 (m, 1H), 7.17-7.04 (m, 1H), 6.92-6.76 (m, 1H), 6.28-6.08 (m, 1H), 5.84-5.63 (m, 1H), 4.03-3.68 (m, 9H), 2.04-1.94 (m, 3H), 1.12-1.03 (m, 3H), 1.01-0.93 (m, 3H)。LCMS (ESI) m/z: 683.4(M+1) +。 Example 8
Figure 02_image445
Step 1: Add n-butyllithium (2.5 mol/L, 15.3 mL) to a solution of compound 8-1 (7.0 g) in tetrahydrofuran (70 mL) at minus 78 degrees Celsius, and the reaction solution is stirred at minus 78 degrees Celsius After 1 hour, the reaction solution was poured into dry ice, the reaction solution was acidified with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate (150 mL*2). The obtained organic phase was washed with saturated brine (150 mL). Dry with anhydrous sodium sulfate and concentrate under reduced pressure to obtain compound 8-2. The crude product was used directly in the next step. The second step: 4A molecular sieve (10.0 g) and triethylamine (7.58 g) were added to a solution of compound 8-2 (8.5 g) in 3-butanol (90 ml) at room temperature, and the reaction solution was heated at 80 degrees Celsius. Stir for 1 hour, then add diphenylphosphoryl azide (10.82 g), the reaction solution was stirred at 80 degrees Celsius for 11 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (200 ml*3), and the filtrate was concentrated to obtain a residue thing. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (200 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-3. The crude product was used directly in the next step. The third step: Compound 8-3 (11.0 g) was dissolved in ethyl acetate hydrochloride (4.0 mol/L, 110.0 mL) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain an intermediate Body 8-4. The crude product was used directly in the next step. The fourth step: Compound 8-4 (9.0 g, hydrochloride) and compound 8-5 (6.29 g) were dissolved in dichloromethane (90 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours , the reaction solution was concentrated to obtain compound 8-6. The crude product was used directly in the next step. LCMS (ESI) m/z: 298.0(M+1) + . The fifth step: Compound 8-6 (10.0 g), compound 8-7 (5.92 g) and cesium carbonate (10.93 g) were dissolved in acetonitrile (120 ml) at room temperature, and the reaction solution was stirred at room temperature For 1 hour, the reaction solution was poured into water (250 mL), and then extracted with ethyl acetate (250 mL*3). The obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compounds 8-8. The crude product was used directly in the next step. LCMS (ESI) m/z: 420.0(M+1) + . The sixth step: Compound 8-8 (14.0 g) and triethylamine (6.74 g) were dissolved in trifluoroethanol (140 ml) at room temperature, and the reaction solution was stirred at 80 degrees Celsius for 12 hours. Acidified with 1/L hydrochloric acid (250 mL), then extracted with ethyl acetate (250 mL*2), the obtained organic phase was washed with saturated brine (250 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8- 9. The crude product was used directly in the next step. LCMS (ESI) m/z: 388.0(M+1) + . The seventh step: 4Å molecular sieve (13.0 g) and triethylamine (6.78 g) were added to a solution of compound 8-9 (13.0 g) in 3-butanol (130 ml) at room temperature, and the reaction solution was stirred at 80 degrees Celsius for 1 After 1 hour, diphenylphosphoryl azide (9.68 g) was added, the reaction solution was stirred at 80°C for 11 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (250 mL*3), and the filtrate was concentrated to obtain a residue. The residue was diluted with ethyl acetate (250 mL), washed with 10% citric acid (250 mL*2), saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-10. The product was used in the next step without purification. LCMS (ESI) m/z: 403.1(M+1-56) + . The eighth step: Compound 8-10 (15.0 g) was dissolved in ethyl acetate hydrochloride (4.0 mol/L, 100.0 mL) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated to obtain residual The residue was separated by reversed-phase chromatography (column model: Welch Ultimate XB_C18 (20-40 μm; 120 A), mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 15-70%, 30 minutes; 70%, 30 minutes) to obtain compound 8-11. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47-8.37 (m, 1H), 7.05-6.97 (m, 1H), 6.59-6.50 (m, 1H), 6.46-6.25 (m, 2H). LCMS (ESI) m/z: 359.0(M+1) + . The ninth step: To a solution of compound 8-11 (2.5 g) in tertiary-butanol (30 mL) was added compound A-2 (2.24 g), BrettPhos Pd G3 (631.13 mg) and cesium carbonate (4.54 g) at room temperature g), the reaction solution was reacted at 105 degrees Celsius under nitrogen protection for 3 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (150 mL*3), the filtrate was concentrated to obtain a residue, and the residue was separated by reverse phase chromatography ( Column model: Welch Ultimate XB_C18 20-40μm; 120 A; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient: 60%, 10 minutes) to obtain compounds 8-12. LCMS (ESI) m/z: 492.1(M+1) + . The tenth step: N-bromosuccinimide (686.96 mg) was added to a solution of compound 8-12 (1.9 g) in dichloromethane (20 ml) at 0 degrees Celsius, and the reaction solution was at 0 degrees Celsius. After stirring for 0.5 hours, the reaction solution was quenched with saturated sodium sulfite (20 mL) at 0°C, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. To the residue was added methanol ( 10 mL), stirred at room temperature for 0.5 h, the mixture was filtered, and the filter cake was dried to obtain compound 8-13. LCMS (ESI) m/z: 572.0(M+3) + . The eleventh step: Zinc powder (54.95 mg), zinc cyanide (131.58 mg) were added to a solution of compound 8-13 (0.8 g) in N,N-dimethylformamide (5 ml) at room temperature, Zinc bromide (15.77 mg), 1,1'-bis(diphenylphosphino)ferrocene (155.30 mg) and tris(dibenzylideneacetone)dipalladium (128.26 mg), the reaction solution was at 120°C under nitrogen Stir under protective conditions for 2 hours, the reaction solution was filtered, the filter cake was washed with ethyl acetate (150 mL*3), the filtrate was concentrated to obtain a residue, methanol (10 mL) was added to the residue, stirred at room temperature for 0.5 hours, and the mixture was filtered , and the filter cake was dried to obtain compound 8-14. LCMS (ESI) m/z: 517.3(M+1) + . The twelfth step: Compound 8-14 (0.6 g) was dissolved in concentrated sulfuric acid (12.0 ml) at room temperature, the reaction solution was stirred at 60 degrees Celsius for 4 hours, and the reaction solution was slowly added dropwise to 2 mol/L hydrogen Sodium oxide (250 mL) aqueous solution, then extracted with ethyl acetate (250 mL*2), the obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-15. The product was used in the next step without purification. LCMS (ESI) m/z: 535.3(M+1) + . Thirteenth step: To a solution of compound 8-15 (0.5 g) in tetrahydrofuran (25 ml) was added sodium hydride (186.80 mg, mass percentage: 60%) and 1,1-carbonyldiimidazole (454.37 mg) at room temperature , the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was poured into saturated aqueous ammonium chloride (150 mL) to quench, and then extracted with ethyl acetate (150 mL*3), and the resulting organic phase was quenched with saturated brine (150 mL). mL), washed with anhydrous sodium sulfate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a residue, methanol (5 mL) was added to the residue, stirred at room temperature for 0.5 h, the mixture was filtered, and the filter cake was dried to obtain compound 8-16. LCMS (ESI) m/z: 561.3(M+1) + . Fourteenth step: To a solution of compound 8-16 (0.3 g) and compound 1-1 (497.74 mg) in tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (345.39 mg) and Tripyrrolidinophosphonium bromide hexafluorophosphate (1.25 g), the reaction solution was stirred at 80 degrees Celsius for 24 hours, the reaction solution was poured into water (150 mL), and then extracted with ethyl acetate (150 mL*3), The obtained organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-17. The product was used in the next step without purification. LCMS (ESI) m/z: 729.4(M+1) + . The fifteenth step: Trifluoroacetic acid (13.86 g) was added to a solution of compound 8-17 (0.3 g) in dichloromethane (9 mL) at room temperature, the reaction solution was stirred at room temperature for 0.5 hours, and the reaction solution was concentrated The trifluoroacetate salt of compound 8-18 was obtained. The product was used in the next step without purification. LCMS (ESI) m/z: 629.4(M+1) + . Sixteenth step: To a solution of compound 8-18 (0.2 g) in tetrahydrofuran (10 mL) and water (2 mL) at 0°C was added potassium carbonate (219.58 mg), followed by compound 1-5 (28.76 mg) ), the reaction solution was stirred at 0°C for 0.5 hours, the reaction solution was poured into water (50 mL), and then extracted with ethyl acetate (50 mL*3). The obtained organic phase was washed with saturated brine (50 mL) and then used Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a residue, which is separated by a preparative chromatography column (column model: Phenomenex Gemini-NX C18 (75*30mm*3μm), mobile phase: [water (0.225% formic acid)-acetonitrile]; Acetonitrile %: 32%-62%, 7 min) was purified to give compound 8. Compound 8 was then passed through preparative SFC (column model: DAICEL CHIRALCEL OD (250mm*30mm, 10um; mobile phase: [methanol (0.1% ammonia water)]; gradient: carbon dioxide critical fluid: 30%-30%, 3.3 minutes, 50 minutes) After all, they were separated by preparative chromatography column (column type: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 32%-62%, 7 minutes) to obtain the compound 8A and Compound 8B. Compound 8A (retention time = 1.688 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.51-8.37 (m, 1H), 8.37-8.30 (m, 1H), 7.41-7.28 ( m, 1H), 7.16-7.05 (m, 1H), 6.92-6.77 (m, 1H), 6.28-6.12 (m, 1H), 5.83-5.69 (m, 1H), 4.02-3.66 (m, 9H), 2.02-1.96 (m, 3H), 1.07-1.04 (m, 3H), 1.01-0.95 (m, 3H). LCMS (ESI) m/z: 683.4(M+1) + . Compound 8B (retention time=1.808 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.49-8.38 (m, 1H), 8.36-8.31 (m, 1H), 7.42-7.28 (m, 1H), 7.17-7.04 (m, 1H) ), 6.92-6.76 (m, 1H), 6.28-6.08 (m, 1H), 5.84-5.63 (m, 1H), 4.03-3.68 (m, 9H), 2.04-1.94 (m, 3H), 1.12-1.03 (m, 3H), 1.01-0.93 (m, 3H). LCMS (ESI) m/z: 683.4 (M+1) + .

實施例9

Figure 02_image447
第一步： 將中間體A（2.5克）的甲酸（12.5毫升）溶液中加熱到100攝氏度，在100攝氏度反應2小時。在15攝氏度將反應混合物倒入飽和的碳酸氫鈉水溶液（100毫升）中，然後用乙酸乙酯（10毫升*3）萃取，合併有機相用飽和的食鹽水（10毫升）洗滌，無水硫酸鈉乾燥，過濾。濾液減壓濃縮，得到化合物9-1。LCMS (ESI) m/z: 518.2(M+1) +。 第二步： 在0攝氏度下向化合物9-1（2.0克）的四氫呋喃（50毫升）溶液中滴加三氟化硼***溶液(1莫耳/升, 30.92毫升)，加畢，在0攝氏度反應1小時。將水（30毫升）滴加到反應混合物中。然後用乙酸乙酯（100毫升）萃取，有機相用飽和的食鹽水（30毫升）洗滌，無水硫酸鈉乾燥，過濾。濾液減壓濃縮，得到化合物9-2。LCMS (ESI) m/z: 504.0(M+1) +。 第三步：
Figure 02_image449
向化合物9-2（1.6克）的四氫呋喃（100毫升）溶液中加入PyBrOP（5.93克）和化合物1-1（4.74克），該反應在70攝氏度反應12小時。將反應液過濾，濾液減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 （250*70mm*10μm）；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：30%-60%，22分鐘）純化，得到的產品用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度：二氧化碳臨界流體45%-45%，2.5分鐘；50分鐘）分離純化得到化合物9-3A (保留時間=1.851min)和化合物9-3B (保留時間=2.297min)。 LCMS (ESI) m/z: 672.5 (M+1) +。 第四步：
Figure 02_image451
Figure 02_image453
將化合物9-3A（200毫克）的乙腈（10毫升）溶液冷卻到0攝氏度，在0攝氏度下將對甲苯磺酸（51.27毫克）和NCS（39.76毫克）加入到反應液中，在氮氣保護下，混合物在60攝氏度反應2小時。向反應液中加入飽和的亞硫酸鈉水溶液（20毫升）和飽和的碳酸氫鈉水溶液（20毫升），用乙酸乙酯（30毫升*2）萃取兩次，有機相用飽和的食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥後過濾，濾液減壓濃縮，得到的殘餘物通過製備TLC（二氧化矽：石油醚：乙酸乙酯：甲醇=8:3:1）純化，分別得到化合物9-4A（Rf=0.26）和10-1A（Rf=0.18）。 化合物9-4A： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.25-8.43 (m, 1H), 7.17-7.27 (m, 2H), 6.94 (s, 1H), 6.91 (br d, J= 4.75Hz, 1H), 6.26-6.43 (m, 1H), 3.80 (br d, J= 4.13Hz, 4H), 3.53-3.69 (m, 4H), 2.66-2.73 (m, 3H), 2.55-2.65 (m, 1 H) 1.97-2.08 (m, 3H), 1.44 (s, 9H), 1.02-1.18 (m, 6H)。LCMS (ESI) m/z: 706.2 (M+1) +。 化合物10-1A：LCMS (ESI) m/z: 706.3 (M+1) +。將化合物9-3B（200毫克）的乙腈（10毫升）溶液冷卻到0攝氏度，在0攝氏度下將對甲苯磺酸（51.27毫克）和NCS（39.76毫克）加入到反應液中，在氮氣保護下，混合物在60攝氏度反應2小時。向反應液中加入飽和的亞硫酸鈉水溶液（20毫升）和飽和的碳酸氫鈉水溶液（20毫升），用乙酸乙酯（30毫升*2）萃取兩次，有機相用飽和的食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥後過濾，濾液減壓濃縮，得到的殘餘物通過製備TLC（二氧化矽：石油醚：乙酸乙酯：甲醇=8:3:1）純化，分別得到化合物9-4B（Rf=0.30）和10-1B（Rf=0.35）。 化合物9-4B：LCMS (ESI) m/z: 706.3 (M+1) +。 化合物10-1B：LCMS (ESI) m/z: 706.2 (M+1) +。 第五步：
Figure 02_image455
分別向化合物9-4A和9-4B（70毫克）的二氯甲烷（0.9毫升）溶液中加入三氟乙酸（462毫克），該反應在10攝氏度反應0.5小時。將反應液直接減壓濃縮得到化合物9-5A和9-5B的三氟乙酸鹽粗品直接用於下一步反應。LCMS (ESI) m/z: 606.3 (M+1) +。 第六步：
Figure 02_image457
分別將化合物9-5A和9-5B（100毫克）溶解在THF（4毫升）和水（1毫升）混合溶液中，依次加入碳酸鉀（49.71毫克）和化合物1-5（10.85毫克），該反應在15攝氏度反應30分鐘。反應液用飽和的碳酸氫鈉水溶液（20毫升）將混合物體系pH調節到8，乙酸乙酯（20毫升*2）萃取兩次，有機相用飽和食鹽水（10毫升）洗滌一次，無水硫酸鈉乾燥後過濾，濾液減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 （150*25mm*10μm）；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：25%-55%，10分鐘）純化，分別得到化合物9A和9B。化合物9A： 1H NMR (400 MHz, METHANOL- d 4) δ 8.36 (d, J= 5.14 Hz, 1H), 7.32-7.39 (m, 1H), 7.29 (s, 1H), 7.24 (br d, J= 5.01 Hz, 1H), 6.83 (dd, J= 16.75, 10.64 Hz, 1H), 6.51 (dd, J= 9.29, 1.34 Hz, 1H), 6.30 (dd, J= 16.75, 1.96 Hz, 1H), 5.80-5.87 (m, 1H), 3.86-4.12 (m, 8H), 2.82 (dt, J= 13.54, 6.86 Hz, 1H), 2.75 (s, 3H), 2.17 (s, 3H), 1.18-1.21 (m, 3H), 1.11 (d, J= 6.85 Hz, 3H)。 LCMS (ESI) m/z: 660.2 (M+1) +。 化合物9B： 1H NMR (400 MHz, METHANOL- d 4) δ 8.36 (d, J= 5.01Hz, 1H), 7.37 (dd, J= 8.93, 5.87Hz, 1H), 7.33 (s, 1H), 7.19 (d, J= 5.01Hz, 1H), 6.84 (dd, J= 16.81, 10.58Hz, 1H), 6.49 (t, J= 8.93Hz, 1H), 6.31 (dd, J= 16.81, 1.90Hz, 1H), 5.78-5.89 (m, 1H), 3.90-4.11 (m, 8H), 2.74-2.86 (m, 1H), 2.67 (s, 3H), 2.12 (s, 3H), 1.19 (d, J= 6.72Hz, 3H), 1.10 (d, J= 6.72 Hz, 3H)；LCMS (ESI) m/z: 660.2 (M+1) +。 Example 9
Figure 02_image447
The first step: A solution of intermediate A (2.5 g) in formic acid (12.5 ml) was heated to 100 degrees Celsius and reacted at 100 degrees Celsius for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL) at 15°C, then extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated brine (10 mL), and anhydrous sodium sulfate Dry, filter. The filtrate was concentrated under reduced pressure to obtain compound 9-1. LCMS (ESI) m/z: 518.2(M+1) + . Step 2: To a solution of compound 9-1 (2.0 g) in tetrahydrofuran (50 mL) was added dropwise boron trifluoride ether solution (1 mol/L, 30.92 mL) at 0 degrees Celsius, and the addition was completed at 0 degrees Celsius. React for 1 hour. Water (30 mL) was added dropwise to the reaction mixture. It was then extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 9-2. LCMS (ESI) m/z: 504.0(M+1) + . third step:
Figure 02_image449
To a solution of compound 9-2 (1.6 g) in tetrahydrofuran (100 ml) were added PyBrOP (5.93 g) and compound 1-1 (4.74 g), and the reaction was carried out at 70°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (250*70mm*10μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 30% -60%, 22 minutes) purification, the obtained product was purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 45%-45% , 2.5 minutes; 50 minutes) separation and purification to obtain compound 9-3A (retention time=1.851min) and compound 9-3B (retention time=2.297min). LCMS (ESI) m/z: 672.5 (M+1) + . the fourth step:
Figure 02_image451
Figure 02_image453
A solution of compound 9-3A (200 mg) in acetonitrile (10 mL) was cooled to 0 °C, and p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the mixture was reacted at 60 degrees Celsius for 2 hours. Saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to the reaction solution, extracted twice with ethyl acetate (30 mL*2), and the organic phase was treated with saturated brine (20 mL). Washed once, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (silicon dioxide: petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 9-4A, respectively (Rf=0.26) and 10-1A (Rf=0.18). Compound 9-4A: 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.25-8.43 (m, 1H), 7.17-7.27 (m, 2H), 6.94 (s, 1H), 6.91 (br d, J = 4.75 Hz, 1H), 6.26-6.43 (m, 1H), 3.80 (br d, J = 4.13Hz, 4H), 3.53-3.69 (m, 4H), 2.66-2.73 (m, 3H), 2.55-2.65 (m , 1 H) 1.97-2.08 (m, 3H), 1.44 (s, 9H), 1.02-1.18 (m, 6H). LCMS (ESI) m/z: 706.2 (M+1) + . Compound 10-1A: LCMS (ESI) m/z: 706.3 (M+1) + . A solution of compound 9-3B (200 mg) in acetonitrile (10 mL) was cooled to 0 °C, and p-toluenesulfonic acid (51.27 mg) and NCS (39.76 mg) were added to the reaction solution at 0 °C under nitrogen protection. , the mixture was reacted at 60 degrees Celsius for 2 hours. Saturated aqueous sodium sulfite solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) were added to the reaction solution, extracted twice with ethyl acetate (30 mL*2), and the organic phase was treated with saturated brine (20 mL). Washed once, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative TLC (silicon dioxide: petroleum ether: ethyl acetate: methanol = 8:3:1) to obtain compound 9-4B, respectively (Rf=0.30) and 10-1B (Rf=0.35). Compound 9-4B: LCMS (ESI) m/z: 706.3 (M+1) + . Compound 10-1B: LCMS (ESI) m/z: 706.2 (M+1) + . the fifth step:
Figure 02_image455
To a solution of compounds 9-4A and 9-4B (70 mg) in dichloromethane (0.9 ml), respectively, was added trifluoroacetic acid (462 mg), and the reaction was carried out at 10 degrees Celsius for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain crude trifluoroacetate salts of compounds 9-5A and 9-5B, which were directly used in the next reaction. LCMS (ESI) m/z: 606.3 (M+1) + . Step 6:
Figure 02_image457
Compounds 9-5A and 9-5B (100 mg) were dissolved in a mixed solution of THF (4 mL) and water (1 mL), respectively, and potassium carbonate (49.71 mg) and compound 1-5 (10.85 mg) were added sequentially. The reaction was carried out at 15 degrees Celsius for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted twice with ethyl acetate (20 mL*2), the organic phase was washed once with saturated brine (10 mL), and anhydrous sodium sulfate After drying, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; acetonitrile: 25%- 55%, 10 min) to obtain compounds 9A and 9B, respectively. Compound 9A: 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.36 (d, J = 5.14 Hz, 1H), 7.32-7.39 (m, 1H), 7.29 (s, 1H), 7.24 (br d, J = 5.01 Hz, 1H), 6.83 (dd, J = 16.75, 10.64 Hz, 1H), 6.51 (dd, J = 9.29, 1.34 Hz, 1H), 6.30 (dd, J = 16.75, 1.96 Hz, 1H), 5.80 -5.87 (m, 1H), 3.86-4.12 (m, 8H), 2.82 (dt, J = 13.54, 6.86 Hz, 1H), 2.75 (s, 3H), 2.17 (s, 3H), 1.18-1.21 (m , 3H), 1.11 (d, J = 6.85 Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) + . Compound 9B: 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.36 (d, J = 5.01 Hz, 1H), 7.37 (dd, J = 8.93, 5.87 Hz, 1H), 7.33 (s, 1H), 7.19 (d, J = 5.01Hz, 1H), 6.84 (dd, J = 16.81, 10.58Hz, 1H), 6.49 (t, J = 8.93Hz, 1H), 6.31 (dd, J = 16.81, 1.90Hz, 1H) , 5.78-5.89 (m, 1H), 3.90-4.11 (m, 8H), 2.74-2.86 (m, 1H), 2.67 (s, 3H), 2.12 (s, 3H), 1.19 (d, J = 6.72Hz , 3H), 1.10 (d, J = 6.72 Hz, 3H); LCMS (ESI) m/z: 660.2 (M+1) + .

實施例10

Figure 02_image459
第一步：
Figure 02_image461
分別向化合物10-1A和10-1B（90毫克）的二氯甲烷（0.9毫升）溶液中加入三氟乙酸（471.33毫克），該反應在10攝氏度反應1小時。分別將反應液直接減壓濃縮得到化合物10-2A和10-2B的三氟乙酸鹽，粗品直接用於下一步反應。LCMS (ESI) m/z: 606.4 (M+1) +。 第二步：
Figure 02_image463
分別將化合物10-2A和10-2B（150毫克）溶解在四氫呋喃（4毫升）和水（1毫升）混合溶液中，依次加入碳酸鉀（102.63毫克）和化合物1-5（22.40毫克），該反應在15攝氏度反應30分鐘。反應液用飽和的碳酸氫鈉水溶液（20毫升）將混合物體系pH調節到8，乙酸乙酯（20毫升*2）萃取，合併有機相用飽和食鹽水（10毫升）洗滌，無水硫酸鈉乾燥後過濾，濾液減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 （150*25mm*10μm），流動相：[0.225%的甲酸水溶液-乙腈]；梯度：乙腈%：20%-50%，10分鐘）純化，分別得到化合物10A的甲酸鹽和10B的甲酸鹽。LCMS (ESI) m/z: 660.4 (M+1) +。 化合物10A的甲酸鹽： 1H NMR (400 MHz, METHANOL- d 4) δ 8.36 (d, J= 5.01Hz, 1H), 7.37 (dd, J= 8.93, 5.87Hz, 1H), 7.33 (s, 1H), 7.19 (d, J= 5.01Hz, 1H), 6.84 (dd, J= 16.81, 10.58Hz, 1H), 6.49 (t, J= 8.93Hz, 1H), 6.31 (dd, J= 16.81, 1.90Hz, 1H), 5.78-5.89 (m, 1H), 3.90-4.11 (m, 8H), 2.74-2.86 (m, 1H), 2.67 (s, 3H), 2.12 (s, 3H), 1.19 (d, J= 6.72Hz, 3H), 1.10 (d, J= 6.72Hz, 3H)。LCMS (ESI) m/z: 660.2 (M+1) +。 化合物10B的甲酸鹽： 1H NMR (400 MHz, METHANOL- d 4) δ 8.36 (d, J= 5.01Hz, 1H), 7.36 (dd, J= 8.86, 5.93Hz, 1H), 7.32 (s, 1H), 7.15-7.20 (m, 1H), 6.84 (dd, J= 16.75, 10.64Hz, 1H), 6.48 (t, J= 8.99Hz, 1H), 6.31 (dd, J= 16.75, 1.83Hz, 1H), 5.84 (dd, J= 10.58, 1.90Hz, 1H), 3.85-4.20 (m, 8H), 2.96 (dt, J= 13.51, 6.69Hz, 1H), 2.67 (s, 3H), 2.04 (s, 3H), 1.14-1.25 (m, 6H)；LCMS (ESI) m/z: 660.2 (M+1) +。 Example 10
Figure 02_image459
first step:
Figure 02_image461
To a solution of compounds 10-1A and 10-1B (90 mg) in dichloromethane (0.9 ml), respectively, was added trifluoroacetic acid (471.33 mg), and the reaction was carried out at 10 degrees Celsius for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the trifluoroacetate salts of compounds 10-2A and 10-2B, and the crude products were directly used in the next reaction. LCMS (ESI) m/z: 606.4 (M+1) + . Step 2:
Figure 02_image463
Compounds 10-2A and 10-2B (150 mg) were dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (1 mL), respectively, and potassium carbonate (102.63 mg) and compound 1-5 (22.40 mg) were added successively. The reaction was carried out at 15 degrees Celsius for 30 minutes. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL*2), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was passed through preparative HPLC (column type: Phenomenex luna C18 (150*25mm*10μm), mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: acetonitrile %: 20% -50%, 10 min) purification to give the formate salt of compound 10A and the formate salt of 10B, respectively. LCMS (ESI) m/z: 660.4 (M+1) + . Formate salt of compound 10A: 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.36 (d, J = 5.01 Hz, 1H), 7.37 (dd, J = 8.93, 5.87 Hz, 1H), 7.33 (s, 1H), 7.19 (d, J = 5.01Hz, 1H), 6.84 (dd, J = 16.81, 10.58Hz, 1H), 6.49 (t, J = 8.93Hz, 1H), 6.31 (dd, J = 16.81, 1.90 Hz, 1H), 5.78-5.89 (m, 1H), 3.90-4.11 (m, 8H), 2.74-2.86 (m, 1H), 2.67 (s, 3H), 2.12 (s, 3H), 1.19 (d, J = 6.72Hz, 3H), 1.10 (d, J = 6.72Hz, 3H). LCMS (ESI) m/z: 660.2 (M+1) + . Formate salt of compound 10B: 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.36 (d, J = 5.01 Hz, 1H), 7.36 (dd, J = 8.86, 5.93 Hz, 1H), 7.32 (s, 1H), 7.15-7.20 (m, 1H), 6.84 (dd, J = 16.75, 10.64Hz, 1H), 6.48 (t, J = 8.99Hz, 1H), 6.31 (dd, J = 16.75, 1.83Hz, 1H) ), 5.84 (dd, J = 10.58, 1.90Hz, 1H), 3.85-4.20 (m, 8H), 2.96 (dt, J = 13.51, 6.69Hz, 1H), 2.67 (s, 3H), 2.04 (s, 3H), 1.14-1.25 (m, 6H); LCMS (ESI) m/z: 660.2 (M+1) + .

實施例11

Figure 02_image465
第一步： 在20-30攝氏度下，向化合物11-1（20克）的乙醇（200毫升）溶液中一次性加入氨水（182克，質量百分比：34%）。反應液在75攝氏度下反應16個小時。反應液濃縮得到殘餘物，用乙酸乙酯（80 mL*3）萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物11-2。 第二步： 在20-30攝氏度下，向化合物11-2（2克）的二氯甲烷（20毫升）溶液中依次加入三乙胺（1.56克）和丙二酸甲酯醯氯（1.57克），反應液在20-30攝氏度下反應4小時。向反應液中加入檸檬酸至pH=6-7，反應液分層，水相用二氯甲烷（50毫升）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=20:1 到3:1）得到化合物11-3。 1H NMR (400MHz, CDCl 3) δ 10.32(br s, 1H) , 8.25-8.15 (m, 1H), 7.59-7.48(m, 1H), 7.11-6.98(m, 1H), 3.85(s, 3H), 3.56(s, 2H)。LCMS (ESI) m/z: 257.1(M+1) +。 第三步： 在20-30攝氏度下，向化合物11-3（15克）的乙腈（150毫升）溶液中依次加入碳酸銫（19.08克）和4-乙氧基-1,1,1-三氟-3-丁烯-2-酮（7.87克），反應液在氮氣保護下於20-30攝氏度下反應3小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=10:1 到0:1）得到化合物11-4。LCMS (ESI) m/z: 379.0(M+1) +。 第四步： 在20-30攝氏度下，向化合物11-4（5克）的乙醇（50毫升）和水（50毫升）混合溶液中依次加入氯化銨（3.54克）和還原鐵粉（3.69克），反應液在80攝氏度下反應16小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=10:1 到0:1）得到化合物11-5。LCMS (ESI) m/z: 317.0(M+1) +。 第五步： 在20-30攝氏度下，向化合物11-5（0.2克）的醋酸（2毫升）溶液中一次性加入NCS（84.46毫克），反應液在20-30攝氏度下反應16小時。向反應液中加入水（20毫升）,然後用乙酸乙酯（20毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=0:1）得到化合物11-6。 1H NMR (400MHz, DMSO- d 6) δ 8.19-8.03(m, 1H) , 7.43-7.26 (m, 1H), 7.18-7.00(m, 2H), 5.65(br s, 2H)。LCMS (ESI) m/z: 351.0(M+1) +。 第六步： 在20-30攝氏度下，向化合物11-6（1.1克）的吡啶（15毫升）溶液中一次性加入液溴（1.55克）。反應液在氮氣保護下於50攝氏度下反應12小時。向反應液中加入水（100毫升）,然後用乙酸乙酯（50毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（洗脫劑：石油醚：乙酸乙酯=10:1到1:1）得到化合物11-7。LCMS (ESI) m/z: 386.9(M+3) +。 第七步： 在20-30攝氏度下，向化合物11-7（1.6克）的1,4-二氧六環（20毫升）溶液中依次加入2-異丙基-4-甲基吡啶-3-胺（498.74毫克），三（二亞苄基丙酮）二鈀（380.03毫克），4,5-雙二苯基膦-9,9-二甲基氧雜蒽（480.26毫克），碳酸銫（2.7克）。反應液在氮氣保護下於100攝氏度反應6小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（洗脫劑：石油醚：乙酸乙酯=10:1 到1:2）得到化合物11-8。LCMS (ESI) m/z: 455.1(M+1) +。 第八步： 在20-30攝氏度下，向化合物11-8（0.3克）的DMF（3毫升）溶液中一次性加入N-溴代丁二醯亞胺（176.09毫克）。反應液在20-30攝氏度下反應一個小時。向反應液中加入水（40毫升），然後用乙酸乙酯（30毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=1:1）得到化合物11-9。LCMS (ESI) m/z: 534.9(M+3) +。 第九步： 在20-30攝氏度下，向化合物11-9（0.17克）的DMF（5毫升）和水（0.05毫升）混合溶液中依次一次性加入鋅粉（210毫克），氰化鋅（300毫克），溴化鋅（71.73毫克），1,1-雙（二苯基膦基）二茂鐵（96.33毫克）和三（二亞苄基丙酮）二鈀（85.00毫克）。反應液在100攝氏度下反應3個小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=1:1）得到化合物11-10。LCMS (ESI) m/z: 480.0(M+1) +。 第十步： 化合物11-10（46毫克）的濃硫酸（1.41 g）於60攝氏度下反應16小時。反應液加入到飽和碳酸氫鈉水溶液（50毫升）中，用乙酸乙酯（20毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物11-11。LCMS (ESI) m/z: 498.1(M+1) +。 第十一步： 在0攝氏度下，向化合物11-11（30毫克）的四氫呋喃（1毫升）溶液中一次性加入氫化鈉（12.05毫克，質量百分比：60%），反應液在0攝氏度下反應0.3小時，然後一次性加入1,1-羰基二咪唑（29.31毫克）。反應液在0-25攝氏度下反應0.7小時。將反應液加入到飽和氯化銨（20毫升）溶液中，用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=1:1）得到化合物11-12。LCMS (ESI) m/z: 524.0(M+1) +。 第十二步： 在20-30攝氏度下，向化合物11-12（30毫克）的THF（2毫升）溶液中一次性加入N,N-二異丙基乙胺（29.60毫克），三吡咯烷基溴化鏻六氟磷酸鹽（106.79毫克），反應液在20-30°C下反應1個小時，然後一次性加入化合物1-1（42.66毫克），反應液在80攝氏度下反應3小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=0:1）得到化合物11-13。LCMS (ESI) m/z: 692.1(M+1) +。 第十三步： 在10-25攝氏度下，向化合物11-13（22毫克）的二氯甲烷（0.6毫升）溶液中一次性加入三氟乙酸（308.00毫克）。反應液在10-25攝氏度下反應0.5小時。將反應液濃縮得到化合物11-14的三氟乙酸鹽，粗品直接用於下一步。 第十四步：
Figure 02_image467
在0攝氏度下，向化合物11-14（22毫克，TFA鹽）的四氫呋喃（1.0毫升）和水（0.2毫升）的混合溶液中依次一次性加入無水碳酸鉀（21.53毫克），丙烯醯氯（2.82毫克）。反應液在0攝氏度下反應0.5小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備板純化（二氯甲烷：甲醇=7:1），得到的化合物11。 化合物11過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，5分鐘，50分鐘）分離純化得到實施例11AM（保留時間=3.325 min和保留時間=4.538 min的混合物）及實施例11CM（保留時間=1.622 min和保留時間=1.789 min的混合物）。 11AM再通過製備SFC（柱型號：DAICEL CHIRALPAK AD（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體25%-25%，5.7分鐘，40分鐘）分離純化得到化合物11A，和化合物11B。 11CM再通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，5.8分鐘，40分鐘）分離純化得到化合物11C和化合物11D。 化合物11A和化合物11B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物11A的保留時間為4.538min，e.e.值為100%；化合物11B的保留時間為3.318min，e.e.值為100%。 化合物11C和化合物11D經SFC檢測[柱型號：Chiralcel OJ-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物11C的保留時間為1.314min，e.e.值為100%；化合物11D的保留時間為1.471min，e.e.值為100%。 化合物11A（保留時間=4.538 min）：LCMS (ESI) m/z: 646.1(M+1) +。 化合物11B（保留時間=3.318 min）：LCMS (ESI) m/z: 646.1(M+1) +。 化合物11C（保留時間=1.314min）： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.36-8.30(m, 1H), 7.25-7.22 (m, 1H), 7.19-7.13(m, 2H), 6.94-6.84(m, 1H), 6.83-6.80(m, 1H), 6.35-6.26(m, 1H), 5.88-5.81(m, 1H), 4.10-4.00(m, 4H), 3.98-3.87(m, 4H), 2.97-2.76(m, 1H), 2.17-2.06(m, 3H), 1.22-1.08(m, 6H)。LCMS (ESI) m/z: 646.1(M+1) +。 化合物11D（保留時間=1.471min）： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.25-8.17(m, 1H), 7.14-7.08 (m, 1H), 7.08-6.99(m, 2H), 6.83-6.66(m, 2H), 6.25-6.15(m, 1H), 5.77-5.69(m, 1H), 4.00-3.90(m, 4H), 3.87-3.74(m, 4H), 2.86-2.63(m, 1H), 2.06-1.94(m, 3H), 1.12-0.95(m, 6H)。LCMS (ESI) m/z: 646.1(M+1) +。 Example 11
Figure 02_image465
Step 1: Add ammonia water (182 g, mass percentage: 34%) to a solution of compound 11-1 (20 g) in ethanol (200 ml) at 20-30 degrees Celsius. The reaction solution was reacted at 75 degrees Celsius for 16 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (80 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-2. Step 2: To a solution of compound 11-2 (2 g) in dichloromethane (20 ml) at 20-30 degrees Celsius, were added triethylamine (1.56 g) followed by methyl malonate chloride (1.57 g) ), the reaction solution was reacted at 20-30 degrees Celsius for 4 hours. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was layered, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=20:1 to 3:1) to obtain compound 11-3. 1 H NMR (400MHz, CDCl 3 ) δ 10.32(br s, 1H) , 8.25-8.15 (m, 1H), 7.59-7.48(m, 1H), 7.11-6.98(m, 1H), 3.85(s, 3H) ), 3.56(s, 2H). LCMS (ESI) m/z: 257.1(M+1) + . The third step: To a solution of compound 11-3 (15 g) in acetonitrile (150 ml) at 20-30 degrees Celsius, was added cesium carbonate (19.08 g) and 4-ethoxy-1,1,1-tris Fluoro-3-buten-2-one (7.87 g), the reaction solution was reacted under nitrogen protection at 20-30 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-4. LCMS (ESI) m/z: 379.0(M+1) + . Step 4: Add ammonium chloride (3.54 g) and reduced iron powder (3.69 g) to a mixed solution of compound 11-4 (5 g) in ethanol (50 ml) and water (50 ml) at 20-30 degrees Celsius. g), the reaction solution was reacted at 80 degrees Celsius for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain compound 11-5. LCMS (ESI) m/z: 317.0(M+1) + . The fifth step: NCS (84.46 mg) was added to a solution of compound 11-5 (0.2 g) in acetic acid (2 ml) at 20-30 degrees Celsius at one time, and the reaction solution was reacted at 20-30 degrees Celsius for 16 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to give compound 11-6. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.19-8.03 (m, 1H), 7.43-7.26 (m, 1H), 7.18-7.00 (m, 2H), 5.65 (br s, 2H). LCMS (ESI) m/z: 351.0(M+1) + . Step 6: To a solution of compound 11-6 (1.1 g) in pyridine (15 ml) was added liquid bromine (1.55 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 50 degrees Celsius for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound 11-7. LCMS (ESI) m/z: 386.9(M+3) + . Step 7: To a solution of compound 11-7 (1.6 g) in 1,4-dioxane (20 mL) at 20-30 degrees Celsius, 2-isopropyl-4-methylpyridine-3 was sequentially added -amine (498.74 mg), tris(dibenzylideneacetone)dipalladium (380.03 mg), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (480.26 mg), cesium carbonate ( 2.7 grams). The reaction solution was reacted at 100 degrees Celsius for 6 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:2) to give compound 11-8. LCMS (ESI) m/z: 455.1(M+1) + . Step 8: To a solution of compound 11-8 (0.3 g) in DMF (3 mL) at 20-30 degrees Celsius was added N-bromosuccinimide (176.09 mg) in one portion. The reaction solution was reacted at 20-30 degrees Celsius for one hour. Water (40 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to give compound 11-9. LCMS (ESI) m/z: 534.9(M+3) + . Step 9: Add zinc powder (210 mg), zinc cyanide ( 300 mg), zinc bromide (71.73 mg), 1,1-bis(diphenylphosphino)ferrocene (96.33 mg) and tris(dibenzylideneacetone)dipalladium (85.00 mg). The reaction solution was reacted at 100 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to obtain compound 11-10. LCMS (ESI) m/z: 480.0(M+1) + . Tenth step: Compound 11-10 (46 mg) was reacted with concentrated sulfuric acid (1.41 g) at 60 degrees Celsius for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-11. LCMS (ESI) m/z: 498.1(M+1) + . Step 11: Add sodium hydride (12.05 mg, mass percentage: 60%) to a solution of compound 11-11 (30 mg) in tetrahydrofuran (1 ml) at 0 degrees Celsius, and the reaction solution is reacted at 0 degrees Celsius After 0.3 hours, 1,1-carbonyldiimidazole (29.31 mg) was added in one portion. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to saturated ammonium chloride (20 mL) solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=1:1) to obtain compound 11-12. LCMS (ESI) m/z: 524.0(M+1) + . Step 12: To a solution of compounds 11-12 (30 mg) in THF (2 mL) at 20-30 °C was added N,N-diisopropylethylamine (29.60 mg), tripyrrolidine in one portion Phosphonium bromide hexafluorophosphate (106.79 mg), the reaction solution was reacted at 20-30 ° C for 1 hour, then compound 1-1 (42.66 mg) was added at one time, and the reaction solution was reacted at 80 ° C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=0:1) to give compound 11-13. LCMS (ESI) m/z: 692.1(M+1) + . Thirteenth step: To a solution of compounds 11-13 (22 mg) in dichloromethane (0.6 mL) was added trifluoroacetic acid (308.00 mg) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 11-14, and the crude product was directly used in the next step. Step 14:
Figure 02_image467
To a mixed solution of compounds 11-14 (22 mg, TFA salt) in tetrahydrofuran (1.0 mL) and water (0.2 mL) at 0 degrees Celsius, anhydrous potassium carbonate (21.53 mg), acrylonitrile chloride (2.82 mL) were sequentially added in one portion. mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (dichloromethane:methanol=7:1) to obtain compound 11. Compound 11 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 5 minutes, 50 minutes) Example 11AM (mixture of RT=3.325 min and RT=4.538 min) and Example 11CM (mixture of RT=1.622 min and RT=1.789 min). 11AM and then separated by preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5.7 minutes, 40 minutes) Purification gave compound 11A, and compound 11B. 11CM was separated by preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5.8 minutes, 40 minutes) Purification gave compound 11C and compound 11D. Compound 11A and compound 11B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient (B% ): 5%-40%] obtained: the retention time of compound 11A is 4.538min, and the ee value is 100%; the retention time of compound 11B is 3.318min, and the ee value is 100%. Compound 11C and compound 11D were detected by SFC [column model: Chiralcel OJ-3 50×4.6 mm ID, 3 μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] obtained: the retention time of compound 11C was 1.314 min, and the ee value was 100%; the retention time of compound 11D was 1.471 min, and the ee value was 100%. Compound 11A (retention time=4.538 min): LCMS (ESI) m/z: 646.1 (M+1) + . Compound 11B (retention time=3.318 min): LCMS (ESI) m/z: 646.1 (M+1) + . Compound 11C (retention time = 1.314 min): 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.36-8.30 (m, 1H), 7.25-7.22 (m, 1H), 7.19-7.13 (m, 2H), 6.94 -6.84(m, 1H), 6.83-6.80(m, 1H), 6.35-6.26(m, 1H), 5.88-5.81(m, 1H), 4.10-4.00(m, 4H), 3.98-3.87(m, 4H), 2.97-2.76(m, 1H), 2.17-2.06(m, 3H), 1.22-1.08(m, 6H). LCMS (ESI) m/z: 646.1(M+1) + . Compound 11D (retention time=1.471 min): 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.25-8.17 (m, 1H), 7.14-7.08 (m, 1H), 7.08-6.99 (m, 2H), 6.83 -6.66(m, 2H), 6.25-6.15(m, 1H), 5.77-5.69(m, 1H), 4.00-3.90(m, 4H), 3.87-3.74(m, 4H), 2.86-2.63(m, 1H), 2.06-1.94(m, 3H), 1.12-0.95(m, 6H). LCMS (ESI) m/z: 646.1(M+1) + .

實施例12

Figure 02_image469
第一步： 向化合物A（600毫克）的四氫呋喃（20毫升）溶液中加入PYBROP（2.29克），DIEA（633.77毫克）以及化合物3-1（2.10克）。反應液在70攝氏度下反應16小時，反應液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex luna C18 （250*50mm*10 μm），流動相：水（0.225%甲酸）-乙腈：35%-65%，20分鐘] 純化得到化合物12-1。LCMS (ESI) m/z: 686.3.(M+1) +。 第二步： 將12-1（300毫克）溶解在二氯甲烷（3毫升）和三氟甲酸（1毫升）的混合溶液中。反應液在25攝氏度下反應1小時，反應液濃縮得到粗品化合物12-2的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 586.2.(M+1) +。 第三步： 向化合物12-2（400毫克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中加入碳酸鉀（203.83毫克），調節pH至8後，向反應液中加入化合物1-5（44.50毫克）。反應液在0攝氏度反應15分鐘，向反應液中加入飽和碳酸氫鈉水溶液，調節pH到8，用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（5毫升*2）洗後經無水硫酸鈉乾燥後濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex Synergi C18 （150*25mm* 10μm），流動相：水（0.1%甲酸）-乙腈：25%-55%，10分鐘]純化，得到化合物12。 化合物12經過製備SFC（柱型號：DAICEL CHIRALPAK AS-H(250mm*30mm,5μm)，流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體15%-15%，4.7分鐘，145分鐘）分離得到化合物12A和化合物12B。 化合物12A和化合物12B經SFC檢測[柱型號：Chiralpak AS-3 50×4.6mm I.D, 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物12A的保留時間為1.014min，e.e.值為98.16%；化合物12B的保留時間為1.104min，e.e.值為99.28%。 化合物12A（保留時間=1.014min）： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.50-8.35 (m, 1H), 7.20-7.12 (m, 1H), 7.05-6.96 (m, 2H), 6.68-6.49 (m, 3H), 6.46-6.34 (m, 1H), 5.86-5.77 (m, 1H), 5.16-4.78 (m, 2H), 4.52-4.32 (m, 1H), 4.29-4.13 (m, 1H), 3.98-3.85 (m, 2H), 3.81-3.64 (m, 2H), 2.85-2.68 (m, 1H), 2.17-2.10 (m, 3H), 1.49-1.40 (m, 6H), 1.26 (br s, 3H), 1.18 (br d, J= 2.0 Hz, 3H) 。LCMS (ESI) m/z: 640.3.(M+1) +。 化合物12B（保留時間=1.104 min）：1H NMR (400 MHz, CHLOROFORM- d) δ 1.11 (br s, 3H), 1.20-1.24 (m, 3H), 1.29-1.37 (m, 3H), 1.43-1.46 (m, 3H), 2.02-2.18 (m, 3H), 2.65-2.73 (m, 1H), 3.46-3.54 (m, 1H), 3.60-3.65 (m, 2H), 3.69-3.78 (m, 1H), 3.82-3.95 (m, 2H), 4.37-4.58 (m, 1H), 4.98-5.13 (m, 1H), 5.77-5.87 (m, 1H), 6.36-6.46 (m, 1H), 6.54-6.59 (m, 2H), 6.91-7.09 (m, 2H), 7.14-7.22 (m, 1H), 7.34-7.56 (m, 1H), 8.34-8.54 (m, 1H)。LCMS (ESI) m/z: 640.3.(M+1) +。 Example 12
Figure 02_image469
Step 1: To a solution of compound A (600 mg) in tetrahydrofuran (20 ml) were added PYBROP (2.29 g), DIEA (633.77 mg) and compound 3-1 (2.10 g). The reaction solution was reacted at 70 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10 μm), mobile phase: water (0.225% formic acid)-acetonitrile: 35%-65%, 20 minutes] to give compound 12-1. LCMS (ESI) m/z: 686.3.(M+1) + . Step 2: Dissolve 12-1 (300 mg) in a mixed solution of dichloromethane (3 mL) and trifluoroformic acid (1 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction solution was concentrated to obtain the trifluoroacetate salt of the crude compound 12-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 586.2.(M+1) + . The third step: Potassium carbonate (203.83 mg) was added to a mixed solution of compound 12-2 (400 mg) in tetrahydrofuran (4 mL) and water (1 mL), and after adjusting the pH to 8, compound 1 was added to the reaction solution -5 (44.50 mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, and saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). It was then dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi C18 (150*25mm*10μm), mobile phase: water (0.1% formic acid)-acetonitrile: 25%-55%, 10 minutes] to give compound 12. Compound 12 was separated by preparative SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 4.7 minutes, 145 minutes) Compound 12A and compound 12B were obtained. Compound 12A and compound 12B were detected by SFC [column model: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] obtained: the retention time of compound 12A was 1.014 min, and the ee value was 98.16%; the retention time of compound 12B was 1.104 min, and the ee value was 99.28%. Compound 12A (retention time = 1.014 min): 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.50-8.35 (m, 1H), 7.20-7.12 (m, 1H), 7.05-6.96 (m, 2H), 6.68 -6.49 (m, 3H), 6.46-6.34 (m, 1H), 5.86-5.77 (m, 1H), 5.16-4.78 (m, 2H), 4.52-4.32 (m, 1H), 4.29-4.13 (m, 1H), 3.98-3.85 (m, 2H), 3.81-3.64 (m, 2H), 2.85-2.68 (m, 1H), 2.17-2.10 (m, 3H), 1.49-1.40 (m, 6H), 1.26 ( br s, 3H), 1.18 (br d, J = 2.0 Hz, 3H). LCMS (ESI) m/z: 640.3.(M+1) + . Compound 12B (retention time = 1.104 min): 1H NMR (400 MHz, CHLOROFORM- d ) δ 1.11 (br s, 3H), 1.20-1.24 (m, 3H), 1.29-1.37 (m, 3H), 1.43-1.46 (m, 3H), 2.02-2.18 (m, 3H), 2.65-2.73 (m, 1H), 3.46-3.54 (m, 1H), 3.60-3.65 (m, 2H), 3.69-3.78 (m, 1H) , 3.82-3.95 (m, 2H), 4.37-4.58 (m, 1H), 4.98-5.13 (m, 1H), 5.77-5.87 (m, 1H), 6.36-6.46 (m, 1H), 6.54-6.59 ( m, 2H), 6.91-7.09 (m, 2H), 7.14-7.22 (m, 1H), 7.34-7.56 (m, 1H), 8.34-8.54 (m, 1H). LCMS (ESI) m/z: 640.3.(M+1) + .

實施例13

Figure 02_image471
第一步： 向中間體A（1克）的乙腈（15毫升）溶液中依次加入對甲苯磺酸（526.94毫克）和N-氯代丁二醯亞胺（544.81毫克），在氮氣保護下，反應液在60攝氏度下反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（10毫升），用乙酸乙酯（20毫升*3）萃取，有機相用飽和的食鹽水（20毫升）洗滌，無水硫酸鈉乾燥後過濾，濾液濃縮得到化合物13-1。LCMS (ESI) m/z: 558.0 (M+1) +。 第二步： 將化合物13-1（1.11克）的四氫呋喃（20毫升）溶液中加入DIEA（770.86毫克），PyBrOP（3.71克）和化合物1-1（2.96克），反應液在70攝氏度下反應12小時。反應混合物過濾，濾液減壓濃縮，得到化合物13-2。LCMS (ESI) m/z: 726.1(M+1) +。 第三步： 向化合物13-2（2.3克）的乙酸乙酯（10毫升）溶液中加入鹽酸乙酸乙酯（4莫耳/升，10毫升）溶液，反應液在15攝氏度反應1小時。將反應液過濾，濾餅溶解在乙酸乙酯（50毫升）和飽和的碳酸氫鈉水溶液（50毫升）中，分層，水相用乙酸乙酯（20毫升）萃取。有機相用飽和的食鹽水（20毫升）洗滌，無水硫酸鈉乾燥後過濾，濾液減壓濃縮得到化合物13-3。LCMS (ESI) m/z: 626.2 (M+1) +。 第四步： 向化合物13-4（28.75毫克）的N,N-二甲基甲醯胺（5毫升）溶液中依次加入DIEA（165.05毫克）和HATU（242.79毫克），反應液在15攝氏度下反應30分鐘。然後加入化合物13-3，在15攝氏度下繼續反應1小時。將反應液倒入水中（20毫升），用乙酸乙酯（20毫升*3）萃取，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，得到的殘餘物通過製備的HPLC（柱型號：Phenomenex luna C18 150*25mm*10μm；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：34%-64%，2分鐘）純化，得到的化合物13。 化合物13用製備SFC（柱型號：DAICEL CHIRALPAK IC (250mm*30mm*10μm)；流動相：甲醇（0.1%氨水）；梯度: 二氧化碳臨界流體50%-50%，2.5分鐘；430分鐘）分離純化得到化合物13A (保留時間=0.649min)和化合物13B（保留時間=1.218min)。 化合物13A和化合物13B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物13A的保留時間為0.649min，e.e.值為100%；化合物13B的保留時間為1.218min，e.e.值為100%。化合物13A (保留時間=0.649min)：LCMS (ESI) m/z: 698.1 (M+1) +。 化合物13B（保留時間=1.218min)：LCMS (ESI) m/z: 698.1 (M+1) +。 Example 13
Figure 02_image471
Step 1: To a solution of Intermediate A (1 g) in acetonitrile (15 mL) was added p-toluenesulfonic acid (526.94 mg) followed by N-chlorobutanediimide (544.81 mg), under nitrogen protection, The reaction solution was reacted at 60 degrees Celsius for 1 hour. Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the compound 13-1. LCMS (ESI) m/z: 558.0 (M+1) + . The second step: DIEA (770.86 mg), PyBrOP (3.71 g) and compound 1-1 (2.96 g) were added to a solution of compound 13-1 (1.11 g) in tetrahydrofuran (20 ml), and the reaction solution was reacted at 70 degrees Celsius 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-2. LCMS (ESI) m/z: 726.1(M+1) + . The third step: To a solution of compound 13-2 (2.3 g) in ethyl acetate (10 mL) was added a solution of ethyl acetate hydrochloride (4 mol/L, 10 mL), and the reaction solution was reacted at 15 degrees Celsius for 1 hour. The reaction solution was filtered, the filter cake was dissolved in ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13-3. LCMS (ESI) m/z: 626.2 (M+1) + . The fourth step: DIEA (165.05 mg) and HATU (242.79 mg) were added to a solution of compound 13-4 (28.75 mg) in N,N-dimethylformamide (5 ml) in turn, and the reaction solution was heated at 15 degrees Celsius. React for 30 minutes. Then compound 13-3 was added, and the reaction was continued at 15 degrees Celsius for 1 hour. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Purification by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 34%-64%, 2 minutes) gave compound 13. Compound 13 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm*10μm); mobile phase: methanol (0.1% ammonia water); gradient: carbon dioxide critical fluid 50%-50%, 2.5 minutes; 430 minutes) to obtain Compound 13A (retention time = 0.649 min) and compound 13B (retention time = 1.218 min). Compound 13A and compound 13B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 13A is 0.649min, and the ee value is 100%; the retention time of compound 13B is 1.218min, and the ee value is 100%. Compound 13A (retention time=0.649 min): LCMS (ESI) m/z: 698.1 (M+1) + . Compound 13B (retention time=1.218 min): LCMS (ESI) m/z: 698.1 (M+1) + .

實施例14

Figure 02_image473
第一步： 在10-20攝氏度下，向化合物14-1（50克）的二氯甲烷（500毫升）溶液中依次加入三乙胺（30.79克）和化合物7-2（43.73克），反應液在10-20攝氏度下反應12小時。向反應液中加入水（500毫升），反應液分層，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1到1:1）得到化合物14-2。LCMS m/z (ESI) : 257.0 (M+1) +。 第二步： 在氮氣保護下化合物14-2（50克）的甲醇（500毫升）溶液中加入濕鈀碳（5克，純度：10%），再用氮氣和氫氣分別置換三次。反應混合物在氫氣氛圍（1個大氣壓），50攝氏度下反應20小時。將反應混合物矽藻土過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1到1:1）得到化合物14-3。LCMS m/z (ESI) : 209.0 (M+1-18) +。 第三步： 向化合物14-3（20克）的乙腈（200毫升）溶液中加入三乙胺（8.95克），在15-20攝氏度下將乙醯氯（10.41克）滴加到反應液中，該反應在20攝氏度反應2小時。向反應混合物中加入飽和食鹽水（200毫升），再用乙酸乙酯（200毫升*3）萃取三次。合併有機相，乾燥，過濾，濃縮得到化合物14-4的粗品，粗品直接用於下一步反應。LCMS m/z (ESI) : 269.0 (M+1) +。 第四步： 向化合物14-4（22克）的乙腈（220毫升）溶液中依次加入碳酸銫（26.72克）和化合物7-4（16.55克），該反應在20攝氏度反應4小時。向反應混合物中加入飽和食鹽水（200毫升），再用乙酸乙酯（200毫升*2）萃取兩次，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物14-5的粗品，粗品直接用於下一步反應。LCMS m/z (ESI) : 390.9 (M+1) +。 第五步： 向化合物14-5（38克）的三氟乙醇（300毫升）溶液中加入三乙胺（19.70克），該反應在100攝氏度反應12小時。將反應液濃縮得到殘餘物，殘餘物用飽和食鹽水（100毫升）溶解，再向反應混合物中加入飽和食鹽水（200毫升），用1莫耳每升的鹽酸溶液將體系pH值調節到2，再用乙酸乙酯（200毫升*3）萃取三次，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物14-6的粗品，粗品直接用於下一步反應。LCMS m/z (ESI) : 359.0 (M+1) +。 第六步： 向化合物14-6（24克）的乙腈（250毫升）溶液中依次加入磷酸鉀（26.02克）和三溴吡啶嗡鹽（58.81克），該反應在50攝氏度反應2小時。向反應混合物中加入飽和亞硫酸鈉水溶液（200毫升），用1莫耳每升的鹽酸溶液將體系pH值調節到2，再用乙酸乙酯（200毫升*2）萃取兩次，有機相用飽和食鹽水（100毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濾液濃縮得殘餘物，殘餘物經矽膠柱純化（洗脫劑：石油醚：乙酸乙酯=5:1到1:1）得到化合物14-7。LCMS m/z (ESI) : 393.0 (M+1) +。 第七步： 向化合物14-7（10克）的二氧六環（100毫升）溶液中依次加入化合物6-4（4.20克）、碳酸鉀（7.03克）、4,5-雙二苯基膦-9,9-二甲基氧雜蒽（2.94克）和三（二亞苄基丙酮）二鈀（2.33克），該反應在氮氣保護下，100攝氏度反應6小時。將反應混合物矽藻土過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=3:1到1:1）得到化合物14-8。LCMS m/z (ESI) : 463.2 (M+1) +。 第八步： 向化合物14-8（5.90克）的二氯甲烷（60毫升）溶液中加入N-溴代丁二醯亞胺（2.77克），該反應在氮氣保護下，10攝氏度反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（10毫升），二氯甲烷（5毫升*2）萃取兩次。有機相用飽和食鹽水（50毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濾液濃縮得化合物14-9。LCMS m/z (ESI) : 541.0 (M+1) +。 第九步： 向化合物14-9（8.00克）的N,N-二甲基甲醯胺（80毫升）溶液中依次加入鋅粉（773.08毫克）、氰化鋅（1.74克）、溴化鋅（332.80毫克）、1,1-雙（二苯基膦基）二茂鐵(1.64克)和三（二亞苄基丙酮）二鈀（1.35克），該反應在氮氣保護下，120攝氏度反應2小時。將反應混合物矽藻土過濾，濾液滴加到水中（300毫升），乙酸乙酯（100毫升*2）萃取兩次。有機相濃縮得到殘餘物。殘餘物用水（100毫升）和乙酸乙酯（100毫升）的混合溶劑溶劑，再用1莫耳每升的鹽酸溶液將體系pH調節到2，然後分層，水相用飽和碳酸氫鈉水溶液調劑pH值到8，乙酸乙酯萃取（50毫升*3）萃取三次。有機相用飽和食鹽水（100毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物14-10。LCMS m/z (ESI) : 487.9 (M+1) +。 第十步： 將化合物14-10（2.5克）加入到裝有濃硫酸（13毫升）的反應瓶中，該反應在氮氣保護下，60攝氏度反應10小時。將反應液滴加到水（130毫升）中，用飽和的碳酸氫鈉水溶液將體系pH調節至8，乙酸乙酯（30毫升*3）萃取三次。有機相用飽和食鹽水（50毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物14-11。LCMS m/z (ESI) : 464.2 (M+1) +。 第十一步：
Figure 02_image475
向化合物14-11（1.6克）的四氫呋喃（20毫升）溶液中依次加入羰基二咪唑（1.68克）和氫化鈉（552.35毫克，質量百分比：60%），該反應在氮氣保護下，20攝氏度反應1小時。將反應液滴加到水（100毫升）中，用1莫耳每升的鹽酸水溶液將體系pH調節至2，再用飽和的碳酸氫鈉水溶液將體系pH調節至8，乙酸乙酯（50毫升*2）萃取兩次。有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物14-12。LCMS m/z (ESI) : 490.0 (M+1) +。 化合物14-12（消旋體）經過製備的HPLC（柱型號：Phenomenex luna C18 (250*70mm,15 μm)；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：40%-70%，35分鐘）純化後再通過製備SFC（柱型號：REGIS (s,s) WHELK-O1 (250mm*50mm,10μm)，流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，4.4分鐘，90分鐘）分離純化得到化合物14-12A（保留時間=1.348min）和14-12M（14-12B、14-12C和14-12D的混合物）。 第十二步：
Figure 02_image477
向14-12M（1.70克）的四氫呋喃（30毫升）溶液中依次加入三吡咯烷基溴化鏻六氟磷酸鹽（2.94克）、化合物1-1（2.03克）和DIEA（0.81克），該反應在氮氣保護下，70攝氏度反應10小時。LC-MS檢測到目標產物已生成。將反應混合物過濾，濾液濃縮得到殘餘物。得到的殘餘物通過製備的HPLC（色譜柱：Phenomenex luna C18 (250*70mm,15μm)；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：40%-70%，35分鐘）純化得到14-13M（14-13B、14-13C和14-13D的混合物）。LCMS m/z (ESI) : 686.3 (M+1) +。 14-13A由14-12A按照14-13M的製備方法合成得到。 第十三步：
Figure 02_image479
向14-13M（920毫克）的二氯甲烷（6毫升）溶液中加入三氟乙酸（3.08克），該反應在氮氣保護下，15攝氏度反應1小時。將反應液減壓濃縮得到14-14M（14-14B、14-14C和14-14D的混合物）的三氟乙酸鹽粗品，14-14M的三氟乙酸鹽，粗品直接用於下一步反應。LCMS m/z (ESI) : 586.1 (M+1) +。 14-14A由14-13A按照14-14M的製備方法合成得到。 第十四步：
Figure 02_image481
向化合物14-14M（1.3克，三氟乙酸鹽）的四氫呋喃（20毫升）和水（4毫升）的混合溶液中依次加入碳酸鉀（0.66克）和化合物1-5（130.33毫克），該反應在15攝氏度下反應10分鐘。向反應混合物中加入飽和食鹽水（20毫升），乙酸乙酯（30毫升*2）萃取兩次，有機相用無水硫酸鈉乾燥，過濾，濃縮得到殘餘物。得到的殘餘物通過製備的HPLC（色譜柱：Phenomenex Synergi Max-RP 250*50mm*10）；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：15%-45%，20分鐘）純化得到14M（14B、14C和14D的混合物）。 14A由14-14A按照14M的製備方法合成得到。 將14M通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體60%-60%，4分鐘，75分鐘）分離純化得到化合物14B（保留時間=2.084 min）及14-P（保留時間=1.937 min和保留時間=2.093 min的混合物）。 14-P再通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體35%-35%，3分鐘，90分鐘）分離純化得到化合物14C（保留時間=1.387 min）和化合物14D（保留時間=1.910 min）。 化合物14B經SFC檢測[柱型號：Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物14B的保留時間為2.084min，e.e.值為100%。 化合物14C和化合物14D經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物14C的保留時間為1.387min，e.e.值為100%；化合物14D的保留時間為1.910min，e.e.值為100%。 化合物14A： 1H NMR (400 MHz, DMSO- d 6) δ 8.34 (d, J= 4.8 Hz, 1H), 7.23-7.02 (m, 3H), 6.98-6.81 (m, 2H), 6.55 (dt, J= 5.6, 8.0 Hz, 1H), 6.33-6.19 (m, 1H), 5.82 (ddd, J= 2.1, 7.3, 9.9 Hz, 1H), 5.42 (s, 2H), 4.85-4.48 (m, 2H), 4.13-3.54 (m, 4H), 2.95-2.79 (m, 1H), 2.05 (s, 3H), 1.46-1.34 (m, 3H), 1.31-1.21 (m, 3H), 1.14-1.02 (m, 6H)。LCMS (ESI) m/z: 640.3 (M+1) +。 化合物14B（保留時間=2.084 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J= 4.9Hz, 1H), 7.13-7.05 (m, 2H), 7.00 (s, 1H), 6.84 (td, J= 10.7, 16.6 Hz, 1H), 6.67 (br d, J= 7.9Hz, 1H), 6.50 (dt, J= 5.5, 8.1 Hz, 1H), 6.27-6.15 (m, 1H), 5.82-5.71 (m, 1H), 5.43 (s, 2H), 4.84-4.47 (m, 2H), 4.20-3.71 (m, 4H), 2.72 (td, J= 6.9, 13.4 Hz, 1H), 2.03 (d, J= 3.8 Hz, 3H), 1.33 (br t, J= 6.8 Hz, 3H), 1.27-1.14 (m, 3H), 1.05 (br d, J= 6.6 Hz, 3H), 0.96 (d, J= 6.5 Hz, 3H)。LCMS (ESI) m/z: 640.3(M+1) +。 化合物14C（保留時間=1.387min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J= 4.8Hz, 1H), 7.19-6.96 (m, 3H), 6.93-6.77 (m, 1H), 6.70 (br d, J= 8.1 Hz, 1H), 6.49 (dt, J= 5.5, 8.1 Hz, 1H), 6.27-6.13 (m, 1H), 5.81-5.70 (m, 1H), 5.38 (s, 2H), 4.81-4.43 (m, 2H), 4.16-3.45 (m, 4H), 2.59 (quin, J= 6.7 Hz, 1H), 2.12 (s, 3H), 1.33 (br t, J= 6.1 Hz, 3H), 1.26-1.11 (m, 3H), 0.98 (dd, J= 6.8, 10.1 Hz, 6H)。LCMS (ESI) m/z: 640.3(M+1) +。 化合物14D（保留時間=1.910min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.28 (d, J= 4.9 Hz, 1H), 7.13-6.95 (m, 3H), 6.88-6.77 (m, 2H), 6.48 (dt, J= 5.6, 8.0 Hz, 1H), 6.19 (dd, J= 2.4, 16.4 Hz, 1H), 5.81-5.70 (m, 1H), 5.36 (s, 2H), 4.82-4.44 (m, 2H), 4.16-3.42 (m, 4H), 3.09-2.92 (m, 1H), 1.90 (d, J= 2.4 Hz, 3H), 1.32 (br t, J= 6.3 Hz, 3H), 1.25-1.14 (m, 3H), 1.07 (br dd, J= 6.5, 15.7 Hz, 6H)。LCMS (ESI) m/z: 640.3 (M+1) +。 Example 14
Figure 02_image473
The first step: Triethylamine (30.79 g) and compound 7-2 (43.73 g) were sequentially added to a solution of compound 14-1 (50 g) in dichloromethane (500 ml) at 10-20 degrees Celsius, and the reaction The solution was reacted at 10-20 degrees Celsius for 12 hours. Water (500 ml) was added to the reaction solution, the layers of the reaction solution were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-2. LCMS m/z (ESI): 257.0 (M+1) + . The second step: Add wet palladium carbon (5 g, purity: 10%) to a solution of compound 14-2 (50 g) in methanol (500 ml) under nitrogen protection, and then replace it with nitrogen and hydrogen three times respectively. The reaction mixture was reacted under a hydrogen atmosphere (1 atm) at 50°C for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 1:1) to obtain compound 14-3. LCMS m/z (ESI): 209.0 (M+1-18) + . The third step: Triethylamine (8.95 g) was added to a solution of compound 14-3 (20 g) in acetonitrile (200 ml), and acetyl chloride (10.41 g) was added dropwise to the reaction solution at 15-20 degrees Celsius , the reaction was carried out at 20 degrees Celsius for 2 hours. Saturated brine (200 mL) was added to the reaction mixture, followed by extraction three times with ethyl acetate (200 mL*3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product of compound 14-4, which was directly used in the next reaction. LCMS m/z (ESI) : 269.0 (M+1) + . Fourth step: To a solution of compound 14-4 (22 g) in acetonitrile (220 ml) were sequentially added cesium carbonate (26.72 g) and compound 7-4 (16.55 g), and the reaction was carried out at 20 degrees Celsius for 4 hours. Saturated brine (200 mL) was added to the reaction mixture, and extracted twice with ethyl acetate (200 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 14-5. The crude product was directly used for the next reaction. LCMS m/z (ESI): 390.9 (M+1) + . Fifth step: To a solution of compound 14-5 (38 g) in trifluoroethanol (300 ml) was added triethylamine (19.70 g), and the reaction was carried out at 100 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue. The residue was dissolved in saturated brine (100 mL), and saturated brine (200 mL) was added to the reaction mixture. The pH of the system was adjusted to 2 with 1 mol/liter hydrochloric acid solution. , and then extracted three times with ethyl acetate (200 mL*3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 14-6, which was directly used in the next reaction. LCMS m/z (ESI): 359.0 (M+1) + . The sixth step: To a solution of compound 14-6 (24 g) in acetonitrile (250 ml) were sequentially added potassium phosphate (26.02 g) and pyridinium tribromide (58.81 g), and the reaction was carried out at 50°C for 2 hours. Saturated aqueous sodium sulfite solution (200 mL) was added to the reaction mixture, the pH of the system was adjusted to 2 with 1 mol/L hydrochloric acid solution, and then extracted twice with ethyl acetate (200 mL*2), and the organic phase was saturated with common salt It was washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue, which was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound 14 -7. LCMS m/z (ESI): 393.0 (M+1) + . The seventh step: Compound 6-4 (4.20 g), potassium carbonate (7.03 g) and 4,5-bisdiphenyl were added to the solution of compound 14-7 (10 g) in dioxane (100 ml) in sequence Phosphine-9,9-dimethylxanthene (2.94 g) and tris(dibenzylideneacetone)dipalladium (2.33 g) were reacted under nitrogen protection at 100 degrees Celsius for 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 14-8. LCMS m/z (ESI) : 463.2 (M+1) + . The eighth step: N-bromosuccinimide (2.77 g) was added to a solution of compound 14-8 (5.90 g) in dichloromethane (60 ml), and the reaction was carried out under nitrogen protection at 10 degrees Celsius for 1 hour . Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (5 mL*2). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-9. LCMS m/z (ESI) : 541.0 (M+1) + . The ninth step: Zinc powder (773.08 mg), zinc cyanide (1.74 g), zinc bromide were added to the N,N-dimethylformamide (80 ml) solution of compound 14-9 (8.00 g) in turn (332.80 mg), 1,1-bis(diphenylphosphino)ferrocene (1.64 g) and tris(dibenzylideneacetone)dipalladium (1.35 g), the reaction was carried out under nitrogen at 120 degrees Celsius 2 hours. The reaction mixture was filtered through celite, the filtrate was added dropwise to water (300 mL), and extracted twice with ethyl acetate (100 mL*2). The organic phase was concentrated to give a residue. The residue was dissolved in a mixed solvent of water (100 mL) and ethyl acetate (100 mL), and the pH of the system was adjusted to 2 with 1 mol/liter hydrochloric acid solution, then the layers were separated, and the aqueous phase was adjusted with saturated aqueous sodium bicarbonate solution The pH value was reached to 8, and ethyl acetate extraction (50 ml*3) was performed three times. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain residue 14-10. LCMS m/z (ESI): 487.9 (M+1) + . The tenth step: Compound 14-10 (2.5 g) was added to a reaction flask containing concentrated sulfuric acid (13 ml), and the reaction was carried out under nitrogen protection at 60 degrees Celsius for 10 hours. The reaction was added dropwise to water (130 mL), the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-11. LCMS m/z (ESI): 464.2 (M+1) + . Step 11:
Figure 02_image475
To a solution of compound 14-11 (1.6 g) in tetrahydrofuran (20 ml), carbonyldiimidazole (1.68 g) and sodium hydride (552.35 mg, mass percentage: 60%) were added successively, and the reaction was carried out under nitrogen protection at 20 degrees Celsius. 1 hour. The reaction was added dropwise to water (100 mL), the pH of the system was adjusted to 2 with 1 mol/L aqueous hydrochloric acid solution, and the pH of the system was adjusted to 8 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (50 mL) *2) Extract twice. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-12. LCMS m/z (ESI) : 490.0 (M+1) + . Compounds 14-12 (racemate) were subjected to preparative HPLC (column type: Phenomenex luna C18 (250*70mm, 15 μm); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 40%-70%, 35 minutes) and purified by preparative SFC (column type: REGIS (s,s) WHELK-O1 (250mm*50mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%- 50%, 4.4 min, 90 min) was isolated and purified to obtain compound 14-12A (retention time = 1.348 min) and 14-12M (mixture of 14-12B, 14-12C and 14-12D). Step 12:
Figure 02_image477
To a solution of 14-12M (1.70 g) in tetrahydrofuran (30 ml) were added tripyrrolidinophosphonium bromide hexafluorophosphate (2.94 g), compound 1-1 (2.03 g) and DIEA (0.81 g) in sequence. The reaction was carried out at 70 degrees Celsius for 10 hours under nitrogen protection. LC-MS detected the formation of the target product. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70mm, 15μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 40%-70%, 35 minutes) to give 14 -13M (mixture of 14-13B, 14-13C and 14-13D). LCMS m/z (ESI) : 686.3 (M+1) + . 14-13A was synthesized from 14-12A according to the preparation method of 14-13M. Step Thirteen:
Figure 02_image479
To a solution of 14-13M (920 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g) and the reaction was allowed to proceed for 1 hour at 15°C under nitrogen. The reaction solution was concentrated under reduced pressure to obtain 14-14M (mixture of 14-14B, 14-14C and 14-14D) crude trifluoroacetate, 14-14M trifluoroacetate, the crude product was directly used in the next reaction. LCMS m/z (ESI): 586.1 (M+1) + . 14-14A was synthesized from 14-13A according to the preparation method of 14-14M. Step 14:
Figure 02_image481
To a mixed solution of compound 14-14M (1.3 g, trifluoroacetate) in tetrahydrofuran (20 ml) and water (4 ml) were sequentially added potassium carbonate (0.66 g) and compound 1-5 (130.33 mg), the reaction React at 15 degrees Celsius for 10 minutes. Saturated brine (20 mL) was added to the reaction mixture, extracted twice with ethyl acetate (30 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 15%-45%, 20 minutes) to give 14M (mixture of 14B, 14C and 14D). 14A was synthesized from 14-14A according to the preparation method of 14M. 14M was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 4 minutes, 75 minutes) Compounds 14B (RT=2.084 min) and 14-P (mixture of RT=1.937 min and RT=2.093 min). 14-P was then separated by preparative SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 3 minutes, 90 minutes) Purification gave compound 14C (retention time=1.387 min) and compound 14D (retention time=1.910 min). Compound 14B was detected by SFC [column type: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient (B%): 5 %-40%] obtained: the retention time of compound 14B was 2.084 min, and the ee value was 100%. Compound 14C and compound 14D were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 14C was 1.387 min, and the ee value was 100%; the retention time of compound 14D was 1.910 min, and the ee value was 100%. Compound 14A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.34 (d, J = 4.8 Hz, 1H), 7.23-7.02 (m, 3H), 6.98-6.81 (m, 2H), 6.55 (dt, J = 5.6, 8.0 Hz, 1H), 6.33-6.19 (m, 1H), 5.82 (ddd, J = 2.1, 7.3, 9.9 Hz, 1H), 5.42 (s, 2H), 4.85-4.48 (m, 2H) , 4.13-3.54 (m, 4H), 2.95-2.79 (m, 1H), 2.05 (s, 3H), 1.46-1.34 (m, 3H), 1.31-1.21 (m, 3H), 1.14-1.02 (m, 6H). LCMS (ESI) m/z: 640.3 (M+1) + . Compound 14B (RT=2.084 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J = 4.9 Hz, 1H), 7.13-7.05 (m, 2H), 7.00 (s, 1H) , 6.84 (td, J = 10.7, 16.6 Hz, 1H), 6.67 (br d, J = 7.9Hz, 1H), 6.50 (dt, J = 5.5, 8.1 Hz, 1H), 6.27-6.15 (m, 1H) , 5.82-5.71 (m, 1H), 5.43 (s, 2H), 4.84-4.47 (m, 2H), 4.20-3.71 (m, 4H), 2.72 (td, J = 6.9, 13.4 Hz, 1H), 2.03 (d, J = 3.8 Hz, 3H), 1.33 (br t, J = 6.8 Hz, 3H), 1.27-1.14 (m, 3H), 1.05 (br d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H). LCMS (ESI) m/z: 640.3(M+1) + . Compound 14C (retention time = 1.387 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J = 4.8 Hz, 1H), 7.19-6.96 (m, 3H), 6.93-6.77 (m, 1H), 6.70 (br d, J = 8.1 Hz, 1H), 6.49 (dt, J = 5.5, 8.1 Hz, 1H), 6.27-6.13 (m, 1H), 5.81-5.70 (m, 1H), 5.38 ( s, 2H), 4.81-4.43 (m, 2H), 4.16-3.45 (m, 4H), 2.59 (quin, J = 6.7 Hz, 1H), 2.12 (s, 3H), 1.33 (br t, J = 6.1 Hz, 3H), 1.26-1.11 (m, 3H), 0.98 (dd, J = 6.8, 10.1 Hz, 6H). LCMS (ESI) m/z: 640.3(M+1) + . Compound 14D (retention time = 1.910 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.28 (d, J = 4.9 Hz, 1H), 7.13-6.95 (m, 3H), 6.88-6.77 (m, 2H), 6.48 (dt, J = 5.6, 8.0 Hz, 1H), 6.19 (dd, J = 2.4, 16.4 Hz, 1H), 5.81-5.70 (m, 1H), 5.36 (s, 2H), 4.82-4.44 (m, 2H), 4.16-3.42 (m, 4H), 3.09-2.92 (m, 1H), 1.90 (d, J = 2.4 Hz, 3H), 1.32 (br t, J = 6.3 Hz, 3H), 1.25 -1.14 (m, 3H), 1.07 (br dd, J = 6.5, 15.7 Hz, 6H). LCMS (ESI) m/z: 640.3 (M+1) + .

實施例15

Figure 02_image483
第一步： 向化合物11-12（400毫克）的四氫呋喃（10毫升）溶液中依次加入三吡咯烷基溴化鏻六氟磷酸鹽（1.01克）、化合物3-2（930.74毫克）和DIEA（280.66毫克），該反應在氮氣保護下，70攝氏度反應10小時。LC-MS檢測到目標產物已生成。將反應混合物過濾，濾液濃縮得到化合物15-1。得到的粗品直接用於下一步反應。LCMS m/z (ESI) : 720.3 (M+1) +。 第二步： 向化合物15-1（500毫克）的二氯甲烷（3毫升）溶液中加入三氟乙酸（1.54克），該反應在氮氣保護下，10攝氏度反應20分鐘。將反應液濃縮得到化合物15-2的三氟乙酸鹽，粗品直接用於下一步反應。LCMS m/z (ESI) : 620.2 (M+1) +。 第三步：
Figure 02_image485
向化合物15-2（600.00毫克，三氟乙酸鹽）的四氫呋喃（6毫升）和水（2毫升）混合溶液中依次加入碳酸鉀（293.34毫克）和化合物1-5（64.03毫克），該反應在10攝氏度下反應10分鐘。向反應混合物中加入飽和碳酸氫鈉水溶液（20毫升），乙酸乙酯（30毫升*3）萃取三次。有機相用飽和食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濃縮得到殘餘物。殘餘物通過製備板純化（二氯甲烷呢：甲醇=20:1）。得到的化合物15。 化合物15通過製備SFC（柱型號：DAICEL CHIRALPAK IC 250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體55%-55%，38分鐘，40分鐘）分離純化得到化合物15A及15-P1。 15-P1再通過製備SFC（REGIS(S,S)WHELK-O1 250mm*25mm,10μm)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，4.3分鐘，570分鐘）分離純化得到化合物15B（和15-P2。 15-P2再通過製備SFC（柱型號：DAICEL CHIRALPAK AD（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體35%-35%，4.1分鐘，50分鐘）分離純化得到化合物15C，和化合物15D。 化合物15A經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物15A的保留時間為0.760min，e.e.值為100%。 化合物15B、化合物15C和化合物15D經SFC檢測[柱型號：(s,s)Whelk-OI 100×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物15B的保留時間為2.255min，e.e.值為100%；化合物15C的保留時間為2.641min，e.e.值為100%；化合物15D的保留時間為2.503min，e.e.值為100%。 化合物15A（保留時間=0.760 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J= 4.8 Hz, 1H), 7.30 (dd, J= 2.2, 11.0 Hz, 1H), 7.10-7.03 (m, 1H), 6.99 (s, 1H), 6.89-6.75 (m, 2H), 6.19 (br d, J= 16.5 Hz, 1H), 5.83-5.70 (m, 1H), 5.66 (s, 2H), 4.84-4.47 (m, 2H), 4.20-3.64 (m, 4H), 2.74 (td, J= 3.3, 6.4 Hz, 1H), 2.01 (br d, J= 4.0 Hz, 3H), 1.33 (br t, J= 6.7 Hz, 3H), 1.25-1.15 (m, 3H), 1.04 (br d, J= 6.4 Hz, 3H), 0.96 (br d, J= 6.5 Hz, 3H)。LCMS (ESI) m/z: 674.3(M+1) +。 化合物15B（保留時間=2.255 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J= 4.9 Hz, 1H), 7.30 (dd, J= 2.2, 10.9 Hz, 1H), 7.14-7.06 (m, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 6.88-6.73 (m, 1H), 6.26-6.15 (m, 1H), 5.81-5.71 (m, 1H), 5.62 (s, 2H), 4.82-4.45 (m, 2H), 4.10-3.76 (m, 4H), 3.55 - 3.46 (m, 1H), 2.16-2.06 (m, 3H), 1.33 (br t, J= 6.0 Hz, 3H), 1.24-1.12 (m, 3H), 0.98 (br d, J= 6.6 Hz, 6H)。LCMS (ESI) m/z: 674.2(M+1) +。 化合物15C（保留時間=2.641min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J= 4.8 Hz, 1H), 7.28 (dd, J= 2.3, 11.0 Hz, 1H), 7.07-7.02 (m, 2H), 7.01 (s, 1H), 6.84 (ddd, J= 5.6, 10.6, 16.5 Hz, 1H), 6.20 (br dd, J= 2.1, 16.6 Hz, 1H), 5.76 (ddd, J= 2.2, 7.4, 10.0 Hz, 1H), 5.60 (s, 2H), 4.81-4.45 (m, 2H), 4.17-3.68 (m, 4H), 2.99 (td, J= 6.4, 13.1 Hz, 1H), 1.91 (d, J= 2.5 Hz, 3H), 1.36-1.29 (m, 3H), 1.22-1.13 (m, 3H), 1.10-1.08 (m, 3H), 1.05 (s, 3H)。LCMS (ESI) m/z: 674.2 (M+1) +。 化合物15D（保留時間=2.503min）： 1H NMR (400 MHz, DMSO- d 6) δ 8.30 (d, J= 4.8 Hz, 1H), 7.28 (dd, J= 2.3, 11.0 Hz, 1H), 7.07-7.02 (m, 2H), 7.01 (s, 1H), 6.84 (ddd, J= 5.6, 10.6, 16.5 Hz, 1H), 6.20 (br dd, J= 2.1, 16.6 Hz, 1H), 5.76 (ddd, J= 2.2, 7.4, 10.0 Hz, 1H), 5.60 (s, 2H), 4.81-4.45 (m, 2H), 4.17-3.75 (m, 4H), 2.99 (td, J= 6.4, 13.1 Hz, 1H), 1.91 (d, J= 2.5 Hz, 3H), 1.39-1.29 (m, 3H), 1.23-1.13 (m, 3H), 1.10-1.07 (m, 3H), 1.05 (s, 3H)。LCMS (ESI) m/z: 674.2 (M+1) +。 Example 15
Figure 02_image483
Step 1: To a solution of compound 11-12 (400 mg) in tetrahydrofuran (10 mL) were added tripyrrolidinophosphonium bromide hexafluorophosphate (1.01 g), compound 3-2 (930.74 mg) and DIEA ( 280.66 mg), the reaction was carried out under nitrogen protection at 70 degrees Celsius for 10 hours. LC-MS detected the formation of the target product. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 15-1. The obtained crude product was directly used in the next reaction. LCMS m/z (ESI) : 720.3 (M+1) + . The second step: To a solution of compound 15-1 (500 mg) in dichloromethane (3 ml) was added trifluoroacetic acid (1.54 g), and the reaction was carried out under nitrogen protection at 10 degrees Celsius for 20 minutes. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 15-2, and the crude product was directly used in the next reaction. LCMS m/z (ESI) : 620.2 (M+1) + . third step:
Figure 02_image485
To a mixed solution of compound 15-2 (600.00 mg, trifluoroacetate) in tetrahydrofuran (6 mL) and water (2 mL) were added potassium carbonate (293.34 mg) and compound 1-5 (64.03 mg) sequentially, and the reaction was carried out in The reaction was carried out at 10 degrees Celsius for 10 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was extracted three times with ethyl acetate (30 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by preparative plate (dichloromethane:methanol=20:1). Compound 15 was obtained. Compound 15 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC 250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 55%-55%, 38 minutes, 40 minutes) to obtain the compound 15A and 15-P1. 15-P1 was then prepared by SFC (REGIS(S,S) WHELK-O1 250mm*25mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.3 minutes, 570 minutes ) was isolated and purified to obtain compound 15B (and 15-P2. 15-P2 was then passed through preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical Fluid 35%-35%, 4.1 minutes, 50 minutes) was separated and purified to obtain compound 15C and compound 15D. Compound 15A was detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: A phase was Supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 40%-40%] to obtain: compound 15A with a retention time of 0.760 min and an ee value of 100%. Compound 15B, Compound 15C and compound 15D were detected by SFC [column type: (s,s)Whelk-OI 100×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 40%-40%] obtained: the retention time of compound 15B is 2.255min, the ee value is 100%; the retention time of compound 15C is 2.641min, the ee value is 100%; the retention time of compound 15D is 2.503min , the ee value is 100%. Compound 15A (retention time = 0.760 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J = 4.8 Hz, 1H), 7.30 (dd, J = 2.2, 11.0 Hz, 1H), 7.10-7.03 (m, 1H), 6.99 (s, 1H), 6.89-6.75 (m, 2H), 6.19 (br d, J = 16.5 Hz, 1H), 5.83-5.70 (m, 1H), 5.66 (s, 2H), 4.84-4.47 (m, 2H), 4.20-3.64 (m, 4H), 2.74 (td, J = 3.3, 6.4 Hz, 1H), 2.01 (br d, J = 4.0 Hz, 3H), 1.33 (br t, J = 6.7 Hz, 3H), 1.25-1.15 (m, 3H), 1.04 (br d, J = 6.4 Hz, 3H), 0.96 (br d, J = 6.5 Hz , 3H). LCMS (ESI) m/z: 674.3(M+1) + . Compound 15B (retention time = 2.255 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.9 Hz, 1H), 7.30 (dd, J = 2.2, 10.9 Hz, 1H), 7.14 -7.06 (m, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 6.88-6.73 (m, 1H), 6.26-6.15 (m, 1H), 5.81-5.71 (m, 1H), 5.62 (s, 2H), 4.82-4.45 (m, 2H), 4.10-3.76 (m, 4H), 3.55 - 3.46 (m, 1H), 2.16-2.06 (m, 3H), 1.33 (br t, J = 6.0 Hz, 3H), 1.24-1.12 (m, 3H), 0.98 (br d, J = 6.6 Hz, 6H). LCMS (ESI) m/z: 674.2(M+1) + . Compound 15C (retention time = 2.641 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.8 Hz, 1H), 7.28 (dd, J = 2.3, 11.0 Hz, 1H), 7.07 -7.02 (m, 2H), 7.01 (s, 1H), 6.84 (ddd, J = 5.6, 10.6, 16.5 Hz, 1H), 6.20 (br dd, J = 2.1, 16.6 Hz, 1H), 5.76 (ddd, J = 2.2, 7.4, 10.0 Hz, 1H), 5.60 (s, 2H), 4.81-4.45 (m, 2H), 4.17-3.68 (m, 4H), 2.99 (td, J = 6.4, 13.1 Hz, 1H) , 1.91 (d, J = 2.5 Hz, 3H), 1.36-1.29 (m, 3H), 1.22-1.13 (m, 3H), 1.10-1.08 (m, 3H), 1.05 (s, 3H). LCMS (ESI) m/z: 674.2 (M+1) + . Compound 15D (retention time = 2.503 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.8 Hz, 1H), 7.28 (dd, J = 2.3, 11.0 Hz, 1H), 7.07 -7.02 (m, 2H), 7.01 (s, 1H), 6.84 (ddd, J = 5.6, 10.6, 16.5 Hz, 1H), 6.20 (br dd, J = 2.1, 16.6 Hz, 1H), 5.76 (ddd, J = 2.2, 7.4, 10.0 Hz, 1H), 5.60 (s, 2H), 4.81-4.45 (m, 2H), 4.17-3.75 (m, 4H), 2.99 (td, J = 6.4, 13.1 Hz, 1H) , 1.91 (d, J = 2.5 Hz, 3H), 1.39-1.29 (m, 3H), 1.23-1.13 (m, 3H), 1.10-1.07 (m, 3H), 1.05 (s, 3H). LCMS (ESI) m/z: 674.2 (M+1) + .

實施例16和實施例17

Figure 02_image487
第一步：
Figure 02_image489
向中間體A（1.00克）的N,N-二甲基乙醯胺（10毫升）溶液中依次加入三吡咯烷基溴化鏻六氟磷酸鹽（1.91克）、化合物3-1（1.75克）和DIEA（0.53克），該反應在氮氣保護下，70攝氏度反應10小時。將反應液倒入水（30毫升）中，有固體析出，過濾，濾餅乾燥得到粗品。粗品通過製備的HPLC（色譜柱：Phenomenex luna C18 (250*70mm,10 μm)；流動相：[0.225%的甲酸水溶液-乙腈]；乙腈：30%-50%，35分鐘）純化得到消旋體。消旋體通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，4.4分鐘，45分鐘）分離純化得到化合物16-1A（保留時間=0.615 min）及化合物16-1B（保留時間=1.066 分鐘）。 化合物16-1A（保留時間=0.615分鐘）： LCMS m/z (ESI) : 686.3 (M+1) +。 化合物16-1B（保留時間=1.910分鐘）： LCMS m/z (ESI) : 686.3 (M+1) +。 第二步：
Figure 02_image491
分別向化合物16-1A和16-1B（280毫克）的乙腈（10毫升）溶液中依次加入N-氯代丁二醯亞胺（52.86毫克）和對甲基苯磺酸（68.17毫克），該反應在氮氣保護下，60攝氏度反應1小時。向反應液中加入飽和的亞硫酸鈉水溶液（20毫升），乙酸乙酯（30毫升*2）萃取兩次。有機相用飽和食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濃縮到殘餘物。殘餘物經矽膠板純化（石油醚：乙酸乙酯：甲醇 = 8：3：1）分別得到化合物16-2A和化合物17-1A、化合物16-2B和化合物17-1B。 16-2A和16-2B:LCMS m/z (ESI) : 720.3 (M+1) +。 17-1A和17-1B:LCMS m/z (ESI) : 720.1 (M+1) +。 化合物16-2A： 1H NMR (400 MHz, CHLOROFORM- d) δ 8.37 (d, J= 4.9 Hz, 1H), 7.24-7.18 (m, 1H), 6.96-6.88 (m, 2H), 6.42 (t, J= 8.9 Hz, 1H), 4.83-4.62 (m, 1H), 4.58-4.29 (m, 1H), 3.97-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.48 (br d, J= 13.5 Hz, 1H), 2.63-2.57 (m, 1H), 2.01 (s, 3H), 1.44 (s, 9H), 1.36 (br d, J= 6.5 Hz, 3H), 1.21-1.19 (m, 3H), 1.12 (d, J= 6.6 Hz, 3H), 1.02 (d, J= 6.8 Hz, 3H)。 第三步：
Figure 02_image493
分別向化合物16-2A、化合物17-1A、化合物16-2B和化合物17-1B（90毫克）的二氯甲烷（1.5毫升）溶液中加入三氟乙酸（770.00毫克），該反應在氮氣保護下，10攝氏度反應0.5小時。分別將反應液濃縮得到化合物16-3A的三氟乙酸鹽、化合物17-2A的三氟乙酸鹽、化合物16-3B的三氟乙酸鹽和化合物17-2B的三氟乙酸鹽，粗品直接用於下一步反應。 16-3A 和16-3B:LCMS m/z (ESI) : 620.3 (M+1) +。 17-2A 和17-2B:LCMS m/z (ESI) : 620.0 (M+1) +。 第四步：
Figure 02_image495
分別向化合物16-3A、化合物17-2A、化合物16-3B和化合物17-2B（101.00毫克，三氟乙酸鹽）的四氫呋喃（6毫升）和水（2毫升）混合溶液中依次加入碳酸鉀（49.38毫克）和化合物1-5（10.78毫克），該反應在10攝氏度下反應20分鐘。向反應混合物中加入飽和碳酸氫鈉水溶液（20毫升），乙酸乙酯（20毫升*3）萃取三次。有機相用飽和食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥，過濾，濃縮得到殘餘物。得到的殘餘物分別通過製備的HPLC（色譜柱：Phenomenex Luna C18 150*25mm*10μm）；流動相：[0.225%的甲酸水溶液-乙腈]；梯度：22%-52%，20分鐘）純化得到實施例16A、16B、17A和17B。 化合物16A: 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J= 4.9 Hz, 1H), 7.35 (dd, J= 5.8, 8.9 Hz, 1H), 7.12-7.00 (m, 2H), 6.92-6.72 (m, 1H), 6.46 (t, J= 9.1 Hz, 1H), 6.20 (br d, J= 16.6 Hz, 1H), 6.00 (s, 2H), 5.81-5.67 (m, 1H), 4.85-4.46 (m, 2H), 4.21-3.66 (m, 4H), 2.72-2.60 (m, 1H), 2.03 (d, J= 3.4 Hz, 3H), 1.33 (t, J= 7.4 Hz, 3H), 1.28-1.17 (m, 3H), 1.07-1.00 (m, 3H), 0.93 (d, J= 6.6 Hz, 3H)。LCMS m/z (ESI) : 674.2 (M+1) +。 化合物16B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (br d, J= 4.5 Hz, 1H), 7.35 (br dd, J= 5.8, 8.3 Hz, 1H), 7.06 (br s, 2H), 6.92-6.75 (m, 1H), 6.46 (br t, J= 8.9 Hz, 1H), 6.19 (br d, J= 16.5 Hz, 1H), 5.97 (br s, 2H), 5.83-5.66 (m, 1H), 4.834.44 (m, 2H), 4.18-3.66 (m, 4H), 2.90-2.73 (m, 1H), 1.92 (br s, 3H), 1.33 (br t, J= 6.4 Hz, 3H), 1.28-1.13 (m, 3H), 1.03 (br d, J= 5.8 Hz, 6H)。LCMS m/z (ESI) : 674.2 (M+1) +。 化合物17A： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J= 4.8 Hz, 1H), 7.26 (t, J= 8.7 Hz, 1H), 7.11-7.02 (m, 2H), 6.83 (td, J= 10.9, 16.5 Hz, 1H), 6.52 (dd, J= 1.3, 9.2 Hz, 1H), 6.26 - 6.14 (m, 1H), 5.89 (s, 2H), 5.75 (ddd, J= 2.3, 6.1, 10.3 Hz, 1H), 4.85-4.45 (m, 2H), 4.21-3.40 (m, 4H), 2.73-2.61 (m, 1H), 2.01 (d, J= 3.5 Hz, 3H), 1.37-1.28 (m, 3H), 1.27-1.15 (m, 3H), 1.04 (d, J= 6.6 Hz, 3H), 0.95 (d, J= 6.6 Hz, 3H)。LCMS m/z (ESI) : 674.3 (M+1) +。 化合物17B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J= 4.9 Hz, 1H), 7.25 (t, J= 8.7 Hz, 1H), 7.11-7.04 (m, 2H), 6.83 (td, J= 9.7, 16.6 Hz, 1H), 6.52 (dd, J= 1.2, 9.2 Hz, 1H), 6.25-6.14 (m, 1H), 5.88 (s, 2H), 5.80-5.70 (m, 1H), 4.82-4.43 (m, 2H), 4.14-3.47 (m, 4H), 2.78 (qd, J= 6.6, 13.3 Hz, 1H), 1.95 (s, 3H), 1.37-1.29 (m, 3H), 1.24-1.14 (m, 3H), 1.03-0.97 (m, 6H)。LCMS m/z (ESI) : 674.3 (M+1) +。 Example 16 and Example 17
Figure 02_image487
first step:
Figure 02_image489
To a solution of Intermediate A (1.00 g) in N,N-dimethylacetamide (10 mL) were added tripyrrolidinophosphonium bromide hexafluorophosphate (1.91 g), compound 3-1 (1.75 g) in this order ) and DIEA (0.53 g), and the reaction was carried out under nitrogen protection at 70 degrees Celsius for 10 hours. The reaction solution was poured into water (30 mL), a solid was precipitated, filtered, and the filter cake was dried to obtain a crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [0.225% formic acid in water-acetonitrile]; acetonitrile: 30%-50%, 35 minutes) to give the racemate . The racemate was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4.4 minutes, 45 minutes) Compound 16-1A (retention time=0.615 min) and compound 16-1B (retention time=1.066 min) were obtained. Compound 16-1A (retention time=0.615 min): LCMS m/z (ESI): 686.3 (M+1)+. Compound 16-1B (retention time=1.910 min): LCMS m/z (ESI): 686.3 (M+1)+. Step 2:
Figure 02_image491
To a solution of compounds 16-1A and 16-1B (280 mg) in acetonitrile (10 mL) were added N-chlorosuccinimide (52.86 mg) and p-toluenesulfonic acid (68.17 mg) sequentially, the The reaction was carried out at 60 degrees Celsius for 1 hour under nitrogen protection. Saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution, followed by extraction twice with ethyl acetate (30 mL*2). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a residue. The residue was purified by silica gel plate (petroleum ether:ethyl acetate:methanol=8:3:1) to obtain compound 16-2A and compound 17-1A, compound 16-2B and compound 17-1B, respectively. 16-2A and 16-2B: LCMS m/z (ESI): 720.3 (M+1) + . 17-1A and 17-1B: LCMS m/z (ESI): 720.1 (M+1) + . Compound 16-2A: 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.37 (d, J = 4.9 Hz, 1H), 7.24-7.18 (m, 1H), 6.96-6.88 (m, 2H), 6.42 (t , J = 8.9 Hz, 1H), 4.83-4.62 (m, 1H), 4.58-4.29 (m, 1H), 3.97-3.84 (m, 1H), 3.78-3.71 (m, 1H), 3.48 (br d, J = 13.5 Hz, 1H), 2.63-2.57 (m, 1H), 2.01 (s, 3H), 1.44 (s, 9H), 1.36 (br d, J = 6.5 Hz, 3H), 1.21-1.19 (m, 3H), 1.12 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H). third step:
Figure 02_image493
To a solution of compound 16-2A, compound 17-1A, compound 16-2B and compound 17-1B (90 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (770.00 mg), respectively, and the reaction was carried out under nitrogen protection , 10 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate of compound 16-3A, the trifluoroacetate of compound 17-2A, the trifluoroacetate of compound 16-3B and the trifluoroacetate of compound 17-2B, and the crude product was directly used for next reaction. 16-3A and 16-3B: LCMS m/z (ESI) : 620.3 (M+1) + . 17-2A and 17-2B: LCMS m/z (ESI) : 620.0 (M+1) + . the fourth step:
Figure 02_image495
Potassium carbonate ( 49.38 mg) and compound 1-5 (10.78 mg), which were reacted at 10 degrees Celsius for 20 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was extracted three times with ethyl acetate (20 mL*3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The obtained residues were purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10μm); mobile phase: [0.225% formic acid in water-acetonitrile]; gradient: 22%-52%, 20 minutes) Examples 16A, 16B, 17A and 17B. Compound 16A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.9 Hz, 1H), 7.35 (dd, J = 5.8, 8.9 Hz, 1H), 7.12-7.00 (m, 2H) , 6.92-6.72 (m, 1H), 6.46 (t, J = 9.1 Hz, 1H), 6.20 (br d, J = 16.6 Hz, 1H), 6.00 (s, 2H), 5.81-5.67 (m, 1H) , 4.85-4.46 (m, 2H), 4.21-3.66 (m, 4H), 2.72-2.60 (m, 1H), 2.03 (d, J = 3.4 Hz, 3H), 1.33 (t, J = 7.4 Hz, 3H) ), 1.28-1.17 (m, 3H), 1.07-1.00 (m, 3H), 0.93 (d, J = 6.6 Hz, 3H). LCMS m/z (ESI): 674.2 (M+1) + . Compound 16B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (br d, J = 4.5 Hz, 1H), 7.35 (br dd, J = 5.8, 8.3 Hz, 1H), 7.06 (br s, 2H) ), 6.92-6.75 (m, 1H), 6.46 (br t, J = 8.9 Hz, 1H), 6.19 (br d, J = 16.5 Hz, 1H), 5.97 (br s, 2H), 5.83-5.66 (m , 1H), 4.834.44 (m, 2H), 4.18-3.66 (m, 4H), 2.90-2.73 (m, 1H), 1.92 (br s, 3H), 1.33 (br t, J = 6.4 Hz, 3H ), 1.28-1.13 (m, 3H), 1.03 (br d, J = 5.8 Hz, 6H). LCMS m/z (ESI): 674.2 (M+1) + . Compound 17A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 4.8 Hz, 1H), 7.26 (t, J = 8.7 Hz, 1H), 7.11-7.02 (m, 2H), 6.83 (td, J = 10.9, 16.5 Hz, 1H), 6.52 (dd, J = 1.3, 9.2 Hz, 1H), 6.26 - 6.14 (m, 1H), 5.89 (s, 2H), 5.75 (ddd, J = 2.3 , 6.1, 10.3 Hz, 1H), 4.85-4.45 (m, 2H), 4.21-3.40 (m, 4H), 2.73-2.61 (m, 1H), 2.01 (d, J = 3.5 Hz, 3H), 1.37- 1.28 (m, 3H), 1.27-1.15 (m, 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H). LCMS m/z (ESI): 674.3 (M+1) + . Compound 17B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.9 Hz, 1H), 7.25 (t, J = 8.7 Hz, 1H), 7.11-7.04 (m, 2H), 6.83 (td, J = 9.7, 16.6 Hz, 1H), 6.52 (dd, J = 1.2, 9.2 Hz, 1H), 6.25-6.14 (m, 1H), 5.88 (s, 2H), 5.80-5.70 (m, 1H) ), 4.82-4.43 (m, 2H), 4.14-3.47 (m, 4H), 2.78 (qd, J = 6.6, 13.3 Hz, 1H), 1.95 (s, 3H), 1.37-1.29 (m, 3H), 1.24-1.14 (m, 3H), 1.03-0.97 (m, 6H). LCMS m/z (ESI): 674.3 (M+1) + .

實施例18

Figure 02_image497
第一步： 在0攝氏度下，向化合物18-1（5克）的乙腈（50毫升）溶液中一次性加入碳酸鉀（1.59克）及化合物7-2（4.71克）。反應液在25-30攝氏度下反應12個小時。反應液濃縮得到殘餘物，用乙酸乙酯（20 毫升*3）萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-2。LCMS (ESI) m/z: 275.04(M+1) +。 第二步： 在0攝氏度下，向化合物18-2（5克）的乙腈（50毫升）溶液中一次性加入碳酸銫（5.94克）及4-乙氧基-1,1,1,-三氟-3-丁烯-2-酮（3.22克）。反應液在25-30攝氏度下反應1個小時。反應液濃縮得到殘餘物，用乙酸乙酯（20毫升*3）萃取，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-3。LCMS (ESI) m/z: 397.04(M+1) +。 第三步： 在20-30攝氏度下，向化合物18-3（5克）的三氟乙醇（50毫升）溶液中一次性加入三乙胺（2.55克）。反應液在80攝氏度下反應12個小時。反應液濃縮得到殘餘物，用水（50毫升）稀釋後加氫氧化鈉（4莫耳/升）調節pH到8，用乙酸乙酯（20毫升*3）萃取，合併水相用鹽酸（1莫耳/升）調節pH到3後，用乙酸乙酯（20毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-4。LCMS (ESI) m/z: 365.01(M+1) +。 第四步： 在0攝氏度下，向化合物18-4（2克）的乙腈（20毫升）溶液中一次性加入三溴吡啶（3.51克）及磷酸鉀（1.40克）。反應液在80攝氏度下反應12個小時。反應液濃縮得到殘餘物，用水（20毫升）稀釋後，用乙酸乙酯（10毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-5。LCMS (ESI) m/z: 398.93(M+1) +。 第五步： 在20-30攝氏度下，向化合物18-5（3.5克）的二氧六環（35毫升）溶液中一次性加入碳酸銫（5.72克）、4,5-雙二苯基磷-9,9-二甲基雜氧雜蒽（507.48毫克）、三（二亞苄基丙酮）二鈀（401.56毫克）及2-異丙基-4-甲基吡啶-3-胺（1.58克）。反應液在100攝氏度下反應12個小時。反應液濃縮得到殘餘物，用水（20毫升）稀釋後，用乙酸乙酯（10毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-6。LCMS (ESI) m/z: 469.12(M+1) +。 第六步： 在0攝氏度下，向化合物18-6（275毫克）的二氯甲烷（5毫升）溶液中一次性加入N-溴代丁二醯亞胺（125.4毫克）。反應液在25攝氏度下反應2個小時。向反應液中加入飽和亞硫酸鈉水溶液淬滅反應後，濃縮得到殘餘物，用水（20毫升）稀釋，用乙酸乙酯（10毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-7。LCMS (ESI) m/z: 547.03(M+1) +。 第七步： 在20-30攝氏度下，向化合物18-7（300毫克）的乙醇與水（5:1）混合溶液中（5毫升）一次性加入氯化銨（146.61毫克）和還原性鐵粉（153.06毫克。反應液在80攝氏度下反應12個小時。反應液過濾濃縮得到殘餘物，用水（10毫升）稀釋，用乙酸乙酯（10毫升*3）萃取，合併有機相，用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-8。LCMS (ESI) m/z: 517.06(M+1) +。 第八步： 在20-30攝氏度下，向化合物18-8（354毫克）的N,N-二甲基甲醯胺（5毫升）溶液中一次性加入鋅粉（22.37毫克）、氰化鋅（64.29毫克）、溴化鋅（7.71毫克）、三（二亞苄基丙酮）二鈀（401.56毫克）及1,1-雙（二苯基磷）二茂氯化鈀（75.88克）。反應液在120攝氏度下反應12個小時。反應液過濾後用乙酸乙酯洗滌3次（5 毫升*3）濃縮得到殘餘物，用水（10毫升）稀釋後，用乙酸乙酯（10毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-9。LCMS (ESI) m/z: 464.14(M+1) +。 第九步： 在20-30攝氏度下，將化合物18-9（2克）直接溶解在濃硫酸（5毫升）溶液中。反應液在60攝氏度下反應12個小時。反應液直接滴加到冰水（10毫升）溶液淬滅反應，用飽和的碳酸氫鈉水溶液調節pH到8後，用乙酸乙酯（10毫升*3）萃取濃縮得到殘餘物，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-10。LCMS (ESI) m/z: 482.15(M+1) +。 第十步： 在0攝氏度下，向化合物18-10（1.16克）的四氫呋喃（12毫升）溶液中一次性加入羰基二咪唑（1.17克）及鈉氫（481.91毫克，質量百分比：60%）。反應液在25攝氏度下反應2個小時。反應液加入到飽和氯化銨水溶液淬滅反應後，用乙酸乙酯（10毫升*3）萃取濃縮得到殘餘物，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-11。LCMS (ESI) m/z: 508.13(M+1) +。 第十一步： 在20-30攝氏度下，向化合物18-11（300毫克）的四氫呋喃（3毫升）溶液中一次性加入三吡咯烷基溴化磷六氟磷酸鹽（1.10克）、二異丙基乙胺（152.82毫克）及化合物3-1（633.54毫克）。反應液在60攝氏度下反應12個小時。反應液用水（20毫升）稀釋後，用乙酸乙酯（10 mL*3）萃取濃縮得到殘餘物，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物18-12。LCMS (ESI) m/z:704.29(M+1) +。 第十二步： 在20-30攝氏度下，向化合物18-12（245毫克）的二氯甲烷（3毫升）溶液中一次性加入三氟乙酸（1.80克）。反應液在25攝氏度下反應1個小時。反應液濃縮得到化合物18-13的三氟乙酸鹽。LCMS (ESI) m/z: 604.24(M+1) +。粗品直接用於下一步。 第十三步：
Figure 02_image499
在0攝氏度下，向化合物18-13（220毫克，TFA鹽）的四氫呋喃（3.0毫升）和水（0.5毫升）的混合溶液中依次一次性加入無水碳酸鉀（251.88毫克），丙烯醯氯（16.49毫克）。反應液在0攝氏度下反應0.5小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備柱純化HPLC(柱型號：Phenomenex Synergi C18 150*25mm*10 μm)，流動相（0.225%甲酸水：乙腈），梯度：21%-54%，11分鐘，得到化合物18。 化合物18通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，5分鐘，40分鐘）分離純化得到化合物18A及18-P1。 18-P1再通過製備SFC（柱型號：DAICEL CHIRALCELOD-H（250mm*30mm，5μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體30%-30%，5分鐘，40分鐘）分離純化得到化合物18B，和18-P2。 18-P2再通過製備SFC（柱型號：Kromasil (S,S) Whelk-O1（250mm*30mm，5μm），流動相：異丙醇（0.05%二乙胺），梯度：二氧化碳臨界流體40%-40%，5分鐘，40分鐘）分離純化得到化合物18C和化合物18D。 化合物18A經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物18A的保留時間為1.952min，e.e.值為100%。 化合物18B經SFC檢測[柱型號：CHIRALPAK OD 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物18B的保留時間為1.471min，e.e.值為100%。 化合物18C和化合物18D經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物18C的保留時間為1.900min，e.e.值為100%；化合物18D的保留時間為2.322min，e.e.值為100%。化合物18A： 1H NMR (400 MHz, DMSO- d 6) δ 8.31-8.31(m, 1H), 7.06-7.03(m, 2H), 6.85-6.78(m, 1H), 6.38-6.19(m, 3H), 6.21-6.03(m, 2H), 6.17-5.13(m, 1H), 4.79-4.52(m, 2H), 3.93-3.92(m, 3H), 3.46-3.39 (m, 1H), 3.25-3.24(m, 1H), 2.00-2.00(m, 3H), 1.34-1.31(m, 3H), 1.25-1.16(m, 3H), 1.05-1.03(m, 3H), 0.95-0.93(m, 3H)。LCMS (ESI) m/z: 658.2(M+1) +。 化合物18B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.32-8.30(m, 1H), 7.09-7.08 (m, 2H), 6.84-6.77(m, 1H), 6.35-6.15(m, 3H), 6.02-5.99(m, 2H), 5.770-5.716(m, 1H), 4.74-4.46(m, 2H), 3.96-3.73(m, 3H), 3.46-3.43(m, 1H), 3.26-3.23(m, 1H), 2.09(m, 3H), 1.34-1.15 (m, 6H), 0.90-0.91(m, 6H)。LCMS (ESI) m/z: 658.2(M+1) +。 化合物18C：1H NMR (400 MHz, DMSO- d 6 ) δ 8.30-8.29(m, 1H), 7.07-7.02 (m, 2H), 6.85-6.78(m, 1H), 6.34-6.16(m, 3H), 6.01(m, 2H), 5.77-5.72(m, 1H), 4.74-4.48(m, 2H), 4.00-3.76(m, 3H), 3.48-3.45(m, 1H), 3.43-3.42(m, 1H), 1.85(m, 3H), 1.32-1.14 (m, 6H), 1.08-1.00(m, 6H)。LCMS (ESI) m/z: 658.2(M+1) +。 化合物18D：1H NMR (400 MHz, DMSO- d 6 ) δ 8.31-8.29(m, 1H), 7.07-7.02(m, 2H), 6.85-6.78(m, 1H), 6.34-6.16(m, 3H), 6.01(m, 2H), 5.77-5.72(m, 1H), 4.74-4.48(m, 2H), 4.01-3.76(m, 3H), 3.48-3.45(m, 1H), 3.43-3.42(m, 1H), 1.85(m, 3H), 1.32-1.14(m, 6H), 1.08-1.02(m, 6H)。LCMS (ESI) m/z: 658.2(M+1) +。 Example 18
Figure 02_image497
Step 1: To a solution of compound 18-1 (5 g) in acetonitrile (50 mL) at 0°C were added potassium carbonate (1.59 g) and compound 7-2 (4.71 g) in one portion. The reaction solution was reacted at 25-30 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-2. LCMS (ESI) m/z: 275.04(M+1) + . Step 2: To a solution of compound 18-2 (5 g) in acetonitrile (50 ml) at 0 degrees Celsius was added cesium carbonate (5.94 g) and 4-ethoxy-1,1,1,-tris in one portion Fluoro-3-buten-2-one (3.22 g). The reaction solution was reacted at 25-30 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-3. LCMS (ESI) m/z: 397.04(M+1) + . Step 3: To a solution of compound 18-3 (5 g) in trifluoroethanol (50 mL) was added triethylamine (2.55 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, which was diluted with water (50 mL) and then adjusted to pH 8 by adding sodium hydroxide (4 mol/L), extracted with ethyl acetate (20 mL*3), and the combined aqueous phases were washed with hydrochloric acid (1 mol/L). After adjusting the pH to 3, it was extracted with ethyl acetate (20 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-4. LCMS (ESI) m/z: 365.01(M+1) + . Step 4: To a solution of compound 18-4 (2 g) in acetonitrile (20 mL) at 0 degrees Celsius was added tribromopyridine (3.51 g) and potassium phosphate (1.40 g) in one portion. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-5. LCMS (ESI) m/z: 398.93(M+1) + . Step 5: To a solution of compound 18-5 (3.5 g) in dioxane (35 ml) at 20-30 degrees Celsius was added cesium carbonate (5.72 g), 4,5-bisdiphenylphosphonium in one portion -9,9-Dimethyloxanthene (507.48 mg), tris(dibenzylideneacetone)dipalladium (401.56 mg) and 2-isopropyl-4-methylpyridin-3-amine (1.58 g) ). The reaction solution was reacted at 100 degrees Celsius for 12 hours. The reaction solution was concentrated to obtain a residue, diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-6. LCMS (ESI) m/z: 469.12(M+1) + . Step 6: To a solution of compound 18-6 (275 mg) in dichloromethane (5 mL) at 0 degrees C was added N-bromosuccinimide (125.4 mg) in one portion. The reaction solution was reacted at 25 degrees Celsius for 2 hours. After adding saturated aqueous sodium sulfite solution to the reaction solution to quench the reaction, concentrated to obtain a residue, diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated Compound 18-7 was obtained. LCMS (ESI) m/z: 547.03(M+1) + . Step 7: To a mixed solution of compound 18-7 (300 mg) in ethanol and water (5:1) (5 mL) at 20-30 degrees Celsius was added ammonium chloride (146.61 mg) and reduced iron in one portion powder (153.06 mg. The reaction solution was reacted at 80 degrees Celsius for 12 hours. The reaction solution was filtered and concentrated to obtain a residue, which was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), and the organic phases were combined and washed with anhydrous sulfuric acid. Dry over sodium, filter, and concentrate the filtrate to give compound 18-8. LCMS (ESI) m/z: 517.06(M+1) + . Eighth step: To compound 18-8 (354 mg) at 20-30 degrees Celsius Zinc powder (22.37 mg), zinc cyanide (64.29 mg), zinc bromide (7.71 mg), tris(dibenzylideneacetone) were added in one portion to a solution of N,N-dimethylformamide (5 mL) Dipalladium (401.56 mg) and 1,1-bis(diphenylphosphonium) palladium chloride (75.88 g). The reaction solution was reacted at 120 degrees Celsius for 12 hours. The reaction solution was filtered and washed 3 times with ethyl acetate (5 mL*3) was concentrated to obtain a residue, diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-9. LCMS (ESI) m/z: 464.14(M+1) + . The ninth step: Compound 18-9 (2 g) was directly dissolved in concentrated sulfuric acid (5 mL) solution at 20-30 degrees Celsius. The reaction solution The reaction was carried out for 12 hours at 60 degrees Celsius. The reaction solution was directly added dropwise to ice-water (10 mL) solution to quench the reaction, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (10 mL*3). Concentrated to obtain a residue, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-10. LCMS (ESI) m/z: 482.15(M+1) + . Tenth step: at 0 degrees Celsius, to To the solution of compound 18-10 (1.16 g) in tetrahydrofuran (12 ml), carbonyldiimidazole (1.17 g) and sodium hydrogen (481.91 mg, mass percentage: 60%) were added at one time. The reaction solution was reacted at 25 degrees Celsius for 2 hours The reaction solution was added to saturated aqueous ammonium chloride solution to quench the reaction, extracted and concentrated with ethyl acetate (10 mL*3) to obtain a residue, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-11. LCMS (ESI) m/z: 508.13(M+1) + . Step 11: To a solution of compound 18-11 (300 mg) in tetrahydrofuran (3 mL) at 20-30 °C was added tripypyrrole in one portion Alkyl phosphorus bromide hexafluorophosphate (1.10 g), diisopropylethylamine (152.82 mg) and compound 3-1 (633.54 mg). The reaction solution was at 60°C The reaction was carried out for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3) and concentrated to obtain a residue. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-12. LCMS (ESI) m/z: 704.29(M+1) + . Step 12: To a solution of compound 18-12 (245 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1.80 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 18-13. LCMS (ESI) m/z: 604.24(M+1) + . The crude product was used directly in the next step. Step Thirteen:
Figure 02_image499
To a mixed solution of compound 18-13 (220 mg, TFA salt) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (251.88 mg), acryl chloride (16.49 mL) were sequentially added in one portion. mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative column HPLC (column type: Phenomenex Synergi C18 150*25mm*10 μm), mobile phase (0.225% formic acid water:acetonitrile), gradient: 21%-54%, 11 minutes to obtain compound 18. Compound 18 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) Compounds 18A and 18-P1. 18-P1 was then passed through preparative SFC (column model: DAICEL CHIRALCELOD-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 5 minutes, 40 min) was isolated and purified to obtain compound 18B, and 18-P2. 18-P2 was then passed through preparative SFC (column type: Kromasil (S,S) Whelk-O1 (250mm*30mm, 5μm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%- 40%, 5 minutes, 40 minutes) separation and purification to obtain compound 18C and compound 18D. Compound 18A was detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B%): 5 %-40%] obtained: the retention time of compound 18A was 1.952 min, and the ee value was 100%. Compound 18B was detected by SFC [column model: CHIRALPAK OD 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient (B%): 5%- 40%] obtained: the retention time of compound 18B was 1.471 min, and the ee value was 100%. Compound 18C and compound 18D were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 18C was 1.900 min, and the ee value was 100%; the retention time of compound 18D was 2.322 min, and the ee value was 100%. Compound 18A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31-8.31(m, 1H), 7.06-7.03(m, 2H), 6.85-6.78(m, 1H), 6.38-6.19(m, 3H) ), 6.21-6.03(m, 2H), 6.17-5.13(m, 1H), 4.79-4.52(m, 2H), 3.93-3.92(m, 3H), 3.46-3.39 (m, 1H), 3.25-3.24 (m, 1H), 2.00-2.00(m, 3H), 1.34-1.31(m, 3H), 1.25-1.16(m, 3H), 1.05-1.03(m, 3H), 0.95-0.93(m, 3H) . LCMS (ESI) m/z: 658.2(M+1) + . Compound 18B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32-8.30 (m, 1H), 7.09-7.08 (m, 2H), 6.84-6.77 (m, 1H), 6.35-6.15 (m, 3H) ), 6.02-5.99(m, 2H), 5.770-5.716(m, 1H), 4.74-4.46(m, 2H), 3.96-3.73(m, 3H), 3.46-3.43(m, 1H), 3.26-3.23 (m, 1H), 2.09 (m, 3H), 1.34-1.15 (m, 6H), 0.90-0.91 (m, 6H). LCMS (ESI) m/z: 658.2(M+1) + . Compound 18C: 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30-8.29(m, 1H), 7.07-7.02 (m, 2H), 6.85-6.78(m, 1H), 6.34-6.16(m, 3H) , 6.01(m, 2H), 5.77-5.72(m, 1H), 4.74-4.48(m, 2H), 4.00-3.76(m, 3H), 3.48-3.45(m, 1H), 3.43-3.42(m, 1H), 1.85(m, 3H), 1.32-1.14 (m, 6H), 1.08-1.00(m, 6H). LCMS (ESI) m/z: 658.2(M+1) + . Compound 18D: 1H NMR (400 MHz, DMSO- d 6 ) δ 8.31-8.29(m, 1H), 7.07-7.02(m, 2H), 6.85-6.78(m, 1H), 6.34-6.16(m, 3H) , 6.01(m, 2H), 5.77-5.72(m, 1H), 4.74-4.48(m, 2H), 4.01-3.76(m, 3H), 3.48-3.45(m, 1H), 3.43-3.42(m, 1H), 1.85(m, 3H), 1.32-1.14(m, 6H), 1.08-1.02(m, 6H). LCMS (ESI) m/z: 658.2(M+1) + .

實施例19

Figure 02_image501
第一步： 在20-30攝氏度下，向化合物19-1（23克）的二氯甲烷（230毫升）溶液中依次加入三乙胺（10.7克）和丙二酸甲酯醯氯（78.04克），反應液在20-30攝氏度下反應16小時。向反應液中加入檸檬酸至pH=6-7，反應液分層，水相用二氯甲烷（50毫升）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1 到2:1）得到化合物19-2。LCMS (ESI) m/z: 274.9(M+1) +。 第二步： 在20-30攝氏度下，向化合物19-2（14克）的甲醇（150毫升））溶液中加入Raney-Ni（1.4克），反應液在15Psi的氫氣氛圍下25攝氏度下反應8小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=10:1 到3:1）得到化合物19-3。LCMS (ESI) m/z: 245.0(M+1)+。 第三步： 在0攝氏度下，向化合物19-3（8克）的乙腈（100毫升）和溶液中加入吡啶溶液（5.18克），逐滴滴加乙醯氯（3.09克），反應液在15攝氏度下反應16小時。反應液加入水（100毫升），用乙酸乙酯（50毫升*2）萃取。合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1 到2:1）得到化合物19-4。 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.25 (s, 1H), 7.70 (br d, J = 11.0 Hz, 1H), 7.19-6.97 (m, 1H), 3.67 (s, 3H), 3.62 (s, 2H), 2.07 (s, 3H)。LCMS (ESI) m/z: 287.1(M+1)+。 第四步： 在20-30攝氏度下，向化合物19-4（9克）的乙腈（100毫升）溶液中依次加入碳酸銫（10.24毫克），4-乙氧基-1,1,1-三氟-3-丁烯-2-酮（5.81克）反應液在20-30攝氏度下反應3小時。向反應液中加入水（100毫升），然後用乙酸乙酯（50毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物19-5。LCMS (ESI) m/z: 409.0(M+1) +。 第五步： 在20-30攝氏度下，向化合物19-5（15克）的三氟乙醇（150毫升）溶液中加入三乙胺（7.44克）。反應液在100攝氏度下反應12小時。向反應液中加入碳酸氫鈉水溶液調節pH至8左右,然後用乙酸乙酯（50毫升*2）萃取，水相用0.1莫耳/升的稀鹽酸調節pH至2左右，用乙酸乙酯（50毫升*2）萃取，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物19-6。LCMS (ESI) m/z: 377.1(M+1) +。 第六步： 在20-30攝氏度下，向化合物19-6（7.2克）的乙腈（80毫升）溶液中依次加入磷酸鉀（12.19克），三溴吡啶（24.48克）。反應液在氮氣保護下於50攝氏度反應2小時。向反應液中加入亞硫酸鈉溶液（100毫升），然後用乙酸乙酯（50毫升*2）萃取，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物19-7。LCMS (ESI) m/z: 412.9(M+3) +。 第七步： 在20-30攝氏度下，向化合物19-7（3.51克）的二氧六環（40毫升）溶液中依次加入2-異丙基-4-甲基吡啶-3-胺（8克），三（二亞苄基丙酮）二鈀（1.78克），4,5-雙二苯基膦-9,9-二甲基氧雜蒽（1.669克）,碳酸銫（12.68克）。反應液在氮氣保護下於100攝氏度反應16小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1 到2:1）得到化合物19-8。LCMS (ESI) m/z: 481.1(M+1) +。 第八步： 在0攝氏度下，向化合物19-8（4克）的二氯甲烷（50毫升）溶液中一次性加入N-溴代丁二醯亞胺（1.48克）。反應液在20攝氏度下反應一個小時。向反應液中加入亞硫酸鈉溶液（50毫升），然後用二氯甲烷（20毫升*2）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到19-9。LCMS (ESI) m/z: 558.9(M+1) +。 第九步： 在60攝氏度下，向化合物19-9（4克）的N,N-二甲基甲醯胺（40毫升）和溶液中依次一次性加入鋅粉（526.09毫克），氰化鋅（1.89克），溴化鋅（362.36毫克），1,1-雙（二苯基膦基）二茂鐵（892.04毫克）和三（二亞苄基丙酮）二鈀（736.73毫克）。反應液在120攝氏度下反應3個小時。反應液過濾，用乙酸乙酯（100毫升）稀釋，用水（50毫升*3）和飽和食鹽水（50毫升）洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到濾液濃縮得到殘餘物。殘餘物經製備板純化（石油醚：乙酸乙酯=5:1到2:1）得到化合物19-10。LCMS (ESI) m/z: 506.0(M+1) +。 第十步： 化合物19-10（4克）的濃硫酸（20毫升）於60攝氏度下反應16小時。反應液加入到飽和碳酸氫鈉水溶液（50毫升）中，用乙酸乙酯（20毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物19-11。LCMS (ESI) m/z: 481.9(M+1) +。 第十一步： 在0攝氏度下，向化合物19-11（2.8克）的四氫呋喃（30毫升）溶液中一次性加入1,1-羰基二咪唑（2.83克），反應液在0攝氏度下反應0.3小時，然後一次性加入氫化鈉（697.87毫克，質量百分比：60%）。反應液在0-25攝氏度下反應0.7小時。將反應液加入到水（100毫升）中，用0.1莫耳/升的稀鹽酸（30毫升）調節pH=3-4，然後用飽和的碳酸氫鈉（50毫升）水溶液調節pH=7-8，用乙酸乙酯（30毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘化合物19-12。LCMS (ESI) m/z: 508.2(M+1) +。 第十二步： 向化合物19-12（1克）的四氫呋喃（15毫升）溶液中加入PYBROP（1.84克），DIEA（764.11毫克）以及化合物3-1（1.06克）。反應液在70攝氏度下反應16小時，反應液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex Synergi Max-RP （250*50mm*10 μm），流動相：水（0.225%甲酸）-乙腈：30%-60%，22分鐘] 純化得到化合物19-13。LCMS (ESI) m/z: 704.4 (M+1) +。
Figure 02_image503
化合物19-13通過製備SFC（柱型號：REGIS (R,R)WHELK-O1(250mm*25mm, 10 μm)，流動相：異丙醇（0.1%氨水 異丙醇），梯度：二氧化碳臨界流體50%-50%，4.5分鐘，90分鐘）分離純化得到化合物19-14A（保留時間=1.098 min），和19-14M（保留時間=1.869 min，為19-14B、19-14C和19-14D的混合物）。 第十三步：
Figure 02_image505
在10-25攝氏度下，向化合物19-14A（460毫克）的二氯甲烷（1毫升）溶液中一次性加入三氟乙酸（0.5毫升）。反應液在10-25攝氏度下反應0.5小時。將反應液濃縮得到化合物19-15A的三氟乙酸鹽， 粗品直接用於下一步。 在10-25攝氏度下，向19-14M（420毫克）的二氯甲烷（2毫升）溶液中一次性加入三氟乙酸（1毫升）。反應液在10-25攝氏度下反應0.5小時。將反應液濃縮得到化合物19-15M（19-15B、19-15C和19-15D的混合物）的三氟乙酸鹽，粗品直接用於下一步。 第十四步： 在0攝氏度下，向化合物19-15A（150毫克，2TFA鹽）的四氫呋喃（2.0毫升）和水（0.5毫升）的混合溶液中依次一次性加入無水碳酸鉀（74.79毫克），丙烯醯氯（16.32毫克）。反應液在0攝氏度下反應0.25小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物通過製備SFC（柱型號：Phenomenex Gemini-NX C18（75mm*30mm，3μm），流動相：水（0.225%甲酸）-乙腈，梯度：二氧化碳臨界流體20%-50%，5分鐘）分離純化得到化合物19A。
Figure 02_image507
在0攝氏度下，向化合物19-15M（450毫克，2TFA鹽）的四氫呋喃（2.0毫升）和水（0.5毫升）的混合溶液中依次一次性加入無水碳酸鉀（224.36毫克），丙烯醯氯（48.97毫克）。反應液在0攝氏度下反應0.25小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物通過製備SFC（柱型號：Phenomenex Gemini-NX C18（75mm*30mm，3μm），流動相：水（0.225%甲酸）-乙腈，梯度：二氧化碳臨界流體20%-50%，7分鐘）分離純化得到化合物19B和19-P1。 19-P1再通過製備SFC（柱型號：DAICEL CHIRALPAK IC(250mm*30mm,10um)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體35%-35%，4.9分鐘，80分鐘）分離純化得到化合物19C和化合物19D。 化合物19A經SFC檢測[柱型號：（R,R）Whelk-O1-3 50×4.6mm I.D., 1.8μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物19A的保留時間為1.653min。 化合物19B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物19B的保留時間為2.22min，e.e.值為100%。 化合物19C和化合物19D經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物19C的保留時間為1.653min，e.e.值為100%；化合物19D的保留時間為2.139min，e.e.值為100%。 化合物19A（保留時間=0.967 min）：LCMS (ESI) m/z: 658.3(M+1) +。 化合物19B（保留時間=2.222 min）：LCMS (ESI) m/z: 658.3(M+1) +。 化合物19C（保留時間=1.653 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J= 4.8 Hz, 1H), 7.30-7.15 (m, 1H), 7.10-6.95 (m, 2H), 6.93-6.70 (m, 2H), 6.27-6.10 (m, 1H), 5.83-5.63 (m, 1H), 5.39-5.15 (m, 2H), 4.83-4.39 (m, 2H), 4.02-3.90 (m, 2H), 3.59-3.40 (m, 1H), 2.88-2.60 (m, 2H), 2.04-1.96 (m, 3H), 1.33-0.97 (m, 12H). LCMS (ESI) m/z: 658.3 (M+1) +。 化合物19D（保留時間=2.139 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (br d, J= 4.8 Hz, 1H), 7.29-7.15 (m, 1H), 7.12-7.05 (m, 1H), 7.00 (s, 1H), 6.90-6.78 (m, 1H), 6.76-6.70 (m, 1H), 6.24-6.15 (m, 1H), 5.80-5.71 (m, 1H), 5.42-5.23 (m, 2H), 4.85-4.47 (m, 2H), 3.96-3.89 (m, 2H), 3.53-3.43 (m, 1H), 2.67 (br s, 2H), 2.08-1.95 (m, 3H), 1.33-0.95 (m, 12H)。LCMS (ESI) m/z: 658.3 (M+1) +。 Example 19
Figure 02_image501
Step 1: To a solution of compound 19-1 (23 g) in dichloromethane (230 ml) at 20-30 degrees Celsius was added triethylamine (10.7 g) followed by methyl malonate chloride (78.04 g) ), the reaction solution was reacted at 20-30 degrees Celsius for 16 hours. Citric acid was added to the reaction solution to pH=6-7, the reaction solution was layered, the aqueous phase was extracted with dichloromethane (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-2. LCMS (ESI) m/z: 274.9(M+1) + . The second step: Raney-Ni (1.4 g) was added to the solution of compound 19-2 (14 g) in methanol (150 ml) at 20-30 degrees Celsius, and the reaction solution was reacted at 25 degrees Celsius under a hydrogen atmosphere of 15 Psi 8 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain compound 19-3. LCMS (ESI) m/z: 245.0(M+1)+. The third step: To the solution of compound 19-3 (8 g) in acetonitrile (100 ml) and the solution was added pyridine solution (5.18 g) at 0 degrees Celsius, acetonitrile chloride (3.09 g) was added dropwise, and the reaction solution was The reaction was carried out at 15 degrees Celsius for 16 hours. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-4. 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.25 (s, 1H), 7.70 (br d, J = 11.0 Hz, 1H), 7.19-6.97 (m, 1H), 3.67 ( s, 3H), 3.62 (s, 2H), 2.07 (s, 3H). LCMS (ESI) m/z: 287.1(M+1)+. Step 4: To a solution of compound 19-4 (9 g) in acetonitrile (100 ml) at 20-30 degrees Celsius, cesium carbonate (10.24 mg), 4-ethoxy-1,1,1-tris Fluoro-3-buten-2-one (5.81 g) was reacted at 20-30 degrees Celsius for 3 hours. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-5. LCMS (ESI) m/z: 409.0(M+1) + . Step 5: To a solution of compound 19-5 (15 g) in trifluoroethanol (150 ml) was added triethylamine (7.44 g) at 20-30 degrees Celsius. The reaction solution was reacted at 100 degrees Celsius for 12 hours. Add sodium bicarbonate aqueous solution to the reaction solution to adjust the pH to about 8, then extract with ethyl acetate (50 ml*2), adjust the pH of the aqueous phase to about 2 with 0.1 mol/L dilute hydrochloric acid, and use ethyl acetate ( 50 mL*2) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-6. LCMS (ESI) m/z: 377.1(M+1) + . The sixth step: To a solution of compound 19-6 (7.2 g) in acetonitrile (80 ml) at 20-30 degrees Celsius, potassium phosphate (12.19 g) and tribromopyridine (24.48 g) were sequentially added. The reaction solution was reacted at 50 degrees Celsius for 2 hours under nitrogen protection. Sodium sulfite solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7. LCMS (ESI) m/z: 412.9(M+3) + . Step 7: To a solution of compound 19-7 (3.51 g) in dioxane (40 mL) was added 2-isopropyl-4-methylpyridin-3-amine (8 g), tris(dibenzylideneacetone)dipalladium (1.78 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (1.669 g), cesium carbonate (12.68 g). The reaction solution was reacted at 100 degrees Celsius for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain compound 19-8. LCMS (ESI) m/z: 481.1(M+1) + . Step 8: To a solution of compound 19-8 (4 g) in dichloromethane (50 mL) was added N-bromosuccinimide (1.48 g) in one portion at 0 degrees Celsius. The reaction solution was reacted at 20 degrees Celsius for one hour. Sodium sulfite solution (50 mL) was added to the reaction solution, then extracted with dichloromethane (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 19-9. LCMS (ESI) m/z: 558.9(M+1) + . The ninth step: at 60 degrees Celsius, to the N,N-dimethylformamide (40 ml) of compound 19-9 (4 g) and the solution were sequentially added zinc powder (526.09 mg), zinc cyanide (1.89 g), zinc bromide (362.36 mg), 1,1-bis(diphenylphosphino)ferrocene (892.04 mg) and tris(dibenzylideneacetone)dipalladium (736.73 mg). The reaction solution was reacted at 120 degrees Celsius for 3 hours. The reaction solution was filtered, diluted with ethyl acetate (100 mL), washed with water (50 mL*3) and saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative plate (petroleum ether:ethyl acetate=5:1 to 2:1) to give compound 19-10. LCMS (ESI) m/z: 506.0(M+1) + . The tenth step: Compound 19-10 (4 g) was reacted with concentrated sulfuric acid (20 ml) at 60 degrees Celsius for 16 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-11. LCMS (ESI) m/z: 481.9(M+1) + . The eleventh step: 1,1-carbonyldiimidazole (2.83 g) was added to a solution of compound 19-11 (2.8 g) in tetrahydrofuran (30 ml) at 0 degrees Celsius at one time, and the reaction solution was reacted at 0 degrees Celsius for 0.3 hour, and then sodium hydride (697.87 mg, mass percentage: 60%) was added at one time. The reaction solution was reacted at 0-25 degrees Celsius for 0.7 hours. The reaction solution was added to water (100 mL), adjusted to pH=3-4 with 0.1 mol/L dilute hydrochloric acid (30 mL), and then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate (50 mL) solution , extracted with ethyl acetate (30 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain residual compounds 19-12. LCMS (ESI) m/z: 508.2(M+1) + . Step 12: To a solution of compound 19-12 (1 g) in tetrahydrofuran (15 ml) were added PYBROP (1.84 g), DIEA (764.11 mg) and compound 3-1 (1.06 g). The reaction solution was reacted at 70 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP (250*50mm*10 μm), mobile phase: water (0.225% formic acid)-acetonitrile: 30%-60%, 22 minutes] to give compounds 19-13 . LCMS (ESI) m/z: 704.4 (M+1) + .
Figure 02_image503
Compounds 19-13 were prepared by preparative SFC (column type: REGIS (R,R) WHELK-O1 (250mm*25mm, 10 μm), mobile phase: isopropanol (0.1% ammonia water isopropanol), gradient: carbon dioxide critical fluid 50 %-50%, 4.5 minutes, 90 minutes) separation and purification to obtain compounds 19-14A (retention time = 1.098 min), and 19-14M (retention time = 1.869 min, for 19-14B, 19-14C and 19-14D mixture). Step Thirteen:
Figure 02_image505
To a solution of compound 19-14A (460 mg) in dichloromethane (1 mL) at 10-25 °C was added trifluoroacetic acid (0.5 mL) in one portion. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 19-15A, and the crude product was directly used in the next step. To a solution of 19-14M (420 mg) in dichloromethane (2 mL) at 10-25 °C was added trifluoroacetic acid (1 mL) in one portion. The reaction solution was reacted at 10-25 degrees Celsius for 0.5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 19-15M (a mixture of 19-15B, 19-15C and 19-15D), and the crude product was used directly in the next step. The fourteenth step: To a mixed solution of compound 19-15A (150 mg, 2TFA salt) in tetrahydrofuran (2.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (74.79 mg) was added in one portion, Acryloyl chloride (16.32 mg). The reaction solution was reacted at 0 degrees Celsius for 0.25 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column type: Phenomenex Gemini-NX C18 (75mm*30mm, 3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 5 minutes) Compound 19A was obtained.
Figure 02_image507
To a mixed solution of compound 19-15M (450 mg, 2TFA salt) in tetrahydrofuran (2.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (224.36 mg), acryl chloride (48.97 mL) were added in one portion. mg). The reaction solution was reacted at 0 degrees Celsius for 0.25 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by preparative SFC (column type: Phenomenex Gemini-NX C18 (75mm*30mm, 3μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: carbon dioxide critical fluid 20%-50%, 7 minutes) Compounds 19B and 19-P1 were obtained. 19-P1 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 35%-35%, 4.9 minutes, 80 minutes) Purification gave compound 19C and compound 19D. Compound 19A was detected by SFC [column type: (R, R) Whelk-O1-3 50×4.6mm ID, 1.8μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine in phase B) ); gradient (B%): 40%-40%] obtained: the retention time of compound 19A was 1.653 min. Compound 19B was detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient (B%): 5 %-40%] obtained: the retention time of compound 19B was 2.22 min, and the ee value was 100%. Compound 19C and compound 19D were detected by SFC [column model: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient (B% ): 40%-40%] obtained: the retention time of compound 19C was 1.653 min, and the ee value was 100%; the retention time of compound 19D was 2.139 min, and the ee value was 100%. Compound 19A (retention time=0.967 min): LCMS (ESI) m/z: 658.3 (M+1) + . Compound 19B (retention time = 2.222 min): LCMS (ESI) m/z: 658.3 (M+1) + . Compound 19C (retention time = 1.653 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J = 4.8 Hz, 1H), 7.30-7.15 (m, 1H), 7.10-6.95 (m, 2H), 6.93-6.70 (m, 2H), 6.27-6.10 (m, 1H), 5.83-5.63 (m, 1H), 5.39-5.15 (m, 2H), 4.83-4.39 (m, 2H), 4.02- 3.90 (m, 2H), 3.59-3.40 (m, 1H), 2.88-2.60 (m, 2H), 2.04-1.96 (m, 3H), 1.33-0.97 (m, 12H). LCMS (ESI) m/z : 658.3 (M+1) + . Compound 19D (retention time = 2.139 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (br d, J = 4.8 Hz, 1H), 7.29-7.15 (m, 1H), 7.12-7.05 (m , 1H), 7.00 (s, 1H), 6.90-6.78 (m, 1H), 6.76-6.70 (m, 1H), 6.24-6.15 (m, 1H), 5.80-5.71 (m, 1H), 5.42-5.23 (m, 2H), 4.85-4.47 (m, 2H), 3.96-3.89 (m, 2H), 3.53-3.43 (m, 1H), 2.67 (br s, 2H), 2.08-1.95 (m, 3H), 1.33-0.95 (m, 12H). LCMS (ESI) m/z: 658.3 (M+1) + .

實施例20

Figure 02_image509
第一步： 在20-30攝氏度下，向化合物20-1（2.0克）的二氧六環（50毫升）和水（25毫升）溶液中加入化合物20-2（1.22克）、四三苯基膦鈀（1.20克）和碳酸鉀（4.30克）。反應液氮氣置換三次後，在100攝氏度下反應2個小時。反應液濃縮得到殘餘物，用乙酸乙酯（30毫升）萃取，食鹽水（30毫升）洗滌，有機相濃縮濾液得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=10:1 到3:1）純化得到化合物20-3。LCMS (ESI) m/z: 199.0(M+1) +。 第二步： 在10-15攝氏度下，向化合物20-3（1.6克）的甲醇（10毫升）溶液中加入甲醇鈉甲醇溶液（1.45克，10毫升，質量百分比：30%）。反應液在15攝氏度下反應0.5個小時。向反應液中加入水（10毫升），乙酸乙酯（50毫升）萃取，食鹽水（50毫升）洗滌，有機相濃縮濾液得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=5:1 到2:1）純化得到化合物20-4。LCMS (ESI) m/z: 195.1(M+1) +。 第三步： 在10-15攝氏度下，向化合物20-4（1.50克）的甲醇（20毫升）溶液中加入濕鈀炭（0.5克，10%純度）。反應液用氫氣置換三次，在15攝氏度下反應2個小時。反應液過濾，濾餅用甲醇（20毫升）洗滌，濾液濃縮得到化合物20-5。LCMS (ESI) m/z: 167.2(M+1) +。 第四步： 在10-15攝氏度下，向化合物20-5（1.75克）的二氧六環（30毫升）溶液中加入化合物20-5A(0.76克）、Pd 2(dba) 3（420.52毫克）、Xantphos（531.43毫克）和碳酸銫（4.49克）。反應液氮氣置換三次後在100攝氏度下反應2個小時。反應液濃縮得到殘餘物，殘餘物中加入水（100毫升），乙酸乙酯（100毫升），分離有機相，濃縮得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=1:1）純化得到化合物20-6。 1H NMR (400 MHz, CHLOROFORM- d) δ 8.48 (d, J= 5.5 Hz, 1H), 8.22-8.11 (m, 1H), 7.73 (dt, J= 5.3, 8.4 Hz, 1H), 7.63 (dt, J= 1.2, 8.3 Hz, 1H), 6.81-6.74 (m, 2H), 6.60 (s, 1H), 5.96 (d, J= 7.8 Hz, 1H), 3.87 (s, 3H), 3.29 (td, J= 6.8, 13.6 Hz, 1H), 1.30-1.21 (m, 6H)。LCMS (ESI) m/z: 467.0(M+1) +。 第五步： 在10-15攝氏度下，向化合物20-6（0.8克）的二氯甲烷（10毫升）溶液中加入NBS（305.30毫克）。反應液氮氣置換三次後，在15攝氏度下反應2個小時。向反應液中加入飽和亞硫酸鈉水溶液（50毫升），有機相分離，濃縮濾液得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=10:1 到1:1）純化得到化合物20-7。LCMS (ESI) m/z: 546.9(M+3) +。 第六步： 在10-15攝氏度下，向化合物20-7（1.5克）的乙醇（50毫升）和水（25毫升）混合溶液中加入鐵粉（768.11毫克）和氯化銨（735.74毫克）。反應液在60攝氏度下反應2個小時。反應液濃縮得到殘餘物，殘餘物中加入食鹽水（50毫升），乙酸乙酯（50毫升），有機相分離，濃縮得到化合物20-8。LCMS (ESI) m/z: 515.0(M+1) +。 第七步： 在10-15攝氏度下，向化合物20-8（1.4克）的N,N-二甲基甲醯胺（30毫升）溶液中加入鋅粉（355.31毫克）、氰化鋅（638.06毫克）、Pd 2(dba) 3（248.79毫克）、溴化鋅（611.83毫克）和DPPF（301.24毫克）。反應液氮氣置換三次後，在110攝氏度下反應12個小時。反應液中加入水（30毫升），乙酸乙酯（30毫升），混合物過濾，濾餅用乙酸乙酯（30毫升）洗滌，有機相分離，濃縮得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=10:1 到1:1）純化得到化合物20-9。LCMS (ESI) m/z: 462.1(M+1) +。 第八步： 在10-15攝氏度下，化合物20-9（1.1克）和濃硫酸（18.40克）的混合物在80攝氏度下反應2個小時。反應液緩慢倒入冰水（1.0升）中，攪拌下，分批加入碳酸鈉固體，至pH約為9，乙酸乙酯（100毫升*2）萃取，合併有機相，濃縮得到化合物20-10。LCMS (ESI) m/z: 480.1(M+1) +。 第九步： 在15攝氏度下，向化合物20-10（0.7克）的四氫呋喃（15毫升）溶液中加入氫化鈉（116.80毫克，質量百分比：60%）和羰基二咪唑（473.50毫克）。反應液氮氣置換三次後，在15攝氏度下反應2個小時。反應液倒入水（30毫升）中，乙酸乙酯（20毫升*2）萃取，合併有機相，飽和食鹽水（30毫升）洗滌，有機相分離，濃縮得到化合物20-11。LCMS (ESI) m/z: 506.1(M+1) +。 第十步： 在15攝氏度下，向化合物20-11（680毫克）的N,N-二甲基乙醯胺（30毫升）溶液中加入化合物3-1（864.98毫克）、PYBROP（1.25克）和DIPEA（521.66毫克）。反應液氮氣置換三次後，在80攝氏度下反應2個小時。反應液倒入水（50毫升）中，乙酸乙酯（50毫升*2）萃取，合併有機相，飽和食鹽水（50毫升）洗滌，有機相分離，濃縮得到殘餘物，殘餘物通過製備TLC(石油醚：乙酸乙酯=0:1)純化得到化合物20-12。LCMS (ESI) m/z: 702.2(M+1) +。 第十一步： 在15攝氏度下，向化合物20-12（500毫克）的二氯甲烷（15毫升）溶液中加入三氟乙酸（4.81克）。反應液在15攝氏度下反應1個小時。反應液濃縮得到化合物20-13的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 602.2(M+1) +。 第十二步：
Figure 02_image511
在15攝氏度下，向化合物20-13（500毫克）的四氫呋喃（10毫升）和水（10毫升）溶液中加入碳酸鉀（193.13毫克）和丙烯醯氯（63.24毫克）。反應液在15攝氏度下反應15分鐘。反應液中加入水（30毫升），乙酸乙酯（30毫升）萃取，有機相分離，濃縮得到殘餘物，殘餘物通過製備HPLC(柱型號：Phenomenex Gemini-NX C18 75*30mm*3um，流動相：[水(0.225%甲酸-乙腈]; 15%-45%,7分鐘)純化得到化合物20。 化合物20通過SFC（柱型號：DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流動相：0.1%氨水-甲醇，梯度：二氧化碳臨界流體60%-60%，2.2分鐘，50分鐘）得到20A和20B。 化合物20A和化合物20B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物20A的保留時間為0.815min，e.e.值為100%；化合物20B的保留時間為2.118min，e.e.值為100%。 化合物20A（保留時間=0.815 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.41-8.27 (m, 1H), 7.09 (dt, J= 6.8, 8.2 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J= 5.8 Hz, 1H), 6.89-6.75 (m, 1H), 6.50 (d, J= 8.4 Hz, 1H), 6.38-6.29 (m, 1H), 6.19 (br d, J= 16.5 Hz, 1H), 5.80-5.70 (m, 1H), 5.63 (s, 2H), 4.86-4.59 (m, 1H), 4.83-4.43 (m, 1H), 4.13 (br dd, J= 2.4, 13.8 Hz, 1H), 3.95-3.75 (m, 3H), 3.70 (s, 3H), 2.71-2.59 (m, 1H), 1.30 (br t, J= 7.3 Hz, 3H), 1.27-1.16 (m, 3H), 1.06-1.01 (m, 3H), 0.96 (d, J= 6.6 Hz, 3H)。LCMS (ESI) m/z: 656.3 (M+1) +。 化合物20B（保留時間=2.118 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.39-8.28 (m, 1H), 7.14-7.04 (m, 1H), 7.03-6.98 (m, 1H), 6.91-6.87 (m, 1H), 6.82 (br dd, J= 10.1, 16.5 Hz, 1H), 6.48 (d, J= 8.3 Hz, 1H), 6.38-6.29 (m, 1H), 6.25-6.13 (m, 1H), 5.81-5.70 (m, 1H), 5.68-5.58 (m, 2H), 4.82-4.43 (m, 2H), 4.16-4.01 (m, 1H), 3.93-3.84 (m, 1H), 3.65 (s, 2H), 3.74-3.58 (m, 1H), 1.36-1.28 (m, 3H), 1.27-1.27 (m, 1H), 1.26-1.20 (m, 1H), 1.26-1.20 (m, 1H), 1.16 (br d, J= 6.5 Hz, 2H), 1.11-1.05 (m, 4H), 1.01 (br d, J= 6.6 Hz, 3H)。LCMS (ESI) m/z: 656.3 (M+1) +。 Example 20
Figure 02_image509
Step 1: To a solution of compound 20-1 (2.0 g) in dioxane (50 mL) and water (25 mL) at 20-30 degrees Celsius was added compound 20-2 (1.22 g), tetrakistriphenyl phosphine palladium (1.20 g) and potassium carbonate (4.30 g). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, which was extracted with ethyl acetate (30 mL), washed with brine (30 mL), and the organic phase was concentrated to the filtrate to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 20-3. LCMS (ESI) m/z: 199.0(M+1) + . The second step: Add sodium methoxide methanol solution (1.45 g, 10 mL, mass percentage: 30%) to a methanol (10 mL) solution of compound 20-3 (1.6 g) at 10-15 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL), washed with brine (50 mL), and the organic phase was concentrated to the filtrate to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 2:1) to give compound 20-4. LCMS (ESI) m/z: 195.1(M+1) + . Step 3: To a solution of compound 20-4 (1.50 g) in methanol (20 mL) was added wet palladium on carbon (0.5 g, 10% purity) at 10-15 degrees Celsius. The reaction solution was replaced with hydrogen three times, and the reaction was carried out at 15 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to obtain compound 20-5. LCMS (ESI) m/z: 167.2(M+1) + . Step 4: To a solution of compound 20-5 (1.75 g) in dioxane (30 mL) at 10-15 degrees Celsius was added compound 20-5A (0.76 g), Pd 2 (dba) 3 (420.52 mg) ), Xantphos (531.43 mg) and cesium carbonate (4.49 g). The reaction liquid was replaced with nitrogen three times and then reacted at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, water (100 ml) and ethyl acetate (100 ml) were added to the residue, and the organic phase was separated and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=1:1) to obtain compound 20-6. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.48 (d, J = 5.5 Hz, 1H), 8.22-8.11 (m, 1H), 7.73 (dt, J = 5.3, 8.4 Hz, 1H), 7.63 (dt , J = 1.2, 8.3 Hz, 1H), 6.81-6.74 (m, 2H), 6.60 (s, 1H), 5.96 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H), 3.29 (td, J = 6.8, 13.6 Hz, 1H), 1.30-1.21 (m, 6H). LCMS (ESI) m/z: 467.0(M+1) + . Step 5: To a solution of compound 20-6 (0.8 g) in dichloromethane (10 mL) was added NBS (305.30 mg) at 10-15 degrees Celsius. After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 15 degrees Celsius for 2 hours. To the reaction solution was added saturated aqueous sodium sulfite solution (50 ml), the organic phase was separated, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound 20-7. LCMS (ESI) m/z: 546.9(M+3) + . Step 6: Add iron powder (768.11 mg) and ammonium chloride (735.74 mg) to a mixed solution of compound 20-7 (1.5 g) in ethanol (50 ml) and water (25 ml) at 10-15 degrees Celsius . The reaction solution was reacted at 60 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, brine (50 ml) and ethyl acetate (50 ml) were added to the residue, the organic phase was separated and concentrated to obtain compound 20-8. LCMS (ESI) m/z: 515.0(M+1) + . Step 7: To a solution of compound 20-8 (1.4 g) in N,N-dimethylformamide (30 ml) at 10-15 degrees Celsius was added zinc powder (355.31 mg), zinc cyanide (638.06 g) mg), Pd 2 (dba) 3 (248.79 mg), zinc bromide (611.83 mg) and DPPF (301.24 mg). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 110 degrees Celsius for 12 hours. Water (30 mL) and ethyl acetate (30 mL) were added to the reaction solution, the mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to give compound 20-9. LCMS (ESI) m/z: 462.1(M+1) + . Eighth step: A mixture of compound 20-9 (1.1 g) and concentrated sulfuric acid (18.40 g) was reacted at 80 degrees Celsius for 2 hours at 10-15 degrees Celsius. The reaction solution was slowly poured into ice water (1.0 L), and with stirring, solid sodium carbonate was added in batches until the pH was about 9, extracted with ethyl acetate (100 mL*2), the organic phases were combined and concentrated to obtain compound 20-10 . LCMS (ESI) m/z: 480.1(M+1) + . The ninth step: To a solution of compound 20-10 (0.7 g) in tetrahydrofuran (15 ml) at 15 degrees Celsius was added sodium hydride (116.80 mg, mass percentage: 60%) and carbonyldiimidazole (473.50 mg). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 15 degrees Celsius for 2 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL*2), the organic phases were combined, washed with saturated brine (30 mL), the organic phases were separated, and concentrated to obtain compound 20-11. LCMS (ESI) m/z: 506.1(M+1) + . Step 10: To a solution of compound 20-11 (680 mg) in N,N-dimethylacetamide (30 mL) at 15°C was added compound 3-1 (864.98 mg), PYBROP (1.25 g) and DIPEA (521.66 mg). After the reaction liquid was replaced with nitrogen three times, the reaction was carried out at 80 degrees Celsius for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, concentrated to obtain a residue, and the residue was passed through preparative TLC ( Petroleum ether: ethyl acetate=0:1) was purified to obtain compound 20-12. LCMS (ESI) m/z: 702.2(M+1) + . Eleventh step: To a solution of compound 20-12 (500 mg) in dichloromethane (15 mL) was added trifluoroacetic acid (4.81 g) at 15 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 20-13, and the crude product was directly used in the next step. LCMS (ESI) m/z: 602.2(M+1) + . Step 12:
Figure 02_image511
To a solution of compound 20-13 (500 mg) in tetrahydrofuran (10 mL) and water (10 mL) at 15°C was added potassium carbonate (193.13 mg) and acryl chloride (63.24 mg). The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was subjected to preparative HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3um, mobile phase : [water (0.225% formic acid-acetonitrile]; 15%-45%, 7 minutes) was purified to give compound 20. Compound 20 was purified by SFC (column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: 0.1% ammonia water - methanol, gradient: carbon dioxide critical fluid 60%-60%, 2.2 min, 50 min) to give 20A and 20B. Compound 20A and compound 20B were detected by SFC [Column model: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm; flow Phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 40%-40%] Obtained: the retention time of compound 20A is 0.815min, and the ee value is 100%; Compound 20B has a retention time of 2.118 min and an ee of 100%. Compound 20A (retention time = 0.815 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.41-8.27 (m, 1H), 7.09 (dt , J = 6.8, 8.2 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J = 5.8 Hz, 1H), 6.89-6.75 (m, 1H), 6.50 (d, J = 8.4 Hz, 1H) , 6.38-6.29 (m, 1H), 6.19 (br d, J = 16.5 Hz, 1H), 5.80-5.70 (m, 1H), 5.63 (s, 2H), 4.86-4.59 (m, 1H), 4.83- 4.43 (m, 1H), 4.13 (br dd, J = 2.4, 13.8 Hz, 1H), 3.95-3.75 (m, 3H), 3.70 (s, 3H), 2.71-2.59 (m, 1H), 1.30 (br t, J = 7.3 Hz, 3H), 1.27-1.16 (m, 3H), 1.06-1.01 (m, 3H), 0.96 (d, J = 6.6 Hz, 3H). LCMS (ESI) m/z: 656.3 ( M+1) + .Compound 20B (retention time=2.118 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.39-8.28 (m, 1H), 7.14-7.04 (m, 1H), 7.03-6.98 (m, 1H), 6.91-6.87 (m, 1H), 6.82 (br dd, J = 10.1, 16.5 Hz, 1H), 6.48 ( d, J = 8.3 Hz, 1H), 6.38-6.29 (m, 1H), 6.25-6.13 (m, 1H), 5.81-5.70 (m, 1H), 5.68-5.58 (m, 2H), 4.82-4.43 ( m, 2H), 4.16-4.01 (m, 1H), 3.93-3.84 (m, 1H), 3.65 (s, 2H), 3.74-3.58 (m, 1H), 1.36-1.28 (m, 3H), 1.27- 1.27 (m, 1H), 1.26-1.20 (m, 1H), 1.26-1.20 (m, 1H), 1.16 (br d, J = 6.5 Hz, 2H), 1.11-1.05 (m, 4H), 1.01 (br d d, J = 6.6 Hz, 3H). LCMS (ESI) m/z: 656.3 (M+1) + .

實施例21

Figure 02_image513
第一步： 在0攝氏度下，向化合物21-1（10克量）和碳酸鉀（5.35克）的乙腈（100毫升）溶液中緩慢加入化合物7-2（12.69克）。反應液在20攝氏度下反應14個小時。反應液濃縮得到殘餘物，用乙酸乙酯（100 mL）和飽和碳酸氫鈉（100毫升）溶解。水相用乙酸乙酯（50毫升）萃取兩次，合併有機相用水（50毫升）和飽和食鹽水（50毫升）洗滌，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到的殘餘物。向殘餘物中加入乙酸乙酯和石油醚（120毫升，1:5）攪拌一小時，過濾，濾餅減壓乾燥得到化合物21-2。LCMS (ESI) m/z: 230.1 (m+1) +。 第二步： 在0攝氏度下，向化合物21-2（13.18克）和碳酸銫（18.74克）的乙腈（140毫升）溶液中逐滴加入化合物7-4（9.86克），反應液在15攝氏度下反應2小時。反應液過濾，濾液濃縮後加入水（100毫升），用乙酸乙酯（50毫升）萃取兩次。合併有機相用水（50毫升）和飽和食鹽水（50毫升）洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。向殘餘物中加入甲基第三丁基醚（40毫升）室溫攪拌2小時，過濾，濾餅減壓乾燥得到化合物21-3。LCMS (ESI) m/z: 352.1(m+1) +。 第三步： 向化合物21-3（18.17克，100%純度）的三氟乙醇（100毫升）溶液中加入三乙胺（10.47克），反應液在80攝氏度下反14小時。反應液濃縮得到殘餘物。殘餘物用乙酸乙酯（50毫升）和飽和碳酸氫鈉（100毫升）。水相用乙酸乙酯（50毫升）洗滌，水相用鹽酸水溶液（3莫耳每升）調節pH到1，隨後水相用乙酸乙酯（100毫升）萃取三次。合併有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物21-4。LCMS (ESI) m/z: 320.1 (m+1) +。 第四步： 在向化合物21-4（13.9克）的乙腈（280毫升）的溶液中依次加入磷酸鉀（18.49克）和三溴吡啶鎓鹽（41.78克），反應液在50攝氏度下反應2小時。反應液用飽和亞硫酸鈉（200毫升）淬滅，隨後用乙酸乙酯（100毫升）萃取兩次。合併有機相用鹽酸水溶液（150毫升，1莫耳每升）和飽和食鹽水（150毫升）洗滌。有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物21-5。LCMS (ESI) m/z: 353.9 (M+1) +。 第五步： 在氮氣氛圍下，向化合物21-5（15.4克）和三（二亞苄基丙酮）二鈀（3.98克）的二氧六環（300毫升）溶液中依次加入化合物6-4（7.84克），Xantphos（5.03克）和碳酸銫（28.34克），反應液在100攝氏度下反應2小時。反應液過濾，向濾液中加入鹽酸乙酸乙酯溶液（200毫升，1莫耳每升），15攝氏度下攪拌1小時。混合液過濾，濾餅用乙酸乙酯（100毫升）和飽和碳酸鈉（200毫升）溶解。然後水相用乙酸乙酯（100毫升）萃取兩次，合併有機相用飽和食鹽水（200毫升）洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。向殘餘物中加入乙醇（30毫升），室溫攪拌1小時。過濾，濾餅減壓乾燥得到化合物21-6。LCMS (ESI) m/z: 424.1 (M+1) +。 第六步： 在0攝氏度下，向化合物21-6（11.85克）的二氯甲烷（120毫升）溶液中一次性加入N-溴代丁二醯亞胺（6.48克）。反應液在15攝氏度下反應1小時。向反應液中加入飽和亞硫酸鈉（200毫升）,然後用二氯甲烷（100毫升）萃取兩次，合併有機相用飽和食鹽水（200毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。向殘餘物中加入甲基第三丁基醚和石油醚（90毫升，1:5）攪拌12小時，過濾，濾餅減壓乾燥得到化合物21-7。LCMS (ESI) m/z: 504.2 (M+3) +。 第七步： 在氮氣氛圍下，向化合物21-7（14.15克）的N,N-二甲基甲醯胺（140毫升）溶液中依次加入鋅粉（1.47克），溴化鋅（634.42毫克），氰化鋅（3.31克），三（二亞苄基丙酮）二鈀（1.29克）和DPPF（1.56克）。反應液在氮氣保護下於120攝氏度反應3小時。反應液過濾，向濾液中加入飽和食鹽水（400毫升），然後用乙酸乙酯（200毫升）萃取兩次，合併有機相用飽和食鹽水（200毫升）洗滌兩次，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（洗脫劑：石油醚：乙酸乙酯=5:1 到3:1（含有5%的甲醇））得到化合物21-8。LCMS (ESI) m/z: 449.1 (M+1) +。 第八步： 化合物21-8（12.4克）的濃硫酸（128.8克）溶液在60攝氏度下反應3小時。反應液繼續在60攝氏度下反應14小時。反應液冷卻到15攝氏度。反應液加入到冰水（1000毫升）中，0攝氏度下緩慢加入氫氧化鈉（100克）的水（300毫升）的溶液，隨後用碳酸氫鈉固體調pH到8。向混合液中加入乙酸乙酯（500毫升），過濾，濾液用乙酸乙酯（200毫升*2）萃取，合併有機相用飽和食鹽水（200毫升*2）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物21-9。LCMS (ESI) m/z: 467.2 (M+1) +。 第九步： 在氮氣氛圍下，向化合物21-9（5.0克）的DMA（50毫升）溶液中加入CDI（5.21克），隨後緩慢加入氫化鈉（1.29克，質量百分比：60%）。反應液在15攝氏度下反應1個小時）。反應液加入到冰水（200毫升）中，用鹽酸水溶液（1莫耳每升）調pH到3，隨後用碳酸氫鈉固體調pH到8。混合液用乙酸乙酯（200毫升）萃取兩次，合併有機相用飽和食鹽水（200毫升）洗滌兩次，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物，殘餘物中加入甲醇（15毫升）攪拌2小時。過濾，濾餅減壓乾燥得到21-10。LCMS (ESI) m/z: 493.2 (M+1) +。 第十步： 在氮氣氛圍下，向化合物21-10（0.6克）的四氫呋喃（10毫升）溶液中加入三吡咯烷基溴化鏻六氟磷酸鹽（2.84克）和化合物1-1（2.27克），反應液在60攝氏度下反應14小時。反應液過濾，濾液濃縮得到殘餘物。殘餘物經製備HPLC純化[柱型號：Phenomenex luna C18 （250*50mm*10 μm），流動相：水（0.225%甲酸）-乙腈，梯度：30%-60%，20分鐘]純化得到化合物21-11。LCMS (ESI) m/z: 661.4 (M+1) +。 第十一步： 向化合物21-11（0.9克）的二氯甲烷（10毫升）溶液中一次性加入三氟乙酸（4.62克）。反應液在15攝氏度下反應0.5小時。反應液濃縮後用乙酸乙酯（10毫升）溶解。將乙酸乙酯溶液逐滴加入到飽和碳酸氫鈉（40毫升）中。混合液用乙酸乙酯（20毫升）萃取兩次，合併有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物21-12的三氟乙酸鹽。LCMS (ESI) m/z: 561.3 (M+1) +。 第十二步：
Figure 02_image515
在氮氣氛圍，0攝氏度下，向化合物21-12（0.37克）的四氫呋喃（8毫升）和水（2毫升）的混合溶液中加入碳酸鉀（136.85毫克），隨後向反應液中加入化合物1-5（65.72毫克）。反應液在0攝氏度反應30分鐘，向反應液中加入水（20毫升），用乙酸乙酯（20毫升）萃取兩次，有機相用飽和食鹽水（20毫升）洗後經無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex luna C18 （150*40mm* 15um），流動相：水（0.225%甲酸）-乙腈：28%-58%，13分鐘]純化，得到的產品用製備SFC（柱型號：DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，3.5分鐘，20分鐘）分離得到化合物21A和化合物21B。 化合物21A和化合物21B經SFC檢測[柱型號：Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇+乙腈（0.05%二乙胺）；梯度（B%）：40%甲醇+乙腈（0.05%二乙胺）]得到：化合物21A的保留時間為0.760min，e.e.值為100%；化合物21B的保留時間為1.548min，e.e.值為100%。 化合物21A（保留時間=0.760min）： 1H NMR (400 MHz, MeOH- d 4) δ 8.32 (d, J= 4.9 Hz, 1H), 7.66-7.52 (m, 1H), 7.32 (s, 1H), 7.22-7.10 (m, 3H), 6.81 (dd, J= 16.8, 10.6 Hz, 1H), 6.29 (dd, J= 16.8, 1.7 Hz, 1H), 5.82 (dd, J= 10.6, 1.7 Hz, 1H), 4.04 (br d, J= 5.9 Hz, 4H), 3.92 (br s, 4H), 2.84 (td, J= 13.5, 6.7 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J= 6.8 Hz, 3H), 1.09 (d, J= 6.8 Hz, 3H)。LCMS (ESI) m/z: 615.3 (m+1) +。 化合物21B（保留時間=1.548 min）： 1H NMR (400 MHz, MeOH- d 4) δ 8.32 (d, J= 4.9 Hz, 1H), 7.66-7.53 (m, 1H), 7.32 (s, 1H), 7.23-7.11 (m, 3H), 6.82 (dd, J= 16.8, 10.6 Hz, 1H), 6.29 (dd, J= 16.8, 1.6 Hz, 1H), 5.82 (dd, J= 10.5, 1.6 Hz, 1H), 4.12-4.00 (m, 4H), 3.92 (br s, 4H), 2.84 (td, J= 13.6, 6.8 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J= 6.7 Hz, 3H), 1.08 (d, J= 6.8 Hz, 3H)。LCMS (ESI) m/z: 615.3 (m+1) +。 Example 21
Figure 02_image513
First step: To a solution of compound 21-1 (10 g amount) and potassium carbonate (5.35 g) in acetonitrile (100 ml) was slowly added compound 7-2 (12.69 g) at 0 degrees Celsius. The reaction solution was reacted at 20 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethyl acetate and petroleum ether (120 mL, 1:5) were added to the residue, stirred for one hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-2. LCMS (ESI) m/z: 230.1 (m+1) + . The second step: Compound 7-4 (9.86 g) was added dropwise to a solution of compound 21-2 (13.18 g) and cesium carbonate (18.74 g) in acetonitrile (140 ml) at 0 °C, and the reaction solution was heated at 15 °C The reaction was continued for 2 hours. The reaction solution was filtered, the filtrate was concentrated, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phase was washed with water (50 ml) and saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Methyl tert-butyl ether (40 ml) was added to the residue, stirred at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-3. LCMS (ESI) m/z: 352.1(m+1) + . The third step: Triethylamine (10.47 g) was added to a solution of compound 21-3 (18.17 g, 100% pure) in trifluoroethanol (100 ml), and the reaction solution was reacted at 80 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was taken up with ethyl acetate (50 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was washed with ethyl acetate (50 ml), the pH of the aqueous phase was adjusted to 1 with aqueous hydrochloric acid (3 mol per liter), and the aqueous phase was extracted three times with ethyl acetate (100 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-4. LCMS (ESI) m/z: 320.1 (m+1) + . The fourth step: To a solution of compound 21-4 (13.9 g) in acetonitrile (280 ml), potassium phosphate (18.49 g) and pyridinium tribromide (41.78 g) were added in sequence, and the reaction solution was reacted at 50 degrees Celsius for 2 Hour. The reaction solution was quenched with saturated sodium sulfite (200 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (150 ml, 1 mole per liter) and saturated brine (150 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-5. LCMS (ESI) m/z: 353.9 (M+1) + . Step 5: To a solution of compound 21-5 (15.4 g) and tris(dibenzylideneacetone)dipalladium (3.98 g) in dioxane (300 ml) was added compound 6-4 sequentially under nitrogen atmosphere (7.84 g), Xantphos (5.03 g) and cesium carbonate (28.34 g), the reaction solution was reacted at 100 degrees Celsius for 2 hours. The reaction solution was filtered, and ethyl acetate solution of hydrochloric acid (200 ml, 1 mol per liter) was added to the filtrate, and the mixture was stirred at 15 degrees Celsius for 1 hour. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (100 mL) and saturated sodium carbonate (200 mL). The aqueous phase was then extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Ethanol (30 ml) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 21-6. LCMS (ESI) m/z: 424.1 (M+1) + . Step 6: To a solution of compound 21-6 (11.85 g) in dichloromethane (120 mL) was added N-bromosuccinimide (6.48 g) in one portion at 0 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 1 hour. Saturated sodium sulfite (200 mL) was added to the reaction solution, then extracted twice with dichloromethane (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . Methyl tert-butyl ether and petroleum ether (90 mL, 1:5) were added to the residue, stirred for 12 hours, filtered, and the filter cake was dried under reduced pressure to obtain compound 21-7. LCMS (ESI) m/z: 504.2 (M+3) + . Step 7: To a solution of compound 21-7 (14.15 g) in N,N-dimethylformamide (140 ml) under a nitrogen atmosphere, zinc powder (1.47 g), zinc bromide (634.42 mg) were sequentially added ), zinc cyanide (3.31 g), tris(dibenzylideneacetone)dipalladium (1.29 g) and DPPF (1.56 g). The reaction solution was reacted at 120 degrees Celsius for 3 hours under nitrogen protection. The reaction solution was filtered, and saturated brine (400 mL) was added to the filtrate, followed by extraction twice with ethyl acetate (200 mL). The combined organic phases were washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1 to 3:1 (containing 5% methanol)) to give compound 21-8. LCMS (ESI) m/z: 449.1 (M+1) + . The eighth step: A solution of compound 21-8 (12.4 g) in concentrated sulfuric acid (128.8 g) was reacted at 60 degrees Celsius for 3 hours. The reaction solution was continued to react at 60 degrees Celsius for 14 hours. The reaction solution was cooled to 15 degrees Celsius. The reaction solution was added to ice water (1000 ml), a solution of sodium hydroxide (100 g) in water (300 ml) was slowly added at 0°C, and the pH was adjusted to 8 with solid sodium bicarbonate. Ethyl acetate (500 mL) was added to the mixture, filtered, the filtrate was extracted with ethyl acetate (200 mL*2), the combined organic phases were washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated to obtain compound 21-9. LCMS (ESI) m/z: 467.2 (M+1) + . The ninth step: To a solution of compound 21-9 (5.0 g) in DMA (50 ml) was added CDI (5.21 g) under nitrogen atmosphere, followed by slowly adding sodium hydride (1.29 g, mass percentage: 60%). The reaction solution was reacted at 15 degrees Celsius for 1 hour). The reaction solution was added to ice water (200 ml), and the pH was adjusted to 3 with aqueous hydrochloric acid (1 mol per liter), followed by the pH adjustment to 8 with solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate (200 mL), the combined organic phases were washed twice with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Methanol (15 mL) was added to the residue. ) and stir for 2 hours. After filtration, the filter cake was dried under reduced pressure to obtain 21-10. LCMS (ESI) m/z: 493.2 (M+1) + . Step 10: To a solution of compound 21-10 (0.6 g) in tetrahydrofuran (10 ml) were added tripyrrolidinophosphonium bromide hexafluorophosphate (2.84 g) and compound 1-1 (2.27 g) under nitrogen atmosphere ), the reaction solution was reacted at 60 degrees Celsius for 14 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (250*50mm*10 μm), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 30%-60%, 20 minutes] to obtain compound 21- 11. LCMS (ESI) m/z: 661.4 (M+1) + . Eleventh step: To a solution of compound 21-11 (0.9 g) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated and dissolved in ethyl acetate (10 ml). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the trifluoroacetate salt of compound 21-12. LCMS (ESI) m/z: 561.3 (M+1) + . Step 12:
Figure 02_image515
To a mixed solution of compound 21-12 (0.37 g) in tetrahydrofuran (8 ml) and water (2 ml) was added potassium carbonate (136.85 mg) under nitrogen atmosphere at 0°C, followed by compound 1- 5 (65.72 mg). The reaction solution was reacted at 0 degrees Celsius for 30 minutes, water (20 mL) was added to the reaction solution, extracted twice with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a residue. The residue was purified by preparative HPLC [column type: Phenomenex luna C18 (150*40mm*15um), mobile phase: water (0.225% formic acid)-acetonitrile: 28%-58%, 13 minutes], and the obtained product was purified by preparative SFC ( Column model: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.5 minutes, 20 minutes) to separate compound 21A and compound 21B. Compound 21A and compound 21B were detected by SFC [column type: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol + acetonitrile (0.05% diethylamine) in phase B; gradient ( B%): 40% methanol + acetonitrile (0.05% diethylamine)] to obtain: compound 21A has a retention time of 0.760 min and an ee value of 100%; compound 21B has a retention time of 1.548 min and an ee value of 100%. Compound 21A (retention time = 0.760 min): 1 H NMR (400 MHz, MeOH- d 4 ) δ 8.32 (d, J = 4.9 Hz, 1H), 7.66-7.52 (m, 1H), 7.32 (s, 1H) , 7.22-7.10 (m, 3H), 6.81 (dd, J = 16.8, 10.6 Hz, 1H), 6.29 (dd, J = 16.8, 1.7 Hz, 1H), 5.82 (dd, J = 10.6, 1.7 Hz, 1H) ), 4.04 (br d, J = 5.9 Hz, 4H), 3.92 (br s, 4H), 2.84 (td, J = 13.5, 6.7 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 615.3 (m+1) + . Compound 21B (RT=1.548 min): 1 H NMR (400 MHz, MeOH- d 4 ) δ 8.32 (d, J = 4.9 Hz, 1H), 7.66-7.53 (m, 1H), 7.32 (s, 1H) , 7.23-7.11 (m, 3H), 6.82 (dd, J = 16.8, 10.6 Hz, 1H), 6.29 (dd, J = 16.8, 1.6 Hz, 1H), 5.82 (dd, J = 10.5, 1.6 Hz, 1H) ), 4.12-4.00 (m, 4H), 3.92 (br s, 4H), 2.84 (td, J = 13.6, 6.8 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H) ), 1.08 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 615.3 (m+1) + .

實施例22

Figure 02_image517
第一步： 在氮氣氛圍下，向化合物21-10（0.5克）的DMAc（10毫升）溶液中加入三吡咯烷基溴化鏻六氟磷酸鹽（951.01毫克）和DIPEA（263.66毫克）反應液在15攝氏度下反應1小時，加入化合物3-1（655.77毫克），反應液在100攝氏度下反應14小時。向反應液中加入水（20毫升），用乙酸乙酯（20毫升）萃取兩次，合併有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物22-1。LCMS (ESI) m/z: 689.4 (M+1) +。 第二步： 在0攝氏度下，向化合物22-1（0.9克）的二氯甲烷（10毫升）溶液中一次性加入三氟乙酸（4.62克）。反應液在15攝氏度下反應0.5小時。反應液旋乾後用乙酸乙酯（10毫升）溶解。將乙酸乙酯溶液逐滴加入到飽和碳酸氫鈉（40毫升）中。混合液用乙酸乙酯（20毫升）萃取兩次，合併有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物22-2。LCMS (ESI) m/z: 589.4 (M+1) +。 第三步：
Figure 02_image519
在氮氣氛圍，0攝氏度下，向化合物22-2（0.55克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中加入碳酸鉀（193.72毫克），隨後向反應液中加入化合物1-5（93.03毫克）。反應液在0攝氏度反應30分鐘，向反應液中加入水（10毫升），用乙酸乙酯（10毫升）萃取兩次，有機相用飽和食鹽水（10毫升）洗後經無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex luna C18 （150*40mm* 15um），流動相：水（0.225%甲酸）-乙腈，梯度：25%-55%，13分鐘]純化，得到化合物22。 化合物22用製備SFC（柱型號：DAICEL CHIRALPAK IC(250mm*30mm,10μm)，流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，8.0分鐘，40分鐘）分離得到化合物22A和化合物22B。 化合物22A和化合物22B經SFC檢測[柱型號：Column: Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物22A的保留時間為1.478min，e.e.值為100%；化合物22B的保留時間為2.993min，e.e.值為99.47%。化合物22A（保留時間=1.478min）： 1H NMR (400 MHz, MeOD- d 4) δ 8.33 (d, J= 5.0 Hz, 1H), 7.70-7.52 (m, 1H), 7.25-7.10 (m, 4H), 6.95-6.73 (m, 1H), 6.29 (ddd, J= 16.7, 6.1, 1.8 Hz, 1H), 5.82 (ddd, J= 10.6, 7.0, 1.8 Hz, 1H), 5.02-4.90 (m, 2H), 4.62-4.14 (m, 2H), 3.98-3.81 (m, 2H), 2.87 (qd, J= 11.0, 6.8 Hz, 1H), 2.07 (s, 3H), 1.49 (d, J= 6.6 Hz, 3H), 1.41-1.29 (m, 3H), 1.18 (dd, J= 6.7, 1.6 Hz, 3H), 1.09 (dd, J= 6.7, 1.6 Hz, 3H)。LCMS (ESI) m/z: 643.4 (m+1) +。 化合物22B（保留時間=2.993min）： 1H NMR (400 MHz, MeOD- d 4) δ 8.33 (d, J= 4.9 Hz, 1H), 7.68-7.54 (m, 1H), 7.24-7.13 (m, 4H), 6.92-6.74 (m, 1H), 6.30 (ddd, J= 16.8, 6.4, 1.8 Hz, 1H), 5.87-5.77 (m, 1H), 4.98-4.89 (m, 2H), 4.60-4.16 (m, 2H), 3.97-3.80 (m, 2H), 2.73 (quin, J= 6.8 Hz, 1H), 2.13 (s, 3H), 1.48 (d, J= 6.6 Hz, 3H), 1.40-1.28 (m, 3H), 1.16 (d, J= 6.7 Hz, 3H), 1.07 (d, J= 6.8 Hz, 3H)。 LCMS (ESI) m/z: 643.4 (m+1) +。 Example 22
Figure 02_image517
Step 1: Tripyrrolidinophosphonium bromide hexafluorophosphate (951.01 mg) and DIPEA (263.66 mg) were added to a solution of compound 21-10 (0.5 g) in DMAc (10 ml) under nitrogen atmosphere The reaction was performed at 15 degrees Celsius for 1 hour, compound 3-1 (655.77 mg) was added, and the reaction solution was reacted at 100 degrees Celsius for 14 hours. Water (20 mL) was added to the reaction solution, extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-1 . LCMS (ESI) m/z: 689.4 (M+1) + . Step 2: To a solution of compound 22-1 (0.9 g) in dichloromethane (10 mL) was added trifluoroacetic acid (4.62 g) in one portion at 0 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was spin-dried and dissolved in ethyl acetate (10 ml). The ethyl acetate solution was added dropwise to saturated sodium bicarbonate (40 mL). The mixture was extracted twice with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 22-2. LCMS (ESI) m/z: 589.4 (M+1) + . third step:
Figure 02_image519
To a mixed solution of compound 22-2 (0.55 g) in tetrahydrofuran (4 ml) and water (1 ml) was added potassium carbonate (193.72 mg) at 0°C under nitrogen atmosphere, followed by adding compound 1- 5 (93.03 mg). The reaction solution was reacted at 0 degrees Celsius for 30 minutes, water (10 mL) was added to the reaction solution, extracted twice with ethyl acetate (10 mL), the organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15um), mobile phase: water (0.225% formic acid)-acetonitrile, gradient: 25%-55%, 13 minutes] to give compound 22. Compound 22 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 8.0 minutes, 40 minutes) to obtain the compound 22A and Compound 22B. Compound 22A and compound 22B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 40%-40%] obtained: the retention time of compound 22A is 1.478min, and the ee value is 100%; the retention time of compound 22B is 2.993min, and the ee value is 99.47%. Compound 22A (retention time = 1.478 min): 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.33 (d, J = 5.0 Hz, 1H), 7.70-7.52 (m, 1H), 7.25-7.10 (m, 4H), 6.95-6.73 (m, 1H), 6.29 (ddd, J = 16.7, 6.1, 1.8 Hz, 1H), 5.82 (ddd, J = 10.6, 7.0, 1.8 Hz, 1H), 5.02-4.90 (m, 2H), 4.62-4.14 (m, 2H), 3.98-3.81 (m, 2H), 2.87 (qd, J = 11.0, 6.8 Hz, 1H), 2.07 (s, 3H), 1.49 (d, J = 6.6 Hz , 3H), 1.41-1.29 (m, 3H), 1.18 (dd, J = 6.7, 1.6 Hz, 3H), 1.09 (dd, J = 6.7, 1.6 Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) + . Compound 22B (retention time = 2.993 min): 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.33 (d, J = 4.9 Hz, 1H), 7.68-7.54 (m, 1H), 7.24-7.13 (m, 4H), 6.92-6.74 (m, 1H), 6.30 (ddd, J = 16.8, 6.4, 1.8 Hz, 1H), 5.87-5.77 (m, 1H), 4.98-4.89 (m, 2H), 4.60-4.16 ( m, 2H), 3.97-3.80 (m, 2H), 2.73 (quin, J = 6.8 Hz, 1H), 2.13 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H), 1.40-1.28 (m , 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 643.4 (m+1) + .

實施例23

Figure 02_image521
第一步： 在化合物23-1 (5克)的乙腈 (50毫升) 溶液中加入碳酸鉀(2.35克)，冷卻到0 攝氏度，分批加入化合物7-2（5.57克)，然後在 25攝氏度攪拌16小時。過濾，濃縮乾，濃縮乾後在乙酸乙酯和石油醚（體積比1:1）的混合溶劑中室溫打漿2小時，過濾濃縮得到化合物23-2。 LCMS (ESI) m/z: 248.0 (M+1) +。 第二步： 在化合物23-2（6.7 克）的乙腈（100毫升）中加入碳酸銫 (8.83 克)，然後在0-5攝氏度分批加入化合物7-4（4.65 克），在25攝氏度  攪拌2小時，過濾濃縮乾得化合物23-3。 LCMS (ESI) m/z: 369.9(M+1) +。 第三步： 在化合物23-3（10 克）的三氟乙醇（50 毫升）溶液中加入三乙胺（5.48g），混合體系在90攝氏度攪拌16小時。濃縮乾，用50毫升的水稀釋，用1莫耳/升的氫氧化鈉水溶液調節pH到8，用乙酸乙酯（50毫升）萃取丟棄，水相用1 莫耳/升的鹽酸水溶液調節pH到3~4，黃色的固體析出，用乙酸乙酯（100毫升）萃取，食鹽水（20毫升）洗滌，無水硫酸鈉乾燥濃縮得到化合物23-4。 1H NMR (400 MHz, CHLOROFORM- d) δ 13.10-12.64 (m, 1H), 8.84-8.67 (m, 1H), 7.55-7.40 (m, 1H), 7.23-7.10 (m, 2H)。 LCMS (ESI) m/z: 337.9 (M+1) +。 第四步： 在化合物23-4（6.7 克）的乙腈 (100毫升)  溶液中加入磷酸鉀 （8.44 克）和三溴吡啶嗡鹽（19.07 克），然後在50攝氏度攪拌2小時，用亞硫酸鈉水溶液（50毫升）淬滅反應，用乙酸乙酯（50毫升*3）萃取三次，合併有機相用飽和食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥，濃縮得到化合物23-5。 LCMS (ESI) m/z: 371.7 (M+1) +。 第五步： 在化合物23-5（7 克)和2-異丙基-4-甲基-吡啶-3-胺（3.11克）的二氧六環（20毫升）中加入Pd 2(dba) 3（861.42 毫克）和 Xantphos（1.09克，碳酸銫（12.26克），反應體系用氮氣置換，加熱到100攝氏度攪拌反應18小時。降溫到25 攝氏度，過濾，濃縮，加入鹽酸乙酸乙酯溶液((1莫耳/升，120毫升)，固體過濾，懸濁在水（100 毫升）和乙酸乙酯（200毫升）溶液中，用飽和亞硫酸鈉水溶液調節 pH=8~9，有機相用水（50毫升）洗滌，然後用飽和食鹽水（50毫升）洗滌，無水硫酸乾燥，過濾，濃縮得到化合物23-6。LCMS (ESI) m/z: 442.0 (M+1) +. 第六步： 在0攝氏度，向化合物23-6（8.1克）的二氯甲烷（100 毫升）溶液中分批加入NBS(3.48克)，在0-25攝氏度攪拌半小時，加入飽和亞硫酸鈉（50毫升）水溶液，分離的有機相用飽和食鹽水（50毫升）洗滌1次，無水硫酸鈉乾燥，濃縮乾得粗品，用石油醚和甲基第三丁基醚混合體系室溫打漿12小時，過濾，乾燥得到化合物23-7。 1H NMR (400 MHz, CHLOROFORM- d) δ 8.44 (d, J= 4.9 Hz, 1H), 7.48-7.35 (m, 1H), 7.16-6.97 (m, 3H), 6.96-6.91 (m, 1H), 3.45-3.32 (m, 1H), 2.20 (d, J= 2.8 Hz, 3H), 1.36-1.31 (m, 3H), 1.26-1.20 (m, 3H)。LCMS (ESI) m/z: 521.9 (M+3) +。 第七步： 在化合物23-7（7.5克)，氰化鋅（3.21克)，鋅粉（894.00毫克）的N,N-二甲基甲醯胺 (100毫升)  溶液中，加入 溴化鋅（153.94毫克)，氮氣置換，加入 DPPF（1.52克）和Pd 2(dba) 3（1.25克），氮氣置換後在100 攝氏度攪拌16小時。冷卻到室溫，過濾後母液倒入純水（300毫升）中，固體過濾，溶解到乙酸乙酯（200毫升）中，水（50毫升*3）洗滌三次，用無水硫酸鈉乾燥，過濾濃縮乾，用石油醚和甲基第三丁基醚混合體系室溫打漿1小時，過濾濃縮得到化合物23-8。LCMS (ESI) m/z: 466.9 (M+1) +。 第八步： 化合物23-8（7克）分批加入到 濃硫酸（35毫升）中，加熱到60 攝氏度攪拌16小時，冷卻到室溫，倒入冰水（300毫升）中，加入10%的氫氧化鈉水溶液至pH為8到9，用乙酸乙酯（500毫升*2）萃取，合併的有機相濃縮得到化合物23-9。LCMS (ESI) m/z: 484.9 (M+1) +。 第九步： 在0攝氏度，向化合物23-9（6.1克）的 DMA (65毫升) 溶液中加入氫化鈉（1.51克，質量百分比：60%）和羰基二咪唑（6.13克），在 0-25攝氏度攪拌1小時，倒入冰水（200毫升）中，用1莫耳的鹽酸水溶液調節pH 到4，然後用固體碳酸氫鈉調節pH=8，用乙酸乙酯（100毫升*2）萃取，合併有機相用食鹽水（20毫升）洗滌一次，無水硫酸鈉乾燥，濃縮得到化合物23-10。LCMS (ESI) m/z: 511.0 (M+1) +。 第十步： 向化合物23-10（3.0克）的 DMAc (30毫升)溶液中加入PYBROP （5.48克）和DIEA（2.28克），在25攝氏度攪拌2 小時。加入化合物1-1（3.29克)，加熱至100攝氏度反應12 小時。反應液倒入水（100毫升）中，固體用乙酸乙酯（50毫升）溶解，飽和食鹽水（20毫升*3）洗滌，有機相濃縮得到殘餘物，殘餘物通過柱層析純化（洗脫劑：石油醚：乙酸乙酯=1:1）得到化合物23-11。LCMS (ESI) m/z: 679.1 (M+1) +。 第十一步： 化合物23-11（4.0克）的二氯甲烷（30毫升）溶液中，加入三氟乙酸（10毫升），反應液在25攝氏度攪拌30分鐘，濃縮得到化合物23-12的三氟乙酸鹽。粗品直接用於下一步。LCMS (ESI) m/z: 579.0 (M+1) +。 第十二步： 化合物23-12（3.0克，三氟乙酸鹽）的四氫呋喃（20毫升）和水（10毫升）溶液中，加入碳酸鉀（1.54克），混合物在25攝氏度 攪拌10分鐘，然後加入化合物1-5（504.97毫克），在25攝氏度攪拌30分鐘。反應液用乙酸乙酯（50毫升）萃取，然後用飽和食鹽水（10毫升）洗滌，濃縮得粗品。粗品通過製備HPLC(柱型號: Phenomenex Synergi Max-RP （250*50mm*10 μm）；流動相: [水(0.225%甲酸)-乙腈]；梯度：25%-55%，25分鐘)純化得到化合物23。LCMS (ESI) m/z: 633.1 (M+1) +。 第十三步：
Figure 02_image523
通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，4分鐘，120分鐘）分離純化得到23M-1（保留時間=1.904和保留時間=2.01 min的混合物）及23M-2（保留時間=1.463 min和保留時間=1.569 min的混合物）。 23M-1通過製備SFC（柱型號：DAICEL CHIRALPAK AD（250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體15%-15%，5.7分鐘，800分鐘）分離純化得到化合物23A和化合物23B。 23M-2通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體15%-15%，9分鐘，530分鐘）分離純化得到化合物23C和化合物23D。 化合物23A和化合物23B經SFC檢測[柱型號：Column: Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物23A的保留時間為1.904min，e.e.值為95.12%；化合物23B的保留時間為2.017min，e.e.值為99.47%。 化合物23C和化合物23D經SFC檢測[柱型號：Column: Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：15%-15%]得到：化合物23C的保留時間為1.463min；化合物23D的保留時間為1.569min。 化合物23A： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.8 Hz, 1H), 7.90-7.77 (m, 1H), 7.52-7.42 (m, 1H), 7.32 (s, 1H), 7.10 (d, J= 4.9 Hz, 1H), 6.90-6.79 (m, 1H), 6.24-6.15 (m, 1H), 5.81-5.73 (m, 1H), 3.99-3.76 (m, 8H), 2.79-2.69 (m, 1H), 1.99 (s, 3H), 1.10-0.93 (m, 6H)。LCMS (ESI) m/z: 633.1 (M+1) +。 化合物23B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.9 Hz, 1H), 7.9 -7.78 (m, 1H), 7.47 (br t, J= 8.8 Hz, 1H), 7.32 (s, 1H), 7.09 (d, J= 4.9 Hz, 1H), 6.96-6.79 (m, 1H), 6.29-6.17 (m, 1H), 5.92-5.70 (m, 1H), 3.99-3.77 (m, 8H), 2.85-2.68 (m, 1H), 2.03-1.93 (m, 3H), 1.13-0.93 (m, 6H)。LCMS (ESI) m/z: 633.1 (M+1) +。 化合物23C： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.8 Hz, 1H), 7.90-7.78 (m, 1H), 7.53-7.44 (m, 1H), 7.32 (s, 1H), 7.10 (d, J= 4.9 Hz, 1H), 6.93-6.76 (m, 1H), 6.27-6.15 (m, 1H), 5.84-5.70 (m, 1H), 3.99-3.73 (m, 8H), 2.78-2.69 (m, 1H), 1.99 (s, 3H), 0.94-1.06 (m, 6H)。LCMS (ESI) m/z: 633.1 (M+1) +。 化合物23D： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.8 Hz, 1H), 7.92-7.80 (m, 1H), 7.56-7.44 (m, 1H), 7.32 (s, 1H), 7.09 (d, J= 5.0 Hz, 1H), 6.94-6.78 (m, 1H), 6.30-6.12 (m, 1H), 5.86-5.70 (m, 1H), 4.04-3.72 (m, 8H), 2.84-2.68 (m, 1H), 1.97 (s, 3H), 1.13-0.94 (m, 6H)。LCMS (ESI) m/z: 633.1 (M+1) +。 Example 23
Figure 02_image521
Step 1: To a solution of compound 23-1 (5 g) in acetonitrile (50 mL) was added potassium carbonate (2.35 g), cooled to 0 °C, added compound 7-2 (5.57 g) in portions, and then at 25 °C Stir for 16 hours. Filtration, concentrated to dryness, concentrated to dryness, slurried in a mixed solvent of ethyl acetate and petroleum ether (volume ratio 1:1) at room temperature for 2 hours, filtered and concentrated to obtain compound 23-2. LCMS (ESI) m/z: 248.0 (M+1) + . Step 2: Add cesium carbonate (8.83 g) to compound 23-2 (6.7 g) in acetonitrile (100 mL), then add compound 7-4 (4.65 g) in batches at 0-5 °C, stir at 25 °C After 2 hours, it was filtered and concentrated to dryness to obtain compound 23-3. LCMS (ESI) m/z: 369.9(M+1) + . The third step: Triethylamine (5.48 g) was added to a solution of compound 23-3 (10 g) in trifluoroethanol (50 ml), and the mixed system was stirred at 90 degrees Celsius for 16 hours. Concentrated to dryness, diluted with 50 mL of water, adjusted to pH 8 with 1 mol/L aqueous sodium hydroxide solution, extracted with ethyl acetate (50 mL) and discarded, the aqueous phase was adjusted to pH with 1 mol/L aqueous hydrochloric acid solution From 3 to 4, a yellow solid was precipitated, extracted with ethyl acetate (100 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain compound 23-4. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 13.10-12.64 (m, 1H), 8.84-8.67 (m, 1H), 7.55-7.40 (m, 1H), 7.23-7.10 (m, 2H). LCMS (ESI) m/z: 337.9 (M+1) + . Step 4: To a solution of compound 23-4 (6.7 g) in acetonitrile (100 mL) was added potassium phosphate (8.44 g) and pyridinium tribromide (19.07 g), then stirred at 50°C for 2 hours, and then added with aqueous sodium sulfite solution. (50 mL) quenched the reaction, extracted three times with ethyl acetate (50 mL*3), and the combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-5. LCMS (ESI) m/z: 371.7 (M+1) + . Step 5: To compound 23-5 (7 g) and 2-isopropyl-4-methyl-pyridin-3-amine (3.11 g) in dioxane (20 mL) was added Pd 2 (dba) 3 (861.42 mg) and Xantphos (1.09 g, cesium carbonate (12.26 g), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 18 hours. Cool to 25 degrees Celsius, filter, concentrate, add hydrochloric acid in ethyl acetate ((( 1 mol/L, 120 mL), the solid was filtered, suspended in a solution of water (100 mL) and ethyl acetate (200 mL), adjusted to pH=8~9 with saturated aqueous sodium sulfite solution, and the organic phase was water (50 mL) Washed, then washed with saturated brine (50 mL), dried with anhydrous sulfuric acid, filtered, and concentrated to give compound 23-6. LCMS (ESI) m/z: 442.0 (M+1) + . The sixth step: at 0 degrees Celsius, To a solution of compound 23-6 (8.1 g) in dichloromethane (100 mL) was added NBS (3.48 g) in portions, stirred at 0-25 degrees Celsius for half an hour, added saturated aqueous sodium sulfite (50 mL), and the organic phase was separated. Washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, concentrated to dryness to obtain a crude product, slurried at room temperature with a mixed system of petroleum ether and methyl tertiary butyl ether for 12 hours, filtered and dried to obtain compound 23-7. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.44 (d, J = 4.9 Hz, 1H), 7.48-7.35 (m, 1H), 7.16-6.97 (m, 3H), 6.96-6.91 (m, 1H) , 3.45-3.32 (m, 1H), 2.20 (d, J = 2.8 Hz, 3H), 1.36-1.31 (m, 3H), 1.26-1.20 (m, 3H). LCMS (ESI) m/z: 521.9 ( M+3) + . Seventh step: A solution of compound 23-7 (7.5 g), zinc cyanide (3.21 g), zinc powder (894.00 mg) in N,N-dimethylformamide (100 mL) Zinc bromide (153.94 mg) was added, nitrogen was replaced, DPPF (1.52 g) and Pd 2 (dba) 3 (1.25 g) were added, and the mixture was stirred at 100 degrees Celsius for 16 hours after nitrogen replacement. Cooled to room temperature, and the mother liquor was filtered. Pour into pure water (300ml), filter the solid, dissolve in ethyl acetate (200ml), wash with water (50ml*3) three times, dry with anhydrous sodium sulfate, filter and concentrate to dryness, use petroleum ether and methyl The tertiary butyl ether mixed system was slurried at room temperature for 1 hour, filtered and concentrated to obtain compound 23-8. LCMS (ESI) m/z: 466.9 (M+1) + . The eighth step: Compound 23-8 (7 g) was added to concentrated sulfuric acid (35 ml) in batches, heated to 60 degrees Celsius, stirred for 16 hours, cooled to room temperature, poured into ice water (300 ml), and added with 10% The aqueous sodium hydroxide solution was adjusted to pH 8 to 9, extracted with ethyl acetate (500 mL*2), and the combined organic phases were concentrated to give compound 23-9. LCMS (ESI) m/z: 484.9 (M+1) + . Step 9: To a solution of compound 23-9 (6.1 g) in DMA (65 ml) at 0 degrees Celsius, sodium hydride (1.51 g, mass percentage: 60%) and carbonyldiimidazole (6.13 g) were added at 0- Stir at 25°C for 1 hour, pour into ice water (200 mL), adjust pH to 4 with 1 molar aqueous hydrochloric acid solution, then adjust pH=8 with solid sodium bicarbonate, extract with ethyl acetate (100 mL*2) , the combined organic phases were washed once with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-10. LCMS (ESI) m/z: 511.0 (M+1) + . Step 10: To a solution of compound 23-10 (3.0 g) in DMAc (30 mL) was added PYBROP (5.48 g) and DIEA (2.28 g) and stirred at 25°C for 2 hours. Compound 1-1 (3.29 g) was added, heated to 100 degrees Celsius and reacted for 12 hours. The reaction solution was poured into water (100 mL), the solid was dissolved in ethyl acetate (50 mL), washed with saturated brine (20 mL*3), the organic phase was concentrated to obtain a residue, and the residue was purified by column chromatography (eluting agent: petroleum ether: ethyl acetate=1:1) to obtain compound 23-11. LCMS (ESI) m/z: 679.1 (M+1) + . The eleventh step: To a solution of compound 23-11 (4.0 g) in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added, the reaction solution was stirred at 25 degrees Celsius for 30 minutes, and concentrated to obtain the trifluoroacetic acid of compound 23-12. Fluoroacetate. The crude product was used directly in the next step. LCMS (ESI) m/z: 579.0 (M+1) + . Step 12: To a solution of compound 23-12 (3.0 g, trifluoroacetate) in tetrahydrofuran (20 mL) and water (10 mL), potassium carbonate (1.54 g) was added, and the mixture was stirred at 25°C for 10 minutes, then Compound 1-5 (504.97 mg) was added, and the mixture was stirred at 25 degrees Celsius for 30 minutes. The reaction solution was extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50mm*10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 25%-55%, 25 minutes) to obtain the compound twenty three. LCMS (ESI) m/z: 633.1 (M+1) + . Step Thirteen:
Figure 02_image523
23M-23M- 1 (mixture of RT=1.904 and RT=2.01 min) and 23M-2 (mixture of RT=1.463 min and RT=1.569 min). 23M-1 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 5.7 minutes, 800 minutes) Compound 23A and compound 23B were obtained. 23M-2 was prepared by SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 15%-15%, 9 minutes, 530 minutes) Compound 23C and compound 23D were obtained by separation and purification. Compound 23A and compound 23B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 40%-40%] obtained: the retention time of compound 23A was 1.904 min, and the ee value was 95.12%; the retention time of compound 23B was 2.017 min, and the ee value was 99.47%. Compound 23C and compound 23D were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; Gradient (B%): 15%-15%] yielded: the retention time of compound 23C was 1.463 min; the retention time of compound 23D was 1.569 min. Compound 23A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.8 Hz, 1H), 7.90-7.77 (m, 1H), 7.52-7.42 (m, 1H), 7.32 (s, 1H), 7.10 (d, J = 4.9 Hz, 1H), 6.90-6.79 (m, 1H), 6.24-6.15 (m, 1H), 5.81-5.73 (m, 1H), 3.99-3.76 (m, 8H) , 2.79-2.69 (m, 1H), 1.99 (s, 3H), 1.10-0.93 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) + . Compound 23B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.9 Hz, 1H), 7.9-7.78 (m, 1H), 7.47 (br t, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.09 (d, J = 4.9 Hz, 1H), 6.96-6.79 (m, 1H), 6.29-6.17 (m, 1H), 5.92-5.70 (m, 1H), 3.99-3.77 ( m, 8H), 2.85-2.68 (m, 1H), 2.03-1.93 (m, 3H), 1.13-0.93 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) + . Compound 23C: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.8 Hz, 1H), 7.90-7.78 (m, 1H), 7.53-7.44 (m, 1H), 7.32 (s, 1H), 7.10 (d, J = 4.9 Hz, 1H), 6.93-6.76 (m, 1H), 6.27-6.15 (m, 1H), 5.84-5.70 (m, 1H), 3.99-3.73 (m, 8H) , 2.78-2.69 (m, 1H), 1.99 (s, 3H), 0.94-1.06 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) + . Compound 23D: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.8 Hz, 1H), 7.92-7.80 (m, 1H), 7.56-7.44 (m, 1H), 7.32 (s, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.94-6.78 (m, 1H), 6.30-6.12 (m, 1H), 5.86-5.70 (m, 1H), 4.04-3.72 (m, 8H) , 2.84-2.68 (m, 1H), 1.97 (s, 3H), 1.13-0.94 (m, 6H). LCMS (ESI) m/z: 633.1 (M+1) + .

實施例24

Figure 02_image525
第一步： 在0-10攝氏度下，向化合物24-1（4克）的乙腈（40毫升）溶液中加入碳酸鉀（1.93克），化合物7-2（5.72克），加完後反應液在25攝氏度下反應12個小時。將反應液過濾，濾餅用乙酸乙酯（20毫升*3）淋洗，濾液減壓濃縮得到殘留物。殘留物中加入石油醚（40毫升）室溫攪拌半小時，過濾，濾餅用石油醚（20毫升*3）淋洗並減壓濃縮得到化合物24-2。LCMS (ESI) m/z: 244.2(M+1)+。 第二步： 在0-10攝氏度下，向化合物24-2（8.33克）的乙腈（85毫升）溶液中加入碳酸銫（11.16克），化合物7-4（5.87克），加完反應液在10-15攝氏度下反應1小時。將反應液墊矽藻土過濾，濾餅用乙酸乙酯（30毫升*3）淋洗，濾液減壓濃縮得到化合物24-3。LCMS (ESI) m/z: 366.1(M+1) +。 第三步： 向化合物24-3（13克）的三氟乙醇（65毫升）溶液中加入三乙胺（7.20克），反應液在80攝氏度下反應11小時。反應液減壓濃縮得到殘餘物，殘餘物經乙酸乙酯（200毫升）和鹽酸（1莫耳/升，50毫升）溶液稀釋，靜置分層，有機相依次用鹽酸（1莫耳/升，50毫升）溶液，飽和食鹽水（50毫升）洗滌，然後經無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物，在10-15攝氏度下，向殘留物中加入甲基第三丁基醚（50毫升），攪拌半小時，過濾，濾餅用甲基第三丁基醚（10毫升*3）淋洗，並減壓濃縮得到化合物24-4。LCMS (ESI) m/z: 334.0(M+1) +。 第四步： 向化合物24-4（5.5克）的乙腈（55毫升）溶液中加入三溴吡啶鎓鹽（10.56克）和磷酸鉀（7.01克），然後反應液在50攝氏度下反應2小時。將亞硫酸鈉（6克）溶于水（30毫升）中淬滅反應，然後混合物過濾，濾餅用乙酸乙酯（10毫升*3）淋洗，濾液減壓濃縮得到殘留物。殘留物用乙酸乙酯（200毫升）稀釋，混合物用鹽酸（1莫耳/升，50毫升*2）溶液洗滌，有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=10:1到8:1）得到化合物24-5。LCMS (ESI) m/z: 367.8(M+1) +。 第五步： 向化合物24-5（6克）的二氧六環（60毫升）溶液中依次加入2-異丙基-4-甲基吡啶-3-胺（2.45克），碳酸銫（10.62克），三（二亞苄基丙酮）二鈀（1.49克）和4,5-雙二苯基膦-9,9-二甲基氧雜蒽（1.89克），反應液在氮氣保護下於100攝氏度反應12小時。 反應液墊矽藻土過濾，濾餅用乙酸乙酯（30毫升*3）洗滌，濾液減壓濃縮得到殘留物，殘留物經矽膠柱純化（石油醚：乙酸乙酯=10:1 到3:1）得到化合物24-6。LCMS (ESI) m/z: 438.3(M+1) +。 第六步： 在0-10攝氏度下，向化合物24-6（5克）的二氯甲烷(50毫升)溶液中加入N-溴代丁二醯亞胺（2.03克），反應液在0-10攝氏度下反應1小時，反應液用飽和亞硫酸鈉水溶液（20毫升）淬滅，然後靜置分層，有機相用飽和食鹽水（20毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物24-7。LCMS (ESI) m/z: 518.1(M+3) +。 第七步： 向化合物24-7（6.12克）的N,N-二甲基甲醯胺（60毫升）溶液中依次一次性加入鋅粉（0.46克），氰化鋅（0.79克），溴化鋅（124.66毫克），1,1-雙（二苯基膦基）二茂鐵（1.23克）和三（二亞苄基丙酮）二鈀（1.01克）。反應液在氮氣保護下於120攝氏度下反應2個小時。反應液墊矽藻土過濾，濾餅用乙酸乙酯（60毫升*3）淋洗，濾液用水（240毫升）稀釋，靜置分層，有機相用飽和食鹽水（60毫升*2）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘餘物。殘餘物經矽膠柱純化（洗脫劑：石油醚：乙酸乙酯=10:1到3:1）得到化合物24-8。LCMS (ESI) m/z: 463.0(M+1) +。 第八步： 化合物24-8（5.8克）的濃硫酸（55.20 g）溶液於60攝氏度下反應7小時。反應液加到冰水（300毫升）和乙酸乙酯（200毫升）中，在0-10攝氏度下將氫氧化鈉（40克）溶解到水（200毫升）緩慢滴加至上面的混合物中，用碳酸氫鈉固體調節水相的pH值到7-8，將混合物過濾，濾餅用乙酸乙酯（100毫升*3）淋洗，濾液靜置分層，合併有機相用飽和食鹽水（150毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濾液濃縮得到化合物24-9。LCMS (ESI) m/z: 481.2(M+1) +。 第九步： 向化合物24-9（4克）的N,N-二甲基甲醯胺(40毫升)溶液中加入1,1-羰基二咪唑（4.46克），在10-15攝氏度下將鈉氫（1.10克，質量百分比：60%）加入到上面混合物，反應液在10-15攝氏度下反應0.5小時。反應液緩慢加入到水（200毫升）中，混合物用乙酸乙酯（100毫升）稀釋，用鹽酸（1莫耳/升）溶液調節水相的pH值到2-3，然後再用碳酸氫鈉固體調節水相的pH值到7-8。靜置分層，水相用乙酸乙酯（100毫升）萃取，合併有機相用水（50毫升*2）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物24-10。LCMS (ESI) m/z: 507.0(M+1) +。 第十步： 向化合物24-10（637毫克）的N，N-二甲基乙醯胺（7毫升）溶液中加入二異丙基乙胺（483.80毫克）和三吡咯烷基溴化鏻六氟磷酸鹽（872.53毫克），然後反應液在15攝氏度下反應1小時。化合物1-1（697.20毫克）加入到上面的混合物中，反應液在60攝氏度下反應12個小時。反應液用水（50毫升）和乙酸乙酯（50毫升）稀釋，水相用乙酸乙酯（25毫升）萃取，合併有機相用飽和食鹽水（25毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到殘留物。殘留物經製備HPLC純化（柱型號：Phenomenex Synergi Max-RP （250*50 mm*10 μm）；流動相：[水(0.225%甲酸)-乙腈]；梯度：30%-60%，22 分鐘）得到化合物24-11。LCMS (ESI) m/z: 675.3(M+1) +。 第十一步： 向化合物24-11（600毫克）的二氯甲烷（6毫升）溶液中加入三氟乙酸（3.08克），反應液在15攝氏度下反應0.5小時。反應液減壓濃縮得到殘留物，殘留物經飽和碳酸氫鈉（40毫升）溶液和乙酸乙酯（40毫升）稀釋後，有機相用飽和食鹽水（10毫升）洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物24-12。LCMS (ESI) m/z: 575.2(M+1) +。 第十二步： 向化合物24-12的四氫呋喃（8毫升）和水（2毫升）的混合溶液中加入碳酸鉀（114.74毫克），然後在15攝氏度下加入丙烯醯氯（75.14毫克），反應液在15攝氏度下反應10分鐘。反應液減壓濃縮得到殘留物，殘留物用乙酸乙酯（40毫升）和飽和食鹽水（20毫升）稀釋，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物24。LCMS (ESI) m/z: 629.3(M+1) +。 Example 24
Figure 02_image525
Step 1: Add potassium carbonate (1.93 g) and compound 7-2 (5.72 g) to a solution of compound 24-1 (4 g) in acetonitrile (40 ml) at 0-10 degrees Celsius. After the addition, the reaction solution React at 25 degrees Celsius for 12 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (20 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. Petroleum ether (40 ml) was added to the residue, stirred at room temperature for half an hour, filtered, and the filter cake was rinsed with petroleum ether (20 ml*3) and concentrated under reduced pressure to obtain compound 24-2. LCMS (ESI) m/z: 244.2(M+1)+. The second step: Add cesium carbonate (11.16 g) and compound 7-4 (5.87 g) to a solution of compound 24-2 (8.33 g) in acetonitrile (85 ml) at 0-10 degrees Celsius. React at 10-15 degrees Celsius for 1 hour. The reaction solution was filtered through a pad of celite, the filter cake was rinsed with ethyl acetate (30 mL*3), and the filtrate was concentrated under reduced pressure to obtain compound 24-3. LCMS (ESI) m/z: 366.1(M+1) + . The third step: Triethylamine (7.20 g) was added to a solution of compound 24-3 (13 g) in trifluoroethanol (65 ml), and the reaction solution was reacted at 80 degrees Celsius for 11 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with a solution of ethyl acetate (200 mL) and hydrochloric acid (1 mol/L, 50 mL). , 50 mL) solution, washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. At 10-15 degrees Celsius, methyl tert-butyl ether was added to the residue. (50 mL), stirred for half an hour, filtered, and the filter cake was rinsed with methyl tert-butyl ether (10 mL*3), and concentrated under reduced pressure to obtain compound 24-4. LCMS (ESI) m/z: 334.0(M+1) + . Fourth step: To a solution of compound 24-4 (5.5 g) in acetonitrile (55 ml) were added pyridinium tribromide (10.56 g) and potassium phosphate (7.01 g), and then the reaction solution was reacted at 50 degrees Celsius for 2 hours. The reaction was quenched by dissolving sodium sulfite (6 g) in water (30 mL), then the mixture was filtered, the filter cake was rinsed with ethyl acetate (10 mL*3), and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (200 mL), the mixture was washed with hydrochloric acid (1 mol/L, 50 mL*2) solution, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and reduced Concentration under pressure gave a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 8:1) to obtain compound 24-5. LCMS (ESI) m/z: 367.8(M+1) + . Step 5: To a solution of compound 24-5 (6 g) in dioxane (60 ml) were successively added 2-isopropyl-4-methylpyridin-3-amine (2.45 g), cesium carbonate (10.62 g), tris(dibenzylideneacetone)dipalladium (1.49 g) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.89 g), the reaction solution was kept at 100 degrees Celsius for 12 hours. The reaction solution was filtered with celite, the filter cake was washed with ethyl acetate (30 ml*3), the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1 to 3:1) 1) Compound 24-6 is obtained. LCMS (ESI) m/z: 438.3(M+1) + . The sixth step: N-bromosuccinimide (2.03 g) was added to a solution of compound 24-6 (5 g) in dichloromethane (50 ml) at 0-10 degrees Celsius, and the reaction solution was at 0- The reaction was carried out at 10 degrees Celsius for 1 hour. The reaction solution was quenched with saturated aqueous sodium sulfite solution (20 mL), then allowed to stand for layers. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 24-7. LCMS (ESI) m/z: 518.1(M+3) + . Step 7: To a solution of compound 24-7 (6.12 g) in N,N-dimethylformamide (60 ml) were added zinc powder (0.46 g), zinc cyanide (0.79 g), bromine Zinc (124.66 mg), 1,1-bis(diphenylphosphino)ferrocene (1.23 g) and tris(dibenzylideneacetone)dipalladium (1.01 g). The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was filtered with celite, the filter cake was rinsed with ethyl acetate (60 mL*3), the filtrate was diluted with water (240 mL), the layers were left to stand, and the organic phase was washed with saturated brine (60 mL*2). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 24-8. LCMS (ESI) m/z: 463.0(M+1) + . The eighth step: The concentrated sulfuric acid (55.20 g) solution of compound 24-8 (5.8 g) was reacted at 60 degrees Celsius for 7 hours. The reaction solution was added to ice water (300 ml) and ethyl acetate (200 ml), and sodium hydroxide (40 g) was dissolved in water (200 ml) at 0-10 degrees Celsius and slowly added dropwise to the above mixture, The pH of the aqueous phase was adjusted to 7-8 with solid sodium bicarbonate, the mixture was filtered, the filter cake was rinsed with ethyl acetate (100 mL*3), the filtrate was left to stand for layers, and the organic phases were combined with saturated brine (150 mL). mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 24-9. LCMS (ESI) m/z: 481.2(M+1) + . Step 9: To a solution of compound 24-9 (4 g) in N,N-dimethylformamide (40 mL) was added 1,1-carbonyldiimidazole (4.46 g), and the Sodium hydrogen (1.10 g, mass percentage: 60%) was added to the above mixture, and the reaction solution was reacted at 10-15 degrees Celsius for 0.5 hours. The reaction solution was slowly added to water (200 mL), the mixture was diluted with ethyl acetate (100 mL), and the pH of the aqueous phase was adjusted to 2-3 with a solution of hydrochloric acid (1 mol/L), followed by sodium bicarbonate. The solids adjust the pH of the aqueous phase to 7-8. The layers were left to stand, the aqueous phase was extracted with ethyl acetate (100 mL), the combined organic phases were washed with water (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-10. LCMS (ESI) m/z: 507.0(M+1) + . Step 10: To a solution of compound 24-10 (637 mg) in N,N-dimethylacetamide (7 mL) were added diisopropylethylamine (483.80 mg) and tripyrrolidinophosphonium hexamide Fluorophosphate (872.53 mg), and then the reaction solution was reacted at 15 degrees Celsius for 1 hour. Compound 1-1 (697.20 mg) was added to the above mixture, and the reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was diluted with water (50 mL) and ethyl acetate (50 mL), the aqueous phase was extracted with ethyl acetate (25 mL), the combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, reduced Concentration under pressure gave a residue. The residue was purified by preparative HPLC (column type: Phenomenex Synergi Max-RP (250*50 mm*10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60% in 22 minutes) Compound 24-11 was obtained. LCMS (ESI) m/z: 675.3(M+1) + . Eleventh step: To a solution of compound 24-11 (600 mg) in dichloromethane (6 ml) was added trifluoroacetic acid (3.08 g), and the reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with saturated sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. , concentrated under reduced pressure to obtain compound 24-12. LCMS (ESI) m/z: 575.2(M+1) + . The twelfth step: To a mixed solution of compound 24-12 in tetrahydrofuran (8 mL) and water (2 mL), potassium carbonate (114.74 mg) was added, and then acryl chloride (75.14 mg) was added at 15 degrees Celsius. The reaction solution React at 15 degrees Celsius for 10 minutes. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (40 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24. LCMS (ESI) m/z: 629.3(M+1) + .

實施例25

Figure 02_image527
第一步： 在氮氣氛圍下，向化合物25-1（23克）的甲苯（230毫升）溶液中依次加入2-苯基碳二亞胺（16.07克），碳酸銫（43.33克），醋酸鈀（995.23毫克）和BINAP（5.52克）。反應液在90攝氏度下反應14個小時。反應液濃縮得到殘餘物，用乙酸乙酯（100 mL）和水（100毫升）溶解。混合液過濾，濾液分層，水相用乙酸乙酯（100毫升）萃取兩次，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物25-2。LCMS (ESI) m/z: 360.2 (m+1) +。 第二步： 向化合物25-2（32克）的四氫呋喃（600毫升）溶液中加入鹽酸水溶液（4莫耳每升，130毫升，）。反應液在15攝氏度下反應2個小時。反應液中加入水（500毫升），用氫氧化鈉水溶液（1莫耳/升）調節pH到5，隨後用碳酸氫鈉固體調節pH到7。用乙酸乙酯（500 mL）萃取兩次，合併有機相用飽和食鹽水（500毫升）洗滌兩次，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到的殘餘物。殘餘物用矽膠柱（洗脫劑：石油醚：乙酸乙酯=50:1）純化得到化合物25-3。 第三步： 在0攝氏度下，向化合物25-3（35克）和碳酸鉀（12.37克）的乙腈（350毫升）溶液中緩慢加入化合物7-2（29.32克）。反應液在25攝氏度下反應14個小時。反應液濃縮得到殘餘物，用乙酸乙酯（200 mL）和飽和碳酸氫鈉（200毫升）溶解。水相用乙酸乙酯（100毫升）萃取兩次，合併有機相用水（200毫升）和飽和食鹽水（200毫升）洗滌，有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到的殘餘物。殘餘物用乙酸乙酯和石油醚（200毫升，1:5）打漿1小時，過濾，濾餅減壓乾燥得到化合物25-4。LCMS (ESI) m/z: 296.0 (M+1) +。 第四步： 在0攝氏度下，向化合物25-4（24.9克）和碳酸銫（27.44克）的乙腈（250毫升）溶液中逐滴加入化合物7-4（14.44克），反應液在15攝氏度下反應2小時。反應液過濾，濾液濃縮後加入水（200毫升），用乙酸乙酯（200毫升）萃取兩次。合併有機相用水（200毫升）和飽和食鹽水（200毫升）洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物25-5。LCMS (ESI) m/z: 418.1(M+1) +。 第五步： 向化合物25-5（36克）的三氟乙醇（180毫升）溶液中加入三乙胺（17.44克），反應液在80攝氏度下反14小時。反應液濃縮得到殘餘物。殘餘物用乙酸乙酯（500毫升）溶解，隨後用鹽酸水溶液（200毫升，1莫耳每升）洗滌兩次，有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到的殘餘物。向殘餘物中加入甲基第三丁基醚和石油醚（240毫升，1:5），室溫攪拌1小時，過濾，濾餅減壓乾燥得到化合物25-6。LCMS (ESI) m/z: 386.1 (M+1) +。 第六步： 向化合物25-6（10克）的乙腈（200毫升）的溶液中依次加入磷酸鉀（11.01克）和三溴吡啶鎓鹽（24.88克），反應液在50攝氏度下反應14小時。反應液用飽和亞硫酸鈉（200毫升）淬滅，隨後用乙酸乙酯（100毫升）萃取兩次。合併有機相用鹽酸水溶液（200毫升，1莫耳每升）和飽和食鹽水（100毫升）洗滌。有機相用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物25-7。LCMS (ESI) m/z: 421.7 (M+3) +。 第七步： 在氮氣氛圍下，向化合物25-7（8.89克）和三（二亞苄基丙酮）二鈀（1.94克）的二氧六環（90毫升）溶液中依次加入化合物6-4（3.18克），Xantphos（2.45克）和碳酸銫（13.78克），反應液在100攝氏度下反應14小時。反應液過濾，向濾液中加入鹽酸乙酸乙酯溶液（100毫升，1莫耳每升），15攝氏度下攪拌1小時。混合液過濾，濾餅用乙酸乙酯（100毫升）和飽和碳酸鈉（100毫升）溶解。然後水相用乙酸乙酯（100毫升）萃取兩次，合併有機相用飽和食鹽水（50毫升）洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。向殘餘物中加入石油醚（50毫升），室溫攪拌1小時。過濾，濾餅減壓乾燥得到化合物25-8。LCMS (ESI) m/z: 490.2 (M+1) +。 第八步： 在0攝氏度下，向化合物25-8（8.68克）的二氯甲烷（86毫升）溶液中一次性加入N-溴代丁二醯亞胺（3.15克）。反應液在15攝氏度下反應1小時。向反應液中加入飽和亞硫酸鈉（100毫升）,然後用二氯甲烷（100毫升）萃取兩次，合併有機相用飽和食鹽水（200毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物用矽膠柱（二氧化矽，石油醚：乙酸乙酯=3:1）純化得到化合物25-9。LCMS (ESI) m/z: 570.2 (M+3) +。 第九步： 在氮氣氛圍下，向化合物25-9（6.5克）的N,N-二甲基甲醯胺（65毫升）溶液中依次加入鋅粉（747.33毫克），溴化鋅（257.38毫克），氰化鋅（1.34克），三（二亞苄基丙酮）二鈀（523.28毫克）和DPPF （633.59毫克）。反應液在氮氣保護下於120攝氏度反應2小時。反應液過濾，向濾液中加入水（100毫升），然後用乙酸乙酯（100毫升）萃取兩次，合併有機相用水（100毫升）和飽和食鹽水（100毫升）洗滌，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經矽膠柱純化（石油醚：乙酸乙酯=5:1 到3:1（含有5%的甲醇））得到化合物25-10。LCMS (ESI) m/z: 515.0 (M+1) +。 第十步： 化合物25-10（400毫克）分批加入到濃硫酸（2毫升，98%純度)中，加熱到60攝氏度攪拌14小時，冷卻到室溫，倒入冰水（10毫升）中，加入飽和碳酸氫鈉水溶液至pH為8，乙酸乙酯（20毫升）萃取，無水硫酸鈉乾燥，過濾濃縮乾，得化合物25-11。LCMS (ESI) m/z: 532.9 (M+1) +。 第十一步： 在0攝氏度下，向化合物25-11（400毫克）的四氫呋喃（10毫升)溶液中加入氫化鈉（120.09毫克，質量百分比：60%），加入羰基二咪唑（365.16毫克），在 25攝氏度下攪拌30分鐘，倒入到冰水（20毫升）中，用1莫耳/升的鹽酸調節pH 到3-4，然後用飽和 碳酸氫鈉溶液調節pH=7-8, 用乙酸乙酯（20毫升）萃取兩次，有機相用無水硫酸鈉乾燥，濃縮乾得到化合物25-12。LCMS (ESI) m/z: 558.9 (M+1) +。 第十二步： 化合物25-12 （400毫克）的四氫呋喃（10毫升）溶液中加入PYBROP (667.33毫克) 和 DIEA (277.51毫克)和化合物1-1 (399.92毫克)，加熱到60攝氏度反應12 小時。濃縮乾，用甲醇（20毫升）溶解，過濾掉不溶解的固體，母液濃縮乾得到殘餘物。殘餘物通過製備HPLC(柱型號：Phenomenex Gemini-NX C18 （75*30mm*3um）；流動相： [水(0.225%甲酸)-乙腈]；梯度：40%-70%，7分鐘))純化得到化合物25-13。LCMS (ESI) m/z: 727.0 (M+1) +。 第十三步： 在20-30攝氏度下，向化合物25-13（200毫克）的二氯甲烷（3毫升）溶液中一次性加入三氟乙酸（1.54克）。反應液在25攝氏度下反應1個小時。反應液濃縮得到化合物25-14的三氟乙酸鹽。LCMS (ESI) m/z: 627.0(M+1) +。粗品直接用於下一步。 第十四步： 在0攝氏度下，向化合物25-14（150毫克，TFA鹽）的四氫呋喃（3.0毫升）和水（0.5毫升）的混合溶液中依次一次性加入無水碳酸鉀（99.19毫克），化合物1-5（21.65毫克）。反應液在0攝氏度下反應0.5小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備柱純化HPLC(柱型號：Shim-pack C18 150*25mm*10 μm)，流動相（0.225%甲酸水：乙腈），梯度：8%-38%，10分鐘）。得化合物25。 1H NMR (400 MHz, DMSO- d 6) δ 8.32-8.31(m, 1H), 7.56-7.52(m, 1H), 7.28-7.23 (m, 1H), 7.18(m, 1H), 7.07-7.05(m, 2H), 6.87-6.78(m, 1H), 6.01-5.96(m, 1H), 5.48-5.43(m, 1H), 3.49-3.49(m, 1H), 3.25-3.24(m, 4H), 2.99-2.97 (m, 4H), 2.22 (m, 3H), 1.38-1.17(m, 6H)。 LCMS (ESI) m/z: 681.17(M+1) +。 Example 25
Figure 02_image527
Step 1: To a solution of compound 25-1 (23 g) in toluene (230 ml) under nitrogen atmosphere were successively added 2-phenylcarbodiimide (16.07 g), cesium carbonate (43.33 g), palladium acetate (995.23 mg) and BINAP (5.52 g). The reaction solution was reacted at 90 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL) and water (100 mL). The mixture was filtered, the filtrate was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-2. LCMS (ESI) m/z: 360.2 (m+1) + . Second step: To a solution of compound 25-2 (32 g) in tetrahydrofuran (600 ml) was added aqueous hydrochloric acid (4 moles per liter, 130 ml,). The reaction solution was reacted at 15 degrees Celsius for 2 hours. Water (500 ml) was added to the reaction solution, and the pH was adjusted to 5 with aqueous sodium hydroxide solution (1 mol/L), followed by the pH adjustment to 7 with solid sodium bicarbonate. It was extracted twice with ethyl acetate (500 mL), the combined organic phases were washed twice with saturated brine (500 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=50:1) to obtain compound 25-3. Step 3: To a solution of compound 25-3 (35 g) and potassium carbonate (12.37 g) in acetonitrile (350 ml) was slowly added compound 7-2 (29.32 g) at 0 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in ethyl acetate (200 mL) and saturated sodium bicarbonate (200 mL). The aqueous phase was extracted twice with ethyl acetate (100 ml). The combined organic phases were washed with water (200 ml) and saturated brine (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was slurried with ethyl acetate and petroleum ether (200 mL, 1:5) for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 25-4. LCMS (ESI) m/z: 296.0 (M+1) + . The fourth step: Compound 7-4 (14.44 g) was added dropwise to a solution of compound 25-4 (24.9 g) and cesium carbonate (27.44 g) in acetonitrile (250 ml) at 0 degrees Celsius, and the reaction solution was at 15 degrees Celsius The reaction was continued for 2 hours. The reaction solution was filtered, the filtrate was concentrated, water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with water (200 ml) and saturated brine (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-5. LCMS (ESI) m/z: 418.1(M+1) + . The fifth step: Triethylamine (17.44 g) was added to a solution of compound 25-5 (36 g) in trifluoroethanol (180 ml), and the reaction solution was reacted at 80 degrees Celsius for 14 hours. The reaction solution was concentrated to obtain a residue. The residue was dissolved in ethyl acetate (500 ml), then washed twice with aqueous hydrochloric acid (200 ml, 1 mol per liter), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. Methyl tert-butyl ether and petroleum ether (240 mL, 1:5) were added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 25-6. LCMS (ESI) m/z: 386.1 (M+1) + . Step 6: To a solution of compound 25-6 (10 g) in acetonitrile (200 ml), potassium phosphate (11.01 g) and pyridinium tribromide (24.88 g) were sequentially added, and the reaction solution was reacted at 50 degrees Celsius for 14 hours . The reaction solution was quenched with saturated sodium sulfite (200 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with aqueous hydrochloric acid (200 ml, 1 mole per liter) and saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 25-7. LCMS (ESI) m/z: 421.7 (M+3) + . Step 7: To a solution of compound 25-7 (8.89 g) and tris(dibenzylideneacetone)dipalladium (1.94 g) in dioxane (90 mL) was added compound 6-4 in sequence under nitrogen atmosphere (3.18 g), Xantphos (2.45 g) and cesium carbonate (13.78 g), the reaction solution was reacted at 100 degrees Celsius for 14 hours. The reaction solution was filtered, and ethyl acetate solution of hydrochloric acid (100 ml, 1 mol per liter) was added to the filtrate, and the mixture was stirred at 15°C for 1 hour. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (100 mL) and saturated sodium carbonate (100 mL). The aqueous phase was then extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. Petroleum ether (50 ml) was added to the residue, followed by stirring at room temperature for 1 hour. After filtration, the filter cake was dried under reduced pressure to obtain compound 25-8. LCMS (ESI) m/z: 490.2 (M+1) + . Step 8: To a solution of compound 25-8 (8.68 g) in dichloromethane (86 mL) at 0 degrees C was added N-bromosuccinimide (3.15 g) in one portion. The reaction solution was reacted at 15 degrees Celsius for 1 hour. Saturated sodium sulfite (100 mL) was added to the reaction solution, then extracted twice with dichloromethane (100 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . The residue was purified by silica gel column (silica, petroleum ether:ethyl acetate=3:1) to obtain compound 25-9. LCMS (ESI) m/z: 570.2 (M+3) + . The ninth step: under nitrogen atmosphere, to a solution of compound 25-9 (6.5 g) in N,N-dimethylformamide (65 ml) were sequentially added zinc powder (747.33 mg), zinc bromide (257.38 mg) ), zinc cyanide (1.34 g), tris(dibenzylideneacetone)dipalladium (523.28 mg) and DPPF (633.59 mg). The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was filtered, water (100 mL) was added to the filtrate, and then extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate=5:1 to 3:1 (containing 5% methanol)) to give compound 25-10. LCMS (ESI) m/z: 515.0 (M+1) + . The tenth step: Compound 25-10 (400 mg) was added to concentrated sulfuric acid (2 ml, 98% purity) in batches, heated to 60 degrees Celsius, stirred for 14 hours, cooled to room temperature, and poured into ice water (10 ml) , add saturated aqueous sodium bicarbonate solution to pH 8, extract with ethyl acetate (20 mL), dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain compound 25-11. LCMS (ESI) m/z: 532.9 (M+1) + . The eleventh step: at 0 degrees Celsius, add sodium hydride (120.09 mg, mass percentage: 60%) to a solution of compound 25-11 (400 mg) in tetrahydrofuran (10 mL), add carbonyldiimidazole (365.16 mg), Stir at 25°C for 30 minutes, pour into ice water (20 mL), adjust pH to 3-4 with 1 mol/L hydrochloric acid, then adjust pH=7-8 with saturated sodium bicarbonate solution, and acetic acid Ethyl ester (20 mL) was extracted twice, the organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 25-12. LCMS (ESI) m/z: 558.9 (M+1) + . The twelfth step: Compound 25-12 (400 mg) in tetrahydrofuran (10 ml) was added PYBROP (667.33 mg) and DIEA (277.51 mg) and compound 1-1 (399.92 mg), heated to 60 degrees Celsius and reacted for 12 hours . Concentrate to dryness, dissolve with methanol (20 mL), filter off insoluble solids, and concentrate the mother liquor to dryness to obtain a residue. The residue was purified by preparative HPLC (column type: Phenomenex Gemini-NX C18 (75*30mm*3um); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 40%-70%, 7 minutes)) to obtain Compounds 25-13. LCMS (ESI) m/z: 727.0 (M+1) + . Thirteenth step: To a solution of compound 25-13 (200 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 25-14. LCMS (ESI) m/z: 627.0(M+1) + . The crude product was used directly in the next step. The fourteenth step: To a mixed solution of compound 25-14 (150 mg, TFA salt) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (99.19 mg) was added in one portion, Compound 1-5 (21.65 mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by HPLC on a preparative column (column type: Shim-pack C18 150*25mm*10 μm), mobile phase (0.225% formic acid in water:acetonitrile), gradient: 8%-38%, 10 minutes). Compound 25 was obtained. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32-8.31(m, 1H), 7.56-7.52(m, 1H), 7.28-7.23 (m, 1H), 7.18(m, 1H), 7.07-7.05 (m, 2H), 6.87-6.78(m, 1H), 6.01-5.96(m, 1H), 5.48-5.43(m, 1H), 3.49-3.49(m, 1H), 3.25-3.24(m, 4H) , 2.99-2.97 (m, 4H), 2.22 (m, 3H), 1.38-1.17 (m, 6H). LCMS (ESI) m/z: 681.17(M+1) + .

實施例26

Figure 02_image529
第一步： 在化合物26-1(10克)的乙腈(100毫升)溶液中加入碳酸鉀(4.275克)，冷卻到0度，分批加入化合物7-2(10.11克)，然後在25 攝氏度 攪拌16小時。過濾，濃縮乾，在乙酸乙酯和石油醚（體積比1:1， 200毫升）的混合溶劑中25攝氏度打漿2小時，過濾濃縮得到化合物26-2。LCMS (ESI) m/z: 261.9 (M+1) +。 第二步： 在0攝氏度，化合物26-2 (13.3克)的乙腈 (150毫升)中加入碳酸銫(16.15克)，然後在分批加入三氟乙醯乙烯基烯醚 (8.50克)，在25攝氏度攪拌2小時，過濾濃縮乾得化合物26-3。LCMS (ESI) m/z: 401.8 (M+1+H 2O) +。 第三步： 在化合物26-3(20克)的三氟乙醇（100毫升）溶液中加入三乙胺（10.54克），混合體系在80攝氏度攪拌12小時。濃縮乾，用水（200 毫升）和乙酸乙酯（200毫升）稀釋，用1莫耳/升的鹽酸水溶液調節pH到3，乙酸乙酯萃取，丟棄有機相，水相用1莫耳/升的氫氧化鈉水溶液調節pH到8，黃色的固體析出，過濾固體，固體懸濁在水（300毫升）中，用1莫耳的鹽酸調節pH到2，用乙酸乙酯（100毫升*2）萃取，合併的有機相用無水硫酸鈉乾燥，過濾濃縮乾得化合物26-4。LCMS (ESI) m/z: 351.8 (M+1) +。 第四步： 在化合物26-4（12克）的乙腈（180毫升）溶液中加入磷酸鉀（14.47克）和三溴吡啶嗡鹽（32.70克），然後在50攝氏度攪拌3小時，用飽和亞硫酸鈉（100毫升）淬滅反應，乙酸乙酯（100毫升）萃取，有機相用飽和食鹽水（50毫升）洗滌，無水硫酸鈉（10克）乾燥，濃縮乾得粗品，粗品在50毫升甲基第三丁基醚中25攝氏度攪拌16小時，過濾，濾餅乾燥得到化合物26-5。 LCMS (ESI) m/z: 387.7 (M+3) +。 第五步： 在化合物26-5（8克）和化合物6-4（3.11克）的二氧六環（150毫升）中加Pd 2(dba) 3（1.89克）和Xantphos（2.39克），碳酸銫 (13.47克)，反應體系用氮氣置換，加熱到100攝氏度攪拌16小時。降溫到25攝氏度，過濾，濃縮乾，用乙酸乙酯（200毫升）稀釋，用水（20毫升）洗滌，飽和食鹽水（20毫升）洗滌，濃縮乾得粗品，柱層析（洗脫劑：石油醚：乙酸乙酯=10:1到20:1）純化得到化合物26-6。 1H NMR (400 MHz, CHLOROFORM- d) δ 8.40 (d, J= 4.9 Hz, 1H), 7.52-7.39 (m, 1H), 7.23 (s, 2H), 7.03 (d, J= 4.8 Hz, 1H), 6.70 (br d, J= 4.4 Hz, 1H), 6.62 (d, J= 7.8 Hz, 1H), 5.73 (d, J= 7.8 Hz, 1H), 3.25-3.06 (m, 1H), 2.20-2.11 (m, 3H), 1.21-1.07 (m, 6H)。LCMS (ESI) m/z: 455.9 (M+1) +。 第六步： 在0攝氏度，向化合物26-6（3.4克)的二氯甲烷(60毫升)溶液中分批加入NBS（1.33克），在28攝氏度攪拌30分鐘，加入飽和亞硫酸鈉（20毫升） ，分離的有機相用飽和食鹽水（20毫升）洗滌， 無水硫酸鈉乾燥，濃縮乾得粗品，用石油醚和甲基第三丁基醚混合體系（體積比1:1,50毫升）25攝氏度打漿2小時，過濾，乾燥得到化合物26-7。LCMS (ESI) m/z: 535.8 (M+3) +。 第七步： 在化合物26-7（4克），氰化鋅（438.82毫克)，鋅粉（488.73 毫克）的二甲基甲醯胺(60毫升)溶液中加入溴化鋅 (168.31毫克)，氮氣置換，加入DPPF（828.69克) 和Pd 2(dba) 3(684.41毫克)，氮氣置換後在120攝氏度攪拌2小時。冷卻到室溫，過濾後母液濃縮乾除去二甲基甲醯胺，然後用乙酸乙酯（150毫升）稀釋，用飽和食鹽水（50毫升）洗滌，濃縮乾得粗品，通過柱層析（洗脫劑乙酸乙酯：石油醚=1:10 到1:3）得到純化得到化合物26-8。LCMS (ESI) m/z: 480.9 (M+1) +。 第八步： 化合物26-8（1.7克）分批加入到濃硫酸 (35毫升，純度98%)中，加熱到60 攝氏度攪拌16小時，冷卻到室溫，倒入的冰水（200毫升）中，加入5莫耳/升的氫氧化鈉水溶液至pH為8，用的乙酸乙酯（200毫升）萃取，合併的有機相用食鹽水（120毫升）洗滌，無水硫酸鈉（10克）乾燥，過濾濃縮得到化合物26-9。LCMS (ESI) m/z: 498.9 (M+1) +。 第九步： 在0攝氏度，向化合物26-9 (1.7克)的N,N-二甲基乙醯胺(20毫升)溶液中加氫化鈉（408.52毫克，質量百分比：60%），反應液在室溫攪拌10分鐘，分批加入羰基二咪唑（1.66 克），反應液在0-25攝氏度攪拌50分鐘。反應液倒入到冰水（100毫升）中，用1莫耳/升的鹽酸水溶液調節pH 到3-4，然後用飽和碳酸氫鈉水溶液調節pH =7-8，用乙酸乙酯（100毫升）萃取，有機相用無水硫酸鈉乾燥，濃縮乾得化合物26-10。LCMS (ESI) m/z: 524.9 (M+1) +。 第十步： 向化合物26-10（1.0克）的N,N-二甲基甲醯胺(10毫升)溶液中加PyBrOP (1.77 克)和二異丙基乙胺(738.10毫克)，在25攝氏度攪拌1小時。加入化合物1-1（1.06克)加熱到100攝氏度反應12小時。冷卻到25度，用乙酸乙酯（100毫升）稀釋，用水（20毫升*3）洗滌，再用飽和食鹽水（50毫升）洗滌，有機相濃縮得到粗品通過製備HPLC((柱型號: Phenomenex Synergi Max-RP （250*50mm*10 μm）；流動相: [水(0.225%甲酸)-乙腈]；梯度：35%-65%，22分鐘))純化得到化合物26-11。LCMS (ESI) m/z: 693.0 (M+1) +。 第十一步： 向化合物26-11 (800 毫克)的二氯甲烷(6毫升) 溶液中，加入三氟乙酸(3毫升)，反應液在25攝氏度攪拌30分鐘，濃縮乾得化合物26-12的三氟乙酸鹽。粗品直接用於下一步。LCMS (ESI) m/z: 593.1 (M+1) +。 第十二步： 向化合物26-12 (940毫克，2三氟乙酸鹽)的四氫呋喃 (20毫升)和水(10毫升)溶液中加入碳酸鉀（316.29毫克），混合物在25攝氏度攪拌10分鐘，然後加入化合物1-5（124.28毫克)，在25攝氏度攪拌20 分鐘。用乙酸乙酯（50毫升）萃取，然後用飽和食鹽水（10毫升）洗滌，有機相濃縮得到化合物26。
Figure 02_image531
化合物26通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，5μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體25%-25%，6.7分鐘，730分鐘）分離純化得化合物26A及化合物26B。 化合物26A和化合物26B經SFC檢測[柱型號：Column: Chiralceel OD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物26A的保留時間為1.62min，e.e.值為100%；化合物26B的保留時間為1.74min，e.e.值為100%。 化合物26A（保留時間=1.62 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J= 4.8 Hz, 1H), 7.82 (t, J= 1.8 Hz, 1H), 7.62 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.07 (d, J= 4.9 Hz, 1H), 6.93-6.79 (m, 1H), 6.27-6.12 (m, 1H), 5.83-5.71 (m, 1H), 4.06-3.73 (m, 8H), 2.72-2.79 (m, 1H), 2.00 (s, 3H), 1.17-0.92 (m, 6H)。LCMS (ESI) m/z: 647.0 (M+1) +。 化合物26B（保留時間=1.74min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J= 4.9 Hz, 1H), 7.93-7.77 (m, 1H), 7.62 (s, 1H), 7.44 (s, 1H), 7.29-7.00 (m, 2H), 6.97-6.79 (m, 1H), 6.26-6.12 (m, 1H), 5.89-5.61 (m, 1H), 4.02-3.75 (m, 8H), 2.81-2.71 (m, 1H), 2.04-1.94 (m, 3H), 1.12-0.95 (m, 6H)。LCMS (ESI) m/z: 647.0 (M+1) +。 Example 26
Figure 02_image529
The first step: Potassium carbonate (4.275 g) was added to a solution of compound 26-1 (10 g) in acetonitrile (100 mL), cooled to 0 degrees, and compound 7-2 (10.11 g) was added in batches, and then at 25 degrees Celsius Stir for 16 hours. Filtered, concentrated to dryness, slurried in a mixed solvent of ethyl acetate and petroleum ether (1:1 by volume, 200 ml) at 25 degrees Celsius for 2 hours, filtered and concentrated to obtain compound 26-2. LCMS (ESI) m/z: 261.9 (M+1) + . Step 2: At 0°C, cesium carbonate (16.15 g) was added to compound 26-2 (13.3 g) in acetonitrile (150 ml), then trifluoroacetonitrile vinylene ether (8.50 g) was added Stir at 25 degrees Celsius for 2 hours, filter and concentrate to dryness to obtain compound 26-3. LCMS (ESI) m/z: 401.8 (M+1+H 2 O) + . The third step: Triethylamine (10.54 g) was added to a solution of compound 26-3 (20 g) in trifluoroethanol (100 ml), and the mixed system was stirred at 80 degrees Celsius for 12 hours. Concentrate to dryness, dilute with water (200 mL) and ethyl acetate (200 mL), adjust the pH to 3 with 1 mol/L aqueous hydrochloric acid, extract with ethyl acetate, discard the organic phase, and use 1 mol/L hydrochloric acid for the aqueous phase Aqueous sodium hydroxide solution was adjusted to pH 8, a yellow solid was precipitated, the solid was filtered, the solid was suspended in water (300 mL), the pH was adjusted to 2 with 1 molar hydrochloric acid, and extracted with ethyl acetate (100 mL*2). , the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give compound 26-4. LCMS (ESI) m/z: 351.8 (M+1) + . The fourth step: Potassium phosphate (14.47 g) and pyridinium tribromide (32.70 g) were added to a solution of compound 26-4 (12 g) in acetonitrile (180 ml), followed by stirring at 50 degrees Celsius for 3 hours, using saturated sodium sulfite (100 mL) quenched the reaction, extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate (10 g), and concentrated to dryness to obtain the crude product, which was added to 50 mL of methyl chloride. The mixture was stirred in tributyl ether at 25°C for 16 hours, filtered, and the filter cake was dried to obtain compound 26-5. LCMS (ESI) m/z: 387.7 (M+3) + . Step 5: Pd 2 (dba) 3 (1.89 g) and Xantphos (2.39 g) were added to the dioxane (150 ml) of compound 26-5 (8 g) and compound 6-4 (3.11 g), Cesium carbonate (13.47 g), the reaction system was replaced with nitrogen, heated to 100 degrees Celsius and stirred for 16 hours. Cooled to 25 degrees Celsius, filtered, concentrated to dryness, diluted with ethyl acetate (200 ml), washed with water (20 ml), washed with saturated brine (20 ml), concentrated to dryness to obtain crude product, column chromatography (eluent: petroleum ether:ethyl acetate=10:1 to 20:1) was purified to give compound 26-6. 1 H NMR (400 MHz, CHLOROFORM- d ) δ 8.40 (d, J = 4.9 Hz, 1H), 7.52-7.39 (m, 1H), 7.23 (s, 2H), 7.03 (d, J = 4.8 Hz, 1H) ), 6.70 (br d, J = 4.4 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 3.25-3.06 (m, 1H), 2.20- 2.11 (m, 3H), 1.21-1.07 (m, 6H). LCMS (ESI) m/z: 455.9 (M+1) + . Step 6: To a solution of compound 26-6 (3.4 g) in dichloromethane (60 mL) was added NBS (1.33 g) in portions at 0°C, stirred at 28°C for 30 minutes, and saturated sodium sulfite (20 mL) was added. , the separated organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product, which was mixed with petroleum ether and methyl tertiary butyl ether (volume ratio 1:1, 50 ml) at 25°C Slurry for 2 hours, filter, and dry to give compound 26-7. LCMS (ESI) m/z: 535.8 (M+3) + . Step 7: To a solution of compound 26-7 (4 g), zinc cyanide (438.82 mg), zinc powder (488.73 mg) in dimethylformamide (60 ml) was added zinc bromide (168.31 mg), After nitrogen replacement, DPPF (828.69 g) and Pd 2 (dba) 3 (684.41 mg) were added, and the mixture was stirred at 120° C. for 2 hours after nitrogen replacement. After cooling to room temperature, the mother liquor was filtered and concentrated to dryness to remove dimethylformamide, then diluted with ethyl acetate (150 mL), washed with saturated brine (50 mL), and concentrated to dryness to obtain crude product, which was subjected to column chromatography (washed). Removal of ethyl acetate: petroleum ether = 1:10 to 1:3) was purified to obtain compound 26-8. LCMS (ESI) m/z: 480.9 (M+1) + . Step 8: Compound 26-8 (1.7 g) was added in batches to concentrated sulfuric acid (35 ml, purity 98%), heated to 60 degrees Celsius, stirred for 16 hours, cooled to room temperature, poured into ice water (200 ml) 5 mol/L aqueous sodium hydroxide solution was added to pH 8, extracted with ethyl acetate (200 mL), the combined organic phases were washed with brine (120 mL), and dried over anhydrous sodium sulfate (10 g). , filtered and concentrated to obtain compound 26-9. LCMS (ESI) m/z: 498.9 (M+1) + . The ninth step: Add sodium hydride (408.52 mg, mass percentage: 60%) to a solution of compound 26-9 (1.7 g) in N,N-dimethylacetamide (20 ml) at 0 degrees Celsius, and the reaction solution After stirring at room temperature for 10 minutes, carbonyldiimidazole (1.66 g) was added in portions, and the reaction solution was stirred at 0-25 degrees Celsius for 50 minutes. The reaction solution was poured into ice water (100 mL), adjusted to pH 3-4 with 1 mol/L aqueous hydrochloric acid solution, then adjusted to pH=7-8 with saturated aqueous sodium bicarbonate solution, and then adjusted to pH=7-8 with ethyl acetate (100 mL). ) extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give compound 26-10. LCMS (ESI) m/z: 524.9 (M+1) + . Step 10: To a solution of compound 26-10 (1.0 g) in N,N-dimethylformamide (10 mL) was added PyBrOP (1.77 g) and diisopropylethylamine (738.10 mg) at 25 Stir for 1 hour in degrees Celsius. Compound 1-1 (1.06 g) was added and heated to 100 degrees Celsius to react for 12 hours. Cooled to 25 degrees, diluted with ethyl acetate (100 mL), washed with water (20 mL*3), and then with saturated brine (50 mL), the organic phase was concentrated to obtain the crude product by preparative HPLC ((column type: Phenomenex Synergi) Max-RP (250*50mm*10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 35%-65%, 22 minutes)) purification gave compound 26-11. LCMS (ESI) m/z: 693.0 (M+1) + . The eleventh step: To a solution of compound 26-11 (800 mg) in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, the reaction solution was stirred at 25 degrees Celsius for 30 minutes, and concentrated to dryness to obtain compound 26-12 of trifluoroacetate. The crude product was used directly in the next step. LCMS (ESI) m/z: 593.1 (M+1) + . Twelfth step: To a solution of compound 26-12 (940 mg, 2 trifluoroacetate) in tetrahydrofuran (20 mL) and water (10 mL) was added potassium carbonate (316.29 mg), and the mixture was stirred at 25°C for 10 minutes, Then compound 1-5 (124.28 mg) was added and stirred at 25 degrees Celsius for 20 minutes. Extracted with ethyl acetate (50 mL), washed with saturated brine (10 mL), and concentrated the organic phase to obtain compound 26.
Figure 02_image531
Compound 26 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 5μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 6.7 minutes, 730 minutes) Compound 26A and Compound 26B. Compound 26A and compound 26B were detected by SFC [Column model: Column: Chiralceel OD-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] obtained: the retention time of compound 26A was 1.62 min, and the ee value was 100%; the retention time of compound 26B was 1.74 min, and the ee value was 100%. Compound 26A (retention time = 1.62 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 4.8 Hz, 1H), 7.82 (t, J = 1.8 Hz, 1H), 7.62 (s , 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.07 (d, J = 4.9 Hz, 1H), 6.93-6.79 (m, 1H), 6.27-6.12 (m, 1H), 5.83- 5.71 (m, 1H), 4.06-3.73 (m, 8H), 2.72-2.79 (m, 1H), 2.00 (s, 3H), 1.17-0.92 (m, 6H). LCMS (ESI) m/z: 647.0 (M+1) + . Compound 26B (retention time = 1.74 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.31 (d, J = 4.9 Hz, 1H), 7.93-7.77 (m, 1H), 7.62 (s, 1H) , 7.44 (s, 1H), 7.29-7.00 (m, 2H), 6.97-6.79 (m, 1H), 6.26-6.12 (m, 1H), 5.89-5.61 (m, 1H), 4.02-3.75 (m, 8H), 2.81-2.71 (m, 1H), 2.04-1.94 (m, 3H), 1.12-0.95 (m, 6H). LCMS (ESI) m/z: 647.0 (M+1) + .

實施例27

Figure 02_image533
第一步： 在20-30攝氏度下，向化合物26-10（300毫克）的四氫呋喃（3毫升）溶液中一次性加入三吡咯烷基溴化磷六氟磷酸鹽（532.47毫克）、二異丙基乙胺（221.43毫克）及化合物3-1（367.16毫克）。反應液在60攝氏度下反應12個小時。反應液物用水（20毫升）稀釋後，用乙酸乙酯（10毫升*3）萃取，合併有機相用無水硫酸鈉乾燥，過濾，濃縮濾液得到化合物27-1。LCMS (ESI) m/z:721.4(M+1) +。 第二步： 在20-30攝氏度下，向化合物27-1（380毫克）的二氯甲烷（3毫升）溶液中一次性加入三氟乙酸（2.93克）。反應液在25攝氏度下反應1個小時。反應液濃縮得到化合物27-2的三氟乙酸鹽。LCMS (ESI) m/z: 621.1(M+1) +。粗品直接用於下一步。 第三步：
Figure 02_image535
在0攝氏度下，向化合物27-2（290毫克，三氟乙酸鹽）的四氫呋喃（3.0毫升）和水（0.5毫升）的混合溶液中依次一次性加入無水碳酸鉀（64.49毫克），丙烯醯氯（42.23毫克）。反應液在0攝氏度下反應0.5小時。向反應液中加入水（10毫升），用乙酸乙酯（10毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備HPLC（柱型號：Phenomenex Gemini-NX C18 75*30mm*3 μm），流動相（0.225%甲酸水：乙腈），梯度：32%-62%，7分鐘）純化得到化合物27。 化合物27再通過SFC（柱型號：Chiralpak IC-3（250*30mm I.D., 5µm），流動相：異丙醇（0.05%二乙胺），梯度：二氧化碳臨界流體40%-40%，5分鐘，40分鐘）分離純化得到化合物27A及化合物27B。 化合物27A和化合物27B經SFC檢測[柱型號：Column: Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：50%-50%]得到：化合物27A的保留時間為2.933min，e.e.值為100%；化合物27B的保留時間為4.568min，e.e.值為100%。 化合物27A（保留時間=2.933 min）：LCMS (ESI) m/z: 675.18(M+1) +。 化合物27B（保留時間=4.568 min）： 1H NMR (400 MHz, DMSO- d 6) δ 8.304-8.292(m, 1H), 7.812(m, 1H), 7.826(m, 1H), 7.418(m, 1H), 7.067-7.054(m, 2H), 6.880-6.788(m, 1H), 6.211-6.189(m, 1H), 5.770-5.735(m, 1H), 4.751-4.457(m, 2H), 4.137-3.745(m, 4H), 3.553-3.455(m, 1H), 1.956(m, 3H), 1.338-1.132(m, 6H), 1.072-0.989(m, 6H)。LCMS (ESI) m/z: 675.18(M+1) +。 Example 27
Figure 02_image533
Step 1: To a solution of compound 26-10 (300 mg) in tetrahydrofuran (3 mL) at 20-30 degrees Celsius was added tripyrrolidinylphosphonium bromide hexafluorophosphate (532.47 mg), diisopropyl chloride in one portion ethylamine (221.43 mg) and compound 3-1 (367.16 mg). The reaction solution was reacted at 60 degrees Celsius for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 27-1. LCMS (ESI) m/z: 721.4(M+1) + . Second step: To a solution of compound 27-1 (380 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (2.93 g) in one portion at 20-30 degrees Celsius. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 27-2. LCMS (ESI) m/z: 621.1(M+1) + . The crude product was used directly in the next step. third step:
Figure 02_image535
To a mixed solution of compound 27-2 (290 mg, trifluoroacetate) in tetrahydrofuran (3.0 mL) and water (0.5 mL) at 0 degrees Celsius, anhydrous potassium carbonate (64.49 mg), acrylonitrile chloride were added in one portion in sequence. (42.23 mg). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3 μm), mobile phase (0.225% formic acid water: acetonitrile), gradient: 32%-62%, 7 minutes) to obtain compound 27. Compound 27 was then passed through SFC (column type: Chiralpak IC-3 (250*30mm ID, 5µm), mobile phase: isopropanol (0.05% diethylamine), gradient: carbon dioxide critical fluid 40%-40%, 5 minutes, 40 minutes) separation and purification to obtain compound 27A and compound 27B. Compound 27A and compound 27B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 50%-50%] obtained: the retention time of compound 27A was 2.933 min, and the ee value was 100%; the retention time of compound 27B was 4.568 min, and the ee value was 100%. Compound 27A (retention time=2.933 min): LCMS (ESI) m/z: 675.18 (M+1) + . Compound 27B (retention time = 4.568 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.304-8.292(m, 1H), 7.812(m, 1H), 7.826(m, 1H), 7.418(m, 1H), 7.067-7.054(m, 2H), 6.880-6.788(m, 1H), 6.211-6.189(m, 1H), 5.770-5.735(m, 1H), 4.751-4.457(m, 2H), 4.137- 3.745(m, 4H), 3.553-3.455(m, 1H), 1.956(m, 3H), 1.338-1.132(m, 6H), 1.072-0.989(m, 6H). LCMS (ESI) m/z: 675.18(M+1) + .

實施例28

Figure 02_image537
第一步： 在10-25攝氏度下，向化合物7-13（0.5克）的DMAC（5毫升）溶液中一次性加入三吡咯烷基溴化鏻六氟磷酸鹽（1.77克），化合物2-1（1.52克，7.59毫莫耳，8.0當量），反應液在60攝氏度下反應12小時。向反應液中緩慢加入水（10毫升），用乙酸乙酯（5毫升*3）萃取，合併有機相，鹽水洗滌（5毫升*3）無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經製備純化得到化合物28-1。LCMS (ESI) m/z: 709.2(M+1) +。 第二步： 在10-25攝氏度下，向化合物28-1（230毫克）的二氯甲烷（5毫升）溶液中一次性加入三氟乙酸（1.54克）。反應液在15攝氏度下反應0.5小時。將反應液濃縮得到殘餘物。向殘餘物中加入水（10毫升），水相用碳酸氫鈉固體調至pH=8，乙酸乙酯（5毫升*3）萃取，合併有機相，鹽水洗滌（10毫升）無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物28-2。 LCMS (ESI) m/z: 609.2(M+1) +。 第三步：
Figure 02_image539
在0攝氏度下，向化合物28-2（0.2克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中依次加入無水碳酸鉀（136.17毫克），丙烯醯氯（29.72毫克）。反應液在15攝氏度下反應15分鐘。向反應液中加入水（10毫升），用乙酸乙酯（5毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備板純化（石油醚：乙酸乙酯：甲醇=3：4：1），得到的化合物28。 化合物28再通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體60%-60%，2.6分鐘，50分鐘）分離純化得到28-P1（保留時間=3.397 min和保留時間=3.789 min的混合物）及28-P2（保留時間=1.402 min和保留時間=1.565 min的混合物）。 28-P1再通過製備SFC（柱型號：DAICEL CHIRALPAK AD（250mm*30mm，5μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體20%-20%，4.6分鐘，120分鐘）分離純化得到化合物28A，和化合物28B。 28-P2再通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體25%-25%，5分鐘，45分鐘）分離純化得到化合物28C和化合物28D。 化合物28A和化合物28B經SFC檢測[柱型號：Column: Chiralpak AD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-15%]得到：化合物28A的保留時間為3.376min，e.e.值為100%；化合物28B的保留時間為3.789min，e.e.值為100%。 化合物28C和化合物28D經SFC檢測[柱型號：Column: Chiralpak AD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物29C的保留時間為1.408min，e.e.值為100%；化合物29D的保留時間為1.571min，e.e.值為100%。化合物28A： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.64 (ddd, J= 5.5, 8.3, 9.1 Hz, 1H), 7.19-7.09 (m, 2H), 7.06 (d, J= 5.0 Hz, 1H), 6.81-6.65 (m, 1H), 6.21 (br dd, J= 3.3, 16.9 Hz, 1H), 5.77-5.67 (m, 1H), 4.83-4.79 (m, 1H), 4.47 (s, 1H), 4.31-4.19 (m, 1H), 3.98 (br d, J= 13.4 Hz, 1H), 3.70-3.55 (m, 2H), 3.15-3.02 (m, 1H), 2.79-2.69 (m, 1H), 2.00 (s, 3H), 1.37 (d, J= 6.6 Hz, 3H), 1.12-1.05 (m, 3H), 0.97 (d, J= 6.9 Hz, 3H)。LCMS (ESI) m/z: 663.3(M+1) +。 化合物28B： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.70-7.59 (m, 1H), 7.20-7.08 (m, 2H), 7.04 (d, J= 5.0 Hz, 1H), 6.82-6.65 (m, 1H), 6.26-6.14 (m, 1H), 5.73 (dd, J= 1.9, 10.5 Hz, 1H), 4.79 (br s, 1H), 4.53-4.31 (m, 1H), 4.30-4.17 (m, 1H), 4.17-3.92 (m, 1H), 3.72-3.55 (m, 2H), 3.14-3.02 (m, 1H), 2.80-2.71 (m, 1H), 1.98 (s, 3H), 1.37 (d, J= 6.8 Hz, 3H), 1.11-1.06 (m, 3H), 1.02-0.97 (m, 3H)。LCMS (ESI) m/z: 663.4(M+1) +。 化合物28C： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.65 (dt, J= 5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H), 7.06 (d, J= 5.0 Hz, 1H), 6.81-6.64 (m, 1H), 6.26-6.15 (m, 1H), 5.73 (dd, J= 1.9, 10.6 Hz, 1H), 4.81 (br s, 1H), 4.53-4.31 (m, 1H), 4.30-4.20 (m, 1H), 4.16-3.94 (m, 1H), 3.70-3.44 (m, 2H), 3.19-3.00 (m, 1H), 2.76-2.64 (m, 1H), 2.01 (s, 3H), 1.38 (d, J= 6.6 Hz, 3H), 1.10-1.06 (m, 3H), 0.97 (d, J= 6.8 Hz, 3H)。LCMS (ESI) m/z: 663.2(M+1) +。 化合物28D： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.64 (dt, J= 5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H), 7.04 (d, J= 5.0 Hz, 1H), 6.73 (dt, J= 10.9, 17.5 Hz, 1H), 6.21 (br d, J= 17.2 Hz, 1H), 5.77-5.68 (m, 1H), 4.83-4.77 (m, 1H), 4.53-4.32 (m, 1H), 4.31-4.20 (m, 1H), 4.17-3.93 (m, 1H), 3.70-3.43 (m, 2H), 3.20-3.02 (m, 1H), 2.72 (br s, 1H), 1.99 (s, 3H), 1.37 (br d, J= 6.6 Hz, 3H), 1.11-1.06 (m, 3H), 0.99 (d, J= 6.7 Hz, 3H)。LCMS (ESI) m/z: 663.1(M+1) +。 Example 28
Figure 02_image537
Step 1: To a solution of compound 7-13 (0.5 g) in DMAC (5 ml) at 10-25 degrees Celsius was added tripyrrolidinophosphonium bromide hexafluorophosphate (1.77 g) in one portion, compound 2- 1 (1.52 g, 7.59 mmol, 8.0 equiv), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was preparatively purified to give compound 28-1. LCMS (ESI) m/z: 709.2(M+1) + . Second step: To a solution of compound 28-1 (230 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated to obtain a residue. Water (10 mL) was added to the residue, the aqueous phase was adjusted to pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain compound 28-2. LCMS (ESI) m/z: 609.2(M+1) + . third step:
Figure 02_image539
To a mixed solution of compound 28-2 (0.2 g) in tetrahydrofuran (4 ml) and water (1 ml) were added anhydrous potassium carbonate (136.17 mg) and acryl chloride (29.72 mg) successively at 0°C. The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether:ethyl acetate:methanol=3:4:1) to obtain compound 28. Compound 28 was separated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 2.6 minutes, 50 minutes) 28-P1 (mixture of RT=3.397 min and RT=3.789 min) and 28-P2 (mixture of RT=1.402 min and RT=1.565 min) were obtained. 28-P1 was then passed through preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 20%-20%, 4.6 minutes, 120 minutes ) was isolated and purified to obtain compound 28A and compound 28B. 28-P2 was then passed through preparative SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 25%-25%, 5 minutes, 45 minutes ) was isolated and purified to obtain compound 28C and compound 28D. Compound 28A and compound 28B were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; Gradient (B%): 5%-15%] obtained: the retention time of compound 28A was 3.376 min, and the ee value was 100%; the retention time of compound 28B was 3.789 min, and the ee value was 100%. Compound 28C and compound 28D were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; Gradient (B%): 5%-40%] obtained: the retention time of compound 29C was 1.408 min, and the ee value was 100%; the retention time of compound 29D was 1.571 min, and the ee value was 100%. Compound 28A: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.64 (ddd, J = 5.5, 8.3, 9.1 Hz, 1H), 7.19-7.09 (m, 2H) ), 7.06 (d, J = 5.0 Hz, 1H), 6.81-6.65 (m, 1H), 6.21 (br dd, J = 3.3, 16.9 Hz, 1H), 5.77-5.67 (m, 1H), 4.83-4.79 (m, 1H), 4.47 (s, 1H), 4.31-4.19 (m, 1H), 3.98 (br d, J = 13.4 Hz, 1H), 3.70-3.55 (m, 2H), 3.15-3.02 (m, 1H), 2.79-2.69 (m, 1H), 2.00 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H), 1.12-1.05 (m, 3H), 0.97 (d, J = 6.9 Hz, 3H) ). LCMS (ESI) m/z: 663.3(M+1) + . Compound 28B: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.70-7.59 (m, 1H), 7.20-7.08 (m, 2H), 7.04 (d, J = 5.0 Hz, 1H), 6.82-6.65 (m, 1H), 6.26-6.14 (m, 1H), 5.73 (dd, J = 1.9, 10.5 Hz, 1H), 4.79 (br s, 1H), 4.53-4.31 (m, 1H), 4.30-4.17 (m, 1H), 4.17-3.92 (m, 1H), 3.72-3.55 (m, 2H), 3.14-3.02 (m, 1H), 2.80-2.71 (m, 1H) , 1.98 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.11-1.06 (m, 3H), 1.02-0.97 (m, 3H). LCMS (ESI) m/z: 663.4(M+1) + . Compound 28C: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.65 (dt, J = 5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H), 7.06 (d, J = 5.0 Hz, 1H), 6.81-6.64 (m, 1H), 6.26-6.15 (m, 1H), 5.73 (dd, J = 1.9, 10.6 Hz, 1H), 4.81 (br s, 1H) ), 4.53-4.31 (m, 1H), 4.30-4.20 (m, 1H), 4.16-3.94 (m, 1H), 3.70-3.44 (m, 2H), 3.19-3.00 (m, 1H), 2.76-2.64 (m, 1H), 2.01 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.10-1.06 (m, 3H), 0.97 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 663.2(M+1) + . Compound 28D: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.64 (dt, J = 5.5, 8.7 Hz, 1H), 7.18-7.09 (m, 2H), 7.04 (d, J = 5.0 Hz, 1H), 6.73 (dt, J = 10.9, 17.5 Hz, 1H), 6.21 (br d, J = 17.2 Hz, 1H), 5.77-5.68 (m, 1H), 4.83- 4.77 (m, 1H), 4.53-4.32 (m, 1H), 4.31-4.20 (m, 1H), 4.17-3.93 (m, 1H), 3.70-3.43 (m, 2H), 3.20-3.02 (m, 1H) ), 2.72 (br s, 1H), 1.99 (s, 3H), 1.37 (br d, J = 6.6 Hz, 3H), 1.11-1.06 (m, 3H), 0.99 (d, J = 6.7 Hz, 3H) . LCMS (ESI) m/z: 663.1(M+1) + .

實施例29

Figure 02_image541
第一步： 在10-25攝氏度下，向化合物7-13（0.5克）的DMAC（10毫升）溶液中一次性加入三吡咯烷基溴化鏻六氟磷酸鹽（1.77克），化合物3-1（1.63克），反應液在60攝氏度下反應12小時。向反應液中緩慢加入水（10毫升），用乙酸乙酯（5毫升*3）萃取，合併有機相，鹽水洗滌（5毫升*3）無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物經製備純化得到化合物29-1。LCMS (ESI) m/z: 723.2(M+1) +。 第二步： 在10-25攝氏度下，向化合物29-1（0.26克）的二氯甲烷（5毫升）溶液中一次性加入三氟乙酸（1.54克）。反應液在15攝氏度下反應0.5小時。將反應液濃縮得到殘餘物。向殘餘物中加入水（10毫升），水相用碳酸氫鈉固體調至pH=8，乙酸乙酯（5毫升*3）萃取，合併有機相，鹽水洗滌（10毫升*1）無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物29-2。LCMS (ESI) m/z: 623.3(M+1) +。 第三步：
Figure 02_image543
在0攝氏度下，向化合物29-2（0.24克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中依次加入無水碳酸鉀（159.73毫克），丙烯醯氯（34.87毫克）。反應液在15攝氏度下反應15分鐘。向反應液中加入水（10毫升），用乙酸乙酯（5毫升*3）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物先經製備板純化（石油醚：乙酸乙酯：甲醇=3：4：1），得到的化合物29。 化合物29通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，3.0分鐘，40分鐘）分離純化得到實施例29-P1（及實施例29-P2。 29-P1再通過製備SFC（柱型號：DAICEL CHIRALPAK AD（250mm*30mm，5μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體15%-15%，5.3分鐘，260分鐘）分離純化得到化合物29A和化合物29B。 29-P2再通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體25%-25%，5.9分鐘，240分鐘）分離純化得到化合物29C和化合物29D。 化合物29A和化合物29B經SFC檢測[柱型號：Column: Chiralpak AD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-15%]得到：化合物29A的保留時間為3.020min，e.e.值為100%；化合物29B的保留時間為3.171min，e.e.值為100%。 化合物29C和化合物29D經SFC檢測[柱型號：Column: Chiralpak AD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物29C的保留時間為1.346min，e.e.值為100%；化合物29D的保留時間為1.483min，e.e.值為100%。 化合物29A： 1H NMR (400MHz,METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz,1H), 7.64 (dt, J= 5.5,8.7 Hz,1H), 7.18-7.10 (m, 2H), 7.06 (d, J= 5.1 Hz, 1H), 6.81-6.63 (m, 1H), 6.24-6.14 (m, 1H), 5.72 (ddd, J= 1.8, 7.1, 10.6 Hz, 1H), 4.88-4.77 (m, 1H), 4.50-4.39 (m, 1H), 4.29-4.18 (m, 1H), 4.13 (br d, J= 14.0 Hz, 1H), 3.86-3.70 (m, 2H), 2.76 (qd, J= 6.7, 10.6 Hz, 1H), 1.93(s, 3H), 1.38 (d, J= 6.6 Hz, 3H), 1.30-1.19 (m, 3H), 1.08 (dd, J= 1.6, 6.7 Hz, 3H), 0.98 (dd, J= 1.8, 6.7 Hz, 3H)。LCMS (ESI) m/z: 677.1(M+1) +。 化合物29B： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.18-7.09 (m, 2H), 7.04 (d, J= 5.5 Hz, 1H), 6.80-6.62 (m, 1H), 6.23-6.14 (m, 1H), 5.77-5.67 (m, 1H), 4.87-4.77 (m, 1H), 4.50-4.40 (m, 1H), 4.28-4.19 (m, 1H), 4.16-4.08 (m, 1H), 3.86-3.68 (m, 2H), , 2.85-2.72 (m, 1H),1.95(s, 3H), 1.38 (d, J= 6.6 Hz, 3H), 1.32-1.19 (m, 3H), 1.08 (dd, J= 1.7, 6.7 Hz, 3H), 1.00 (dd, J= 1.5, 6.8 Hz, 3H)。LCMS (ESI) m/z: 677.1(M+1) +。 化合物29C： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J= 5.0 Hz, 1H), 7.64 (dt, J= 5.6, 8.7 Hz, 1H), 7.19-7.03 (m, 3H), 6.81-6.62 (m, 1H), 6.19 (ddd, J= 1.7, 6.3, 16.7 Hz, 1H), 5.72 (ddd, J= 1.7, 7.0, 10.5 Hz, 1H), 4.86-4.80 (m, 1H), 4.48-4.40 (m, 1H), 4.27-4.07 (m, 2H), 3.90-3.69 (m, 2H), 2.63 (quin, J= 6.8 Hz, 1H), 1.98(s, 3H), 1.38 (d, J= 6.6 Hz, 3H), 1.28-1.19 (m, 3H), 1.05 (d, J= 6.7 Hz, 3H), 0.96 (d, J= 6.8 Hz, 3H)。LCMS (ESI) m/z: 677.3(M+1) +。 化合物29D： 1H NMR (400MHz, METHANOL- d 4 ) δ 8.24 (d, J= 4.9 Hz, 1H), 7.65 (dt, J= 5.6, 8.7 Hz, 1H), 7.21-7.01 (m, 3H), 6.81-6.61 (m, 1H), 6.19 (ddd, J= 1.5, 6.2, 16.7 Hz, 1H), 5.77-5.67 (m, 1H), 4.88-4.82 (m, 1H), 4.49-4.40 (m, 1H), 4.28-4.07 (m, 2H), 3.87-3.71 (m, 2H), , 2.65 (td, J= 6.7, 13.5 Hz, 1H), 1.96(s, 3H), 1.38 (d, J= 6.7 Hz, 3H), 1.28 (br d, J= 6.7 Hz, 2H), 1.22 (s, 1H), 1.06 (d, J= 6.7 Hz, 3H), 0.99 (d, J= 6.8 Hz, 3H)。LCMS (ESI) m/z: 677.3(M+1) +。 Example 29
Figure 02_image541
Step 1: To a solution of compound 7-13 (0.5 g) in DMAC (10 mL) at 10-25 °C was added tripyrrolidinophosphonium bromide hexafluorophosphate (1.77 g) in one portion, compound 3- 1 (1.63 g), the reaction solution was reacted at 60 degrees Celsius for 12 hours. Water (10 mL) was slowly added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (5 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was preparatively purified to give compound 29-1. LCMS (ESI) m/z: 723.2(M+1) + . Step 2: To a solution of compound 29-1 (0.26 g) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g) in one portion at 10-25 degrees Celsius. The reaction solution was reacted at 15 degrees Celsius for 0.5 hour. The reaction solution was concentrated to obtain a residue. To the residue was added water (10 mL), the aqueous phase was adjusted to pH=8 with solid sodium bicarbonate, extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with brine (10 mL*1) anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to give compound 29-2. LCMS (ESI) m/z: 623.3(M+1) + . third step:
Figure 02_image543
To a mixed solution of compound 29-2 (0.24 g) in tetrahydrofuran (4 ml) and water (1 ml) were added anhydrous potassium carbonate (159.73 mg) and acryl chloride (34.87 mg) successively at 0°C. The reaction solution was reacted at 15 degrees Celsius for 15 minutes. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was first purified by preparative plate (petroleum ether:ethyl acetate:methanol=3:4:1) to obtain compound 29. Compound 29 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 3.0 minutes, 40 minutes) Example 29-P1 (and Example 29-P2. 29-P1 was then passed through preparative SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia), gradient: carbon dioxide Critical fluid 15%-15%, 5.3 minutes, 260 minutes) separation and purification to obtain compound 29A and compound 29B. 29-P2 was then passed through preparative SFC (column type: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropyl Alcohol (0.1% ammonia water, gradient: carbon dioxide critical fluid 25%-25%, 5.9 minutes, 240 minutes) was separated and purified to obtain compound 29C and compound 29D. Compound 29A and compound 29B were detected by SFC [Column model: Column: Chiralpak AD- 3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; gradient (B%): 5%-15%] yield: compound 29A The retention time was 3.020 min, and the ee value was 100%; the retention time of compound 29B was 3.171 min, and the ee value was 100%. Compound 29C and compound 29D were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm ID , 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%] obtained: the retention time of compound 29C is 1.346min, Compound 29D has a retention time of 1.483 min and an ee of 100%. Compound 29A: 1 H NMR (400 MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.64 ( dt, J = 5.5, 8.7 Hz, 1H), 7.18-7.10 (m, 2H), 7.06 (d, J = 5.1 Hz, 1H), 6.81-6.63 (m, 1H), 6.24-6.14 (m, 1H) , 5.72 (ddd, J = 1.8, 7.1, 10.6 Hz, 1H), 4.88-4.77 (m, 1H), 4.50-4.39 (m, 1H), 4.29-4.18 (m, 1H), 4.13 ( br d, J = 14.0 Hz, 1H), 3.86-3.70 (m, 2H), 2.76 (qd, J = 6.7, 10.6 Hz, 1H), 1.93(s, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.30-1.19 (m, 3H), 1.08 (dd, J = 1.6, 6.7 Hz, 3H), 0.98 (dd, J = 1.8, 6.7 Hz, 3H). LCMS (ESI) m/z: 677.1(M+1) + . Compound 29B: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.18-7.09 (m, 2H), 7.04 (d, J = 5.5 Hz, 1H), 6.80-6.62 (m, 1H), 6.23-6.14 (m, 1H), 5.77-5.67 (m, 1H), 4.87-4.77 (m, 1H), 4.50-4.40 (m, 1H) ), 4.28-4.19 (m, 1H), 4.16-4.08 (m, 1H), 3.86-3.68 (m, 2H), , 2.85-2.72 (m, 1H), 1.95(s, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.32-1.19 (m, 3H), 1.08 (dd, J = 1.7, 6.7 Hz, 3H), 1.00 (dd, J = 1.5, 6.8 Hz, 3H). LCMS (ESI) m/z: 677.1(M+1) + . Compound 29C: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.23 (d, J = 5.0 Hz, 1H), 7.64 (dt, J = 5.6, 8.7 Hz, 1H), 7.19-7.03 (m, 3H), 6.81-6.62 (m, 1H), 6.19 (ddd, J = 1.7, 6.3, 16.7 Hz, 1H), 5.72 (ddd, J = 1.7, 7.0, 10.5 Hz, 1H), 4.86-4.80 (m, 1H), 4.48-4.40 (m, 1H), 4.27-4.07 (m, 2H), 3.90-3.69 (m, 2H), 2.63 (quin, J = 6.8 Hz, 1H), 1.98(s, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.28-1.19 (m, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 677.3(M+1) + . Compound 29D: 1 H NMR (400MHz, METHANOL- d 4 ) δ 8.24 (d, J = 4.9 Hz, 1H), 7.65 (dt, J = 5.6, 8.7 Hz, 1H), 7.21-7.01 (m, 3H), 6.81-6.61 (m, 1H), 6.19 (ddd, J = 1.5, 6.2, 16.7 Hz, 1H), 5.77-5.67 (m, 1H), 4.88-4.82 (m, 1H), 4.49-4.40 (m, 1H) ), 4.28-4.07 (m, 2H), 3.87-3.71 (m, 2H), , 2.65 (td, J = 6.7, 13.5 Hz, 1H), 1.96(s, 3H), 1.38 (d, J = 6.7 Hz , 3H), 1.28 (br d, J = 6.7 Hz, 2H), 1.22 (s, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). LCMS (ESI) m/z: 677.3(M+1) + .

實施例30

Figure 02_image545
第一步： 在20-30攝氏度下，向化合物30-1（14克）的乙腈（140毫升）溶液中加入化合物7-2（17.77克）和碳酸鉀（7.49克），反應液在15攝氏度下反應16小時。向反應液中加入乙酸乙酯（300毫升）和水（300毫升），有機相分離，飽和食鹽水（300毫升）洗滌，有機相減壓濃縮得到殘餘物。殘餘物用石油醚（100毫升）打漿半小時，過濾，濾餅乾燥得到化合物30-2。LCMS (ESI) m/z: 230.1(M+1) +。 第二步： 在20-30攝氏度下，向化合物30-2（24.50克）的乙腈（245毫升）溶液中依次加入碳酸銫（34.83克）和化合物7-4（18.87克），反應液在氮氣保護下於15攝氏度下反應3小時。向反應液中加入乙酸乙酯（200毫升）和水（200毫升），有機相分離，飽和食鹽水（200毫升）洗滌，有機相減壓濃縮得到殘餘物。向殘餘物中加入石油醚：乙酸乙酯=10:1（60毫升）攪拌半小時，過濾，濾餅乾燥得到化合物30-3。LCMS (ESI) m/z: 352.2(M+1) +。 第三步： 在20-30攝氏度下，向化合物30-3（20克）的三氟乙醇（200毫升）溶液中加入三乙胺（17.29克），反應液在氮氣保護下於95攝氏度下反應16小時。反應液濃縮得到殘餘物，向殘餘物中加入石油醚（100毫升）攪拌1小時，混合物過濾，濾餅乾燥得到化合物30-4。LCMS (ESI) m/z: 320.2(M+1) +。 第四步： 在20-30攝氏度下，向化合物30-4（12克）的乙腈（150毫升）溶液中依次加入三溴吡啶嗡鹽（24.05克）和磷酸鉀（11.97克），反應液在15攝氏度下反應18小時。向反應液中加入飽和亞硫酸鈉水溶液（100毫升），混合物用乙酸乙酯（200毫升）萃取，有機相用飽和食鹽水（200毫升）洗滌，有機相減壓濃縮得到化合物30-5。粗品直接用於下一步。LCMS (ESI) m/z: 353.9(M+1) +。 第五步： 在20-30攝氏度下，向化合物30-5（10克）的二氧六環（140毫升）溶液中依次加入化合物6-4（4.67克），Pd 2(dba) 3（2.59克），Xantphos（3.27克）和碳酸銫（18.40克），反應液氮氣保護，在100攝氏度下反應2小時。反應液濃縮得到殘餘物，殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=10:1 到3:1）純化得到化合物30-6。LCMS (ESI) m/z: 424.1(M+1) +。 第六步： 在20-30攝氏度下，向化合物30-6（1.0克）的二氯甲烷（10毫升）溶液中加入NBS（420.39毫克），反應液氮氣保護，在15攝氏度下反應13小時。向反應液中加入飽和亞硫酸鈉水溶液（15毫升），有機相分離，食鹽水（20毫升）洗滌。有機相濃縮得到殘餘物，向殘餘物中加入甲醇（3毫升）攪拌0.5小時，混合物過濾，濾餅乾燥得到化合物30-7。LCMS (ESI) m/z: 503.9(M+3) +。 第七步： 在20-30攝氏度下，向化合物30-7（600毫克）的N,N-二甲基甲醯胺（6毫升）溶液中依次加入鋅粉（78.11毫克）、氰化鋅（140.27毫克）、Pd 2(dba) 3（109.39毫克）、DPPF（132.45毫克）和溴化鋅（53.80毫克），反應液氮氣保護，在110攝氏度下反應2小時。反應液過濾，濾餅用乙酸乙酯（15毫升）洗滌，濾液用食鹽水（30毫升）洗滌，分離有機相，濃縮得到殘餘物，殘餘物用矽膠柱（洗脫劑：石油醚：乙酸乙酯=10:1到3:1）純化得到化合物30-8。LCMS (ESI) m/z:449.0(M+1) +。 第八步： 化合物30-8（0.5克）的濃硫酸（4.60 g）溶液於90攝氏度下反應1.5小時。反應液加入到飽和碳酸氫鈉水溶液（250毫升）中，用乙酸乙酯（20毫升*2）萃取，合併有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物30-9。LCMS (ESI) m/z: 467.1(M+1) +。 第九步： 在0攝氏度下，向化合物30-9（0.4克）的N,N-二甲基乙醯胺（4毫升）溶液中加入羰基二咪唑（417.19毫克）和氫化鈉（102.91毫克，質量百分比：60%），反應液在15攝氏度下反應0.5小時。反應液倒入水（30毫升）中，緩慢滴加鹽酸（2莫耳/升）至pH約為1。向混合物中加入飽和碳酸氫鈉水溶液至pH約為10，混合物用乙酸乙酯（30毫升*2）萃取，合併有機相，飽和食鹽水（50毫升）洗滌，分出有機相，無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物30-10。粗品直接用於下一步。LCMS (ESI) m/z: 493.1(M+1) +。 第十步： 在10-15攝氏度下，向化合物30-10（500毫克）的N,N-二甲基乙醯胺（5毫升）溶液中加入N,N-二異丙基乙胺（393.72毫克）和三吡咯烷基溴化鏻六氟磷酸鹽（946.76毫克）和化合物1-1（567毫克），反應液在氮氣保護下，110攝氏度反應12個小時。反應液倒入水（100毫升）中，乙酸乙酯（40毫升*2）萃取，合併有機相，飽和食鹽水（50毫升）洗滌，分出有機相，濃縮得到殘餘物。殘餘物通過矽膠柱（洗脫劑：石油醚：乙酸乙酯=1:1 到0:1）純化得到化合物30-11。LCMS (ESI) m/z: 661.1(M+1) +。 第十一步： 在10-15攝氏度下，向化合物30-11（550毫克）的二氯甲烷（12毫升）溶液中加入三氟乙酸（6.16克，54.02微莫耳，4毫升，64.89當量）。反應液在氮氣保護下，15攝氏度反應1個小時。反應液濃縮得到化合物30-12的三氟乙酸鹽。粗品直接用於下一步。LCMS (ESI) m/z: 561.1(M+1) +。 第十二步：
Figure 02_image547
在10-15攝氏度下，向化合物30-12（700毫克，三氟乙酸鹽）的四氫呋喃（14毫升）和水（7毫升）溶液中加入碳酸鉀（286.84毫克）和丙烯醯氯（93.92毫克）。反應液在氮氣保護下，15攝氏度反應15分鐘。向反應液中加入乙酸乙酯（30毫升）和水（30毫升），分離有機相，飽和食鹽水（50毫升）洗滌，有機相濃縮得到消旋體化合物30。化合物30通過製備SFC（柱型號：DAICEL CHIRALPAK IG (250*30mm, 10μm)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，4分鐘，30分鐘）分離純化得到化合物30A（保留時間=0.540 min）及化合物30B（保留時間=0.735 min）。 化合物30A和化合物30B經SFC檢測[柱型號：Column: Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物30A的保留時間為0.540min，e.e.值為100%；化合物30B的保留時間為0.753min，e.e.值為100%。 化合物30A（保留時間=0.540 min）： 1H NMR (400 MHz, DMSO- d 6) δ 8.30 (d, J= 4.9 Hz, 1H), 7.47 (tt, J= 2.2, 9.3 Hz, 1H), 7.29 (br d, J= 8.6 Hz, 1H), 7.16 (s, 1H), 7.14 (br d, J= 8.6 Hz, 1H), 7.06 (d, J= 4.9 Hz, 1H), 6.85 (dd, J= 10.4, 16.7 Hz, 1H), 6.19 (dd, J= 2.3, 16.7 Hz, 1H), 5.78-5.74 (m, 1H), 3.98-3.72 (m, 8H), 2.75 (quin, J= 6.7 Hz, 1H), 1.99 (s, 3H), 1.08-0.97 (m, 6H)。LCMS (ESI) m/z: 615.1(M+1) +。 化合物30B（保留時間=0.735 min）： 1H NMR (400 MHz, DMSO- d 6) δ 8.29 (d, J= 4.9 Hz, 1H), 7.47 (tt, J= 2.3, 9.3 Hz, 1H), 7.29 (br d, J= 8.6 Hz, 1H), 7.19-7.10 (m, 2H), 7.06 (d, J= 5.4 Hz, 1H), 6.85 (dd, J= 10.4, 16.7 Hz, 1H), 6.18 (dd, J= 2.3, 16.7 Hz, 1H), 5.79-5.68 (m, 1H), 3.97-3.71 (m, 8H), 2.74 (quin, J= 6.6 Hz, 1H), 1.98 (s, 3H), 1.12-0.94 (m, 6H)。LCMS (ESI) m/z: 615.1(M+1) +。 Example 30
Figure 02_image545
The first step: Compound 7-2 (17.77 g) and potassium carbonate (7.49 g) were added to a solution of compound 30-1 (14 g) in acetonitrile (140 ml) at 20-30 degrees Celsius. The reaction solution was heated at 15 degrees Celsius. The reaction was continued for 16 hours. Ethyl acetate (300 ml) and water (300 ml) were added to the reaction solution, the organic phase was separated, washed with saturated brine (300 ml), and the organic phase was concentrated under reduced pressure to obtain a residue. The residue was slurried with petroleum ether (100 mL) for half an hour, filtered, and the filter cake was dried to obtain compound 30-2. LCMS (ESI) m/z: 230.1(M+1) + . The second step: To a solution of compound 30-2 (24.50 g) in acetonitrile (245 ml) at 20-30 degrees Celsius, cesium carbonate (34.83 g) and compound 7-4 (18.87 g) were added successively, and the reaction solution was heated under nitrogen. The reaction was carried out at 15 degrees Celsius for 3 hours under protection. Ethyl acetate (200 ml) and water (200 ml) were added to the reaction solution, the organic phase was separated, washed with saturated brine (200 ml), and the organic phase was concentrated under reduced pressure to obtain a residue. Petroleum ether:ethyl acetate=10:1 (60 mL) was added to the residue, stirred for half an hour, filtered, and the filter cake was dried to obtain compound 30-3. LCMS (ESI) m/z: 352.2(M+1) + . The third step: Triethylamine (17.29 g) was added to a solution of compound 30-3 (20 g) in trifluoroethanol (200 ml) at 20-30 degrees Celsius, and the reaction solution was reacted at 95 degrees Celsius under nitrogen protection 16 hours. The reaction solution was concentrated to obtain a residue, petroleum ether (100 ml) was added to the residue and stirred for 1 hour, the mixture was filtered, and the filter cake was dried to obtain compound 30-4. LCMS (ESI) m/z: 320.2(M+1) + . Step 4: To a solution of compound 30-4 (12 g) in acetonitrile (150 ml) at 20-30 degrees Celsius, add pyridinium tribromide (24.05 g) and potassium phosphate (11.97 g) in turn, the reaction solution was The reaction was carried out at 15 degrees Celsius for 18 hours. Saturated aqueous sodium sulfite solution (100 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (200 mL), the organic phase was washed with saturated brine (200 mL), and the organic phase was concentrated under reduced pressure to obtain compound 30-5. The crude product was used directly in the next step. LCMS (ESI) m/z: 353.9(M+1) + . The fifth step: at 20-30 degrees Celsius, compound 6-4 (4.67 g), Pd 2 (dba) 3 (2.59 g), Xantphos (3.27 g) and cesium carbonate (18.40 g), the reaction liquid was protected by nitrogen and reacted at 100 degrees Celsius for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate=10:1 to 3:1) to obtain compound 30-6. LCMS (ESI) m/z: 424.1(M+1) + . The sixth step: NBS (420.39 mg) was added to a solution of compound 30-6 (1.0 g) in dichloromethane (10 ml) at 20-30 degrees Celsius, the reaction liquid was protected with nitrogen, and the reaction was carried out at 15 degrees Celsius for 13 hours. Saturated aqueous sodium sulfite solution (15 mL) was added to the reaction solution, the organic phase was separated, and washed with brine (20 mL). The organic phase was concentrated to obtain a residue, methanol (3 mL) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 30-7. LCMS (ESI) m/z: 503.9(M+3) + . Step 7: Add zinc powder (78.11 mg), zinc cyanide ( 140.27 mg), Pd 2 (dba) 3 (109.39 mg), DPPF (132.45 mg) and zinc bromide (53.80 mg), the reaction liquid was protected with nitrogen, and reacted at 110 degrees Celsius for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (15 mL), the filtrate was washed with brine (30 mL), the organic phase was separated, concentrated to obtain a residue, and the residue was washed with silica gel column (eluent: petroleum ether: ethyl acetate) ester = 10:1 to 3:1) was purified to give compound 30-8. LCMS (ESI) m/z: 449.0(M+1) + . The eighth step: The concentrated sulfuric acid (4.60 g) solution of compound 30-8 (0.5 g) was reacted at 90 degrees Celsius for 1.5 hours. The reaction solution was added to saturated aqueous sodium bicarbonate solution (250 mL), extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 30-9. LCMS (ESI) m/z: 467.1(M+1) + . Step 9: To a solution of compound 30-9 (0.4 g) in N,N-dimethylacetamide (4 ml) at 0 degrees Celsius was added carbonyldiimidazole (417.19 mg) and sodium hydride (102.91 mg, mass percentage: 60%), the reaction solution was reacted at 15 degrees Celsius for 0.5 hours. The reaction solution was poured into water (30 mL), and hydrochloric acid (2 mol/L) was slowly added dropwise to pH about 1. Saturated aqueous sodium bicarbonate solution was added to the mixture until the pH was about 10, the mixture was extracted with ethyl acetate (30 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated to obtain compound 30-10. The crude product was used directly in the next step. LCMS (ESI) m/z: 493.1(M+1) + . Step 10: To a solution of compound 30-10 (500 mg) in N,N-dimethylacetamide (5 mL) at 10-15°C was added N,N-diisopropylethylamine (393.72 mg) and tripyrrolidinophosphonium bromide hexafluorophosphate (946.76 mg) and compound 1-1 (567 mg), the reaction solution was reacted under nitrogen protection at 110 degrees Celsius for 12 hours. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL*2), the organic phases were combined, washed with saturated brine (50 mL), the organic phase was separated, and concentrated to obtain a residue. The residue was purified by silica gel column (eluent: petroleum ether: ethyl acetate = 1:1 to 0:1) to give compound 30-11. LCMS (ESI) m/z: 661.1(M+1) + . Step Eleven: To a solution of compound 30-11 (550 mg) in dichloromethane (12 mL) was added trifluoroacetic acid (6.16 g, 54.02 μmol, 4 mL, 64.89 equiv) at 10-15 °C . The reaction solution was reacted at 15°C for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 30-12. The crude product was used directly in the next step. LCMS (ESI) m/z: 561.1(M+1) + . Step 12:
Figure 02_image547
To a solution of compound 30-12 (700 mg, trifluoroacetate) in tetrahydrofuran (14 mL) and water (7 mL) at 10-15 °C was added potassium carbonate (286.84 mg) and acryl chloride (93.92 mg) . The reaction solution was reacted at 15 degrees Celsius for 15 minutes under nitrogen protection. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, the organic phase was separated, washed with saturated brine (50 mL), and the organic phase was concentrated to obtain a racemate compound 30. Compound 30 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IG (250*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 4 minutes, 30 minutes) Compound 30A (retention time = 0.540 min) and compound 30B (retention time = 0.735 min). Compound 30A and compound 30B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 40%-40%] obtained: the retention time of compound 30A is 0.540min, and the ee value is 100%; the retention time of compound 30B is 0.753min, and the ee value is 100%. Compound 30A (retention time = 0.540 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.30 (d, J = 4.9 Hz, 1H), 7.47 (tt, J = 2.2, 9.3 Hz, 1H), 7.29 (br d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.14 (br d, J = 8.6 Hz, 1H), 7.06 (d, J = 4.9 Hz, 1H), 6.85 (dd, J = 10.4, 16.7 Hz, 1H), 6.19 (dd, J = 2.3, 16.7 Hz, 1H), 5.78-5.74 (m, 1H), 3.98-3.72 (m, 8H), 2.75 (quin, J = 6.7 Hz, 1H) ), 1.99 (s, 3H), 1.08-0.97 (m, 6H). LCMS (ESI) m/z: 615.1(M+1) + . Compound 30B (RT=0.735 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.29 (d, J = 4.9 Hz, 1H), 7.47 (tt, J = 2.3, 9.3 Hz, 1H), 7.29 (br d, J = 8.6 Hz, 1H), 7.19-7.10 (m, 2H), 7.06 (d, J = 5.4 Hz, 1H), 6.85 (dd, J = 10.4, 16.7 Hz, 1H), 6.18 (dd , J = 2.3, 16.7 Hz, 1H), 5.79-5.68 (m, 1H), 3.97-3.71 (m, 8H), 2.74 (quin, J = 6.6 Hz, 1H), 1.98 (s, 3H), 1.12- 0.94 (m, 6H). LCMS (ESI) m/z: 615.1(M+1) + .

實施例31

Figure 02_image549
第一步： 向化合物30-10（300毫克）的DMAC（5毫升）溶液中加入PYBROP（568.05毫克），DIEA（157.49毫克）以及化合物3-1（391.70毫克）。反應液在100攝氏度下反應16小時，反應液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex luna C18（150*40mm*15 μm），流動相：水（0.1%三氟乙酸）-乙腈，梯度：29%-59%，11分鐘] 純化得到化合物31-1。LCMS (ESI) m/z: 689.3.(M+1) +。 第二步： 將化合物31-1（120毫克）溶解在二氯甲烷（2毫升）和三氟乙酸（0.5毫升）的混合溶液中。反應液在25攝氏度下反應1小時，反應液濃縮得到化合物31-2的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 589.3(M+1) +。 第三步：
Figure 02_image551
向化合物31-2（150毫克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中加入碳酸鉀（35.22毫克），調節pH至8後，向反應液中加入化合物1-5（23.07毫克）。反應液在0攝氏度反應15分鐘，向反應液中加入飽和碳酸氫鈉水溶液，調節pH到8，用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（5毫升*2）洗後經無水硫酸鈉乾燥後濃縮得到化合物31。 化合物31用製備SFC（柱型號：DAICEL CHIRALPAK IC(250mm*30mm,10um)，流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體50%-50%，6.7分鐘，50 分鐘）分離得到化合物31A和化合物31B。 化合物31A和化合物31B經SFC檢測[柱型號：Column: Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物31A的保留時間為1.845min；化合物31B的保留時間為2.980min。 化合物31A（保留時間=1.845min）： LCMS (ESI) m/z: 643.3.(M+1) +。 化合物31B（保留時間=2.980 min）： LCMS (ESI) m/z: 643.3.(M+1) +。 Example 31
Figure 02_image549
Step 1: To a solution of compound 30-10 (300 mg) in DMAC (5 mL) was added PYBROP (568.05 mg), DIEA (157.49 mg) and compound 3-1 (391.70 mg). The reaction solution was reacted at 100 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex luna C18 (150*40mm*15 μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 29%-59%, 11 minutes] to give compound 31 -1. LCMS (ESI) m/z: 689.3.(M+1) + . Second step: Compound 31-1 (120 mg) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 31-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.3(M+1) + . third step:
Figure 02_image551
Potassium carbonate (35.22 mg) was added to a mixed solution of compound 31-2 (150 mg) in tetrahydrofuran (4 ml) and water (1 ml), and the pH was adjusted to 8, and compound 1-5 (23.07 mg) was added to the reaction solution. mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, and saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). Then, it was dried over anhydrous sodium sulfate and concentrated to obtain compound 31. Compound 31 was separated by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10um), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 50%-50%, 6.7 minutes, 50 minutes) to obtain the compound 31A and compound 31B. Compound 31A and compound 31B were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 40%-40%] obtained: the retention time of compound 31A is 1.845min; the retention time of compound 31B is 2.980min. Compound 31A (retention time = 1.845 min): LCMS (ESI) m/z: 643.3. (M+1) + . Compound 31B (retention time=2.980 min): LCMS (ESI) m/z: 643.3. (M+1) + .

實施例32

Figure 02_image553
第一步： 將化合物32-1(10克)和丙二酸甲酯醯氯（11.26克）溶於二氯甲烷（100毫升）中，反應液在20攝氏度下反應1小時。反應液濃縮得粗品化合物32-2，粗品直接用於下一步。LCMS (ESI) m/z: 246.0.(M+1) +。 第二步： 向化合物32-2（17克）的乙腈（200毫升）溶液中依次加入碳酸銫（22.55克）和4-乙氧基-1,1,1-三氟-3-丁烯-2-酮（12.22克），反應液在20攝氏度下反應1小時。反應液倒入水（250毫升）中，然後用乙酸乙酯（250毫升*3）萃取，合併有機相經飽和食鹽水（250毫升）洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得粗品化合物32-3，粗品直接用於下一步。LCMS (ESI) m/z: 368.0.(M+1) +。 第三步： 將化合物32-3(25克)和三乙胺（13.76克）溶於三氟乙醇（250毫升）中，反應液在80攝氏度下攪拌12小時。反應液用1莫耳/升的鹽酸水溶液（250毫升）酸化，然後用乙酸乙酯（250毫升*2）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得粗品化合物32-4，粗品直接用於下一步。LCMS (ESI) m/z: 336.0.(M+1) +。 第四步： 向化合物32-4(23克)的乙腈（250毫升）溶液中加入三溴化吡啶鎓(43.83克)和磷酸鉀(29.09克)，反應液在50攝氏度下攪拌12小時。反應液倒入水（200毫升）中，然後用乙酸乙酯（200毫升*3）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得粗品化合物32-5，粗品直接用於下一步。LCMS (ESI) m/z: 369.9.(M+1) +。 第五步： 向化合物32-5(20克)的二氧六環（200毫升）溶液中加入2-異丙基-4-甲基吡啶-3-胺(8.51克)，碳酸銫(4.54克)，三(二亞苄基丙酮)二鈀(4.94克)和4,5-雙(二苯基磷)-9,9-二甲基氧雜蒽(6.25克)，反應液在100攝氏度下，氮氣保護條件下攪拌12小時。反應液過濾，濾餅用乙酸乙酯（150毫升*3）洗滌，濾液濃縮得殘餘物，向殘餘物中加入石油醚/乙酸乙酯（200毫升/200毫升）攪拌1小時，混合物過濾，濾餅烘乾得到化合物32-6。LCMS (ESI) m/z: 440.1(M+1) +。 第六步： 在0攝氏度下，向化合物32-6 (11克)的二氯甲烷（120毫升）溶液中加入N-溴代丁二醯亞胺（4.45克），反應液在0攝氏度下攪拌0.5小時。反應液在0攝氏度條件下用飽和亞硫酸鈉水溶液（150毫升）淬滅，經飽和食鹽水(150毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得粗品化合物32-7，粗品直接用於下一步。LCMS (ESI) m/z: 518.0.(M+1) +。 第七步： 向化合物32-7 (13克)的N,N-二甲基甲醯胺（150毫升）溶液中加入鋅粉(1.10克)，氰化鋅(2.5克)，溴化鋅(282.19毫克)，1,1’-雙(二苯基膦)二茂鐵(2.78克)和三(二亞苄基丙酮)二鈀(2.29克)，反應液在120攝氏度，氮氣保護條件下攪拌2小時。反應液過濾，濾餅用乙酸乙酯（250毫升*3）洗滌，濾液濃縮得殘餘物，向殘餘物中加入甲醇（50毫升）攪拌0.5小時，混合物過濾，濾餅烘乾得到化合物32-8。LCMS (ESI) m/z: 465.1(M+1) +。 第八步： 化合物32-8（8克）的濃硫酸（40毫升）溶液於60攝氏度下反應12小時。反應液緩慢滴加到2莫耳/升的氫氧化鈉（600毫升）水溶液中，然後用乙酸乙酯（250毫升*3）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到粗品化合物32-9，粗品直接用於下一步。LCMS (ESI) m/z: 483.1.(M+1) +。 第九步： 向化合物32-9（8克）的四氫呋喃（100毫升）溶液中一次性加入氫化鈉（1.99毫克，質量百分比：60%）和1,1-羰基二咪唑(5.37克)，反應液在20攝氏度下攪拌0.5小時。反應液倒入水（250毫升）中，用1莫耳/升的鹽酸（50毫升）酸化，然後用乙酸乙酯（150毫升*3）萃取，所得有機相經飽和食鹽水(200毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到粗品化合物32-10，粗品直接用於下一步。LCMS (ESI) m/z: 508.9.(M+1) +。 第十步： 向化合物32-10（8.5克）的N,N-二甲基乙醯胺（100毫升）溶液中加入N,N-二異丙基乙胺（6.48克）和三吡咯烷基溴化鏻六氟磷酸鹽（15.57克）。反應液在20攝氏度下反應2小時後加入化合物1-1（9.33克）。反應液在80攝氏度下反應10小時。反應液倒入水（300毫升）中，然後用乙酸乙酯（150毫升*3）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex luna C18 （250*50mm*10 μm），流動相：水（0.1%三氟乙酸）-乙腈，梯度：25%-55%，20分鐘] 純化得到化合物32-11。LCMS (ESI) m/z: 677.3.(M+1) +。 第十一步： 向化合物32-11（11克）的二氯甲烷（100毫升）溶液中加入三氟乙酸（30.80克）。反應液在20攝氏度下反應0.5小時，反應液濃縮得到化合物32-12的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 577.3.(M+1) +。 第十二步：
Figure 02_image555
在0攝氏度下，向化合物32-12（11克，三氟乙酸鹽）的四氫呋喃（100.0毫升）和水（20毫升）的混合溶液中依次加入無水碳酸鉀（11.0克），丙烯醯氯（1.44克）。反應液在0攝氏度下反應0.5小時。向反應液中加入水（250毫升），用乙酸乙酯（250毫升*3）萃取，所得有機相經飽和食鹽水(250毫升)洗滌後用無水硫酸鈉乾燥，過濾，濾液濃縮得到化合物32。化合物32通過製備SFC（柱型號：DAICEL CHIRALPAK IC（250mm*30mm，10μm），流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體60%-60%，5.5分鐘，150分鐘）分離純化得到32-P1（保留時間=1.956 min）及32-P2（保留時間=4.491 min）。 32-P1再通過製備SFC（柱型號：DAICEL CHIRALPAK IG（250mm*30mm，10μm），流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體40%-40%，6.0分鐘，95分鐘）分離純化得到32A和32B。 32-P2再通過製備SFC（柱型號：DAICEL CHIRALPAK OD（250mm*30mm，10μm），流動相：乙醇（0.1%氨水），梯度：二氧化碳臨界流體30%-30%，6.2分鐘，180分鐘）分離純化得到化合物32C和化合物32D。 化合物32A和化合物32B經SFC檢測[柱型號：Column: Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物32A的保留時間為2.274min，e.e.值為56.29%；化合物32B的保留時間為2.642min，e.e.值為28.83%。 化合物32C和化合物32D經SFC檢測[柱型號：Column: Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為乙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物32C的保留時間為1.724min，e.e.值為66.46%；化合物32D的保留時間為1.915min，e.e.值為38.83%。化合物32A： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.43-8.20 (m, 1H), 7.92-7.72 (m, 1H), 7.52 (br t, J= 7.5 Hz, 2H), 7.30-7.18 (m, 1H), 7.14-7.00 (m, 1H), 6.92-6.76 (m, 1H), 6.28-6.13 (m, 1H), 5.83-5.69 (m, 1H), 3.97-3.74 (m, 8H), 2.84-2.68 (m, 1H), 2.05-1.92 (m, 3H), 1.10-1.04 (m, 3H), 1.02-0.95 (m, 3H)。 LCMS (ESI) m/z: 631.2(M+1) +。 化合物32B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.35-8.27 (m, 1H), 7.86-7.70 (m, 1H), 7.55-7.36 (m, 2H), 7.30-7.21 (m, 1H), 7.14-7.02 (m, 1H), 6.93-6.78 (m, 1H), 6.28-6.13 (m, 1H), 5.83-5.70 (m, 1H), 3.97-3.77 (m, 8H), 2.74-2.67 (m, 1H), 2.04-1.94 (m, 3H), 1.10-0.97 (m, 6H)。LCMS (ESI) m/z: 631.2 (M+1) +。 化合物32C： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.36-8.28 (m, 1H), 7.85-7.75 (m, 1H), 7.54-7.37 (m, 2H), 7.28-7.20 (m, 1H), 7.14-7.04 (m, 1H), 6.92-6.79 (m, 1H), 6.26-6.13 (m, 1H), 5.82-5.71 (m, 1H), 3.96-3.75 (m, 8H), 2.84-2.70 (m, 1H), 2.03-1.93 (m, 3H), 1.09-1.04 (m, 3H), 1.01-0.96 (m, 3H)。LCMS (ESI) m/z: 631.2 (M+1) +。 化合物32D： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.35-8.30 (m, 1H), 7.84-7.72 (m, 1H), 7.55-7.34 (m, 2H), 7.28-7.20 (m, 1H), 7.12-7.03 (m, 1H), 6.91-6.79 (m, 1H), 6.26-6.14 (m, 1H), 5.80-5.72 (m, 1H), 3.99-3.76 (m, 8H), 2.78-2.67 (m, 1H), 2.03-1.94 (m, 3H), 1.08-0.97 (m, 6H)。LCMS (ESI) m/z: 631.2 (M+1) +。 Example 32
Figure 02_image553
The first step: Compound 32-1 (10 g) and methyl malonate chloride (11.26 g) were dissolved in dichloromethane (100 ml), and the reaction solution was reacted at 20 degrees Celsius for 1 hour. The reaction solution was concentrated to obtain the crude compound 32-2, which was directly used in the next step. LCMS (ESI) m/z: 246.0.(M+1) + . Step 2: To a solution of compound 32-2 (17 g) in acetonitrile (200 mL) were added cesium carbonate (22.55 g) and 4-ethoxy-1,1,1-trifluoro-3-butene- 2-keto (12.22 g), the reaction solution was reacted at 20 degrees Celsius for 1 hour. The reaction solution was poured into water (250 mL), then extracted with ethyl acetate (250 mL*3). The combined organic phases were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-3, the crude product was directly used in the next step. LCMS (ESI) m/z: 368.0.(M+1) + . The third step: Compound 32-3 (25 g) and triethylamine (13.76 g) were dissolved in trifluoroethanol (250 ml), and the reaction solution was stirred at 80 degrees Celsius for 12 hours. The reaction solution was acidified with 1 mol/L aqueous hydrochloric acid solution (250 mL), and then extracted with ethyl acetate (250 mL*2). The obtained organic phase was washed with saturated brine (250 mL), dried with anhydrous sodium sulfate, and filtered. , the filtrate was concentrated to obtain the crude compound 32-4, which was directly used in the next step. LCMS (ESI) m/z: 336.0.(M+1) + . Fourth step: To a solution of compound 32-4 (23 g) in acetonitrile (250 ml) were added pyridinium tribromide (43.83 g) and potassium phosphate (29.09 g), and the reaction solution was stirred at 50 degrees Celsius for 12 hours. The reaction solution was poured into water (200 mL), and then extracted with ethyl acetate (200 mL*3). The obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-5, the crude product was used directly in the next step. LCMS (ESI) m/z: 369.9.(M+1) + . Step 5: To a solution of compound 32-5 (20 g) in dioxane (200 ml) was added 2-isopropyl-4-methylpyridin-3-amine (8.51 g), cesium carbonate (4.54 g) ), tris(dibenzylideneacetone)dipalladium (4.94 g) and 4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene (6.25 g), the reaction solution was heated at 100 degrees Celsius , and stirred for 12 hours under nitrogen protection. The reaction solution was filtered, the filter cake was washed with ethyl acetate (150 mL*3), and the filtrate was concentrated to obtain a residue. To the residue was added petroleum ether/ethyl acetate (200 mL/200 mL) and stirred for 1 hour. The mixture was filtered and filtered. The cake was dried to obtain compound 32-6. LCMS (ESI) m/z: 440.1(M+1) + . The sixth step: N-bromosuccinimide (4.45 g) was added to a solution of compound 32-6 (11 g) in dichloromethane (120 ml) at 0 °C, and the reaction solution was stirred at 0 °C 0.5 hours. The reaction solution was quenched with saturated aqueous sodium sulfite solution (150 mL) at 0 degrees Celsius, washed with saturated brine (150 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-7, which was directly used in the next step. LCMS (ESI) m/z: 518.0.(M+1) + . The seventh step: Zinc powder (1.10 g), zinc cyanide (2.5 g), zinc bromide ( 282.19 mg), 1,1'-bis(diphenylphosphino)ferrocene (2.78 g) and tris(dibenzylideneacetone)dipalladium (2.29 g), the reaction solution was stirred at 120 degrees Celsius under nitrogen protection 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (250 ml*3), the filtrate was concentrated to obtain a residue, methanol (50 ml) was added to the residue and stirred for 0.5 hours, the mixture was filtered, and the filter cake was dried to obtain compound 32-8 . LCMS (ESI) m/z: 465.1(M+1) + . The eighth step: A solution of compound 32-8 (8 g) in concentrated sulfuric acid (40 ml) was reacted at 60 degrees Celsius for 12 hours. The reaction solution was slowly added dropwise to a 2 mol/L aqueous solution of sodium hydroxide (600 mL), and then extracted with ethyl acetate (250 mL*3). The obtained organic phase was washed with saturated brine (250 mL) and then washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to obtain crude compound 32-9, which is used directly in the next step. LCMS (ESI) m/z: 483.1.(M+1) + . The ninth step: To a solution of compound 32-9 (8 g) in tetrahydrofuran (100 ml), sodium hydride (1.99 mg, mass percentage: 60%) and 1,1-carbonyldiimidazole (5.37 g) were added at one time to react. The solution was stirred at 20 degrees Celsius for 0.5 hours. The reaction solution was poured into water (250 mL), acidified with 1 mol/L hydrochloric acid (50 mL), and then extracted with ethyl acetate (150 mL*3). The obtained organic phase was washed with saturated brine (200 mL). Then, it was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound 32-10, which was directly used in the next step. LCMS (ESI) m/z: 508.9.(M+1) + . Step 10: To a solution of compound 32-10 (8.5 g) in N,N-dimethylacetamide (100 mL) was added N,N-diisopropylethylamine (6.48 g) and tripyrrolidinyl Phosphonium bromide hexafluorophosphate (15.57 g). The reaction solution was reacted at 20 degrees Celsius for 2 hours, and then compound 1-1 (9.33 g) was added. The reaction solution was reacted at 80 degrees Celsius for 10 hours. The reaction solution was poured into water (300 mL), then extracted with ethyl acetate (150 mL*3). The obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue . The residue was purified by preparative HPLC [column type: Phenomenex luna C18 (250*50mm*10 μm), mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile, gradient: 25%-55%, 20 minutes] to give compound 32 -11. LCMS (ESI) m/z: 677.3.(M+1) + . Eleventh step: To a solution of compound 32-11 (11 g) in dichloromethane (100 ml) was added trifluoroacetic acid (30.80 g). The reaction solution was reacted at 20 degrees Celsius for 0.5 hours, and the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 32-12, and the crude product was directly used in the next step. LCMS (ESI) m/z: 577.3.(M+1) + . Step 12:
Figure 02_image555
To a mixed solution of compound 32-12 (11 g, trifluoroacetate) in tetrahydrofuran (100.0 mL) and water (20 mL) at 0 degrees Celsius were successively added anhydrous potassium carbonate (11.0 g), acrylonitrile chloride (1.44 g) gram). The reaction solution was reacted at 0 degrees Celsius for 0.5 hours. Water (250 mL) was added to the reaction solution, extracted with ethyl acetate (250 mL*3), the obtained organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32. Compound 32 was isolated and purified by preparative SFC (column type: DAICEL CHIRALPAK IC (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 60%-60%, 5.5 minutes, 150 minutes) 32-P1 (retention time = 1.956 min) and 32-P2 (retention time = 4.491 min). 32-P1 was then passed through preparative SFC (column model: DAICEL CHIRALPAK IG (250mm*30mm, 10μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 40%-40%, 6.0 minutes, 95 minutes ) were isolated and purified to give 32A and 32B. 32-P2 was then separated by preparative SFC (column type: DAICEL CHIRALPAK OD (250mm*30mm, 10μm), mobile phase: ethanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 30%-30%, 6.2 minutes, 180 minutes) Purification gave compound 32C and compound 32D. Compound 32A and compound 32B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; Gradient (B%): 5%-40%] obtained: the retention time of compound 32A was 2.274 min, and the ee value was 56.29%; the retention time of compound 32B was 2.642 min, and the ee value was 28.83%. Compound 32C and compound 32D were detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, ethanol (0.05% diethylamine) in phase B; gradient ( B%): 5%-40%] obtained: the retention time of compound 32C was 1.724 min, and the ee value was 66.46%; the retention time of compound 32D was 1.915 min, and the ee value was 38.83%. Compound 32A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.43-8.20 (m, 1H), 7.92-7.72 (m, 1H), 7.52 (br t, J = 7.5 Hz, 2H), 7.30-7.18 (m, 1H), 7.14-7.00 (m, 1H), 6.92-6.76 (m, 1H), 6.28-6.13 (m, 1H), 5.83-5.69 (m, 1H), 3.97-3.74 (m, 8H) , 2.84-2.68 (m, 1H), 2.05-1.92 (m, 3H), 1.10-1.04 (m, 3H), 1.02-0.95 (m, 3H). LCMS (ESI) m/z: 631.2(M+1) + . Compound 32B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35-8.27 (m, 1H), 7.86-7.70 (m, 1H), 7.55-7.36 (m, 2H), 7.30-7.21 (m, 1H) ), 7.14-7.02 (m, 1H), 6.93-6.78 (m, 1H), 6.28-6.13 (m, 1H), 5.83-5.70 (m, 1H), 3.97-3.77 (m, 8H), 2.74-2.67 (m, 1H), 2.04-1.94 (m, 3H), 1.10-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) + . Compound 32C: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.36-8.28 (m, 1H), 7.85-7.75 (m, 1H), 7.54-7.37 (m, 2H), 7.28-7.20 (m, 1H) ), 7.14-7.04 (m, 1H), 6.92-6.79 (m, 1H), 6.26-6.13 (m, 1H), 5.82-5.71 (m, 1H), 3.96-3.75 (m, 8H), 2.84-2.70 (m, 1H), 2.03-1.93 (m, 3H), 1.09-1.04 (m, 3H), 1.01-0.96 (m, 3H). LCMS (ESI) m/z: 631.2 (M+1) + . Compound 32D: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.35-8.30 (m, 1H), 7.84-7.72 (m, 1H), 7.55-7.34 (m, 2H), 7.28-7.20 (m, 1H) ), 7.12-7.03 (m, 1H), 6.91-6.79 (m, 1H), 6.26-6.14 (m, 1H), 5.80-5.72 (m, 1H), 3.99-3.76 (m, 8H), 2.78-2.67 (m, 1H), 2.03-1.94 (m, 3H), 1.08-0.97 (m, 6H). LCMS (ESI) m/z: 631.2 (M+1) + .

實施例33

Figure 02_image557
第一步： 向化合物21-10（500毫克）的DMAC（10毫升）溶液中加入PYBROP（1.42克），DIEA（328.10毫克）以及化合物4-2（870.45毫克）。反應液在100攝氏度下反應16小時，反應液濃縮得到殘餘物。殘餘物通過製備HPLC[柱型號：Phenomenex Synergi Max-RP 250*50mm*10 μm，流動相：水（0.225%甲酸-乙腈，梯度：32%-62%，20分鐘] 純化得到化合物33-1。LCMS (ESI) m/z: 689.1.(M+1) +。 第二步： 將化合物33-1（100毫克）溶解在二氯甲烷（3毫升）和三氟乙酸（1毫升）的混合溶液中。反應液在25攝氏度下反應1小時，反應液濃縮得到化合物33-2的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 589.2(M+1) +。 第三步：
Figure 02_image559
向化合物33-2（140毫克）的四氫呋喃（4毫升）和水（1毫升）的混合溶液中加入碳酸鉀（71.08毫克），調節pH至8後，向反應液中加入化合物1-5（15.52毫克）。反應液在0攝氏度反應15分鐘，向反應液中加入飽和碳酸氫鈉水溶液，調節pH到8，用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（5毫升*2）洗後經無水硫酸鈉乾燥後濃縮得到化合物33。化合物33用製備SFC（柱型號：Phenomenex Gemini-NX C18 (75*30mm*3um)，流動相：水0.225%甲酸）乙腈，梯度：二氧化碳臨界流體28%-58%，7分鐘）分離得到化合物33A和化合物33B。 化合物33A和化合物33B經SFC檢測[柱型號：Column: Chiralpak IG-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇+乙腈（0.05%二乙胺）；梯度（B%）：40%甲醇+（0.05%二乙胺）]得到：化合物33A的保留時間為0.663min；化合物33B的保留時間為1.128min。 化合物33A（保留時間=0.663min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.32 (d, J= 4.9 Hz, 1H), 7.77-7.61 (m, 1H), 7.44-7.30 (m, 3H), 7.16-7.05 (m, 1H), 6.89-6.74 (m, 1H), 6.30-6.10 (m, 1H), 5.89-5.68 (m, 1H), 4.70-4.51 (m, 2H), 4.40-4.04 (m, 3H), 2.78-2.63 (m, 2H), 2.02-1.94 (m, 3H), 1.43-1.34 (m, 6H), 1.06-0.94 (m, 6H)。LCMS (ESI) m/z: 643.2.(M+1) +化合物33B（保留時間=1.128 min）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.36-8.25 (m, 1H), 7.75-7.60 (m, 1H), 7.42-7.30 (m, 3H), 7.13-7.05 (m, 1H), 6.89-6.74 (m, 1H), 6.24-6.14 (m, 1H), 5.79-5.70 (m, 1H), 4.73-4.51 (m, 2H), 4.36-3.97 (m, 3H), 2.75-2.67 (m, 2H), 1.99-1.97 (m, 3H), 1.42-1.36 (m, 6H), 1.06-0.95 (m, 6H)。LCMS (ESI) m/z: 643.2.(M+1) +。 Example 33
Figure 02_image557
Step 1: To a solution of compound 21-10 (500 mg) in DMAC (10 mL) was added PYBROP (1.42 g), DIEA (328.10 mg) and compound 4-2 (870.45 mg). The reaction solution was reacted at 100 degrees Celsius for 16 hours, and the reaction solution was concentrated to obtain a residue. The residue was purified by preparative HPLC [column model: Phenomenex Synergi Max-RP 250*50mm*10 μm, mobile phase: water (0.225% formic acid-acetonitrile, gradient: 32%-62%, 20 minutes] to give compound 33-1. LCMS (ESI) m/z: 689.1.(M+1) + . Second step: Compound 33-1 (100 mg) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL) The reaction solution was reacted at 25 degrees Celsius for 1 hour, the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 33-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 589.2(M+1) + . Three steps:
Figure 02_image559
Potassium carbonate (71.08 mg) was added to a mixed solution of compound 33-2 (140 mg) in tetrahydrofuran (4 mL) and water (1 mL), and the pH was adjusted to 8. Compound 1-5 (15.52 mg) was added to the reaction solution. mg). The reaction solution was reacted at 0 degrees Celsius for 15 minutes, and saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, extracted with ethyl acetate (10 mL*2), and the organic phase was washed with saturated brine (5 mL*2). Then, it was dried over anhydrous sodium sulfate and concentrated to obtain compound 33. Compound 33 was separated by preparative SFC (column type: Phenomenex Gemini-NX C18 (75*30mm*3um), mobile phase: water 0.225% formic acid) acetonitrile, gradient: carbon dioxide critical fluid 28%-58%, 7 minutes) to obtain compound 33A and compound 33B. Compound 33A and compound 33B were detected by SFC [Column model: Column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, methanol + acetonitrile (0.05% diethylamine) in phase B; Gradient (B%): 40% methanol + (0.05% diethylamine)] yielded: the retention time of compound 33A was 0.663 min; the retention time of compound 33B was 1.128 min. Compound 33A (retention time = 0.663 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.32 (d, J = 4.9 Hz, 1H), 7.77-7.61 (m, 1H), 7.44-7.30 (m, 3H), 7.16-7.05 (m, 1H), 6.89-6.74 (m, 1H), 6.30-6.10 (m, 1H), 5.89-5.68 (m, 1H), 4.70-4.51 (m, 2H), 4.40- 4.04 (m, 3H), 2.78-2.63 (m, 2H), 2.02-1.94 (m, 3H), 1.43-1.34 (m, 6H), 1.06-0.94 (m, 6H). LCMS (ESI) m/z: 643.2. (M+1) + compound 33B (retention time=1.128 min): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.36-8.25 (m, 1H), 7.75- 7.60 (m, 1H), 7.42-7.30 (m, 3H), 7.13-7.05 (m, 1H), 6.89-6.74 (m, 1H), 6.24-6.14 (m, 1H), 5.79-5.70 (m, 1H) ), 4.73-4.51 (m, 2H), 4.36-3.97 (m, 3H), 2.75-2.67 (m, 2H), 1.99-1.97 (m, 3H), 1.42-1.36 (m, 6H), 1.06-0.95 (m, 6H). LCMS (ESI) m/z: 643.2.(M+1) + .

實施例34

Figure 02_image561
第一步： 向化合物23-10(2克)的二甲基甲醯胺 (20毫升）溶液中加入PYBROP（3.64克），二異丙基乙胺（1.51克），在25攝++氏度攪拌1小時，加入化合物3-1（2.10克）。反應液在100攝氏度下反應12小時，反應液倒入水（50毫升）中，固體過濾，濾餅溶解在乙酸乙酯（100毫升）中，通過柱層析分離純化（洗脫劑：石油醚：乙酸乙酯=5:1 到2:1）得到化合物34-1。LCMS (ESI) m/z: 707.0 (M+1) +。 第二步： 向化合物34-1（3.0克）的二氯甲烷（20毫升）溶液中加入三氟乙酸（10毫升）。反應液在25攝氏度下反應1小時，反應液濃縮得到化合物34-2的三氟乙酸鹽，粗品直接用於下一步。LCMS (ESI) m/z: 607.0 (M+1) +。 第三步： 向化合物34-2（3.0克）的四氫呋喃（20毫升）和水（10毫升）的混合溶液中加入碳酸鉀（1.49克）和化合物1-5（389.46毫克）。反應液在25攝氏度反應30分鐘，用乙酸乙酯（10毫升*2）萃取，有機相用飽和食鹽水（5毫升*2）洗後經無水硫酸鈉乾燥後濃縮得到殘餘物。殘餘物通過製備HPLC(柱型號: Phenomenex luna C18 (250*70mm,10 μm)；流動相：[水(0.225%甲酸)-乙腈]；梯度：30%-60%，20分鐘)純化得到化合物34。得到的產品用製備SFC（柱型號：DAICEL CHIRALPAK AS-H(250mm*30mm,10μm)，流動相：甲醇（0.1%氨水），梯度：二氧化碳臨界流體45%-45%，5分鐘，605分鐘）分離得到34-P1（34C和34D的混合物）和34-P2。 化合物34-P1（34C和34D的混合物）經SFC檢測[柱型號：Column: Chiralpak IC-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為甲醇（0.05%二乙胺）；梯度（B%）：40%-40%]得到：化合物34-P1的保留時間為0.977min。
Figure 02_image563
34-P1（34C和34D的混合物）： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m, 1H), 7.21 (s, 1H), 7.14-7.06 (m, 1H), 6.92-6.72 (m, 1H), 6.28-6.16 (m, 1H), 5.88-5.65 (m, 1H), 4.87-4.42 (m, 2H), 4.19-3.73 (m, 4H), 2.84-2.71 (m, 1H), 2.00-1.91 (m, 3H), 1.38-1.31 (m, 3H), 1.27-1.16 (m, 3H), 1.11-1.04 (m, 3H), 1.03-0.95 (m, 3H)。LCMS (ESI) m/z: 661.1 (M+1) +。 34-P2（保留時間=1.425 min）再通過SFC（柱型號：DAICEL CHIRALPAK AS-H(250mm*30mm,5μm)，流動相：異丙醇（0.1%氨水），梯度：二氧化碳臨界流體5%-40%，3分鐘，510分鐘）分離得到化合物34A（保留時間=1.217min）和化合物34B（保留時間=1.401 min）。 化合物34A和化合物34B經SFC檢測[柱型號：Column: Chiralpak AD-3 50×4.6mm I.D., 3μm；流動相：A相為超臨界二氧化碳，B相為異丙醇（0.05%二乙胺）；梯度（B%）：5%-40%]得到：化合物34A的保留時間為1.217min，ee值為100%；化合物34B的保留時間為1.401min，ee值為93.15%。 化合物34A： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J= 4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m, 1H), 7.21 (s, 1H), 7.14-7.06 (m, 1H), 6.92-6.72 (m, 1H), 6.28-6.16 (m, 1H), 5.88-5.65 (m, 1H), 4.87-4.42 (m, 2H), 4.19-3.73 (m, 4H), 2.84-2.71 (m, 1H), 2.00-1.91 (m, 3H), 1.38-1.31 (m, 3H), 1.27-1.16 (m, 3H), 1.11-1.04 (m, 3H), 1.03-0.95 (m, 3H)。LCMS (ESI) m/z: 661.1 (M+1) +。 化合物34B： 1H NMR (400 MHz, DMSO- d 6 ) δ 8.39-8.29 (m, 1H), 7.95-7.75 (m, 1H), 7.58-7.42 (m, 1H), 7.25-7.20 (m, 1H), 7.14-7.08 (m, 1H), 6.92-6.75 (m, 1H), 6.26-6.15 (m, 1H), 5.86-5.72 (m, 1H), 4.88-4.43 (m, 2H), 4.20-3.98 (m, 1H), 3.94-3.70 (m, 2H), 3.48-3.38 (m, 1H), 2.72-2.59 (m, 1H), 2.07-1.99 (m, 3H), 1.39-1.32 (m, 3H), 1.27-1.17 (m, 3H), 1.06-0.95 (m, 6H)。LCMS (ESI) m/z: 661.1 (M+1) +。 Example 34
Figure 02_image561
Step 1: To a solution of compound 23-10 (2 g) in dimethylformamide (20 mL) was added PYBROP (3.64 g), diisopropylethylamine (1.51 g) at 25°C++ After stirring for 1 hour, compound 3-1 (2.10 g) was added. The reaction solution was reacted at 100 degrees Celsius for 12 hours, the reaction solution was poured into water (50 mL), the solid was filtered, the filter cake was dissolved in ethyl acetate (100 mL), and separated and purified by column chromatography (eluent: petroleum ether). : ethyl acetate=5:1 to 2:1) to obtain compound 34-1. LCMS (ESI) m/z: 707.0 (M+1) + . Second step: To a solution of compound 34-1 (3.0 g) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction solution was concentrated to obtain the trifluoroacetate salt of compound 34-2, and the crude product was directly used in the next step. LCMS (ESI) m/z: 607.0 (M+1) + . Third step: To a mixed solution of compound 34-2 (3.0 g) in tetrahydrofuran (20 ml) and water (10 ml) were added potassium carbonate (1.49 g) and compound 1-5 (389.46 mg). The reaction solution was reacted at 25°C for 30 minutes, extracted with ethyl acetate (10 mL*2), the organic phase was washed with saturated brine (5 mL*2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by preparative HPLC (column type: Phenomenex luna C18 (250*70mm, 10 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: 30%-60%, 20 minutes) to give compound 34 . The obtained product was prepared by preparative SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 10μm), mobile phase: methanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 45%-45%, 5 minutes, 605 minutes) 34-P1 (a mixture of 34C and 34D) and 34-P2 were isolated. Compound 34-P1 (a mixture of 34C and 34D) was detected by SFC [Column model: Column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A and methanol (0.05% bisulfite in phase B) ethylamine); gradient (B%): 40%-40%] yielded: compound 34-P1 with a retention time of 0.977 min.
Figure 02_image563
34-P1 (mixture of 34C and 34D): 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m , 1H), 7.21 (s, 1H), 7.14-7.06 (m, 1H), 6.92-6.72 (m, 1H), 6.28-6.16 (m, 1H), 5.88-5.65 (m, 1H), 4.87-4.42 (m, 2H), 4.19-3.73 (m, 4H), 2.84-2.71 (m, 1H), 2.00-1.91 (m, 3H), 1.38-1.31 (m, 3H), 1.27-1.16 (m, 3H) , 1.11-1.04 (m, 3H), 1.03-0.95 (m, 3H). LCMS (ESI) m/z: 661.1 (M+1) + . 34-P2 (retention time = 1.425 min) was then passed through SFC (column type: DAICEL CHIRALPAK AS-H (250mm*30mm, 5μm), mobile phase: isopropanol (0.1% ammonia water), gradient: carbon dioxide critical fluid 5%- 40%, 3 min, 510 min) to separate compound 34A (retention time = 1.217 min) and compound 34B (retention time = 1.401 min). Compound 34A and compound 34B were detected by SFC [Column model: Column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: supercritical carbon dioxide in phase A, isopropanol (0.05% diethylamine) in phase B; Gradient (B%): 5%-40%] obtained: the retention time of compound 34A was 1.217 min, and the ee value was 100%; the retention time of compound 34B was 1.401 min, and the ee value was 93.15%. Compound 34A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.33 (d, J = 4.9 Hz, 1H), 7.94-7.76 (m, 1H), 7.57-7.42 (m, 1H), 7.21 (s, 1H), 7.14-7.06 (m, 1H), 6.92-6.72 (m, 1H), 6.28-6.16 (m, 1H), 5.88-5.65 (m, 1H), 4.87-4.42 (m, 2H), 4.19- 3.73 (m, 4H), 2.84-2.71 (m, 1H), 2.00-1.91 (m, 3H), 1.38-1.31 (m, 3H), 1.27-1.16 (m, 3H), 1.11-1.04 (m, 3H) ), 1.03-0.95 (m, 3H). LCMS (ESI) m/z: 661.1 (M+1) + . Compound 34B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.39-8.29 (m, 1H), 7.95-7.75 (m, 1H), 7.58-7.42 (m, 1H), 7.25-7.20 (m, 1H) ), 7.14-7.08 (m, 1H), 6.92-6.75 (m, 1H), 6.26-6.15 (m, 1H), 5.86-5.72 (m, 1H), 4.88-4.43 (m, 2H), 4.20-3.98 (m, 1H), 3.94-3.70 (m, 2H), 3.48-3.38 (m, 1H), 2.72-2.59 (m, 1H), 2.07-1.99 (m, 3H), 1.39-1.32 (m, 3H) , 1.27-1.17 (m, 3H), 1.06-0.95 (m, 6H). LCMS (ESI) m/z: 661.1 (M+1) + .

實驗例1：細胞實驗Experimental Example 1: Cell Experiment

實驗目的： 本實驗旨在驗證本申請化合物對KRAS G12C突變的NCI-H358人非小細胞肺癌細胞和KRAS野生型的A375人惡性黑色素瘤細胞的增殖抑制效果。 Purpose: The purpose of this experiment is to verify the proliferation inhibitory effect of the compounds of the present application on KRAS G12C-mutated NCI-H358 human non-small cell lung cancer cells and KRAS wild-type A375 human malignant melanoma cells.

實驗材料： 細胞株NCI-H358（購自中國科學院細胞庫）、細胞株A375（購自中國科學院細胞庫）、DMEM培養基，盤尼西林/鏈黴素抗生素購自維森特，胎牛血清購自Biosera。CellTiter-Glo（細胞活率化學發光檢測試劑）試劑購自Promega。 Experimental Materials: Cell line NCI-H358 (purchased from Cell Bank of Chinese Academy of Sciences), cell line A375 (purchased from Cell Bank of Chinese Academy of Sciences), DMEM medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter-Glo (chemiluminescence detection reagent for cell viability) reagent was purchased from Promega.

實驗方法： 1）             NCI-H358細胞抗增殖實驗： 將NCI-H358細胞種于白色96孔板中，80μL細胞懸液每孔，其中包含4000個NCI-H358細胞。細胞板置於二氧化碳培養箱中過夜培養。將待測化合物用排槍進3倍稀釋至第9個濃度，即從2 mM稀釋至304nM，設置雙複孔實驗。向中間板中加入78 μL培養基，再按照對應位置，轉移2 μL每孔的梯度稀釋化合物至中間板，混勻後轉移20μL每孔到細胞板中。轉移到細胞板中的化合物濃度範圍是10μM至1.52nM。細胞板置於二氧化碳培養箱中培養5天。另準備一塊細胞板，在加藥當天讀取信號值作為最大值（下面方程式中Max值）參與數據分析。向此細胞板每孔加入25 μL細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光信號穩定。採用多標記分析儀讀數。向細胞板中加入每孔25 μL的細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光信號穩定。採用多標記分析儀讀數。 2）             A375細胞抗增殖實驗： 將A375細胞種于白色96孔板中，80μL細胞懸液每孔，其中包含2000個A375細胞。細胞板置於二氧化碳培養箱中過夜培養。將待測化合物用排槍進3倍稀釋至第9個濃度，即從2 mM稀釋至304nM，設置雙複孔實驗。向中間板中加入78 μL培養基，再按照對應位置，轉移2 μL每孔的梯度稀釋化合物至中間板，混勻後轉移20μL每孔到細胞板中。轉移到細胞板中的化合物濃度範圍是10μM至1.52nM。細胞板置於二氧化碳培養箱中培養5天。另準備一塊細胞板，在加藥當天讀取信號值作為最大值（下面方程式中Max值）參與數據分析。向此細胞板每孔加入25 μL細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光信號穩定。採用多標記分析儀讀數。向細胞板中加入每孔25 μL的細胞活率化學發光檢測試劑，室溫孵育10分鐘使發光信號穩定。採用多標記分析儀讀數。 experimental method: 1) Anti-proliferation experiment of NCI-H358 cells: NCI-H358 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 3-fold to the ninth concentration, that is, from 2 mM to 304 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the serially diluted compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 1.52 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read as the maximum value (Max value in the equation below) on the day of drug addition to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. Add 25 μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. 2) Anti-proliferation experiment of A375 cells: A375 cells were seeded in white 96-well plates, 80 μL of cell suspension per well, which contained 2000 A375 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 3-fold to the ninth concentration, that is, from 2 mM to 304 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the serially diluted compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 1.52 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read as the maximum value (Max value in the equation below) on the day of drug addition to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. Add 25 μL of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.

數據分析： 利用方程式(Sample-Min)/(Max-Min)*100%將原始數據換算成抑制率，IC 50的值即可通過四參數進行曲線擬合得出（GraphPad Prism中"log(inhibitor) vs. response -- Variable slope" 模式得出）。 Data analysis: Using the equation (Sample-Min)/(Max-Min)*100% to convert the original data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor" in GraphPad Prism) ) vs. response -- Variable slope" pattern).

實驗結果： 本申請化合物對NCI-H358（G12C突變）細胞和A375（野生型）細胞的抗增殖活性IC 50的數據在表1中展示。 Experimental results: The IC 50 data of the antiproliferative activity of the compounds of the present application on NCI-H358 (G12C mutant) cells and A375 (wild type) cells are shown in Table 1.

實驗結論： 本申請化合物對於KRAS G12C突變型細胞NCI-H358顯示了較高的細胞抗增殖活性，同時對於野生型的A375細胞抗增殖活性較弱，體現了高的選擇性。 表1 細胞實驗結果 受試化合物 NCI-H358 IC 50（nM） A375 IC 50（nM） 1A 1.6 9590 1B 3.2 -- 2A 1.5 ＞10000 2B 4 -- 3A ＜1.5 4561 3B 1.8 -- 4A ＜0.2 -- 4B 0.3 -- 5A 2 -- 5B 3 -- 8A 7.8 -- 9A 1.2 -- 9B 3.6 -- 12B 4 -- 14B 12 -- 15A 15 -- 16A 7.6 -- 16B 21 -- 17A 5.4 -- 18A 10 -- 20A 12 -- 22A 4 ＞10000 26A 10 -- 27A 11 -- 28B 8 -- 29B 5 -- “--”表示尚未檢測。 Experimental conclusion: The compound of the present application shows high anti-proliferative activity on KRAS G12C mutant cells NCI-H358, while it has weak anti-proliferative activity on wild-type A375 cells, showing high selectivity. Table 1 Results of cell experiments test compound NCI-H358 IC50 (nM) A375 IC50 (nM) 1A 1.6 9590 1B 3.2 -- 2A 1.5 >10000 2B 4 -- 3A <1.5 4561 3B 1.8 -- 4A <0.2 -- 4B 0.3 -- 5A 2 -- 5B 3 -- 8A 7.8 -- 9A 1.2 -- 9B 3.6 -- 12B 4 -- 14B 12 -- 15A 15 -- 16A 7.6 -- 16B twenty one -- 17A 5.4 -- 18A 10 -- 20A 12 -- 22A 4 >10000 26A 10 -- 27A 11 -- 28B 8 -- 29B 5 -- "--" means not yet detected.

實驗例2：血漿蛋白結合試驗 實驗目的：採用平衡透析法測定受試化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人血漿中的蛋白結合率。 實驗方法：首先，採用上述五個物種的血漿分別配製受試化合物和對照化合物濃度為2 μM的血漿樣品；其次，將這些血漿樣品放置于培養箱中在37±1°C預孵育4 h；然後，測定緩衝液樣品和透析後的血漿樣品。本實驗採用華法林作為對照化合物。樣品中待測物的濃度用LC-MS/MS法進行測定。 實驗結果：實驗結果見表2。 表2 化合物血漿蛋白結合試驗結果 受試化合物 物種 PPB（血漿蛋白結合比率）/% 化合物22A 人 72.3 食蟹猴 84.0 比格犬 79.7 SD大鼠 81.3 CD-1小鼠 88.6 實驗結論：本申請化合物在五個物種中表現出適中的血漿蛋白結合率。 Experimental Example 2: Plasma Protein Binding Test Experimental Objective: Equilibrium dialysis method was used to determine the protein binding rate of test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human plasma. Experimental method: First, the plasma samples of the test compound and the control compound with a concentration of 2 μM were prepared with the plasma of the above five species; secondly, the plasma samples were placed in an incubator at 37±1°C for pre-incubation for 4 h; Then, buffer samples and dialyzed plasma samples were assayed. Warfarin was used as the control compound in this experiment. The concentration of the analyte in the sample was determined by LC-MS/MS method. Experimental results: The experimental results are shown in Table 2. Table 2 Compound plasma protein binding test results test compound species PPB (plasma protein binding ratio)/% Compound 22A people 72.3 cynomolgus monkey 84.0 Beagles 79.7 SD rat 81.3 CD-1 mice 88.6 Experimental conclusion: The compound of the present application showed moderate plasma protein binding rate in five species.

實驗例3：雄性CD-1小鼠單次靜脈推注與灌胃給予受試化合物的藥代動力學研究 實驗目的： 以雄性CD-1小鼠為試驗動物，評價受試化合物單次靜脈推注和灌胃給藥後的藥代動力學行為，考察灌胃給藥後的生物利用度，為臨床研究提供動物試驗資料。 實驗方案： 試驗動物：雄性CD-1小鼠6只，周齡7-9周，分成2組，IV組3只，PO組3只。動物購買自維通利華實驗動物技術有限公司。 藥物配製：IV 組：溶媒為10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液，用0.22μm濾膜過濾。 PO 組：溶媒為10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液。 給藥：3只靜脈推注給藥組動物給藥前不禁食，3只灌胃給藥組動物在給藥前禁食至少12小時，給藥4小時後恢復供食，禁食時間不超過20小時。試驗當天，IV 組動物通過尾靜脈單次注射給予受試化合物；PO 組通過單次灌胃給予受試化合物， 實驗操作： 雄性CD-1小鼠靜脈推注組分別給與受試化合物後，通過隱靜脈分別0.083，0.25，0.5，1，2，4，8，及24小時採集全血樣品（約0.03 mL）；灌胃給藥組分別給與受試化合物後，分別在0.25，0.5，1，2，4，8，12，及24小時採集全血樣品（約0.03 mL），並記錄實際採血時間。所有血樣立即轉移至貼有標簽的含K2-EDTA的商品化離心管中。血樣採集後，4 °C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 實驗結果：見表3。 表3 雄性CD-1小鼠單次靜脈推注與灌胃給予受試化合物的藥代動力學研究結果 組別 化合物22A IV（3 mg/kg） Cl (mL/Kg/min) 58.2 V d(L/kg) 1.13 AUC (nM·h) 1365 T 1/2(h) 0.35 PO（10 mg/kg） C max(nM) 2570 T max(h) 0.33 AUC (nM·h) 2143 F (%) 47.3 注：Cl：清除率；V d：分佈容積；AUC：暴露量；T 1/2：半衰期；C max：口服給藥後化合物濃度最大值；T max：達到C max的時間；F：生物利用度。 實驗結論：本申請化合物顯示出較高的暴露量和口服生物利用度，具有較好的藥代動力學性質。 Experimental Example 3: Pharmacokinetic study of test compound administered by single intravenous bolus and gavage to male CD-1 mice Experimental purpose: Using male CD-1 mice as the experimental animal, to evaluate the single intravenous bolus of the test compound Pharmacokinetic behavior after injection and intragastric administration, and bioavailability after intragastric administration were investigated to provide animal test data for clinical research. Experimental scheme: Experimental animals: 6 male CD-1 mice, aged 7-9 weeks, were divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd. Drug preparation: IV group: vehicle is 10% DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter. PO group: the solvent was 10%DMSO+30%PEG400+60%Water. An appropriate amount of compound was weighed, the corresponding volume of solvent was added, and a clear solution was obtained by vortexing. Administration: 3 animals in the intravenous bolus administration group did not fast before administration, and 3 animals in the gavage administration group fasted for at least 12 hours before administration, and resumed feeding 4 hours after administration, and the fasting time was not long. more than 20 hours. On the day of the test, the animals in the IV group were given the test compound by a single injection through the tail vein; the PO group was given the test compound by a single gavage. Whole blood samples (about 0.03 mL) were collected through the saphenous vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively; after the test compound was administered to the gavage group, at 0.25, 0.5, Collect whole blood samples (about 0.03 mL) at 1, 2, 4, 8, 12, and 24 hours, and record the actual blood collection time. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge the supernatant plasma at 3200g for 10 minutes at 4 °C, aspirate the supernatant plasma, quickly place in dry ice, and then store at -60 °C or lower for LC-MS/MS analysis. Experimental results: see Table 3. Table 3 Pharmacokinetic study results of single intravenous bolus injection and intragastric administration of test compounds in male CD-1 mice group Compound 22A IV (3 mg/kg) Cl (mL/Kg/min) 58.2 V d (L/kg) 1.13 AUC (nM h) 1365 T 1/2 (h) 0.35 PO (10 mg/kg) Cmax (nM) 2570 Tmax (h) 0.33 AUC (nM h) 2143 F (%) 47.3 Note: Cl: clearance; Vd : volume of distribution; AUC: exposure; T1 /2 : half-life; Cmax : maximum compound concentration after oral administration; Tmax : time to reach Cmax ; F: bioavailability Spend. Experimental conclusion: The compound of the present application shows high exposure and oral bioavailability, and has good pharmacokinetic properties.

實驗例4：雄性SD大鼠單次靜脈推注與灌胃給予受試化合物的藥代動力學研究 實驗目的： 以雄性SD大鼠為試驗動物，評價受試化合物單次靜脈推注和灌胃給藥後的藥代動力學行為，考察灌胃給藥後的生物利用度，為臨床研究提供動物試驗資料。 實驗方案： 試驗動物：雄性SD大鼠6只，周齡7-9周，分成2組，IV組3只，PO組3只。動物購買自維通利華實驗動物技術有限公司 藥物配製：IV 組：溶媒為10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液，用0.22μm濾膜過濾。 PO 組：溶媒為10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液。 給藥：3只靜脈推注給藥組動物給藥前不禁食，3只灌胃給藥組動物在給藥前禁食至少12小時，給藥4小時後恢復供食，禁食時間不超過20小時。試驗當天，IV組動物通過尾靜脈單次注射給予受試化合物；PO組通過單次灌胃給予受試化合物， 實驗操作： 雄性SD大鼠靜脈推注組分別給與受試化合物後，通過隱靜脈分別0.083，0.25，0.5，1，2，4，6，8，及24小時採集全血樣品（約0.2 mL）；灌胃給藥組分別給與受試化合物後，分別在0.25，0.5，1，2，4，6，8，及24小時採集全血樣品（約0.2 mL），並記錄實際採血時間。所有血樣立即轉移至貼有標簽的含K2-EDTA的商品化離心管中。血樣採集後，4°C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 Experimental Example 4: Pharmacokinetic study of test compounds administered by single intravenous bolus injection and gavage to male SD rats Purpose: Male SD rats were used as experimental animals to evaluate the pharmacokinetic behavior of the test compounds after single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration, so as to provide animal test data for clinical research. Experimental program: Experimental animals: 6 male SD rats, aged 7-9 weeks, were divided into 2 groups, 3 in IV group and 3 in PO group. Animals were purchased from Weitong Lihua Laboratory Animal Technology Co., Ltd. Drug preparation: IV group: vehicle is 10% DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter. PO group: the solvent was 10%DMSO+30%PEG400+60%Water. An appropriate amount of compound was weighed, the corresponding volume of solvent was added, and a clear solution was obtained by vortexing. Administration: 3 animals in the intravenous bolus administration group did not fast before administration, and 3 animals in the gavage administration group fasted for at least 12 hours before administration, and resumed feeding 4 hours after administration, and the fasting time was not long. more than 20 hours. On the test day, animals in IV group were given the test compound by a single injection through the tail vein; PO group was given the test compound by a single gavage, Experimental operation: Male SD rats in the intravenous injection group were given the test compounds, and whole blood samples (about 0.2 mL) were collected through the saphenous vein for 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively; After the gastric administration group was administered the test compound, whole blood samples (about 0.2 mL) were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively, and the actual blood collection time was recorded. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200g for 10 minutes at 4°C to aspirate the supernatant plasma, quickly place in dry ice, and then store at -60°C or lower for LC-MS/MS analysis.

實驗例5：雄性食蟹猴單次靜脈注射或灌胃給予受試化合物後的藥代動力學研究 實驗目的： 以雄性食蟹猴為試驗動物，評價單次靜脈注射或灌胃給予受試化合物後雄性食蟹猴的藥代動力學行為。 實驗方案： 試驗動物：靜脈注射採用2只雄性食蟹猴，口服給藥採用雄性食蟹猴3只，年齡2-5年。 藥物配製：靜脈注射溶媒：10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液，用0.22μm濾膜過濾。 口服溶媒：10%DMSO+30%PEG400+60%Water。稱量適量化合物，加入相應體積溶媒，通過攪拌、超聲得到澄清溶液。 實驗操作： 靜脈注射：靜脈注射給與受試化合物後，試驗動物均將在未被麻醉狀態下，通過外周靜脈採集血樣，分別在0.083，0.25，0.5，1，2，4，6，8，及24小時採集全血樣品（約0.5 mL），並記錄實際採血時間。血樣採集後轉移至含K2-EDTA抗凝劑的商品化離心管中，血樣採集後，4°C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 口服：灌胃給藥給與受試化合物後，試驗動物均將在未被麻醉狀態下，通過外周靜脈採集血樣，分別在0.25，0.5，1，2，4，6，8，及24小時採集全血樣品（約0.5 mL），並記錄實際採血時間。血樣採集後轉移至含K2-EDTA抗凝劑的商品化離心管中，血樣採集後，4°C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 Experimental Example 5: Pharmacokinetic study of male cynomolgus monkeys after single intravenous injection or intragastric administration of test compounds Purpose: Male cynomolgus monkeys were used as test animals to evaluate the pharmacokinetic behavior of male cynomolgus monkeys after single intravenous injection or gavage administration of test compounds. Experimental program: Experimental animals: 2 male cynomolgus monkeys were used for intravenous injection, and 3 male cynomolgus monkeys were used for oral administration, aged 2-5 years. Drug preparation: Intravenous injection Vehicle: 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter. Oral vehicle: 10%DMSO+30%PEG400+60%Water. Weigh an appropriate amount of the compound, add the corresponding volume of solvent, and obtain a clear solution by stirring and sonicating. Experimental operation: Intravenous injection: After intravenous administration of the test compound, the experimental animals will be under anesthesia, and blood samples will be collected through peripheral veins at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. Collect a whole blood sample (approximately 0.5 mL) and record the actual blood collection time. Transfer the blood sample to a commercial centrifuge tube containing K2-EDTA anticoagulant after collection. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or Lower temperature for LC-MS/MS analysis. Oral: After the test compound is administered by gavage, the test animals will collect blood samples through peripheral veins without anesthesia at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, respectively. Whole blood sample (approximately 0.5 mL), and record the actual blood collection time. Transfer the blood sample to a commercial centrifuge tube containing K2-EDTA anticoagulant after collection. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or Lower temperature for LC-MS/MS analysis.

實驗例6：比格犬單次靜脈注射或灌胃給予受試化合物後的藥代動力學研究 實驗目的： 以比格犬為試驗動物評價單次靜脈注射或灌胃給予受試化合物後雄性比格犬的藥代動力學行為。 試驗動物：靜脈注射採用2只雄性比格犬，口服給藥採用3只雄性比格犬。 溶媒： 靜脈注射溶媒：10%DMSO+30%PEG400+60%水。稱量適量化合物，加入相應體積溶媒，渦旋得到澄清溶液，用0.22μm濾膜過濾。 口服溶媒：10%DMSO+30%PEG400+60%水。稱量適量化合物，加入相應體積溶媒，通過攪拌、超聲得到澄清溶液。 實驗方案： 靜脈注射：靜脈注射給與受試化合物後，通過外周靜脈採集血樣，分別在0.083，0.25，0.5，1，2，4，8，及24小時採集全血樣品，並記錄實際採血時間。血樣採集後轉移至含K2-EDTA抗凝劑的商品化離心管中，血樣採集後，4°C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 口服：灌胃給藥給與受試化合物後，試驗動物均將在未被麻醉狀態下，通過外周靜脈採集血樣，分別在0.083，0.25，0.5，1，2，4，8，及24小時採集全血樣品，並記錄實際採血時間。血樣採集後轉移至含K2-EDTA抗凝劑的商品化離心管中，血樣採集後，4°C，3200g離心10分鐘吸取上清血漿，迅速置於乾冰中，然後保存在-60°C或更低溫度，用於LC-MS/MS分析。 Experimental Example 6: Pharmacokinetic study after single intravenous injection or intragastric administration of test compounds in beagle dogs Purpose: The pharmacokinetic behavior of male Beagle dogs after a single intravenous injection or intragastric administration of test compounds was evaluated by using Beagle dogs as experimental animals. Experimental animals: 2 male Beagle dogs were used for intravenous injection, and 3 male Beagle dogs were used for oral administration. Solvent: Vehicle for intravenous injection: 10% DMSO + 30% PEG400 + 60% water. Weigh an appropriate amount of compound, add the corresponding volume of solvent, and vortex to obtain a clear solution, which is filtered through a 0.22 μm filter. Oral vehicle: 10% DMSO + 30% PEG400 + 60% water. Weigh an appropriate amount of the compound, add the corresponding volume of solvent, and obtain a clear solution by stirring and sonicating. Experimental program: Intravenous injection: After intravenous administration of the test compound, blood samples were collected from peripheral veins, and whole blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and the actual blood collection time was recorded. Transfer the blood sample to a commercial centrifuge tube containing K2-EDTA anticoagulant after collection. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or Lower temperature for LC-MS/MS analysis. Oral: After the test compound is administered by gavage, the test animals will collect blood samples through peripheral veins without anesthesia at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, respectively. Whole blood samples were taken, and the actual blood collection time was recorded. Transfer the blood sample to a commercial centrifuge tube containing K2-EDTA anticoagulant after collection. After the blood sample is collected, centrifuge at 3200g for 10 minutes at 4°C to absorb the supernatant plasma, quickly place it in dry ice, and then store it at -60°C or Lower temperature for LC-MS/MS analysis.

實驗例7：體內藥效試驗（一） 實驗目的： 評價受試化合物在人非小細胞肺癌NCI-H358皮下異體移植腫瘤模型上的體內藥效。 實驗操作： BALB/c裸小鼠，雌性，6-8周齡，體重18-23克。共需48只。由上海市計劃生育科學研究所實驗動物經營部提供。將NCI-H358腫瘤細胞重懸於PBS中，製備成0.2 mL（1×10 7個）的細胞懸液，皮下接種於每只小鼠的右後背（1×10 7/只）等待腫瘤生長。在腫瘤平均體積達到約100-150 mm 3時開始進行隨機分組給藥，每組8只動物，口服灌胃給藥頻率為一天一次，給藥劑量如表4所示。每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。化合物的抑瘤療效用TGI(%)評價。TGI(%)，反映腫瘤生長抑制率。TGI(%)的計算：TGI(%)=[(1-（某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積)/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)]×100%。 實驗結果：見表4。 實驗結論：本申請化合物在人非小細胞肺癌NCI-H358皮下異體移植腫瘤模型中展示出顯著的抑瘤效果。 表4 非小細胞肺癌NCI-H358皮下異體移植腫瘤模型試驗結果 組別 腫瘤體積 (mm 3)（第27天） TGI (%) 溶媒對照組 733 -- 化合物22A 5 mg/kg (0-27天) 67 108 化合物22A 15 mg/kg (0-27天) 52 110 Experimental Example 7: In vivo efficacy test (1) Experimental purpose: To evaluate the in vivo efficacy of the test compound on the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358. Experimental operation: BALB/c nude mice, female, 6-8 weeks old, weighing 18-23 grams. A total of 48 are required. Provided by the Laboratory Animal Management Department of Shanghai Institute of Family Planning. The NCI-H358 tumor cells were resuspended in PBS, prepared into 0.2 mL (1×10 7 cells) of cell suspension, and subcutaneously inoculated into the right back of each mouse (1×10 7 /mice) to wait for tumor growth. When the average tumor volume reached about 100-150 mm 3 , random group administration was started, with 8 animals in each group, and the frequency of oral gavage administration was once a day, and the administration doses were shown in Table 4. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group -The average tumor volume of the solvent control group at the beginning of treatment)] × 100%. Experimental results: see Table 4. Experimental conclusion: the compounds of the present application show significant tumor inhibition in the human non-small cell lung cancer NCI-H358 subcutaneous xenograft tumor model Table 4. Test results of NCI-H358 subcutaneous xenograft tumor model for non-small cell lung cancer group Tumor volume (mm 3 ) (day 27) TGI (%) vehicle control group 733 -- Compound 22A 5 mg/kg (Day 0-27) 67 108 Compound 22A 15 mg/kg (Day 0-27) 52 110

實驗例8：體內藥效試驗（二） 實驗目的： 評價受試化合物在人結腸癌CO-04-0070皮下異體移植腫瘤模型上的體內藥效。 實驗操作： BALB/c裸小鼠，雌性，6-8周齡，體重18-20克。共需48只。由上海靈暢生物科技有限公司提供。將 20~30 mm 3的CO-04-0070 FP4腫瘤組織塊皮下接種於的每只小鼠的右後背等待腫瘤生長，腫瘤平均體積達到約153 mm 3時開始進行隨機分組給藥，每組8只動物，口服給藥頻率為一天一次，給藥劑量如表5所示。每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。化合物的抑瘤療效用TGI(%)評價。TGI(%)，反映腫瘤生長抑制率。TGI(%)的計算：TGI(%)=[(1-（某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積)/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)]×100%。 實驗結果：見表5。 實驗結論：本申請化合物在人結腸癌CO-04-0070皮下異體移植腫瘤模型中展示出顯著的抑瘤效果，且量效關係明確。 表5 人結腸癌CO-04-0070皮下異體移植腫瘤模型試驗結果 組別 腫瘤體積 (mm 3)（第20天） TGI (%) 溶媒對照組 1606 -- 化合物22A 15 mg/kg (0-21天) 166 99.10 化合物22A 45 mg/kg (0-21天) 50 107.10 Experimental Example 8: In vivo efficacy test (2) Experimental purpose: To evaluate the in vivo efficacy of the test compound on the human colon cancer CO-04-0070 subcutaneous xenograft tumor model. Experimental operation: BALB/c nude mice, female, 6-8 weeks old, weighing 18-20 grams. A total of 48 are required. Provided by Shanghai Lingchang Biotechnology Co., Ltd. 20~30 mm 3 of CO-04-0070 FP4 tumor tissue was subcutaneously inoculated into the right back of each mouse to wait for tumor growth. When the average tumor volume reached about 153 mm 3 , randomization was started, with 8 in each group. The animals were administered orally once a day at the doses shown in Table 5. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group -The average tumor volume of the solvent control group at the beginning of treatment)] × 100%. Experimental results: see Table 5. Experimental conclusion: the compounds of the present application show significant tumor inhibition in the human colon cancer CO-04-0070 subcutaneous xenograft tumor model Table 5 Test results of human colon cancer CO-04-0070 subcutaneous xenograft tumor model group Tumor volume (mm 3 ) (day 20) TGI (%) vehicle control group 1606 -- Compound 22A 15 mg/kg (Day 0-21) 166 99.10 Compound 22A 45 mg/kg (Day 0-21) 50 107.10

實驗例9：體內藥效試驗（三） 實驗目的： 評價受試化合物在人胰腺癌MIAPACA2細胞BALB/c 裸小鼠皮下異體移植腫瘤模型上的體內藥效。 實驗操作： BALB/c裸小鼠，雌性，7-8周齡。共需48只。由上海市計劃生育科學研究所實驗動物經營部提供。在小鼠腋下接種MIAPACA2細胞，接種量為5×10 6/0.2mL，腫瘤平均體積達到約125 mm 3時開始進行隨機分組給藥，每組8只動物，口服灌胃給藥頻率為一天一次，給藥劑量如表6所示。每週兩次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為：V = 0.5a × b 2，a和b分別表示腫瘤的長徑和短徑。化合物的抑瘤療效用TGI(%)評價。TGI(%)，反映腫瘤生長抑制率。TGI(%)的計算：TGI(%)=[(1-（某處理組給藥結束時平均瘤體積－該處理組開始給藥時平均瘤體積)/(溶劑對照組治療結束時平均瘤體積－溶劑對照組開始治療時平均瘤體積)]×100%。 實驗結果：見表6。 實驗結論： 本申請化合物在人胰腺癌MIAPACA2皮下異體移植腫瘤模型中展示出顯著的抑瘤效果，且量效關係明確。 表6 人胰腺癌MIAPACA2皮下異體移植腫瘤模型試驗結果 組別 腫瘤體積 (mm 3)（第22天） TGI (%) 溶媒對照組 1743 -- 化合物22A 3 mg/kg (0-22天) 353 85.9 化合物22A 10 mg/kg (0-22天) 159 97.9 Experimental Example 9: In vivo efficacy test (3) Experimental purpose: To evaluate the in vivo efficacy of the test compound on the human pancreatic cancer MIAPACA2 cell BALB/c nude mouse subcutaneous xenograft tumor model. Experimental operation: BALB/c nude mice, female, 7-8 weeks old. A total of 48 are required. Provided by the Laboratory Animal Management Department of Shanghai Institute of Family Planning. MIAPACA2 cells were inoculated in the armpits of mice at an inoculation volume of 5×10 6 /0.2 mL. When the average tumor volume reached about 125 mm 3 , random group administration began, with 8 animals in each group, and the frequency of oral gavage was one day. Once, the doses administered are shown in Table 6. Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%), reflecting tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group -The average tumor volume of the solvent control group at the beginning of treatment)] × 100%. Experimental results: see Table 6. Experimental conclusion: The compound of the present application showed a significant tumor-inhibiting effect in the human pancreatic cancer MIAPACA2 subcutaneous xenograft tumor model, and the amount of Table 6 Test results of human pancreatic cancer MIAPACA2 subcutaneous xenograft tumor model group Tumor volume (mm 3 ) (day 22) TGI (%) vehicle control group 1743 -- Compound 22A 3 mg/kg (Day 0-22) 353 85.9 Compound 22A 10 mg/kg (Day 0-22) 159 97.9

無none

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Claims (19)

一種式（I）化合物或其藥學上可接受的鹽，
Figure 03_image001
其中， X選自CR 13和N； Q和Y分別獨立地選自CH和N； R 1選自H、F、Cl、Br、I、C 1-3烷基，所述C 1-3烷基任選被1、2或3個鹵素取代； R 2、R 3、R 4、R 5和R 6分別獨立地選自H、F、Cl、Br、I、OH、C 1-3烷基、NH 2和-NH-C 1-3烷基，所述C 1-3烷基任選被1、2或3個鹵素取代； R 7、R 8、R 9和R 10分別獨立地選自H和CH 3； R 11選自H和F； R 12和R 13分別獨立地選自H、C 1-6烷基、環丙基和C 1-3烷氧基。 A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure 03_image001
Wherein, X is selected from CR 13 and N; Q and Y are independently selected from CH and N; R 1 is selected from H, F, Cl, Br, I, C 1-3 alkyl, the C 1-3 alkane The group is optionally substituted with 1, 2 or 3 halogens; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, C 1-3 alkyl , NH 2 and -NH-C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 halogens; R 7 , R 8 , R 9 and R 10 are each independently selected from H and CH 3 ; R 11 is selected from H and F; R 12 and R 13 are each independently selected from H, C 1-6 alkyl, cyclopropyl and C 1-3 alkoxy. 根據請求項1所述的化合物或其藥學上可接受的鹽，其中，化合物選自
Figure 03_image074
， 其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12和R 13如請求項1所定義。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
Figure 03_image074
, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are as defined in claim 1. 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，R 1選自H、F、Cl、Br、I、CH 3，所述CH 3任選被1、2或3個鹵素取代。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, Cl, Br, I, CH 3 , and said CH 3 is optionally replaced by 1, 2 or 3 halogen substituted. 根據請求項3所述的化合物或其藥學上可接受的鹽，其中，R 1選自H、F和CF 3。 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F and CF 3 . 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，R 2、R 3、R 4、R 5和R 6分別獨立地選自H、F、Cl、Br、I、OH、CF 3、CH 3、NH 2和-NHCH 3。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from H, F, Cl, Br, I, OH, CF3 , CH3 , NH2 and -NHCH3 . 根據請求項5所述的化合物或其藥學上可接受的鹽，其中，R 2選自H、F、NH 2和-NHCH 3。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, F, NH 2 and -NHCH 3 . 根據請求項5所述的化合物或其藥學上可接受的鹽，其中，R 3選自H、F和Cl。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F and Cl. 根據請求項5所述的化合物或其藥學上可接受的鹽，其中，R 4選自H和F。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H and F. 根據請求項5所述的化合物或其藥學上可接受的鹽，其中，R 5選自H、F、Cl和CH 3。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, F, Cl and CH 3 . 根據請求項5所述的化合物或其藥學上可接受的鹽，其中，R 6選自H、F和CF 3。 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, F and CF 3 . 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，R 12選自
Figure 03_image005
。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from
Figure 03_image005
. 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，R 13選自CH 3和OCH 3。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from CH 3 and OCH 3 . 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image007
選自
Figure 03_image009
、
Figure 03_image011
、
Figure 03_image013
、
Figure 03_image015
和
Figure 03_image017
。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure 03_image007
selected from
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
and
Figure 03_image017
. 根據請求項1或2所述的化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image021
選自
Figure 03_image023
、
Figure 03_image025
、
Figure 03_image027
、
Figure 03_image029
、
Figure 03_image031
、
Figure 03_image033
、
Figure 03_image035
、
Figure 03_image037
、
Figure 03_image039
、
Figure 03_image041
、
Figure 03_image043
、
Figure 03_image045
、
Figure 03_image047
、
Figure 03_image049
、
Figure 03_image051
、
Figure 03_image053
、
Figure 03_image055
、
Figure 03_image057
、
Figure 03_image059
、
Figure 03_image061
和
Figure 03_image063
。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure 03_image021
selected from
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
,
Figure 03_image031
,
Figure 03_image033
,
Figure 03_image035
,
Figure 03_image037
,
Figure 03_image039
,
Figure 03_image041
,
Figure 03_image043
,
Figure 03_image045
,
Figure 03_image047
,
Figure 03_image049
,
Figure 03_image051
,
Figure 03_image053
,
Figure 03_image055
,
Figure 03_image057
,
Figure 03_image059
,
Figure 03_image061
and
Figure 03_image063
. 根據請求項1所述的化合物或其藥學上可接受的鹽，其中，結構單元
Figure 03_image067
選自
Figure 03_image069
、
Figure 03_image071
。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure 03_image067
selected from
Figure 03_image069
,
Figure 03_image071
. 一種化合物或其藥學上可接受的鹽，其選自
Figure 03_image124
、
Figure 03_image126
、
Figure 03_image128
、
Figure 03_image130
、
Figure 03_image132
、
Figure 03_image134
、
Figure 03_image136
、
Figure 03_image138
、
Figure 03_image140
、
Figure 03_image142
、
Figure 03_image144
、
Figure 03_image146
、
Figure 03_image148
、
Figure 03_image150
、
Figure 03_image152
、
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
和
Figure 03_image190
。 A compound or a pharmaceutically acceptable salt thereof selected from
Figure 03_image124
,
Figure 03_image126
,
Figure 03_image128
,
Figure 03_image130
,
Figure 03_image132
,
Figure 03_image134
,
Figure 03_image136
,
Figure 03_image138
,
Figure 03_image140
,
Figure 03_image142
,
Figure 03_image144
,
Figure 03_image146
,
Figure 03_image148
,
Figure 03_image150
,
Figure 03_image152
,
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
and
Figure 03_image190
. 根據請求項16所述的化合物或其藥學上可接受的鹽，其選自
Figure 03_image192
、
Figure 03_image194
、
Figure 03_image196
、
Figure 03_image198
、
Figure 03_image200
、
Figure 03_image202
、
Figure 03_image204
、
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_image224
、
Figure 03_image226
、
Figure 03_image228
、
Figure 03_image230
、
Figure 03_image232
、
Figure 03_image234
、
Figure 03_image236
、
Figure 03_image238
、
Figure 03_image240
、
Figure 03_image242
、
Figure 03_image244
、
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_image266
、
Figure 03_image268
、
Figure 03_image270
、
Figure 03_image272
、
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_image298
、
Figure 03_image300
、
Figure 03_image302
、
Figure 03_image304
、
Figure 03_image306
、
Figure 03_image308
、
Figure 03_image310
、
Figure 03_image312
、
Figure 03_image314
、
Figure 03_image316
、
Figure 03_image318
、
Figure 03_image320
、
Figure 03_image322
、
Figure 03_image324
、
Figure 03_image326
、
Figure 03_image328
、
Figure 03_image330
、
Figure 03_image332
、
Figure 03_image334
、
Figure 03_image336
、
Figure 03_image338
、
Figure 03_image340
、
Figure 03_image342
、
Figure 03_image344
、
Figure 03_image346
、
Figure 03_image348
、
Figure 03_image350
、
Figure 03_image352
、
Figure 03_image354
、
Figure 03_image356
、
Figure 03_image358
、
Figure 03_image360
、
Figure 03_image362
、
Figure 03_image364
、
Figure 03_image366
、
Figure 03_image368
、
Figure 03_image370
、
Figure 03_image372
、
Figure 03_image374
、
Figure 03_image376
、
Figure 03_image378
、
Figure 03_image380
、
Figure 03_image382
、
Figure 03_image384
、
Figure 03_image386
、
Figure 03_image388
、
Figure 03_image390
、
Figure 03_image392
和
Figure 03_image394
。 The compound according to claim 16 or a pharmaceutically acceptable salt thereof, which is selected from
Figure 03_image192
,
Figure 03_image194
,
Figure 03_image196
,
Figure 03_image198
,
Figure 03_image200
,
Figure 03_image202
,
Figure 03_image204
,
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_image224
,
Figure 03_image226
,
Figure 03_image228
,
Figure 03_image230
,
Figure 03_image232
,
Figure 03_image234
,
Figure 03_image236
,
Figure 03_image238
,
Figure 03_image240
,
Figure 03_image242
,
Figure 03_image244
,
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_image266
,
Figure 03_image268
,
Figure 03_image270
,
Figure 03_image272
,
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_image298
,
Figure 03_image300
,
Figure 03_image302
,
Figure 03_image304
,
Figure 03_image306
,
Figure 03_image308
,
Figure 03_image310
,
Figure 03_image312
,
Figure 03_image314
,
Figure 03_image316
,
Figure 03_image318
,
Figure 03_image320
,
Figure 03_image322
,
Figure 03_image324
,
Figure 03_image326
,
Figure 03_image328
,
Figure 03_image330
,
Figure 03_image332
,
Figure 03_image334
,
Figure 03_image336
,
Figure 03_image338
,
Figure 03_image340
,
Figure 03_image342
,
Figure 03_image344
,
Figure 03_image346
,
Figure 03_image348
,
Figure 03_image350
,
Figure 03_image352
,
Figure 03_image354
,
Figure 03_image356
,
Figure 03_image358
,
Figure 03_image360
,
Figure 03_image362
,
Figure 03_image364
,
Figure 03_image366
,
Figure 03_image368
,
Figure 03_image370
,
Figure 03_image372
,
Figure 03_image374
,
Figure 03_image376
,
Figure 03_image378
,
Figure 03_image380
,
Figure 03_image382
,
Figure 03_image384
,
Figure 03_image386
,
Figure 03_image388
,
Figure 03_image390
,
Figure 03_image392
and
Figure 03_image394
. 根據請求項1~16任意一項所述的化合物或其藥學上可接受的鹽在製備KRAS G12C突變蛋白抑制劑的應用。Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a KRAS G12C mutein inhibitor. 根據請求項1~16任意一項所述的化合物或其藥學上可接受的鹽在製備治療非小細胞肺癌藥物中的應用。Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.
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