TW202210488A - Pyrazine derivative and applications in SHP2 inhibition thereof capable of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions. - Google Patents

Pyrazine derivative and applications in SHP2 inhibition thereof capable of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions. Download PDF

Info

Publication number
TW202210488A
TW202210488A TW110132447A TW110132447A TW202210488A TW 202210488 A TW202210488 A TW 202210488A TW 110132447 A TW110132447 A TW 110132447A TW 110132447 A TW110132447 A TW 110132447A TW 202210488 A TW202210488 A TW 202210488A
Authority
TW
Taiwan
Prior art keywords
membered
alkyl
group
mmol
compound
Prior art date
Application number
TW110132447A
Other languages
Chinese (zh)
Inventor
孫海豐
李家鵬
張貴平
王奎鋒
Original Assignee
大陸商勤浩醫藥(蘇州)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大陸商勤浩醫藥(蘇州)有限公司 filed Critical 大陸商勤浩醫藥(蘇州)有限公司
Publication of TW202210488A publication Critical patent/TW202210488A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to a pyrazine derivative and applications of SHP2 inhibition thereof, a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic labelling material thereof, the structure of the compound of formula (I) is as follows. The pyrazine derivative provided by the present invention having an excellent SHP2 inhibitory activity, and can be used for preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

Description

吡嗪類衍生物及其在抑制SHP2中的應用Pyrazine derivatives and their application in inhibiting SHP2

本發明屬於醫藥領域，涉及一種吡嗪類衍生物、其製備方法及其在醫藥中的應用，具體涉及一種吡嗪類衍生物及其作為蛋白酪胺酸磷酸酶2（SHP2）抑制劑在預防和/或治療蛋白酪胺酸磷酸酶2（SHP2）活性異常相關疾病中的用途。The invention belongs to the field of medicine, and relates to a pyrazine derivative, a preparation method thereof and its application in medicine, in particular to a pyrazine derivative and its use as a protein tyrosine phosphatase 2 (SHP2) inhibitor in the prevention and treatment of And/or use in the treatment of diseases related to abnormal protein tyrosine phosphatase 2 (SHP2) activity.

SHP2是PTPN11編碼的非受體蛋白酪胺酸磷酸酶，由2個N端SH2結構域、1個蛋白磷酸酶結構域組成。SHP2蛋白主要定位於細胞質中，基礎狀態下為自抑制構象，N端SH2結構域與磷酸酶結構域相互作用，隱藏其催化位點；接收上游信號後激活為活化構象，暴露出催化位點，發揮磷酸酶功能。SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11, consisting of two N-terminal SH2 domains and one protein phosphatase domain. The SHP2 protein is mainly localized in the cytoplasm and is in an auto-inhibitory conformation in the basal state. The N-terminal SH2 domain interacts with the phosphatase domain to hide its catalytic site. After receiving upstream signals, it is activated to an activated conformation, exposing the catalytic site. function as a phosphatase.

SHP2是連接細胞內多個重要致癌信號途徑的關鍵節點，如JAK/STAT、PI3K/AKT、RAS/RAF/MAPK、PD-1/PD-L1等。SHP2蛋白突變或過表達與多種疾病和腫瘤相關。SHP2 is a key node connecting multiple important oncogenic signaling pathways in cells, such as JAK/STAT, PI3K/AKT, RAS/RAF/MAPK, PD-1/PD-L1, etc. Mutation or overexpression of SHP2 protein is associated with various diseases and tumors.

SHP2突變主要發生在努南症候群（50%）、豹症候群（80%）、單核細胞白血病（35%）、骨髓增生異常症候群（10%）、B細胞急性淋巴細胞白血病（7%）、急性髓性白血病（4%）等；在實體瘤如肺癌、直結腸癌、黑色素瘤、肝癌、乳腺癌等也發現了SHP2的突變；異常活化的生長因子、細胞因子等需要通過SHP2將信號傳導，野生型的SHP2活性在很多類型的腫瘤中也至關重要；SHP2還處於PD-1、BTLA等免疫檢查點下游，對腫瘤微環境中的巨噬細胞功能也有一定影響，參與到腫瘤免疫逃逸的機制中，在腫瘤免疫方向也有重要的功能。SHP2 mutations mainly occur in Noonan syndrome (50%), Leopard syndrome (80%), monocytic leukemia (35%), myelodysplastic syndrome (10%), B-cell acute lymphoblastic leukemia (7%), acute Myeloid leukemia (4%), etc.; SHP2 mutations have also been found in solid tumors such as lung cancer, colorectal cancer, melanoma, liver cancer, breast cancer, etc. Abnormally activated growth factors, cytokines, etc. require signal transduction through SHP2, Wild-type SHP2 activity is also crucial in many types of tumors; SHP2 is also downstream of immune checkpoints such as PD-1 and BTLA, and has a certain impact on the function of macrophages in the tumor microenvironment, and is involved in tumor immune escape. In the mechanism, it also has important functions in the direction of tumor immunity.

由於SHP2在腫瘤中的重要作用，對SHP2催化位點抑制劑的研究已經有數十年，但是SHP2的磷酸酶域高度保守且為正電，一直未有藥物推進至臨床階段。Due to the important role of SHP2 in tumors, the research on inhibitors of the catalytic site of SHP2 has been carried out for decades, but the phosphatase domain of SHP2 is highly conserved and positively charged, and no drugs have been advanced to the clinical stage.

發明要解決的問題：至今尚未有任何一個關於蛋白酪胺酸磷酸酶的藥物上市，且現有技術中的化合物抑制SHP2的活性較差（如WO2016/203406A1）。本發明的目的在於提供一種吡嗪類衍生物，此類化合物具有優異的SHP2抑制活性，能夠用於預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症。The problem to be solved by the invention: so far, there has not been any drug related to protein tyrosine phosphatase on the market, and the compounds in the prior art have poor activity in inhibiting SHP2 (eg WO2016/203406A1). The object of the present invention is to provide pyrazine derivatives, which have excellent SHP2 inhibitory activity and can be used for the prevention and/or treatment of non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

用於解決問題的方案：為了解決上述技術問題，本發明提供了一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，所述式（Ⅰ）化合物的結構為：

Figure 02_image001
， 其中： R1 和R2 各自相同或不同，其各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基；或R1 和R2 形成3-8元環烷基、環烯基或雜環基，任選的，所述3-8元環烷基、環烯基或雜環基被選自由-OH、-NH2 、-CN、NO2 、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、C3 -C12 環烷基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； X選自化學鍵、-NH-、-CONH-；
Figure 02_image005
選自C6 -C10 芳基、5-10元雜芳基、C4 -C12 環烷基、3-12元雜環基、C6 -C14 橋環基或者螺環基、C6 -C14 橋雜環基或者螺雜環基；其中所述5-10元雜芳基、3-12元雜環基、C6 -C14 橋雜環基或者螺雜環基含有1-3個任選自N、NH、O、S、C(O)、S(O) 的雜原子或基團； 每一個R3 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：C1 -C10 烷基、C1 -C10 烷胺基、-C1 -C10 烷基醯胺、C1 -C10 烷氧基、-NH2 、C3 -C12 環烷基、3-12元雜環基、C6 -C10 芳基或5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CONH2 、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基、C6 -C10 芳基或3-12元雜環基中的一個或多個取代基所取代；或任意相鄰的兩個R3 形成3-6元飽和或者不飽和的環，任選的，所述3-6元飽和或者不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C3 -C12 環烷胺基、C1 -C10 烷基胺基、C3 -C12 環烷基、鹵代C1 -C10 烷基胺基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； R4 、R5 、R6 、R7 、R8 、R9 、R10 、R11 各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基或C6 -C10 芳基中的一個或多個取代基所取代； m為0、1、2、3或4； n為0、1或2。Solution for solving the problem: In order to solve the above technical problem, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, said The structure of the compound of formula (I) is:
Figure 02_image001
, wherein: R 1 and R 2 are each the same or different, each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups : -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyloxy , 3-12 membered heterocyclyl, C6 - C10 aryl, 5-10 membered heteroaryl; or R 1 and R 2 form a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl, optionally , the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group is selected from -OH, -NH 2 , -CN, NO 2 , halogen atom, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl and 5-10 membered heteroaryl substituted by any 1-3 in the group; X is selected from chemical bonds, -NH-, -CONH-;
Figure 02_image005
Selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 4 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 14 bridged cyclyl or spirocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl contains 1-3 a heteroatom or group optionally selected from N, NH, O, S, C(O), S(O); each R is the same or different, independently selected from H, D, halogen atoms, - CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups: C 1 -C 10 alkyl, C 1 -C 10 alkylamino, -C 1 -C 10 alkyl amide Amine, C 1 -C 10 alkoxy, -NH 2 , C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 10 membered aryl or 5-10 membered heteroaryl, said The substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, halogen atom, -NH 2 , -CN, -COOH, -CONH 2 , -CHO, -OH, -NO 2 , hydroxy-C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, 5-10 membered heteroaryl, C 6 -C 10 aryl Or substituted by one or more substituents in the 3-12-membered heterocyclic group; or any adjacent two R 3 form a 3-6-membered saturated or unsaturated ring, optionally, the 3-6-membered ring The saturated or unsaturated ring is selected from -OH, -NH 2 , -CN, halogen atom, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkylamino, C 1 -C 10 alkylamine group, C 3 -C 12 cycloalkyl group, halogenated C 1 -C 10 alkylamine group, C 6 -C 10 aryl group and 5-10 membered heteroaryl group Any 1-3 substituted; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are each independently selected from H, D, halogen atom, -CN, -COOH, -CHO , -OH, -NO 2 , substituted or unsubstituted following groups: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 - C 12 cycloalkyl, C 3 -C 12 cycloalkyloxy, 3-12 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, the substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH 2 , -CN, -COOH, -CHO, -OH, -NO 2 , hydroxyl -C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C Substituted by one or more substituents in 1 -C 10 alkylamino group, 5-10-membered heteroaryl group or C 6 -C 10 aryl group; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2.

本發明還提供了一種藥物組合物，其包含上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物。The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label.

本發明還提供了一種藥物製劑，其包括上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物或者上述的藥物組合物，所述製劑為片劑、膠囊劑、注射劑、顆粒劑、粉劑、栓劑、丸劑、乳膏劑、糊劑、凝膠劑、散劑、口服溶液、吸入劑、混懸劑、乾懸劑、貼劑、洗劑中的任一種。The present invention also provides a pharmaceutical preparation, which comprises any one of the above-mentioned compounds of formula (I) or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels or the above-mentioned compounds Pharmaceutical compositions, the preparations are tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions , patch or lotion.

本發明還提供了上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者上述的藥物組合物，或上述的藥物製劑，其用作預防和治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症。The present invention also provides a compound of formula (I) described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or the above-mentioned pharmaceutical composition, or The above-mentioned pharmaceutical preparation for use in the prevention and treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions.

本發明還提供了上述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者上述的藥物組合物，或者上述的藥物製劑用作預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的用途。The present invention also provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation Use for the prevention and/or treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions.

上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者上述的藥物組合物，或者上述的藥物製劑在製備預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的藥物中的應用。One of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation in Use in the preparation of a medicament for preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

本發明還提供了一種預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的方法，其包括下列步驟：將治療有效量的上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者上述的藥物組合物，或者上述的藥物製劑施用於對其有需求的患者。The present invention also provides a method for preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions, comprising the steps of: adding a therapeutically effective amount of any one of the above-mentioned formulas ( I) A compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above is administered to a patient in need thereof.

本發明還提供了一種醫藥品，其包含至少一種額外的治療劑，以及上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者上述的藥物組合物，或者上述的藥物製劑。The present invention also provides a pharmaceutical product comprising at least one additional therapeutic agent, and a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, pro- A drug or isotopic label, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation.

發明的效果：本發明所提供的吡嗪類衍生物，具有優異的抑制SHP2的活性，例如相比於現有技術中的SHP2抑制劑（如WO2016/203406A1的表9中的化合物96）具有明顯更優的抑制SHP2的活性。本發明所述的吡嗪類衍生物，能夠用於預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症。Effect of the invention: The pyrazine derivatives provided by the present invention have excellent activity of inhibiting SHP2, for example, compared with the SHP2 inhibitors in the prior art (such as compound 96 in Table 9 of WO2016/203406A1), it has significantly higher activity. Excellent inhibition of SHP2 activity. The pyrazine derivatives of the present invention can be used to prevent and/or treat diseases or conditions that are not mediated or dependent on receptor protein tyrosine phosphatase.

首先，本發明提供了一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，所述式（Ⅰ）化合物的結構為：

Figure 02_image007
其中： R1 和R2 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基；或R1 和R2 形成3-8元環烷基、環烯基或雜環基，任選的，所述3-8元環烷基、環烯基或雜環基被選自由-OH、-NH2 、-CN、-NO2 、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、C3 -C12 環烷基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； X選自化學鍵、-NH-、-CONH-；
Figure 02_image005
選自C6 -C10 芳基、5-10元雜芳基、C4 -C12 環烷基、3-12元雜環基、C6 -C14 橋環基或者螺環基、C6 -C14 橋雜環基或者螺雜環基；其中所述5-10元雜芳基、3-12元雜環基、C6 -C14 橋環基或者螺環基含有1-3個任選自N、NH、O、S、C(O)、S(O)的雜原子或基團； 每一個R3 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、胺基醯基、取代或未取代的下列基團：C1 -C10 烷基、C1 -C10 烷胺基、-C1 -C10 烷基醯胺、C1 -C10 烷氧基、-NH2 、C3 -C12 環烷基、3-12元雜環基、C6 -C10 芳基或5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CONH2 、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基或C6 -C10 芳基中的一個或多個取代基所取代；或任意相鄰的兩個R3 形成3-6元飽和或者不飽和的環，任選的，所述3-6元飽和或者不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C3 -C12 環烷胺基、C1 -C10 烷胺基、C3 -C12 環烷基、鹵代C1 -C10 烷胺基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； R4 、R5 、R6 、R7 、R8 、R9 、R10 、R11 各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基、3-12元雜環基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基或C6 -C10 芳基中的一個或多個取代基所取代； m為0、1、2、3或4； n為0、1或2。First, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, and the structure of the compound of formula (I) is:
Figure 02_image007
wherein: R 1 and R 2 are each the same or different, and are each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups:- NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyloxy, 3 -12-membered heterocyclyl, C6 - C10 -aryl, 5-10-membered heteroaryl; or R 1 and R 2 form 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl, optionally, The 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl is selected from -OH, -NH 2 , -CN, -NO 2 , halogen atom, C 1 -C 10 alkyl, C 1 -C 10 Substituted by any 1-3 of the group consisting of alkoxy, C 1 -C 10 alkylamino, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl and 5-10 membered heteroaryl; X Selected from chemical bond, -NH-, -CONH-;
Figure 02_image005
Selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 4 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 14 bridged cyclyl or spirocyclyl, C 6 -C 14 bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclic group, C 6 -C 14 bridged ring group or spirocyclic group contains 1-3 arbitrary A heteroatom or group selected from N, NH, O, S, C(O), S(O); each R is the same or different, and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , amido, substituted or unsubstituted following groups: C 1 -C 10 alkyl, C 1 -C 10 alkylamino, -C 1 -C 10 Alkylamide, C 1 -C 10 alkoxy, -NH 2 , C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 10 membered aryl or 5-10 membered heteroaryl , the substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12-membered heterocyclic group, halogen atom, -NH 2 , -CN, -COOH, -CONH 2 , -CHO, -OH, -NO 2 , hydroxy-C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, 5-10 membered heteroaryl or C 6 -C 10 substituted by one or more substituents in the aryl group; or any adjacent two R 3 form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring Ring is selected from -OH, -NH 2 , -CN, halogen atom, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkylamino, C 1 -C 10 alkane substituted by any 1-3 of the group consisting of amino, C 3 -C 12 cycloalkyl, halogenated C 1 -C 10 alkylamino, C 6 -C 10 aryl and 5-10-membered heteroaryl; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are each independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 -cycloalkyloxy, 3-12-membered heterocyclyl, C 6 -C 10 -aryl, 5-10-membered heteroaryl, 3-12-membered heterocyclyl, the substitution is selected from C 1 -C 10 alkyl group, C 3 -C 12 cycloalkyl group, 3-12 membered heterocyclic group, halogen atom, -NH 2 , -CN, -COOH, -CHO, -OH, -NO 2 , hydroxyl -C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C Substituted by one or more substituents in 1 -C 10 alkylamino group, 5-10-membered heteroaryl group or C 6 -C 10 aryl group; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2.

為了更為清晰地描述本發明的內容，現將所涉及的全部術語定義如下。此外，一個特定的術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，而應該按照本領域普通的含義去理解。In order to describe the content of the present invention more clearly, all terms involved are now defined as follows. Furthermore, a particular term should not be considered ambiguous or unclear unless specifically defined, but should be construed according to its ordinary meaning in the art.

術語“被取代”是指特定原子上的任意一個或多個氫原子被取代基取代，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。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.

術語“任選”、“任選的”或“任選地”是指隨後描述的事件或情況可以發生或不發生，該描述包括發生所述事件或情況和不發生所述事件或情況。例如，甲基任選被鹵素取代，表示甲基可以是未被取代的、被鹵素單取代或多取代的。術語“鹵素原子”指單獨或者以組合方式表示氟、氯、溴或碘，特別的是氟、氯或溴。The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, a methyl group is optionally substituted with a halogen, meaning that the methyl group can be unsubstituted, mono- or polysubstituted with a halogen. The term "halogen atom" means fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine, alone or in combination.

本文中的Ca -Cb ，是該部分具有給定範圍中的整數個碳原子。例如，“C1 -C6 ”是指該基團可具有1個碳原子、2個碳原子、3個碳原子、4個碳原子、5個碳原子或6個碳原子。本文中的以“a-b”、“a至b”或“a到b”的形式給出的關於基團個數或原子個數的數值範圍，表明給定範圍內的所有整數。例如，被“1-3個”取代基所取代，表明被1個、2個或者3個取代基所取代；“3-12元雜環基”表明包括3元、4元、5元、6元、7元、8元、9元、10元、11元、12元雜環基。C a -C b herein, is that the moiety has an integer number of carbon atoms in the given range. For example, " C1 - C6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Numerical ranges given herein in the form "ab", "a to b" or "a to b" with respect to the number of groups or atoms are intended to mean all integers within the given range. For example, being substituted by "1-3" substituents means substituted by 1, 2 or 3 substituents; "3-12-membered heterocyclyl" means including 3-membered, 4-membered, 5-membered, 6-membered Member, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered heterocyclic group.

術語“C1 -C10 烷基”單獨或者以組合方式表示包含1-10個碳原子的飽和直鏈或支鏈的烷基，例如，包括甲基、乙基、丙基、異丙基、丁基、第二丁基、異丁基、第三丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3,-二甲基-2-丁基等。在一些實施方案中，優選地，“C1 -C10 烷基”是甲基、乙基、正丙基、異丙基、第三丁基中的任一種。類似的，術語“C1-6 烷基”單獨或者以組合方式表示包含1-6個碳原子的飽和直鏈或支鏈的烷基，例如，包括甲基、乙基、丙基、異丙基等。The term "C 1 -C 10 alkyl" alone or in combination denotes a saturated straight or branched chain alkyl group containing 1-10 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl , 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl base, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3,- Dimethyl-2-butyl, etc. In some embodiments, preferably, "C 1 -C 10 alkyl" is any of methyl, ethyl, n-propyl, isopropyl, tert-butyl. Similarly, the term "C 1-6 alkyl" alone or in combination means a saturated straight or branched chain alkyl group containing 1-6 carbon atoms, for example, including methyl, ethyl, propyl, isopropyl Base et al.

術語“C1 -C10 烷氧基”單獨或者以組合方式表示基團C1 -C10 烷基-O-，其中“C1 -C10 烷基”表示如以上所定義，例如，其包括（但不限於）甲氧基（-OCH3 ）、乙氧基（-OCH2 CH3 ）、正丙氧基（-OCH2 CH2 CH3 ）、異丙氧基（-OCH(CH3 )2 ）、正丁氧基（-OCH2 CH2 CH2 CH3 ）、第二丁氧基（-OCH(CH3 )CH2 CH3 ）、異丁氧基（-OCH2 CH(CH3 )2 ）、第三丁氧基（-OC(CH3 )3 ）、正戊氧基（-OCH2 CH2 CH2 CH2 CH3 ）、新戊氧基（-OCH2 C(CH3 )3 ）等。The term "C 1 -C 10 alkoxy" alone or in combination denotes the group C 1 -C 10 alkyl-O-, wherein "C 1 -C 10 alkyl" means as defined above, eg, which includes (but not limited to) methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), second butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 C(CH 3 ) 3 )Wait.

術語“C3 -C12 環烷基”指單獨或者以組合方式表示具有3到12個碳原子的單環或多環環烷基，例如，包括環丙基、環丁基、環戊基、環己基、環庚基等。在一些實施方案中，“C3 -C12 環烷基”優選為“C3 -C8 環烷基”。The term "C 3 -C 12 cycloalkyl" refers to, alone or in combination, a monocyclic or polycyclic cycloalkyl group having 3 to 12 carbon atoms, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, etc. In some embodiments, "C 3 -C 12 cycloalkyl" is preferably "C 3 -C 8 cycloalkyl".

術語“C3 -C12 環烷基氧基”單獨或者以組合方式表示基團C3 -C12 環烷基-O-，其中C3 -C12 環烷基表示如以上所定義。The term "C 3 -C 12 cycloalkyloxy" alone or in combination denotes the group C 3 -C 12 cycloalkyl-O-, wherein C 3 -C 12 cycloalkyl means as defined above.

術語“3-12元雜環基”是指包含3-12個碳原子和雜原子或雜原子基團的飽和或部分不飽和單環或多環雜環基（即碳原子和雜原子的數量之和為3-12個），所述雜原子或雜原子基團選自N、NH、O、C(O)、S(O)m （其中m是0、1或2）。例如，所述3-12元雜環基包括氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、丁內醯胺基、戊內醯胺基、己內醯胺基、丁內酯基、戊內酯基、己內酯基、丁二醯亞胺或

Figure 02_image008
等。在一些實施方案中，“3-12元雜環基”優選為“5-12元雜環基”或“5-7元雜環基”；優選的，所述3-12元雜環基包括丁內醯胺基、吡咯烷基、丁二醯亞胺或
Figure 02_image008
，更優選的，所述3-12元雜環基為
Figure 02_image008
。The term "3-12 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclyl containing 3-12 carbon atoms and a heteroatom or group of heteroatoms (i.e. the number of carbon atoms and heteroatoms The sum is 3-12), the heteroatom or heteroatom group is selected from N, NH, O, C(O), S(O) m (where m is 0, 1 or 2). For example, the 3-12 membered heterocyclyl group includes aziridinyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperidine oxazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactone, butyrolactone, Valerolactone, caprolactone, succinimide or
Figure 02_image008
Wait. In some embodiments, "3-12 membered heterocyclyl" is preferably "5-12 membered heterocyclyl" or "5-7 membered heterocyclyl"; preferably, the 3-12 membered heterocyclyl includes Butyrolactone, pyrrolidinyl, butanediimide or
Figure 02_image008
, more preferably, the 3-12-membered heterocyclic group is
Figure 02_image008
.

術語“芳基”表示任何穩定的6-10元單環或雙環芳香族基團，包括苯基、萘基、四氫萘基、2,3-二氫化茚基或聯苯基等。“芳基”上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, 2,3-indenyl, or biphenyl, and the like. The hydrogen atoms on the "aryl group" are independently optionally substituted with one or more substituents described herein.

術語“雜芳基”表示環上的碳原子被至少一個選自硫、氧或氮的雜原子置換形成的芳香環基團。在一些實施方案中，此芳香環基團可以是5-7元單環或7-12雙環基團。在一些實施方案中，雜芳基中雜原子個數優選1、2、3或4，例如噻吩基、吡啶基、嘧啶基、吡嗪基、噠嗪基、吡啶-2（1H ）-酮基、吡啶-4（1H ）-酮基、吡咯基、吡唑基、噻唑基、1,2,3-***基、1,2,4-***基、咪唑基、四氮唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、噁二唑基、萘基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、異喹啉基、喹唑啉基、吲唑基、吲哚[1,2-a]吡嗪基、4,7-二氮雜吲哚、吡唑并嘧啶基、咪唑并嘧啶基、噁唑并嘧啶基、異噁唑并嘧啶基、咪唑并吡嗪基、吡唑并吡嗪、吡咯并吡嗪基、呋喃并吡嗪基、噻吩并吡嗪基、吡啶并嘧啶酮基、苯并噁唑基或苯并噻唑基等。“雜芳基”上的氫原子獨立任選地被一個或多個本發明所描述的取代基所取代。The term "heteroaryl" refers to an aromatic ring group formed by replacing a carbon atom on the ring with at least one heteroatom selected from sulfur, oxygen, or nitrogen. In some embodiments, this aromatic ring group can be a 5-7 membered monocyclic or 7-12 bicyclic group. In some embodiments, the number of heteroatoms in the heteroaryl group is preferably 1, 2, 3, or 4, eg, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridin-2( 1H )-one base, pyridin-4( 1H )-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl , isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl , quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole[1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazolyl Pyrimidyl, oxazolopyrimidyl, isoxazolopyrimidyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidone base, benzoxazolyl or benzothiazolyl, etc. The hydrogen atoms on a "heteroaryl" group are independently optionally substituted with one or more substituents described herein.

術語“C6-10 芳基” 表示具有6-10個碳原子的芳基，其中芳基表示如以上所定義。The term " C6-10 aryl" denotes an aryl group having 6-10 carbon atoms, wherein aryl means as defined above.

術語“5-10元雜芳基”表述具有5-10個碳原子和雜原子的雜芳基，其中雜芳基如以上所定義。The term "5-10 membered heteroaryl" denotes a heteroaryl group having 5-10 carbon atoms and a heteroatom, wherein heteroaryl is as defined above.

術語“3-8元環烷基、環烯基或雜環基”中的“3-8元環烷基”表示具有3-8個碳原子的飽和單環或稠環環烷基，例如，包括環丙基、環丁基、環戊基、環己基、環庚基等。其中“3-8元環烯基” 具有3-8個碳原子的部分不飽和的單環或稠環基團。其中“3-8元雜環基”表示具有3-8個碳原子和雜原子或雜原子基團的雜環基，所述雜原子或雜原子基團選自N、NH、O、S(O)m （其中m是0、1、2）；例如氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基等；在一些實施方案中“3-8元雜環基”優選“3-6元雜環基”或“5-6元雜環基”。"3-8 membered cycloalkyl" in the term "3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl" means a saturated monocyclic or fused ring cycloalkyl group having 3-8 carbon atoms, for example, Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. wherein "3-8 membered cycloalkenyl" is a partially unsaturated monocyclic or condensed ring group having 3 to 8 carbon atoms. Wherein "3-8 membered heterocyclic group" refers to a heterocyclic group having 3-8 carbon atoms and a heteroatom or heteroatom group selected from N, NH, O, S ( O) m (where m is 0, 1, 2); for example, aziridinyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholine group, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, etc.; in some embodiments, "3-8 membered heterocyclyl" is preferably "3-6 membered heterocyclyl" or "5-6 membered heterocyclyl".

術語“-CONH-”表示-C(=O)-NH-，具體可以表示C(=O)與

Figure 02_image005
相連或者NH與
Figure 02_image005
相連，優選為C(=O)與
Figure 02_image005
相連。The term "-CONH-" means -C(=O)-NH-, specifically, C(=O) and
Figure 02_image005
connected or NH with
Figure 02_image005
connected, preferably C(=O) with
Figure 02_image005
connected.

術語“胺基”單獨或者以組合方式表示一級胺基（-NH2 ），二級胺基（-NH-）或三級胺基（

Figure 02_image010
）。The term "amine group" alone or in combination means a primary amine group ( -NH2 ), a secondary amine group (-NH-) or a tertiary amine group (
Figure 02_image010
).

術語“C1 -C10 烷胺基” 單獨或者以組合方式表示如上所定義的胺基基團，其中胺基基團的氫原子被至少一個C1 -C10 烷基所取代，其中“C1 -C10 烷基”表示如以上所定義。相應地，“C1 -C10 烷胺基”例如包括甲基胺基、乙基胺基、丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、2-丁基胺基、第三丁基胺基、正戊基胺基、2-戊基胺基、3-戊基胺基、2-甲基-2-丁基胺基、3-甲基-2-丁基胺基、3-甲基-1-丁基胺基、2-甲基-1-丁基胺基、正己基胺基、2-己基胺基、3-己基胺基、2-甲基-2-戊基胺基、3-甲基-2-戊基胺基、4-甲基-2-戊基胺基、3-甲基-3-戊基胺基、2-甲基-3-戊基胺基、2,3-二甲基-2-丁基胺基、3,3-二甲基-2-丁基胺基等。特別的“C1 -C10 烷胺基”是甲基胺基、乙基胺基、異丙基胺基、第三丁基胺基等。The term "C 1 -C 10 alkylamino" alone or in combination denotes an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C 1 -C 10 alkyl group, wherein "C 1 - C10Alkyl " means as defined above. Correspondingly, "C 1 -C 10 alkylamino" includes, for example, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2- Butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2 -Butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl yl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl- 3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, etc. Particular "C 1 -C 10 alkylamino" groups are methylamino, ethylamino, isopropylamino, tert-butylamino, and the like.

術語“C3 -C12 環烷胺基”表示單獨或者以組合方式表示如上所定義的胺基基團，其中胺基基團的氫原子被至少一個C3 -C12 環烷基所取代，“C3 -C12 環烷基”表示如以上所定義。The term "C 3 -C 12 cycloalkylamino" denotes an amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is replaced by at least one C 3 -C 12 cycloalkyl, "C 3 -C 12 cycloalkyl" means as defined above.

術語“異構體”包含所有的同分異構形式包括對映異構體、非對映異構體、互變異構體和幾何異構體（包括順反異構體）。因此，本發明中所設計的化合物的單個立體化學異構體或其對映異構體、非對映異構體、互變異構體或幾何異構體（或順反異構體）的混合物都屬於本發明的範圍。The term "isomer" includes all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Thus, a single stereochemical isomer of a compound contemplated in the present invention or a mixture of its enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) All belong to the scope of the present invention.

術語“藥學上可接受的鹽”表示本發明的化合物以它們的藥用鹽的形式存在，包括酸加成鹽和鹼加成鹽。藥學上可接受的鹽在S.M.Berge在J. Pharmaceutical Sciences（66卷:1-19頁,1977年）中描述的pharmaceutically salts中有所描述。在本發明中，藥學上可接受的無毒的酸加成鹽表示本發明中的化合物與有機或無機酸形成的鹽。藥學上可接受的無毒的鹼加成鹽表示本發明中的化合物與有機或無機鹼所形成的鹽。The term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in Pharmaceutical salts by S.M. Berge in J. Pharmaceutical Sciences (Vol. 66: pp. 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compound of the present invention with an organic or inorganic acid. Pharmaceutically acceptable non-toxic base addition salts represent salts of the compounds of the present invention with organic or inorganic bases.

術語“溶劑化物”表示一個或多個溶劑分子與本發明中的化合物所形成的締合物。形成溶劑化物的溶劑包括但不限於水、甲醇、乙醇、異丙醇、乙酸乙酯、四氫呋喃、N,N -二甲基甲醯胺、二甲基亞碸等。“藥學上可接受的鹽”可通過一般的化學方法合成。The term "solvate" refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N -dimethylformamide, dimethylsulfoxide, and the like. "Pharmaceutically acceptable salts" can be synthesized by conventional chemical methods.

術語“酯”用於表示有機酯，例如包括單酯、二酯、三酯、和更通常地多酯。The term "ester" is used to refer to organic esters, including, for example, monoesters, diesters, triesters, and more generally polyesters.

術語“前藥”表示作為本發明的化合物的化學衍生物，該衍生物在體內通過發生化學反應轉換成通式I所表示的化合物。The term "prodrug" refers to a chemical derivative of a compound of the present invention, which is converted into a compound represented by general formula I by undergoing a chemical reaction in vivo.

術語“同位素衍生物”表示通式（I）中的氫原子被1-6個氘原子（D）所取代得到的同位素衍生物、通式（I）中的碳原子被1-3個碳14原子（14 C）所取代得到的同位素衍生物。The term "isotopic derivatives" refers to isotopic derivatives obtained by replacing the hydrogen atom in general formula (I) with 1-6 deuterium atoms (D), and the carbon atom in general formula (I) by 1-3 carbon atoms. Isotopic derivatives obtained by substitution of atoms ( 14 C).

詞語“包括（comprise）”或“包含（comprise）”及其英文變體例如comprises或comprising應理解為開放的、非排他性的意義，即“包括但不限於”。The words "comprise" or "comprise" and their English variants such as comprises or comprising are to be understood in an open, non-exclusive sense, ie, "including but not limited to".

以上對本發明的涉及的術語進行了定義，本領域技術人員還可以結合現有技術對以上術語進行理解，以下基於本發明的內容以及對術語的定義進一步進行描述。The terms involved in the present invention are defined above, and those skilled in the art can also understand the above terms in combination with the prior art. The following is further described based on the content of the present invention and the definitions of terms.

在一項優選的實施方案中，所述式（Ⅰ）化合物具有式(Ⅰ-1)所示的結構：

Figure 02_image012
X選自化學鍵、-NH-、-CONH-；
Figure 02_image005
選自C6 -C10 芳基、5-10元雜芳基、C4 -C12 環烷基、3-12元雜環基、C6 -C14 橋環基或者螺環基、C6 -C14 橋雜環基或者螺雜環基；其中所述5-10元雜芳基、3-12元雜環基、C6 -C14 橋雜環基或者螺雜環基含有1-3個任選自N、NH、O、S、C(O)、S(O) 的雜原子或基團； 每一個R3 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、胺基醯基、取代或未取代的下列基團：C1 -C10 烷基、C1 -C10 烷胺基、-C1 -C10 烷基醯胺、C1 -C10 烷氧基、-NH2 、C3 -C12 環烷基、3-12元雜環基、C6 -C10 芳基或5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CONH2 、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基、C6 -C10 芳基或3-12元雜環基中的一個或多個取代基所取代；或任意相鄰的兩個R5 形成3-6元飽和或者不飽和的環，任選的，所述3-6元飽和或者不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C3 -C12 環烷胺基、C1 -C10 烷基胺基、C3 -C12 環烷基、鹵代C1 -C10 烷基胺基、C6 -C10 芳基和5-10元雜芳基組成的組中的1-3個所取代； m為0、1、2、3或4； 在一項更優選的實施方案中，式(Ⅰ-1)所示結構中，四氫呋喃環上取代的甲基和胺基處於四氫呋喃環的同一側。In a preferred embodiment, the compound of formula (I) has the structure shown in formula (I-1):
Figure 02_image012
X is selected from chemical bonds, -NH-, -CONH-;
Figure 02_image005
Selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 4 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 14 bridged cyclyl or spirocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl contains 1-3 a heteroatom or group optionally selected from N, NH, O, S, C(O), S(O); each R is the same or different, independently selected from H, D, halogen atoms, - CN, -COOH, -CHO, -OH, -NO 2 , amido, substituted or unsubstituted following groups: C 1 -C 10 alkyl, C 1 -C 10 alkylamino, -C 1 - C 10 alkylamide, C 1 -C 10 alkoxy, -NH 2 , C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 10 membered aryl or 5-10 membered heterocycle Aryl, the substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, halogen atom, -NH 2 , -CN, -COOH, -CONH 2 , -CHO, -OH, -NO 2 , hydroxy-C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, 5-10-membered heteroaryl, C 6 -C 10 aryl group or 3-12-membered heterocyclic group is substituted by one or more substituents; or any adjacent two R 5 form a 3-6-membered saturated or unsaturated ring, optionally, the The 3-6 membered saturated or unsaturated ring is selected from -OH, -NH 2 , -CN, halogen atom, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 12 ring Alkylamino, C 1 -C 10 alkylamine, C 3 -C 12 cycloalkyl, halogenated C 1 -C 10 alkylamine, C 6 -C 10 aryl and 5-10 membered heteroaryl substituted with 1-3 in the group consisting of; m is 0, 1, 2, 3 or 4; In a more preferred embodiment, in the structure represented by formula (I-1), the methyl substituted on the tetrahydrofuran ring The group and the amine group are on the same side of the tetrahydrofuran ring.

在一項優選的實施方案中，一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其特徵在於，

Figure 02_image005
選自苯基、萘基、5-10元雜芳基或3-12元雜環基； 其中所述5-10元雜芳基、3-12元雜環基含有1-3個任選自N、NH、O、S、C(O)雜原子或基團， 優選的，所述5-10元雜芳環選自噻吩基、吡啶基、嘧啶基、吡嗪基、噠嗪基、吡咯基、吡唑基、噻唑基、1,2,3-***基、1,2,4-***基、咪唑基、四氮唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、異喹啉基、喹唑啉基、吲唑基、吲哚[1,2-a]吡嗪基、4,7-二氮雜吲哚、吡唑并嘧啶基、咪唑并嘧啶基、噁唑并嘧啶基、異噁唑并嘧啶基、咪唑并吡嗪基、吡唑并吡嗪、吡咯并吡嗪基、呋喃并吡嗪基、噻吩并吡嗪基、吡啶并嘧啶酮基、苯并噁唑基、苯并噻唑基中的任一種；所述3-12元雜環基選自氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、丁內醯胺基、戊內醯胺基、己內醯胺基、丁內酯基、戊內酯基、己內酯基、丁二醯亞胺或
Figure 02_image008
中的任一種；更優選的，所述3-12元雜環基選自丁內醯胺基、吡咯烷基、丁二醯亞胺基或
Figure 02_image008
中的任一種； 每一個R3 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、胺基醯基、取代或未取代的下列基團：C1 -C10 烷基、C1 -C10 烷基胺基、-C1 -C6 烷基CONH2 、C1 -C10 烷氧基、-NH2 ，所述取代是被選自C1 -C10 烷基、鹵素原子、-NH2 、-CN、-OH、-NO2 中的一個或多個取代基所取代；或任意相鄰的兩個R5 形成3-6元飽和或者不飽和的環，任選的，所述3-6元飽和或者不飽和的環被1-3個-OH、-NH2 、-CN、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基所取代。In a preferred embodiment, a compound of formula (I), or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, is characterized in that,
Figure 02_image005
Selected from phenyl, naphthyl, 5-10-membered heteroaryl or 3-12-membered heterocyclic group; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclic group contains 1-3 optional from N, NH, O, S, C(O) heteroatom or group, preferably, the 5-10 membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrole base, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, Thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole base, indole[1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidyl, isoxazolopyrimidyl, imidazole any of pyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl, and benzothiazolyl; The 3-12-membered heterocyclic group is selected from aziridinyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazine base, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactone, valerolactam, caprolactone, butyrolactone, pentyl Lactone group, caprolactone group, succinimide or
Figure 02_image008
any one; more preferably, the 3-12-membered heterocyclic group is selected from butyrolactone, pyrrolidinyl, butanediimide or
Figure 02_image008
Any one of; each R 3 is the same or different, each independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , amido, substituted or unsubstituted Substituted the following groups: C 1 -C 10 alkyl, C 1 -C 10 alkylamine, -C 1 -C 6 alkyl CONH 2 , C 1 -C 10 alkoxy, -NH 2 , the Substitution is substituted by one or more substituents selected from C 1 -C 10 alkyl, halogen atom, -NH 2 , -CN, -OH, -NO 2 ; or any adjacent two R 5 form 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is replaced by 1-3 -OH, -NH2 , -CN, halogen atom, C1 - C10 Alkyl, C 1 -C 10 alkoxy substituted.

在一項更優選的實施方案中，所述式（Ⅰ）化合物選自表1所示化合物。 表1：

Figure 02_image014
Figure 02_image016
Figure 02_image018
Figure 02_image020
Figure 02_image022
Figure 02_image024
Figure 02_image026
Figure 02_image028
Figure 02_image030
Figure 02_image032
Figure 02_image034
Figure 02_image036
Figure 02_image038
Figure 02_image040
Figure 02_image042
Figure 02_image026
Figure 02_image028
Figure 02_image030
Figure 02_image046
Figure 02_image048
Figure 02_image050
 In a more preferred embodiment, the compound of formula (I) is selected from the compounds shown in Table 1. Table 1:
Figure 02_image014
Figure 02_image016
Figure 02_image018
Figure 02_image020
Figure 02_image022
Figure 02_image024
Figure 02_image026
Figure 02_image028
Figure 02_image030
Figure 02_image032
Figure 02_image034
Figure 02_image036
Figure 02_image038
Figure 02_image040
Figure 02_image042
Figure 02_image026
Figure 02_image028
Figure 02_image030
Figure 02_image046
Figure 02_image048
Figure 02_image050

本發明還提供了一種藥物組合物，其包含上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物。The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label.

在本發明的一些實施方案中，上述藥物組合物還包含藥學上可接受的載體。In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

在一項更優選的實施方案中，上述藥物組合物還包括： -藥學上可接受的載體； -輔劑；和/或 -賦形劑。In a more preferred embodiment, the above-mentioned pharmaceutical composition further comprises: - a pharmaceutically acceptable carrier; - adjuvants; and/or -excipient.

本發明還提供了一種製備上述藥物組合物的方法，其包括將包含上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物與藥學上可接受的載體、輔劑（如稀釋劑）和/或賦形劑相混合。The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises adding any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate or prodrug thereof. Or the isotopic label is mixed with pharmaceutically acceptable carriers, adjuvants (eg diluents) and/or excipients.

本發明還提供了一種藥物製劑，其包括上述任一所述的一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物或者藥物組合物，所述製劑可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳劑、硬或軟膠囊或糖漿劑。可按照本領域任何已知製備藥用組合物的方法製備口服組合物，此類組合物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥物製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用賦形劑。這些賦形劑可以是惰性賦形劑，造粒劑和崩解劑、以及潤滑劑。這些片劑可以不包衣或可通過掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。例如，可使用水溶性味道掩蔽物質。The present invention also provides a pharmaceutical preparation, which comprises any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label or pharmaceutical combination thereof The preparations may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups. Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring and preservative agents to provide pleasing to the eye and tasty pharmaceutical preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating and disintegrating agents, and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time. For example, water soluble taste masking substances can be used.

也可以用其中活性成分與惰性固體稀釋劑，或其中活性成分與水溶性載體混合的軟明膠膠囊提供口服製劑。Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier.

水懸浮液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑；分散劑或濕潤劑可以是天然產生的磷脂。水混懸液也可以含有一種或多重防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents; dispersing or wetting agents can be naturally occurring phospholipids. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

油混懸液可通過使活性成分懸浮於植物油或礦物油中配置而成。油混懸液可含有增稠劑，可加入上述的甜味劑和矯味劑，以提供可口的製劑，可通過加入抗氧劑保存這些組合物。Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents, and sweetening and flavoring agents such as those mentioned above may be added to provide a palatable preparation, and these compositions may be preserved by the addition of antioxidants.

通過加入水可使適用於製備水混懸液的可分散粉末和顆粒提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑、適宜的分散劑或濕潤劑和懸浮劑可說明上述的例子。也可介入其它賦形劑例如甜味劑、矯味劑和著色劑，通過加入抗氧劑例如抗壞血酸保存這些組合物。Dispersible powders and granules suitable for preparation of an aqueous suspension may be made by the addition of water to provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives, suitable dispersing or wetting agents and suspending agents for mixing. Agents may illustrate the above-mentioned examples. Other excipients such as sweetening, flavoring and coloring agents may also be interposed, and these compositions preserved by the addition of antioxidants such as ascorbic acid.

本發明的藥物組合物也可以是水包油乳劑的形式。油相可以是植物油或礦物油或其混合物。適宜的乳化劑可以是天然產生的磷脂。可用的甜味劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil or mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. Available sweeteners. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

本發明的藥物製劑可以是無菌注射水溶液形式，也可以使用的可接受的溶媒或者溶劑有水、格力氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳，可通過局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本發明化合物恆定迴圈濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置，這種裝置的實例是Deltec CADD-PLUS. TM. 5400型靜脈注射泵。The pharmaceutical preparations of the present invention can be in the form of sterile injectable aqueous solutions, and acceptable vehicles or solvents that can be used include water, Griez's solution and isotonic sodium chloride solution. A sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used, an example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

本發明的藥物製劑可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或潤濕劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可介紹的無毒稀釋劑或製劑匯總製備的無菌注射溶液或混懸液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。此外，脂肪酸也可以製備注射劑。The pharmaceutical formulations of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally introduceable non-toxic diluent or formulation set. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. In addition, fatty acids are also available in the preparation of injectables.

可按用於直腸給藥的栓劑形式給予本發明化合物。可通過將藥物與在普通溫度下為固體但在直腸中為液體，因為在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些藥物組合物。The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum because it will melt in the rectum to release the drug.

如本領域技術人員所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用具體化合物的活性、或者患者的年齡、或者患者的體重、或者患者的健康狀況、或者患者的飲食、給藥時間、給藥方式、***的速率、藥物的組合等；另外，最佳的治療方式如治療的模式、通式化合物（Ⅰ）的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。As is well known to those skilled in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, or the age of the patient, or the weight of the patient, or the state of health of the patient, or The patient's diet, administration time, administration mode, rate of excretion, combination of drugs, etc.; in addition, the optimal treatment mode, such as the mode of treatment, the daily dosage of the compound of general formula (I) or the type of pharmaceutically acceptable salts It can be verified according to the traditional treatment plan.

本發明還提供了上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑，其用作預防和治療非受體蛋白酪胺酸磷酸酶（SHP2，Src Homolgy-2 phospahtase）媒介的或依賴的疾病或病症。The present invention also provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or the pharmaceutical composition, or the drug Formulations for use in the prevention and treatment of non-receptor protein tyrosine phosphatase (SHP2, Src Homolgy-2 phospahtase) mediated or dependent diseases or conditions.

本發明還提供了上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑用作預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的用途。The present invention also provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or the pharmaceutical composition, or the drug Use of the formulations for the prevention and/or treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions.

本發明還提供了上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑在製備預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的藥物中的應用。The present invention also provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or the pharmaceutical composition, or the drug The use of the preparation in the preparation of a medicament for preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

其中，上述非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症選自癌症、中樞神經系統缺陷、心血管系統缺陷、血液系統缺陷、免疫或炎症疾病、易感染性疾病、代謝缺陷、神經缺陷、精神缺陷和生殖缺陷。其中所述癌症可以為乳腺癌、子宮內膜癌、頭頸癌、皮膚癌、肺癌、肝癌、白血病、卵巢癌、宮頸癌、***癌、膽管癌、食管癌、胰腺癌、結直腸癌、腦膠質瘤、平滑肌瘤輸卵管腫瘤、腎癌、骨髓瘤、骨癌、甲狀腺癌。所述中樞神經系統缺陷可以是酒精中毒或偏頭疼；所述心血管系統缺陷可以為主動脈瘤、易感性心肌梗死、主動脈瓣硬化、心血管疾病、冠狀動脈疾病、高血壓；所述血液系統缺陷可以為深靜脈血栓形成；所述免疫及炎症疾病可以為關節炎、多發性硬化症、肝硬化；所述易感染性疾病可以為乙型肝炎、慢性肝炎、骨質減少、骨質疏鬆症；所述神經缺陷可以為阿爾茨海默症、帕金森病、偏頭疼、眩暈；所述精神缺陷可以為神經性厭食、注意力缺陷伴多動障礙、癡呆、嚴重抑鬱障礙、精神病；所述生殖缺陷可以為月經初潮年齡、子宮內膜異位症、不育症等。Wherein, the above-mentioned non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions are selected from cancer, central nervous system defects, cardiovascular system defects, blood system defects, immune or inflammatory diseases, susceptible diseases, metabolic defects , neurological, psychiatric and reproductive defects. The cancer can be breast cancer, endometrial cancer, head and neck cancer, skin cancer, lung cancer, liver cancer, leukemia, ovarian cancer, cervical cancer, prostate cancer, bile duct cancer, esophageal cancer, pancreatic cancer, colorectal cancer, brain glial cancer Tumor, leiomyoma, fallopian tube tumor, kidney cancer, myeloma, bone cancer, thyroid cancer. The central nervous system defect may be alcoholism or migraine; the cardiovascular system defect may be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood The system defect can be deep vein thrombosis; the immune and inflammatory diseases can be arthritis, multiple sclerosis, liver cirrhosis; the susceptible diseases can be hepatitis B, chronic hepatitis, osteopenia, osteoporosis; The neurological deficit can be Alzheimer's disease, Parkinson's disease, migraine, vertigo; the mental deficit can be anorexia nervosa, attention deficit hyperactivity disorder, dementia, major depressive disorder, psychosis; the reproductive Defects can be age at menarche, endometriosis, infertility, and the like.

本發明還提供了一種預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的方法，其包括下列步驟：將治療有效量的上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑施用於對其有需求的患者。The present invention also provides a method for preventing and/or treating a non-receptor protein tyrosine phosphatase-mediated or dependent disease or condition, comprising the steps of: adding a therapeutically effective amount of the above compound of formula (I) or its A pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or the pharmaceutical composition, or the pharmaceutical formulation is administered to a patient in need thereof.

術語“治療有效量”是指能夠誘發細胞、組織、器官或生物體（例如患者）產生生物或醫學反應的藥物活性成分的劑量。The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient capable of eliciting a biological or medical response in a cell, tissue, organ or organism (eg, a patient).

術語“施用”是指將藥物活性成分（比如本發明的化合物）或包含藥物活性成分的藥物組合物（例如本發明的藥物組合物）應用於患者或其細胞、組織、器官、生物流體等部位，以便使藥物活性成分或藥物組合物與患者或其細胞、組織、器官、生物流體等部位接觸的過程。常見的施用方式包括（但不限於）口服施用、皮下施用、肌內施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直腸施用、***施用等。The term "administration" refers to the application of a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (eg, a pharmaceutical composition of the present invention) to a patient or a site of its cells, tissues, organs, biological fluids, etc. , the process of contacting a patient or its cells, tissues, organs, biological fluids, etc. with active pharmaceutical ingredients or pharmaceutical compositions. Common modes of administration include, but are not limited to, oral, subcutaneous, intramuscular, subperitoneal, ocular, nasal, sublingual, rectal, vaginal, and the like.

術語“對其有需求”是指醫生或其他護理人員對患者需要或者將要從預防和/或治療過程中獲益的判斷，該判斷的得出基於醫生或其他護理人員在其專長領域中的各種因素。The term "in need of it" refers to a physician or other caregiver's judgment that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, based on the physician or other caregiver's various areas of expertise. factor.

術語“患者”（或稱受試者）是指人類或非人類的動物（例如哺乳動物）。The term "patient" (or subject) refers to a human or non-human animal (eg, mammal).

本發明還提供了一種醫藥品，其包含至少一種額外的預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的治療劑，以及上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑。The present invention also provides a medicinal product comprising at least one additional therapeutic agent for preventing and/or treating non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions, and the above-mentioned compound of formula (I) or A pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or said pharmaceutical composition, or said pharmaceutical preparation.

本發明的上述具有式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者所述的藥物組合物，或者所述的藥物製劑可與包括但不限於下述化合物或者抗體進行聯合用藥或者與抗體藥物進行抗體偶聯藥物。The above-mentioned compounds of the present invention having the formula (I) or their pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels, or the pharmaceutical compositions, or the pharmaceutical preparations can be Combination administration with compounds or antibodies including but not limited to the following, or antibody drug conjugates with antibody drugs.

本發明還提供了一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物的製備方法，以下通過描述了式I所示化合物的幾種典型的合成路線，以進一步描述本發明的技術方案，具體說明如下： （1）化合物I-a和化合物I-b在鹼的作用下反應得到化合物I-c，其中I-b中A為鹵素原子，優選為氯、溴或碘，X為化學鍵； （2）化合物I-c經脫保護得到化合物I-d； （3）化合物I-d和化合物I-e反應得到化合物I-f，其中化合物I-e中的B為鹵素原子，優選為氯、溴或碘； （4）化合物I-f和I-g在鹼的作用下反應得到化合物（I）。 合成路線圖如下：

Figure 02_image052
The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof. The following describes several aspects of the compound of formula I. A typical synthetic route, to further describe the technical scheme of the present invention, is specified as follows: (1) Compound Ia and compound Ib are reacted under the action of a base to obtain compound Ic, wherein A in Ib is a halogen atom, preferably chlorine, bromine or iodine, X is a chemical bond; (2) compound Ic is deprotected to obtain compound Id; (3) compound Id and compound Ie are reacted to obtain compound If, wherein B in compound Ie is a halogen atom, preferably chlorine, bromine or iodine; (4) Compound If and Ig are reacted under the action of a base to obtain compound (I). The synthetic route map is as follows:
Figure 02_image052

在一項優選的實施方案中，步驟（1）中，反應的催化劑為碘化亞銅和鹼，鹼優選為氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸鈉、甲醇鈉、乙醇鈉、第三丁醇鈉、第三丁醇鉀或第三丁醇鋰。In a preferred embodiment, in step (1), the catalyst for the reaction is cuprous iodide and a base, and the base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, Sodium tributoxide, potassium tertiary butoxide or lithium tertiary butoxide.

在一項優選的實施方案中，步驟（2）中，脫保護反應的催化劑為質子酸或路易士酸，優選為三氯化鋁。In a preferred embodiment, in step (2), the catalyst for the deprotection reaction is a protic acid or a Lewis acid, preferably aluminum trichloride.

在一項優選的實施方案中，步驟（3）中，反應的催化劑為有機鹼或無機鹼催化劑，其中無機鹼優選為氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸鈉，有機鹼優選為三乙胺、二乙胺、二異丙胺或N, N-二異丙基乙胺。In a preferred embodiment, in step (3), the catalyst for the reaction is an organic base or an inorganic base catalyst, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and the organic base is preferably three Ethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

在一項優選的實施方案中，步驟（4）中，反應的催化劑為有機鹼或無機鹼催化劑，其中無機鹼優選為氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸鈉，有機鹼優選為三乙胺、二乙胺、二異丙胺或N,N-二異丙基乙胺。In a preferred embodiment, in step (4), the catalyst for the reaction is an organic base or an inorganic base catalyst, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and the organic base is preferably three Ethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

本發明還提供了另一種製備化合物I-c的方法，用化合物I-aa和化合物I-b反應得到化合物I-c，反應催化劑為偶聯反應催化劑，優選為四(三苯基磷)鈀。合成路線圖如下：

Figure 02_image054
The present invention also provides another method for preparing compound Ic, by reacting compound I-aa and compound Ib to obtain compound Ic, and the reaction catalyst is a coupling reaction catalyst, preferably tetrakis(triphenylphosphorus)palladium. The synthetic route map is as follows:
Figure 02_image054

本發明還提供給了另一種合成化合物（I）的方法，包括 （1）化合物I-h和化合物I-i反應得到化合物I-j，化合物I-i中的A為鹵素原子，優選為氯、溴或碘； （2）化合物I-j和化合物I-k反應得到化合物I-l，化合物I-l中的X為-CONH-； （3）化合物I-l和化合物I-g反應得到化合物（I）。The present invention also provides another method for synthesizing compound (I), comprising: (1) Compound I-h is reacted with compound I-i to obtain compound I-j, and A in compound I-i is a halogen atom, preferably chlorine, bromine or iodine; (2) Compound I-j is reacted with compound I-k to obtain compound I-l, and X in compound I-l is -CONH-; (3) Compound I-l and compound I-g are reacted to obtain compound (I).

在一項優選的實施方案中，步驟（1）中，反應的催化劑為有機鹼或無機鹼，其中無機鹼優選為氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸鈉，碳酸銫，有機鹼優選為三乙胺、二乙胺、二異丙胺或N,N-二異丙基乙胺。In a preferred embodiment, in step (1), the catalyst for the reaction is an organic base or an inorganic base, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and the organic base is preferably It is triethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

在一項優選的實施方案中，步驟（2）中，反應催化劑為氯化亞碸和/或有機鹼，有機鹼優選為三乙胺、二乙胺、二異丙胺或N,N-二異丙基乙胺、吡啶或4-二甲胺基吡啶。In a preferred embodiment, in step (2), the reaction catalyst is sulfite chloride and/or an organic base, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N,N-diisopropylamine propylethylamine, pyridine or 4-dimethylaminopyridine.

在一項優選的實施方案中，步驟（2）中，反應催化劑為有機鹼，有機鹼優選為三乙胺、二乙胺、二異丙胺、N，N-二異丙基乙胺、吡啶或4-二甲胺基吡啶。In a preferred embodiment, in step (2), the reaction catalyst is an organic base, and the organic base is preferably triethylamine, diethylamine, diisopropylamine, N,N-diisopropylethylamine, pyridine or 4-Dimethylaminopyridine.

合成路線圖如下：

Figure 02_image056
The synthetic route map is as follows:
Figure 02_image056

下面的實施例可以對本發明做進一步的描述，然而，這些實施例不應作為對本發明的範圍的限制。The following examples may further describe the present invention, however, these examples should not be construed as limiting the scope of the present invention.

中間體 Int-1 的製備

Figure 02_image058
Figure 02_image060
Preparation of Intermediate Int-1
Figure 02_image058
Figure 02_image060

向Int- 1a (104 g，1.0 mol)的二氯甲烷（600 mL）溶液中，加入咪唑（102 g，1.5 mol），冰水浴冷卻下滴加第三丁基二甲基矽烷（165 g，1.1 mol）的二氯甲烷（200 mL）溶液，室溫反應16小時。將反應液用二氯甲烷稀釋，水洗3次，有機相用無水硫酸鈉乾燥。過濾乾燥劑，濾液濃縮，得到Int-1 b 粗品（237 g，產率100%），直接用於下一步反應。1 H NMR (400 MHz, CDCl3 )δ 4.32 (q,J = 8.0 Hz, 1H), 3.71 (s, 3H), 1.39 (d,J = 8.0 Hz 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H)。

Figure 02_image062
To a solution of Int - 1a (104 g, 1.0 mol) in dichloromethane (600 mL), imidazole (102 g, 1.5 mol) was added, and tert-butyldimethylsilane (165 g, 1.5 mol) was added dropwise under ice-water cooling. 1.1 mol) in dichloromethane (200 mL), react at room temperature for 16 hours. The reaction solution was diluted with dichloromethane, washed three times with water, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was filtered, and the filtrate was concentrated to obtain crude Int-1 b (237 g, yield 100%), which was directly used in the next reaction. 1 H NMR (400 MHz, CDCl 3 ) δ 4.32 (q, J = 8.0 Hz, 1H), 3.71 (s, 3H), 1.39 (d, J = 8.0 Hz 3H), 0.89 (s, 9H), 0.09 ( s, 3H), 0.06 (s, 3H).
Figure 02_image062

冰水浴下，向Int- 1b (120 g，0.55 mol)的二氯甲烷（600 mL）溶液中，滴加二異丁基氫化鋁（367 mL，0.55 mol，1.5 M甲苯溶液），反應16小時。滴加甲醇（100 mL）淬滅反應，加入矽藻土攪拌均勻。過濾，濾液用二氯甲烷稀釋，水洗3次，有機相用無水硫酸鈉乾燥。過濾乾燥劑，濾液濃縮，殘留物用矽膠管柱純化（石油醚/乙酸乙酯=10/1淋洗）得到Int- 1c （56 g，產率54%）。 1 H NMR (400 MHz, CDCl3 )δ 9.61 (s, 1H), 4.08 (q,J = 8.0 Hz, 1H), 1.27 (d,J = 8.0 Hz 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H)。

Figure 02_image064
In an ice-water bath, diisobutylaluminum hydride (367 mL, 0.55 mol, 1.5 M toluene solution) was added dropwise to a solution of Int - 1b (120 g, 0.55 mol) in dichloromethane (600 mL), and the reaction was carried out for 16 hours. . Methanol (100 mL) was added dropwise to quench the reaction, and diatomaceous earth was added and stirred well. After filtration, the filtrate was diluted with dichloromethane, washed three times with water, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was filtered, the filtrate was concentrated, and the residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate=10/1) to obtain Int - 1c (56 g, yield 54%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.61 (s, 1H), 4.08 (q, J = 8.0 Hz, 1H), 1.27 (d, J = 8.0 Hz 3H), 0.91 (s, 9H), 0.10 ( s, 3H), 0.09 (s, 3H).
Figure 02_image064

氮氣保護下，將二異丙胺(23.4 mL，166 mmol)溶解於無水四氫呋喃 (220 mL)中，降溫至-20℃，滴加正丁基鋰 (64 mL，160 mmol，2.5 M的正己烷溶液)，反應1小時後，滴加N-第三丁氧羰基-4-哌啶甲酸乙酯（27.5g，107 mmol）的無水四氫呋喃（50 mL）溶液，升溫至0℃反應1小時，加入Int- 1c （20.5 mL，102 mmol），0℃反應3小時。以5%碳酸氫鈉溶液淬滅反應，乙酸乙酯萃取3次，無水硫酸鈉乾燥有機相。過濾，減壓濃縮，殘留物用矽膠管柱純化（石油醚/乙酸乙酯=2/1）得到Int- 1d （32.6 g，產率72%）。MSm/z [M+H]+ : 446.7。

Figure 02_image066
Under nitrogen protection, diisopropylamine (23.4 mL, 166 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL), cooled to -20 °C, and n-butyllithium (64 mL, 160 mmol, 2.5 M in n-hexane was added dropwise) ), react for 1 hour, add dropwise a solution of N-tert-butoxycarbonyl-4-piperidinecarboxylic acid ethyl ester (27.5 g, 107 mmol) in anhydrous tetrahydrofuran (50 mL), warm to 0 °C and react for 1 hour, add Int - 1c (20.5 mL, 102 mmol) at 0°C for 3 hours. The reaction was quenched with 5% sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. It was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether/ethyl acetate=2/1) to obtain Int - 1d (32.6 g, yield 72%). MS m/z [M+H] + : 446.7.
Figure 02_image066

冰水浴下，向Int- 1d (31.7 g，71 mmol)的四氫呋喃（600 mL）溶液中分批加入硼氫化鋰（2.3 g，107 mmol），加完後，室溫反應16小時。冰水浴冷卻至0℃，加入飽和碳酸氫鈉溶液淬滅反應，乙酸乙酯萃取3次，有機相用無水硫酸鈉乾燥。過濾乾燥劑，濾液濃縮，得到Int- 1e 粗品（30.2 g，產率100%），直接用於下一步。MSm/z [M+H]+ : 404.5, [M-H]- : 402.4。

Figure 02_image068
Lithium borohydride (2.3 g, 107 mmol) was added in portions to a solution of Int - 1d (31.7 g, 71 mmol) in tetrahydrofuran (600 mL) under an ice-water bath. After the addition, the reaction was carried out at room temperature for 16 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was filtered, and the filtrate was concentrated to give crude Int - 1e (30.2 g, 100% yield), which was used directly in the next step. MS m/z [M+H] + : 404.5, [MH] - : 402.4.
Figure 02_image068

將Int- 1e (59.0 g， 146 mmol)溶解於四氫呋喃(600 mL)中，加入四丁基氟化銨(35 g， 109 mmol)，室溫攪拌16小時。反應液中加入飽和碳酸氫鈉溶液淬滅反應，加乙酸乙酯分層，水相萃取至無產物，合併有機相並用飽和食鹽水洗滌。有機相用無水硫酸鈉乾燥，過濾乾燥劑，濾液減壓濃縮，管柱層析得到Int- 1f （24 g，產率57%）。1 H NMR (400 MHz, CDCl3 )δ 3.94-4.00 (m, 1H), 3.65-3.81 (m, 5H), 3.07-3.15 (m, 2H), 1.60-1.71 (m, 4H), 1.45 (s, 9H), 1.33 (d,J = 4.0 Hz, 3H)。MSm/z [M+H]+ : 290.3, [M-H]- : 288.3。

Figure 02_image070
Int - 1e (59.0 g, 146 mmol) was dissolved in tetrahydrofuran (600 mL), tetrabutylammonium fluoride (35 g, 109 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, ethyl acetate was added to separate the layers, the aqueous phase was extracted until no product was obtained, the organic phases were combined and washed with saturated brine. The organic phase was dried with anhydrous sodium sulfate, the drying agent was filtered, the filtrate was concentrated under reduced pressure, and Int - 1f was obtained by column chromatography (24 g, yield 57%). 1 H NMR (400 MHz, CDCl 3 ) δ 3.94-4.00 (m, 1H), 3.65-3.81 (m, 5H), 3.07-3.15 (m, 2H), 1.60-1.71 (m, 4H), 1.45 (s , 9H), 1.33 (d, J = 4.0 Hz, 3H). MS m/z [M+H] + : 290.3, [MH] - : 288.3.
Figure 02_image070

將鈉氫（2.3 g，57.44 mmol）加入四氫呋喃（80 mL）中，降溫至-15℃，滴加Int- 1f (8.3 g，28.72 mmol)的四氫呋喃(50 mL)溶液，繼續滴加對甲苯磺醯氯(1.72 g， 9 mmol)的四氫呋喃(15 mL)溶液，反應16小時。將反應液降溫至-15℃，滴加飽和氯化銨溶液至無氣泡產生，加乙酸乙酯分層，水相萃取至無產物，合併有機相用飽和食鹽水洗滌。有機相用無水硫酸鈉乾燥，過濾乾燥劑，濾液減壓濃縮，管柱層析得到Int- 1g （5 g，產率64%）。 1 H NMR (400 MHz, CDCl3 )δ 4.08-4.14 (m, 1H), 3.01-3.80 (m, 7H), 1.68-1.81 (m, 4H), 1.46 (s, 9H), 1.26 (d,J = 8.0 Hz, 3H).

Figure 02_image072
Sodium hydrogen (2.3 g, 57.44 mmol) was added to tetrahydrofuran (80 mL), the temperature was lowered to -15 °C, a solution of Int - 1f (8.3 g, 28.72 mmol) in tetrahydrofuran (50 mL) was added dropwise, and p-toluenesulfonic acid was added dropwise. A solution of acyl chloride (1.72 g, 9 mmol) in tetrahydrofuran (15 mL) was reacted for 16 hours. The reaction solution was cooled to -15°C, saturated ammonium chloride solution was added dropwise until no bubbles were formed, ethyl acetate was added to separate the layers, the aqueous phase was extracted until no product was obtained, and the combined organic phases were washed with saturated brine. The organic phase was dried with anhydrous sodium sulfate, the drying agent was filtered, the filtrate was concentrated under reduced pressure, and Int - 1g (5 g, yield 64%) was obtained by column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 4.08-4.14 (m, 1H), 3.01-3.80 (m, 7H), 1.68-1.81 (m, 4H), 1.46 (s, 9H), 1.26 (d, J = 8.0 Hz, 3H).
Figure 02_image072

將Int- 1g （13.5 g，49.7 mmol）加入到二氯甲烷（160 mL）中，-10℃下分批加入戴斯-馬丁氧化劑（42 g，99 mmol），0℃反應16小時。加入***（500 mL），大量固體析出，過濾，用***（100 mL）洗一次，濾液用飽和碳酸氫鈉水溶液和飽和硫代硫酸鈉水溶液依次洗一次，有機相用無水硫酸鈉乾燥。過濾乾燥劑，濾液減壓濃縮，管柱層析分離得到Int- 1h （5.5 g，產率41%）。 1 H NMR (400 MHz, CDCl3 )δ 4.19 (d,J = 8.0 Hz, 1H), 3.83-3.92 (m, 4H), 2.96-3.16 (m, 2H), 1.55-1.79 (m, 4H), 1.46 (s, 9H), 1.32 (d,J = 8.0 Hz, 3H)。

Figure 02_image074
Int - 1 g (13.5 g, 49.7 mmol) was added to dichloromethane (160 mL), Dess-Martin oxidant (42 g, 99 mmol) was added in portions at -10 °C, and the reaction was carried out at 0 °C for 16 hours. Diethyl ether (500 mL) was added, a large amount of solid was precipitated, filtered, washed once with diethyl ether (100 mL), the filtrate was washed once with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution, and the organic phase was dried with anhydrous sodium sulfate. The desiccant was filtered, the filtrate was concentrated under reduced pressure, and Int - 1h (5.5 g, yield 41%) was obtained by column chromatography. 1 H NMR (400 MHz, CDCl 3 ) δ 4.19 (d, J = 8.0 Hz, 1H), 3.83-3.92 (m, 4H), 2.96-3.16 (m, 2H), 1.55-1.79 (m, 4H), 1.46 (s, 9H), 1.32 (d, J = 8.0 Hz, 3H).
Figure 02_image074

將Int- 1h (20.0 g，274.3 mmol)和R-(+)-第三丁基亞磺醯胺(33.2 g， 274.3 mmol)溶解於四氫呋喃(350 mL)溶液，加入鈦酸四乙酯(67.7 g， 297 mmol)，氮氣置換， 100℃下反應20小時。冷卻至-25℃後加入甲醇（30 mL），分批加入硼氫化鋰（5.97 g，274.3 mmol），加完後在-10℃反應45分鐘。在-10℃下加入飽和氯化銨溶液，大量固體析出，抽濾，濾餅用乙酸乙酯洗，濾液分層，水相再用乙酸乙酯萃取至無產品，有機相用飽和食鹽水洗一次，硫酸鈉乾燥，過濾乾燥劑，有機相減壓濃縮，管柱層析分離得到Int- 1i （12.4 g，產率59%）。 1 H NMR (400 MHz, CDCl3 )δ 4.15-4.19 (m, 1H), 3.63-3.88 (m, 4H), 3.30-3.44 (m, 2H), 2.92 (s, 1H), 1.80 (s, 2H), 1.60 (s, 2H),1.44 (s, 9H), 1.25 (s, 9H), 1.20 (d,J = 8.0 Hz, 3H) 。MSm/z [M+H]+ : 375.3, [M-H]- : 373.5。

Figure 02_image076
Int - 1h (20.0 g, 274.3 mmol) and R-(+)-tert-butylsulfinamide (33.2 g, 274.3 mmol) were dissolved in tetrahydrofuran (350 mL), and tetraethyl titanate (67.7 mmol) was added. g, 297 mmol), replaced with nitrogen, and reacted at 100 °C for 20 hours. After cooling to -25°C, methanol (30 mL) was added, and lithium borohydride (5.97 g, 274.3 mmol) was added in portions, and the reaction was carried out at -10°C for 45 minutes after the addition. Saturated ammonium chloride solution was added at -10 °C, a large amount of solid was precipitated, suction filtered, the filter cake was washed with ethyl acetate, the filtrate was separated, the aqueous phase was extracted with ethyl acetate until no product was obtained, and the organic phase was washed once with saturated brine , dried over sodium sulfate, filtered with desiccant, the organic phase was concentrated under reduced pressure, and separated by column chromatography to obtain Int - 1i (12.4 g, yield 59%). 1 H NMR (400 MHz, CDCl 3 ) δ 4.15-4.19 (m, 1H), 3.63-3.88 (m, 4H), 3.30-3.44 (m, 2H), 2.92 (s, 1H), 1.80 (s, 2H) ), 1.60 (s, 2H), 1.44 (s, 9H), 1.25 (s, 9H), 1.20 (d, J = 8.0 Hz, 3H). MS m/z [M+H] + : 375.3, [MH] - : 373.5.
Figure 02_image076

將Int- 1i (12.0 g，32.1 mmol) 溶解於甲醇（150 mL）中，加入HCl的二氧六環溶液（15 mL，4 M），升溫至40℃，攪拌反應1小時，停止反應。反應液冷卻至室溫，減壓濃縮，得到Int- 1 （7.85 g，產率100%）。 1 H NMR (400 MHz, DMSO):δ 9.25 (br, 2H), 8.38 (br, 3H), 4.20-4.23 (m, 1H), 3.81 (d,J = 8.0 Hz, 1H), 3.62 (d,J = 8.0 Hz, 1H), 3.46 (br, 1H), 3.14-3.23 (m, 2H), 2.84-2.92 (m, 2H), 1.69-2.01 (m, 4H), 1.22 (d,J = 8.0 Hz, 3H)。MSm/z [M+H]+ : 171.2。 Int - 1i (12.0 g, 32.1 mmol) was dissolved in methanol (150 mL), HCl in dioxane solution (15 mL, 4 M) was added, the temperature was raised to 40 °C, and the reaction was stirred for 1 hour to stop the reaction. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain Int - 1 (7.85 g, yield 100%). 1 H NMR (400 MHz, DMSO): δ 9.25 (br, 2H), 8.38 (br, 3H), 4.20-4.23 (m, 1H), 3.81 (d, J = 8.0 Hz, 1H), 3.62 (d, J = 8.0 Hz, 1H), 3.46 (br, 1H), 3.14-3.23 (m, 2H), 2.84-2.92 (m, 2H), 1.69-2.01 (m, 4H), 1.22 (d, J = 8.0 Hz , 3H). MS m/z [M+H] + : 171.2.

中間體 Int-2 的製備

Figure 02_image078
Preparation of Intermediate Int-2
Figure 02_image078

將1-溴-3-氟-2-三氟甲苯（Int-1a ，10.0 g，41.1 mmol），碳酸銫（26.8 g，82.3 mmol），第三丁基硫醇（4.4 g，49.3 mmol），N,N-二甲基甲醯胺（100 mL）加入反應瓶中，50℃反應過夜。反應完後加水淬滅，乙酸乙酯萃取，有機相減壓濃縮，重結晶得中間體Int-2 （10.0 g，產率77.6%）。1 H NMR (400 MHz, CDCl3 ):δ 7.74 (d,1H), 7.67 (d, 1H), 7.26 (t, 1H), 1.31 (s, 9H).Combine 1-bromo-3-fluoro-2-trifluorotoluene ( Int-1a , 10.0 g, 41.1 mmol), cesium carbonate (26.8 g, 82.3 mmol), tert-butylthiol (4.4 g, 49.3 mmol), N,N-dimethylformamide (100 mL) was added to the reaction flask, and the reaction was carried out at 50 °C overnight. After the reaction, water was added to quench, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and recrystallized to obtain the intermediate Int-2 (10.0 g, yield 77.6%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, 1H), 7.67 (d, 1H), 7.26 (t, 1H), 1.31 (s, 9H).

實施例 1

Figure 02_image080
Figure 02_image082
Figure 02_image084
Example 1
Figure 02_image080
Figure 02_image082
Figure 02_image084

將Int-2 （1.5 g，4.8 mmol），1- 甲基 -1H - 吡唑 -5- 硼酸頻哪醇酯 （1.0 g，4.8 mmol），磷酸鉀 （4.0 g，19.1 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （0.7 g，0.9 mmol）加入水（20 mL）和1,4-二氧六環（80mL）中，氮氣置換，回流反應6小時。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到1a （1.2 g，產率79.7%）。1 H NMR (400 MHz, CDCl3 ):δ 7.23 (dd,1H), 7.45 (m, 2H), 7.35 (d, 1H), 6.29 (d, 1H), 3.95 (s, 3H),1.34 (s, 9H).

Figure 02_image086
Int-2 (1.5 g, 4.8 mmol), 1 -methyl - 1H - pyrazole- 5- boronic acid pinacol ester (1.0 g, 4.8 mmol), potassium phosphate (4.0 g, 19.1 mmol), [1 ,1' -Bis ( diphenylphosphino ) ferrocene ] palladium dichloride (0.7 g, 0.9 mmol) was added to water (20 mL) and 1,4-dioxane (80 mL), nitrogen was replaced, The reaction was refluxed for 6 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1a (1.2 g, yield 79.7%). 1 H NMR (400 MHz, CDCl 3 ): δ 7.23 (dd, 1H), 7.45 (m, 2H), 7.35 (d, 1H), 6.29 (d, 1H), 3.95 (s, 3H), 1.34 (s , 9H).
Figure 02_image086

將1a （1.0 g，3.2 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到1b 粗品（0.5 g，產率60.8%）。1 H NMR (400 MHz, CDCl3 )δ 7.29 (m,4H), 6.29 (d, 1H), 3.95 (s, 3H).

Figure 02_image088
1a (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 1b (0.5 g, yield 60.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (m, 4H), 6.29 (d, 1H), 3.95 (s, 3H).
Figure 02_image088

將1b （0.5 g，1.9 mmol），2,5- 二氯吡嗪 （1.4 g，9.6 mmol），碳酸鉀（530.3 mg，3.8 mmol）加入乙腈（5 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到1c （300 mg，產率41.8%）。1 H NMR (400 MHz, CDCl3 )δ 8.35 (d,1H), 8.05 (d, 1H), 7.70 (m, 1H), 7.58 (m, 2H), 7.39 (d, 1H) , 6.33 (d, 1H), 3.95 (s, 3H).

Figure 02_image090
1b (0.5 g, 1.9 mmol), 2,5- dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80 °C to react overnight. It was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1c (300 mg, yield 41.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, 1H), 8.05 (d, 1H), 7.70 (m, 1H), 7.58 (m, 2H), 7.39 (d, 1H) , 6.33 (d, 1H), 3.95 (s, 3H).
Figure 02_image090

向反應瓶中加入1c （100.0 mg，0.27 mmol），Int-1 （138.0 mg，0.81 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （164.0 mg，1.1 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到1 （20.0 mg，產率14.7%）。MSm/z [M+H]+ : 505.2; 1 H NMR (400 MHz, CDCl3 ):δ 8.96 (d,1H), 8.41 (d,1H), 8.25 (d, 1H), 7.73 (d, 1H), 7.47 (t, 1H), 7.26 (d, 1H) , 7.14 (d, 1H), 6.30 (d, 1H), 4.07 (t, 1H), 3.91 (m, 6H), 3.69 (d, 1H), 3.54 (m, 2H), 2.92 (d, 1H), 1.76 (m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.08 (d, 3H).To the reaction flask was added 1c (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8 -diazabicycloundec- 7- ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 1 (20.0 mg, 14.7% yield). MS m/z [M+H] + : 505.2; 1 H NMR (400 MHz, CDCl 3 ): δ 8.96 (d, 1H), 8.41 (d, 1H), 8.25 (d, 1H), 7.73 (d, 1H), 7.47 (t, 1H), 7.26 (d, 1H) , 7.14 (d, 1H), 6.30 (d, 1H), 4.07 (t, 1H), 3.91 (m, 6H), 3.69 (d, 1H) ), 3.54 (m, 2H), 2.92 (d, 1H), 1.76 (m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.08 (d, 3H) .

實施例 2

Figure 02_image092
Figure 02_image094
Figure 02_image096
Example 2
Figure 02_image092
Figure 02_image094
Figure 02_image096

將三正丁基氫錫 （2.8 g，9.6 mmol）溶於四氫呋喃（20 mL）中，0℃滴加LDA（2M，4.8 mL，9.6 mmol）後反應1小時，降溫至-78℃，緩慢加入2a （1.0 g，8.7mmol）的四氫呋喃（5 mL）溶液，加完後繼續反應4小時，加入飽和氟化鉀溶液（20 mL）後升至室溫攪拌1小時，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到2b （1.5 g，產率46.5%）。1 H NMR (400 MHz, CDCl3 ):δ 8.71-8.73 (m, 1H), 8.57(d, 1H), 8.36-8.40 (m, 1H), 1.54-1.62 (m, 6H), 1.30-1.39 (m, 6H), 1.16-1.20 (m, 6H), 0.90 (t, 9H).

Figure 02_image098
Tri-n-butyltin hydride (2.8 g, 9.6 mmol) was dissolved in tetrahydrofuran (20 mL), LDA (2M, 4.8 mL, 9.6 mmol) was added dropwise at 0°C, reacted for 1 hour, cooled to -78°C, slowly added A solution of 2a (1.0 g, 8.7 mmol) in tetrahydrofuran (5 mL) was added, and the reaction was continued for 4 hours. After adding saturated potassium fluoride solution (20 mL), the solution was warmed to room temperature and stirred for 1 hour. The organic phase was extracted with ethyl acetate. Washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2b (1.5 g, yield 46.5%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.71-8.73 (m, 1H), 8.57 (d, 1H), 8.36-8.40 (m, 1H), 1.54-1.62 (m, 6H), 1.30-1.39 ( m, 6H), 1.16-1.20 (m, 6H), 0.90 (t, 9H).
Figure 02_image098

將Int-2 （1.5 g，4.8 mmol），2b （1.5 g，4.0 mmol），四三苯基膦鈀（0.55 g，0.47 mmol）溶於二甲苯（10 mL）中，氮氣置換，140℃反應過夜。反應完全後，加入水，乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到2c （0.9 g，產率60.2%）。1 H NMR (400 MHz, CDCl3 )δ 8.60 (m,3H), 7.87 (d, 1H), 7.56 (m, 1H), 7.37 (m, 1H), 1.38 (s, 9H).

Figure 02_image100
Dissolve Int-2 (1.5 g, 4.8 mmol), 2b (1.5 g, 4.0 mmol), tetrakistriphenylphosphine palladium (0.55 g, 0.47 mmol) in xylene (10 mL), replace with nitrogen, and react at 140 °C overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2c (0.9 g, yield 60.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (m, 3H), 7.87 (d, 1H), 7.56 (m, 1H), 7.37 (m, 1H), 1.38 (s, 9H).
Figure 02_image100

將2c （0.9 g，2.9 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到2d 粗品（0.5 g，產率67.7%）。1 H NMR (400 MHz, CDCl3 )δ 8.61 (m,3H), 7.50 (d, 1H), 7.41 (t, 1H), 7.17 (d, 1H).

Figure 02_image102
2c (0.9 g, 2.9 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 2d (0.5 g, yield 67.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (m, 3H), 7.50 (d, 1H), 7.41 (t, 1H), 7.17 (d, 1H).
Figure 02_image102

將2d （0.5 g，2.0 mmol），2,5- 二氯吡嗪 （0.9 g，5.8 mmol），碳酸鉀（0.8 g，5.8 mmol）加入乙腈（10 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到2e （300 mg，產率41.7%）。MSm/z [M+H]+ : 368.9.

Figure 02_image104
2d (0.5 g, 2.0 mmol), 2,5- dichloropyrazine (0.9 g, 5.8 mmol), potassium carbonate (0.8 g, 5.8 mmol) were added to acetonitrile (10 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, added water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2e (300 mg, yield 41.7%). MS m/z [M+H] + : 368.9.
Figure 02_image104

向反應瓶中加入2e （100.0 mg，0.27 mmol），Int-1 （92.3 mg，0.54 mmol），1,8-二氮雜二環十一碳-7-烯（206.4 mg，1.36 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到2 （5.5 mg，產率4.0%）。 MSm/z [M+H]+ : 503.2; 1 H NMR (400 MHz, CDCl3 )δ 8.64 (d, 2H), 8.59 (d, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.39 (q, 2H) , 7.20 (d, 1H), 5.35 (m, 1H), 4.19 (t, 1H), 3.93 (m, 2H), 3.82 (d, 1H), 3.69 (d, 1H), 3.48 (m, 1H), 3.36 (m, 1H), 3.27 (m, 1H), 3.00(s, 1H), 2.02(m, 1H), 1.89 (m, 1H), 1.77 (m, 2H), 1.24(d, 3H).To the reaction flask was added 2e (100.0 mg, 0.27 mmol), Int-1 (92.3 mg, 0.54 mmol), 1,8-diazabicycloundec-7-ene (206.4 mg, 1.36 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 2 (5.5 mg, 4.0% yield). MS m/z [M+H] + : 503.2; 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, 2H), 8.59 (d, 1H), 8.24 (s, 1H), 8.18 (s, 1H) ), 7.39 (q, 2H), 7.20 (d, 1H), 5.35 (m, 1H), 4.19 (t, 1H), 3.93 (m, 2H), 3.82 (d, 1H), 3.69 (d, 1H) , 3.48 (m, 1H), 3.36 (m, 1H), 3.27 (m, 1H), 3.00(s, 1H), 2.02(m, 1H), 1.89 (m, 1H), 1.77 (m, 2H), 1.24(d, 3H).

實施例 3

Figure 02_image106
Figure 02_image108
Figure 02_image110
Example 3
Figure 02_image106
Figure 02_image108
Figure 02_image110

將Int-2 （2.4 g，7.7 mmol），1- 甲基 -1H - 吡唑 -4- 硼酸 （1.0 g，7.7 mmol），磷酸鉀 （4.0 g，19.1 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （1.1 g，1.5 mmol）加入水（20 mL）和1,4-二氧六環（80mL）中，氮氣置換，回流反應6小時。反應完全後，加入水，乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到3a （1.9 g，產率78.8%）。1 H NMR (400 MHz, CDCl3 )δ 7.68 (m,1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.31 (m,1H), 3.95 (s, 3H), 1.33 (s, 9H).

Figure 02_image112
Combine Int-2 (2.4 g, 7.7 mmol), 1 -methyl - 1H - pyrazole- 4 - boronic acid (1.0 g, 7.7 mmol), potassium phosphate (4.0 g, 19.1 mmol), [1,1'- Bis ( diphenylphosphino ) ferrocene ] palladium dichloride (1.1 g, 1.5 mmol) was added to water (20 mL) and 1,4-dioxane (80 mL), nitrogen was replaced, and the reaction was refluxed for 6 hours . After the reaction was completed, water was added and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 3a (1.9 g, yield 78.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (m, 1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.31 (m, 1H), 3.95 (s, 3H), 1.33 (s, 9H).
Figure 02_image112

將3a （1.0 g，3.2 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到3b 粗品（0.5 g，產率60.8%）。1 H NMR (400 MHz, CDCl3 )δ 7.45 (s,1H), 7.42 (s, 1H), 7.20 (d, 2H), 7.02 (d,1H), 3.88 (s, 3H).

Figure 02_image114
3a (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude 3b (0.5 g, yield 60.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (s, 1H), 7.42 (s, 1H), 7.20 (d, 2H), 7.02 (d, 1H), 3.88 (s, 3H).
Figure 02_image114

將3b （0.5 g，1.9 mmol），2,5- 二氯吡嗪 （1.4 g，9.6 mmol），碳酸鉀（530.3 mg，3.8 mmol）加入乙腈（5 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到3c （300 mg，產率41.8%）。1 H NMR (400 MHz, CDCl3 )δ 8.36 (d,1H), 8.09 (d, 1H), 7.63 (m, 1H), 7.53 (m,1H), 7.49 (s, 1H), 7.42 (m,2H),3.96 (s, 3H).

Figure 02_image116
3b (0.5 g, 1.9 mmol), 2,5- dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 3c (300 mg, yield 41.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, 1H), 8.09 (d, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.49 (s, 1H), 7.42 (m, 2H), 3.96 (s, 3H).
Figure 02_image116

向反應瓶中加入3c （100.0 mg，0.27 mmol），Int-1 （138.0 mg，0.81 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （164.0 mg，1.1 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到3 （5.0 mg，產率3.7%）。MSm/z [M+H]+ : 505.2; 1 H NMR (400 MHz, CDCl3 )δ 8.22 (d,1H), 8.17 (d, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.26 (t, 1H) , 7.10 (t, 2H), 4.21 (q, 1H), 3.97 (m, 1H), 3.95 (m, 4H), 3.83 (d, 1H), 3.72 (d, 1H), 3.53 (m, 1H), 3.32 (m, 1H), 3.02 (d, 1H), 2.01 (m, 1H), 1.79(m, 1H), 1.76(m, 1H), 1.72 (m, 1H), 1.26 (d, 3H).To the reaction flask was added 3c (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8 -diazabicycloundec- 7- ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 3 (5.0 mg, 3.7% yield). MS m/z [M+H] + : 505.2; 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, 1H), 8.17 (d, 1H), 7.50 (s, 1H), 7.41 (s, 1H) ), 7.26 (t, 1H), 7.10 (t, 2H), 4.21 (q, 1H), 3.97 (m, 1H), 3.95 (m, 4H), 3.83 (d, 1H), 3.72 (d, 1H) , 3.53 (m, 1H), 3.32 (m, 1H), 3.02 (d, 1H), 2.01 (m, 1H), 1.79(m, 1H), 1.76(m, 1H), 1.72 (m, 1H), 1.26(d, 3H).

實施例 4

Figure 02_image118
Figure 02_image120
Figure 02_image122
Example 4
Figure 02_image118
Figure 02_image120
Figure 02_image122

將Int-2 （1.4 g，4.5 mmol），1- 乙基 -1H - 吡唑 -4- 硼酸頻那醇酯 （1.0 g，4.5 mmol），磷酸鉀 （2.4 g，11.2 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （163.5 mg，0.2 mmol）加入水（20 mL）和1,4-二氧六環（80mL）中，氮氣置換，回流反應6小時。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到4a （1.2 g，產率81.7%）。1 H NMR (400 MHz, CDCl3 )δ 7.67 (m,1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.39 (m, 1H), 7.32 (m, 1H) , 4.21 (q, 2H), 1.53 (t, 3H), 1.33 (s, 9H).

Figure 02_image124
Int-2 (1.4 g, 4.5 mmol), 1- ethyl - 1H - pyrazole- 4 - boronic acid pinacol ester (1.0 g, 4.5 mmol), potassium phosphate (2.4 g, 11.2 mmol), [1 ,1' -Bis ( diphenylphosphino ) ferrocene ] palladium dichloride (163.5 mg, 0.2 mmol) was added to water (20 mL) and 1,4-dioxane (80 mL), nitrogen was replaced, The reaction was refluxed for 6 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 4a (1.2 g, yield 81.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (m, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.39 (m, 1H), 7.32 (m, 1H) , 4.21 (q, 2H), 1.53 (t, 3H), 1.33 (s, 9H).
Figure 02_image124

將4a （1.2 g，3.7 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到4b 粗品（0.6 g，產率60.3%）。 MSm/z [M+H]+ : 273.2.

Figure 02_image126
4a (1.2 g, 3.7 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude 4b (0.6 g, yield 60.3%). MS m/z [M+H] + : 273.2.
Figure 02_image126

將4b （0.6 g，2.2 mmol），2,5- 二氯吡嗪 （1.0 g，6.6 mmol），碳酸鉀（910.3 mg，6.6 mmol）加入乙腈（5 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到4c （300 mg，產率35.4%）。1 H NMR (400 MHz, CDCl3 )δ 8.36 (d,1H), 8.08 (d, 1H), 7.63 (dd, 1H), 7.55 (s, 1H), 7.51 (m, 1H) , 7.44 (m, 2H), 4.23 (q, 3H), 1.54 (t, 3H).

Figure 02_image128
4b (0.6 g, 2.2 mmol), 2,5- dichloropyrazine (1.0 g, 6.6 mmol), potassium carbonate (910.3 mg, 6.6 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 4c (300 mg, yield 35.4%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.63 (dd, 1H), 7.55 (s, 1H), 7.51 (m, 1H) , 7.44 (m, 2H), 4.23 (q, 3H), 1.54 (t, 3H).
Figure 02_image128

向反應瓶中加入4c （100.0 mg，0.26 mmol），Int-1 （88.5 mg，0.52 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （200.0 mg，1.3 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到4 （34.6 mg，產率25.7%）。 MSm/z [M+H]+ : 519.3; 1 H NMR (400 MHz, CDCl3 ): δ 8.42 (d,1H), 8.25 (d, 1H), 7.88 (s, 1H), 7.49 (s, 1H), 7.43 (t, 1H) , 7.21 (d, 1H), 7.04 (d, 1H), 4.17 (q, 2H), 4.11 (t, 1H), 3.96 (m, 2H), 3.74 (d, 1H), 3.54 (d, 1H), 3.39 (m, 2H), 3.04 (d, 1H), 1.73 (m, 2H), 1.54 (m, 2H), 1.38(t, 3H), 1.11(d, 3H).To the reaction flask was added 4c (100.0 mg, 0.26 mmol), Int-1 (88.5 mg, 0.52 mmol), 1,8 -diazabicycloundec- 7- ene (200.0 mg, 1.3 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 4 (34.6 mg, 25.7% yield). MS m/z [M+H] + : 519.3; 1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (d, 1H), 8.25 (d, 1H), 7.88 (s, 1H), 7.49 (s, 1H), 7.43 (t, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 4.17 (q, 2H), 4.11 (t, 1H), 3.96 (m, 2H), 3.74 (d, 1H) ), 3.54 (d, 1H), 3.39 (m, 2H), 3.04 (d, 1H), 1.73 (m, 2H), 1.54 (m, 2H), 1.38(t, 3H), 1.11(d, 3H) .

實施例 5

Figure 02_image130
Figure 02_image132
Figure 02_image134
Example 5
Figure 02_image130
Figure 02_image132
Figure 02_image134

將Int-2 （1.3 g，4.2 mmol），1-(2- 羥基乙基 )-1H - 吡唑 -4- 硼酸頻哪醇酯 （1.0 g，4.2 mmol），磷酸鉀 （2.2 g，10.5 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （153.0 mg，0.2 mmol）加入水（10 mL）和1,4-二氧六環（40mL）中，氮氣置換，回流反應6小時。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到5a （1.2 g，產率82.9%）。1 H NMR (400 MHz, CDCl3 )δ (ppm) 7.69 (dd,1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.42 (m,1H), 7.31 (m, 1H), 4.28 (t, 2H), 4.05 (t, 2H), 1.33 (s, 9H).

Figure 02_image136
Int-2 (1.3 g, 4.2 mmol), 1-(2- hydroxyethyl )-1H - pyrazole- 4 - boronic acid pinacol ester (1.0 g, 4.2 mmol), potassium phosphate (2.2 g, 10.5 mmol), [1,1'- bis ( diphenylphosphino ) ferrocene ] palladium dichloride (153.0 mg, 0.2 mmol) was added to water (10 mL) and 1,4-dioxane (40 mL) nitrogen was replaced, and the reaction was refluxed for 6 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 5a (1.2 g, yield 82.9%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.69 (dd, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.42 (m, 1H), 7.31 (m, 1H), 4.28 (t, 2H), 4.05 (t, 2H), 1.33 (s, 9H).
Figure 02_image136

將5a （1.0 g，2.9 mmol）溶於25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到5b 粗品（0.5 g，產率59.7%）。1 H NMR (400 MHz, CDCl3 )δ (ppm) 7.83 (d,1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.44 (t,1H), 7.21 (d, 1H), 4.31 (t, 2H), 4.05 (t, 2H).

Figure 02_image138
5a (1.0 g, 2.9 mmol) was dissolved in 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude 5b (0.5 g, yield 59.7%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.83 (d, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.44 (t, 1H), 7.21 (d, 1H), 4.31 (t, 2H), 4.05 (t, 2H).
Figure 02_image138

將5b （0.5 g，1.7 mmol），2,5-二氯吡嗪（1.4 g，9.6 mmol），碳酸鉀（530.3 mg，3.8 mmol）加入乙腈（5 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到5c （280 mg，產率40.3%）。1 H NMR (400 MHz, CDCl3 )δ (ppm) 8.33 (s,2H), 7.75 (d, 1H), 7.49 (s, 2H), 7.37 (t,1H), 7.15 (d, 1H), 4.24 (t, 2H), 3.96 (s, 2H).

Figure 02_image140
5b (0.5 g, 1.7 mmol), 2,5-dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 5c (280 mg, yield 40.3%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.33 (s, 2H), 7.75 (d, 1H), 7.49 (s, 2H), 7.37 (t, 1H), 7.15 (d, 1H), 4.24 (t, 2H), 3.96 (s, 2H).
Figure 02_image140

向反應瓶中加入5c （100.0 mg，0.25 mmol），Int-1 （85.0 mg，0.5 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （266.0 mg，1.7 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到5 （5.1 mg，產率3.8%）。MSm/z [M+H]+ : 535.2; 1 H NMR (400 MHz, CDCl3 ):δ (ppm) 8.39 (s,1H), 8.22 (s, 1H), 7.80 (s, 1H), 7.48 (s, 1H), 7.41 (t, 1H) , 7.19 (d, 1H), 7.03 (d, 1H), 4.18 (t, 2H), 4.09 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.77 (t, 2H), 3.72 (d, 2H), 3.53 (d, 1H), 3.01 (d, 1H), 2.02 (m, 1H), 1.71(m, 1H), 1.68(m, 1H), 1.56 (m, 1H), 1.12 (d, 3H).To the reaction flask was added 5c (100.0 mg, 0.25 mmol), Int-1 (85.0 mg, 0.5 mmol), 1,8 -diazabicycloundec- 7- ene (266.0 mg, 1.7 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 5 (5.1 mg, 3.8% yield). MS m/z [M+H] + : 535.2; 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.39 (s, 1H), 8.22 (s, 1H), 7.80 (s, 1H), 7.48 (s, 1H), 7.41 (t, 1H) , 7.19 (d, 1H), 7.03 (d, 1H), 4.18 (t, 2H), 4.09 (m, 1H), 4.02 (m, 1H), 3.94 ( m, 2H), 3.77 (t, 2H), 3.72 (d, 2H), 3.53 (d, 1H), 3.01 (d, 1H), 2.02 (m, 1H), 1.71(m, 1H), 1.68(m , 1H), 1.56 (m, 1H), 1.12 (d, 3H).

實施例 6

Figure 02_image142
Figure 02_image144
Figure 02_image146
Example 6
Figure 02_image142
Figure 02_image144
Figure 02_image146

將Int-2 （5.0 g，15.9 mmol），聯硼酸頻哪醇酯 （8.0 g，31.9 mmol），醋酸鉀 （6.3 g，63.9 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （1.1 g，1.6 mmol）加入1,4-二氧六環（100mL）中，氮氣置換，80℃反應過夜。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到6a （3.6 g，產率62.6%）。1 H NMR (400 MHz, CDCl3 )δ (ppm) 7.72 (t,1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).

Figure 02_image148
Int-2 (5.0 g, 15.9 mmol), pinacol diboronate (8.0 g, 31.9 mmol), potassium acetate (6.3 g, 63.9 mmol), [1,1' -bis ( diphenylphosphino ) Ferrocene ] palladium dichloride (1.1 g, 1.6 mmol) was added to 1,4-dioxane (100 mL), nitrogen was replaced, and the reaction was performed at 80 °C overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6a (3.6 g, yield 62.6%). 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.72 (t, 1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).
Figure 02_image148

將6a （2.5 g，6.9 mmol），2- 溴嘧啶 （1.0 g，6.3 mmol），磷酸鉀 （4.0 g，18.9 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （460.0 mg，0.6 mmol）加入水（10 mL）和1,4-二氧六環（50mL）中，氮氣置換，回流反應過夜。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到6b （1.3 g，產率66.2%）。MSm/z [M+H]+ : 313.1。

Figure 02_image150
Combine 6a (2.5 g, 6.9 mmol), 2 - bromopyrimidine (1.0 g, 6.3 mmol), potassium phosphate (4.0 g, 18.9 mmol), [1,1'- bis ( diphenylphosphino ) ferrocene ] Palladium dichloride (460.0 mg, 0.6 mmol) was added to water (10 mL) and 1,4-dioxane (50 mL), nitrogen was replaced, and the reaction was refluxed overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6b (1.3 g, yield 66.2%). MS m/z [M+H] + : 313.1.
Figure 02_image150

將6b （1.0 g，3.2 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到6c 粗品（0.5 g，產率60.9%）。MSm/z [M+H]+ : 256.9。

Figure 02_image152
6b (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude 6c (0.5 g, yield 60.9%). MS m/z [M+H] + : 256.9.
Figure 02_image152

將6c （0.5 g，1.9 mmol），2,5- 二氯吡嗪 （1.4 g，9.6 mmol），碳酸鉀（560.3 mg，3.8 mmol）加入乙腈（5 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到6d （300 mg，產率41.7%）。MSm/z [M+H]+ : 368.9。

Figure 02_image154
6c (0.5 g, 1.9 mmol), 2,5- dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (560.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, added water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6d (300 mg, yield 41.7%). MS m/z [M+H] + : 368.9.
Figure 02_image154

向反應瓶中加入6d （100.0 mg，0.27 mmol），Int-1 （138.0 mg，0.81 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （164.0 mg，1.1 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到6 （40.0 mg，產率29.3%）。 1 H NMR (400 MHz, CDCl3 ):δ (ppm) 8.82 (d,2H), 8.17 (d, 2H), 7.73 (m, 4H), 4.23 (s, 1H), 4.07 (m, 2H) , 3.91 (s, 1H), 3.74 (d, 1H), 3.23 (m, 2H), 3.13 (s, 1H), 1.89 (s, 1H), 1.75 (s, 3H), 1.28 (d, 3H); MSm/z [M+H]+ : 503.1。To the reaction flask was added 6d (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8 -diazabicycloundec- 7- ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 6 (40.0 mg, 29.3% yield). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 8.82 (d, 2H), 8.17 (d, 2H), 7.73 (m, 4H), 4.23 (s, 1H), 4.07 (m, 2H) , 3.91 (s, 1H), 3.74 (d, 1H), 3.23 (m, 2H), 3.13 (s, 1H), 1.89 (s, 1H), 1.75 (s, 3H), 1.28 (d, 3H); MS m/z [M+H] + : 503.1.

實施例 7

Figure 02_image156
Figure 02_image158
Figure 02_image160
Example 7
Figure 02_image156
Figure 02_image158
Figure 02_image160

將7a （500 mg，1.80 mmol），噁唑 （149 mg，2.16 mmol），醋酸鈀 （40.4 mg，0.18 mmol），Xantphos （4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽） （208 mg，0.36mmol），第三丁醇鉀（403.4 mg， 3.60mmol）加入甲苯（8 mL）中，氮氣置換，110℃反應16小時。反應完全後，加入50 mL 水，乙酸乙酯萃取三次，有機相合併，飽和氯化鈉水溶液洗滌一遍，無水硫酸鈉乾燥，有機相濃縮後管柱層析得到7b （83 mg，產率：15.1%）。 1 H NMR (400 MHz, CDCl3 ):δ 7.85 (s, 1H), 7.70-7.63 (m, 2H), 7.42-7.33 (m, 2H)。

Figure 02_image162
7a (500 mg, 1.80 mmol), oxazole (149 mg, 2.16 mmol), palladium acetate (40.4 mg, 0.18 mmol), Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethylene) xanthene) (208 mg, 0.36 mmol), potassium tert-butoxide (403.4 mg, 3.60 mmol) was added to toluene (8 mL), nitrogen was replaced, and the reaction was carried out at 110 °C for 16 hours. After the reaction was completed, 50 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and column chromatography to obtain 7b (83 mg, yield: 15.1 %). 1 H NMR (400 MHz, CDCl 3 ): δ 7.85 (s, 1H), 7.70-7.63 (m, 2H), 7.42-7.33 (m, 2H).
Figure 02_image162

向反應瓶中加入7b （250.0 mg，1.08 mmol），第三丁基硫醇 （300.0 mg，3.27 mmol），碳酸銫 （703.4 mg，2.16mmol），N,N-二甲基甲醯胺（10 mL），130℃反應16小時。反應完全後，先將反應液冷卻到室溫，加入50 mL 水，乙酸乙酯萃取三次，有機相合併，飽和氯化鈉水溶液洗滌一遍，無水硫酸鈉乾燥，有機相濃縮後管柱層析得到7c （300 mg，產率：82.4%）。 1 H NMR (400 MHz, CDCl3 )δ 7.92-7.90 (m, 1H), 7.82 (s, 1H), 7.70-7.68 (m, 1H), 7.61-7.57 (m, 1H), 7.31 (s, 1H),1.39 (m, 9H)。

Figure 02_image164
To the reaction flask was added 7b (250.0 mg, 1.08 mmol), tert-butyl mercaptan (300.0 mg, 3.27 mmol), cesium carbonate (703.4 mg, 2.16 mmol), N,N-dimethylformamide (10 mL), and reacted at 130 °C for 16 hours. After the reaction was completed, the reaction solution was first cooled to room temperature, 50 mL of water was added, extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and then obtained by column chromatography. 7c (300 mg, yield: 82.4%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92-7.90 (m, 1H), 7.82 (s, 1H), 7.70-7.68 (m, 1H), 7.61-7.57 (m, 1H), 7.31 (s, 1H) ), 1.39 (m, 9H).
Figure 02_image164

7c (300 mg，0.99 mmol) 加入鹽酸（12M，12 mL）和乙腈（4 mL）中，90℃反應6小時，加水和乙酸乙酯萃取2次，飽和食鹽水洗一次，硫酸鈉乾燥，過濾乾燥劑，減壓濃縮乾，將得到的7d直接用於下一步反應。

Figure 02_image166
7c (300 mg, 0.99 mmol) was added to hydrochloric acid (12M, 12 mL) and acetonitrile (4 mL), reacted at 90°C for 6 hours, extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and dried by filtration was concentrated to dryness under reduced pressure, and the obtained 7d was directly used in the next reaction.
Figure 02_image166

將7d （211 mg，1.09 mmol），2- 溴 -5- 氯吡嗪 （19 mg，0.1 mmol），Pd2 (dba)3 （91.2 mg，0.09 mmol），Xantphos（57 mg，0.09 mmol），二乙基異丙胺（39 mg，0.29 mmol）加入1,4-二氧六環（10 mL），氮氣保護，100℃反應16小時。反應結束後，加入水，乙酸乙酯萃取，硫酸鈉乾燥，有機相濃縮後管柱層析得到7e （90 mg，產率：25.2%）。

Figure 02_image168
Combine 7d (211 mg, 1.09 mmol), 2- bromo -5 -chloropyrazine (19 mg, 0.1 mmol), Pd2(dba )3 ( 91.2 mg, 0.09 mmol), Xantphos (57 mg, 0.09 mmol), Diethylisopropylamine (39 mg, 0.29 mmol) was added to 1,4-dioxane (10 mL), under nitrogen protection, and reacted at 100 °C for 16 hours. After the reaction, water was added, extracted with ethyl acetate, dried over sodium sulfate, and the organic phase was concentrated to obtain 7e (90 mg, yield: 25.2%) by column chromatography.
Figure 02_image168

向反應瓶中加入7e （90.0 mg，0.25 mmol），Int-1 （73.0 mg，0.30 mmol），磷酸鉀 （320.0 mg，1.51 mmol），N,N-二甲基甲醯胺（5 mL），90℃反應4小時。反應完全後，加入水，乙酸乙酯萃取，硫酸鈉乾燥。有機相濃縮後管柱層析得到7 （36 mg，產率：29.1%）。 1 H NMR (400 MHz, CDCl3 )δ 8.45 (s, 1H),8.34-8.32 (m, 2H),7.67-7.55 (m, 2H), 7.45 (s, 1H),7.39-7.36 (m, 1H), 4.12-4.09 (m, 1H),3.96-3.90 (m, 2H), 3.71-3.66 (m, 1H), 3.53-3.51 (m, 2H), 3.46-3.43 (m, 1H), 2.96-2.94 (m, 1H), 1.82-1.49 (m, 4H), 1.12-1.10 (m, 3H); MSm/z [M+H]+ : 492.3。To the reaction flask was added 7e (90.0 mg, 0.25 mmol), Int-1 (73.0 mg, 0.30 mmol), potassium phosphate (320.0 mg, 1.51 mmol), N,N-dimethylformamide (5 mL), The reaction was carried out at 90°C for 4 hours. After the reaction was completed, water was added, extracted with ethyl acetate, and dried over sodium sulfate. The organic phase was concentrated and column chromatography gave 7 (36 mg, yield: 29.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.34-8.32 (m, 2H), 7.67-7.55 (m, 2H), 7.45 (s, 1H), 7.39-7.36 (m, 1H) ), 4.12-4.09 (m, 1H), 3.96-3.90 (m, 2H), 3.71-3.66 (m, 1H), 3.53-3.51 (m, 2H), 3.46-3.43 (m, 1H), 2.96-2.94 (m, 1H), 1.82-1.49 (m, 4H), 1.12-1.10 (m, 3H); MS m/z [M+H] + : 492.3.

實施例 8

Figure 02_image169
Figure 02_image171
Figure 02_image173
Example 8
Figure 02_image169
Figure 02_image171
Figure 02_image173

將Int-2 （108 mg，0.3 mmol），1- 苄基 -1H - 吡唑 -4- 硼酸頻哪醇酯 （34.6 mg，0.3 mmol），四（三苯基膦）鈀 （34.6 mg，0.03 mmol），碳酸鉀（83 mg，0.6 mmol）加入1,4-二氧六環（1.5 mL）和水（1.5 mL）中，氮氣置換，100-105℃反應16小時。反應完全後， 濃縮後管柱層析得到8a （75 mg，產率：64%）。 1 H NMR (400 MHz, CDCl3 )δ 7.67 (d,J = 8.0 Hz,1H), 7.57 (s,1H), 7.42 (s,1H), 7.39-7.37 (m, 2H), 7.35-7.30 (m, 3H), 7.25-7.23 (m, 3H), 5.36 (s, 2H), 1.32 (s, 9H)。

Figure 02_image175
Int-2 (108 mg, 0.3 mmol), 1- benzyl- 1 H - pyrazole- 4 - boronic acid pinacol ester (34.6 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (34.6 mg, 0.03 mmol), potassium carbonate (83 mg, 0.6 mmol) was added to 1,4-dioxane (1.5 mL) and water (1.5 mL), nitrogen was replaced, and the reaction was carried out at 100-105 °C for 16 hours. After the reaction was completed, 8a (75 mg, yield: 64%) was obtained by column chromatography after concentration. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.39-7.37 (m, 2H), 7.35-7.30 ( m, 3H), 7.25-7.23 (m, 3H), 5.36 (s, 2H), 1.32 (s, 9H).
Figure 02_image175

8a (90 mg，0.23 mmol) 加入鹽酸（12M，3 mL）中，80-90℃ 反應2小時，TLC檢測，反應結束後濃縮，加入2- 溴 -5- 氯吡嗪 （43 mg，0.23 mmol），Pd2 (dba)3 （21 mg，0.023 mmol），Xantphos（26 mg，0.046 mmol），二乙基異丙胺（89 mg，0.63 mmol）和1,4-二氧六環（2.3 mL），氮氣保護，100℃反應16小時。反應結束後，直接濃縮後管柱層析得到8c （30 mg，產率：29%）。 1 H NMR(400 MHz, CDCl3 ):δ 8.35 (m, 1H), 8.08 (m, 1H), 7.62 (d,J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.49 (t,J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.42 (d,J = 8.0 Hz, 1H), 7.36 (d,J = 8.0 Hz, 1H), 7.34 (d,J = 4.0 Hz, 1H), 7.24 (m, 1H), 7.23 (m, 1H), 5.36 (s, 2H)。

Figure 02_image169
8a (90 mg, 0.23 mmol) was added to hydrochloric acid (12M, 3 mL), reacted at 80-90 °C for 2 hours, detected by TLC, concentrated after the reaction was completed, and 2- bromo -5 -chloropyrazine (43 mg, 0.23 mmol) was added. ), Pd 2 (dba) 3 (21 mg, 0.023 mmol), Xantphos (26 mg, 0.046 mmol), diethylisopropylamine (89 mg, 0.63 mmol) and 1,4-dioxane (2.3 mL) , nitrogen protection, 100 ℃ reaction for 16 hours. After the reaction was completed, 8c (30 mg, yield: 29%) was obtained by column chromatography after direct concentration. 1 H NMR (400 MHz, CDCl 3 ): δ 8.35 (m, 1H), 8.08 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.24 (m, 1H), 7.23 (m, 1H), 5.36 (s, 2H).
Figure 02_image169

向反應瓶中加入8c （110.0 mg，0.25 mmol），Int-1 （72.0 mg，0.3 mmol），磷酸鉀 （159 mg，0.75 mmol），異丙醇（2.5 mL），80-85℃反應16小時。反應完全後，直接濃縮後管柱層析得到8 （90 mg，產率：62%）。 1 H NMR (400 MHz, CDCl3 )δ 8.24 (m, 1H), 8.20 (m, 1H), 7.60 (s, 1H), 7.46 (m, 1H), 7.42-7.33 (m, 3H), 7.28-7.26 (m, 3H), 7.16 (s, 1H), 7.14 (s, 1H), 5.39 (s, 2H), 4.24-4.21 (m, 1H), 4.00-3.90 (m, 2H), 3.85 (d,J =8.0 Hz, 1H), 3.73 (d,J = 12.0 Hz, 1H), 3.53-3.47 (m, 1H), 3.43-3.36 (m, 1H), 3.04 (d,J = 4.0 Hz,1H), 1.96-1.89 (m, 1H), 1.81-1.71 (m, 3H), 1.27 (d,J = 4.0 Hz, 3H); MSm/z [M+H]+ : 581.6。Add 8c (110.0 mg, 0.25 mmol), Int-1 (72.0 mg, 0.3 mmol), potassium phosphate (159 mg, 0.75 mmol), isopropanol (2.5 mL) to the reaction flask, and react at 80-85 °C for 16 hours . After the reaction was completed, 8 (90 mg, yield: 62%) was obtained by column chromatography after direct concentration. 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (m, 1H), 8.20 (m, 1H), 7.60 (s, 1H), 7.46 (m, 1H), 7.42-7.33 (m, 3H), 7.28- 7.26 (m, 3H), 7.16 (s, 1H), 7.14 (s, 1H), 5.39 (s, 2H), 4.24-4.21 (m, 1H), 4.00-3.90 (m, 2H), 3.85 (d, J =8.0 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.53-3.47 (m, 1H), 3.43-3.36 (m, 1H), 3.04 (d, J = 4.0 Hz, 1H), 1.96-1.89 (m, 1H), 1.81-1.71 (m, 3H), 1.27 (d, J = 4.0 Hz, 3H); MS m/z [M+H] + : 581.6.

實施例 9

Figure 02_image178
Figure 02_image180
Figure 02_image182
Example 9
Figure 02_image178
Figure 02_image180
Figure 02_image182

向100 mL單口瓶中加入9a （200 mg，1.10 mmol），9a-2 （266.2 mg，1.66 mmol），Pd2 (dba)3 （50.4 mg，0.06 mmol），BINAP（347.6 mg， 0.54mmol），Cs2 CO3 （1.08 g， 3.34mmol），Dioxane（8 mL）。在100 ℃下反應16h。後處理，先將反應液冷卻到室溫，加入50 mL 水，乙酸乙酯萃取三次，有機相合併，飽和氯化鈉水溶液洗滌一遍，無水硫酸鈉乾燥，過柱純化得9b （100 mg， 產率：34.3%）。1 H NMR (400 MHz, CDCl3 )δ 8.46-8.44 (m, 2H), 8.15-8.12 (m, 1H), 7.54-7.46 (m, 2H), 6.91-6.82 (m, 1H).

Figure 02_image184
9a (200 mg, 1.10 mmol), 9a-2 (266.2 mg, 1.66 mmol), Pd 2 (dba) 3 (50.4 mg, 0.06 mmol), BINAP (347.6 mg, 0.54 mmol), Cs2CO3 ( 1.08 g, 3.34 mmol), Dioxane (8 mL). The reaction was carried out at 100 °C for 16 h. After post-processing, the reaction solution was cooled to room temperature, 50 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column to obtain 9b (100 mg, yield 9b). rate: 34.3%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46-8.44 (m, 2H), 8.15-8.12 (m, 1H), 7.54-7.46 (m, 2H), 6.91-6.82 (m, 1H).
Figure 02_image184

向100 mL單口瓶中加入9b （100 mg，0.39 mmol），9b-2 （105 mg，1.16 mmol），Cs2 CO3 （251 mg， 3.34mmol），DMF（8 mL）。在130 ℃下反應16h。後處理，先將反應液冷卻到室溫，加入50 mL 水，乙酸乙酯萃取三次，有機相合併，飽和氯化鈉水溶液洗滌一遍，無水硫酸鈉乾燥，過柱純化得9c （90mg產率70.4%）。1 H NMR (400 MHz, CD3 OD)δ 8.26-8.25 (m, 2H), 7.26-7.43 (m, 3H), 6.72-6.71 (m, 1H), 1.23 (m, 9H).

Figure 02_image186
9b (100 mg, 0.39 mmol), 9b-2 (105 mg, 1.16 mmol), Cs 2 CO 3 (251 mg, 3.34 mmol), DMF (8 mL) were added to a 100 mL single-neck flask. The reaction was carried out at 130 °C for 16 h. After post-processing, the reaction solution was cooled to room temperature first, 50 mL of water was added, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column to obtain 9c (90 mg in a yield of 70.4 %). 1 H NMR (400 MHz, CD 3 OD) δ 8.26-8.25 (m, 2H), 7.26-7.43 (m, 3H), 6.72-6.71 (m, 1H), 1.23 (m, 9H).
Figure 02_image186

將9c ( 90 mg，0.50 mmol )溶解於乙腈(2 mL )中，濃鹽酸（12 M，6 mL），120 ℃反應5小時。加水和乙酸乙酯萃取2次，飽和食鹽水洗一次，硫酸鈉乾燥，過濾乾燥劑，減壓濃縮乾，直接用於下一步反應。

Figure 02_image188
9c (90 mg, 0.50 mmol) was dissolved in acetonitrile (2 mL), concentrated hydrochloric acid (12 M, 6 mL), and reacted at 120 °C for 5 hours. Water and ethyl acetate were added for extraction twice, washed once with saturated brine, dried over sodium sulfate, filtered with a desiccant, concentrated to dryness under reduced pressure, and used directly for the next reaction.
Figure 02_image188

將9d-2 (58.4 mg，0.3 mmol)，Xantphos (16 mg，0.02 mmol)，Pd2 (dba)3 (25 mg，0.02 mmol)，DIEA (106.7 mg，0.82 mmol)，Dioxane（8 mL）加入上一步的瓶子中，氮氣保護，100 ℃反應16小時。加入水，乙酸乙酯萃取，硫酸鈉乾燥，過濾乾燥劑，減壓濃縮乾，管柱層析純化得9e （100 mg， 產率76%）。1 H NMR (400 MHz, CDCl3 )δ 8.49-8.48 (m, 2H), 8.39-8.37 (m, 2H), 8.12 (s, 1H), 7.51-7.46 (m, 2H),6.89-6.86 (m, 1H).

Figure 02_image190
9d-2 (58.4 mg, 0.3 mmol), Xantphos (16 mg, 0.02 mmol), Pd2(dba )3 ( 25 mg, 0.02 mmol), DIEA (106.7 mg, 0.82 mmol), Dioxane (8 mL) were added In the bottle from the previous step, under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. Add water, extract with ethyl acetate, dry with sodium sulfate, filter the drying agent, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain 9e (100 mg, yield 76%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49-8.48 (m, 2H), 8.39-8.37 (m, 2H), 8.12 (s, 1H), 7.51-7.46 (m, 2H), 6.89-6.86 (m , 1H).
Figure 02_image190

向100 mL單口瓶中加入化合物9e （80 mg，0.20 mmol），再加入Int-1 （61 mg，0.25 mmol），DMF（5 mL），再加入磷酸鉀（256 mg，1.25 mmol），加熱至110 ℃，反應2小時。加入水，乙酸乙酯萃取，硫酸鈉乾燥，過濾乾燥劑，減壓濃縮乾，管柱層析純化得9 （4 mg，收率44%）。1 H NMR (400 MHz, CDCl3 )δ 8.39-8.38 (m, 2H), 8.31 (s, 1H), 8.25 (s, 1H), 7.54-7.52 (m, 1H), 7.45-7.42 (m, 1H), 7.04-7.02 (m, 1H), 6.85-6.83 (m, 1H) , 4.33-4.27 (m, 1H), 4.21-4.12 (m, 2H), 3.96-3.93 (m, 1H), 3.81-3.79 (m, 1H), 3.45-3.30 (m, 2H), 3.16-3.14 (m, 2H), 1.92-1.69(m, 4H),1.29-1.27 (m, 3H); MSm/z [M+H]+ : 518.2。Compound 9e (80 mg, 0.20 mmol) was added to a 100 mL single-neck flask, then Int-1 (61 mg, 0.25 mmol), DMF (5 mL), potassium phosphate (256 mg, 1.25 mmol) were added, and the mixture was heated to 110 °C, the reaction was carried out for 2 hours. Add water, extract with ethyl acetate, dry with sodium sulfate, filter the drying agent, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain 9 (4 mg, yield 44%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.39-8.38 (m, 2H), 8.31 (s, 1H), 8.25 (s, 1H), 7.54-7.52 (m, 1H), 7.45-7.42 (m, 1H) ), 7.04-7.02 (m, 1H), 6.85-6.83 (m, 1H) , 4.33-4.27 (m, 1H), 4.21-4.12 (m, 2H), 3.96-3.93 (m, 1H), 3.81-3.79 (m, 1H), 3.45-3.30 (m, 2H), 3.16-3.14 (m, 2H), 1.92-1.69(m, 4H), 1.29-1.27 (m, 3H); MS m/z [M+H ] + : 518.2.

實施例 10

Figure 02_image192
Figure 02_image194
Figure 02_image196
Example 10
Figure 02_image192
Figure 02_image194
Figure 02_image196

將Int-2 （5.0 g，15.9 mmol），聯硼酸頻哪醇酯 （8.0 g，31.9 mmol），醋酸鉀 （6.3 g，63.9 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （1.1 g，1.6 mmol）加入1,4-二氧六環（100mL）中，氮氣置換，80℃反應過夜。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到10a （3.6 g，產率62.6%）。1 H NMR (400 MHz, CDCl3 )δ 7.72 (t,1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).

Figure 02_image198
Int-2 (5.0 g, 15.9 mmol), pinacol diboronate (8.0 g, 31.9 mmol), potassium acetate (6.3 g, 63.9 mmol), [1,1' -bis ( diphenylphosphino ) Ferrocene ] palladium dichloride (1.1 g, 1.6 mmol) was added to 1,4-dioxane (100 mL), nitrogen was replaced, and the reaction was performed at 80 °C overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10a (3.6 g, yield 62.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (t, 1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).
Figure 02_image198

將10a （2.0 g，5.5 mmol），5- 溴吡唑并 [1,5-a ] 嘧啶 （1.0 g，5.1 mmol），磷酸鉀 （3.5 g，16.7 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （400.0 mg，0.5 mmol）加入水（10 mL）和1,4-二氧六環（50mL）中，氮氣置換，回流反應過夜。反應完全後，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到10b （1.4 g，產率71.7%）。1 H NMR (400 MHz, CDCl3 )δ 8.69 (dd,1H), 8.17 (d, 1H), 7.85 (d,1H), 7.56 (t, 1H), 7.45 (d,1H), 6.83 (d, 1H), 6.73 (dd,1H), 1.38 (s, 9H).

Figure 02_image200
Combine 10a (2.0 g, 5.5 mmol), 5- bromopyrazolo [1,5- a ] pyrimidine (1.0 g, 5.1 mmol), potassium phosphate (3.5 g, 16.7 mmol), [1,1' -bis ( Diphenylphosphino ) ferrocene ] palladium dichloride (400.0 mg, 0.5 mmol) was added to water (10 mL) and 1,4-dioxane (50 mL), nitrogen was replaced, and the reaction was refluxed overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10b (1.4 g, yield 71.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (dd, 1H), 8.17 (d, 1H), 7.85 (d, 1H), 7.56 (t, 1H), 7.45 (d, 1H), 6.83 (d, 1H), 6.73 (dd, 1H), 1.38 (s, 9H).
Figure 02_image200

將10b （1.4 g，3.9 mmol）加入25% 鹽酸（10 mL）中，回流反應2小時。冷卻至室溫，用二氯甲烷萃取，有機相減壓濃縮得到10c 粗品（0.8 g，產率68.0%）。1 H NMR (400 MHz, CDCl3 )δ 8.85 (s,1H), 8.16 (s, 1H), 7.38 (d,2H), 7.16 (s, 1H), 6.83 (s,1H), 6.70 (s, 1H).

Figure 02_image202
10b (1.4 g, 3.9 mmol) was added to 25% hydrochloric acid (10 mL), and the reaction was refluxed for 2 hours. It was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude 10c (0.8 g, yield 68.0%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.38 (d, 2H), 7.16 (s, 1H), 6.83 (s, 1H), 6.70 (s, 1H).
Figure 02_image202

將10c （0.8 g，2.7 mmol），2,5- 二氯吡嗪 （1.2 g，8.1 mmol），碳酸鉀（1.1 g，8.1 mmol）加入乙腈（10 mL）中，升溫至80℃反應過夜。冷卻至室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗，硫酸鈉乾燥，過濾，減壓濃縮，管柱層析分離得到10d （300 mg，產率27.1%）。1 H NMR (400 MHz, CDCl3 )δ 8.65 (dd,1H), 8.30 (d, 1H), 8.11 (m,2H), 7.74 (d, 1H), 7.59 (t,1H), 7.51 (d, 1H), 6.81 (d,1H), 6.68 (dd, 1H).

Figure 02_image204
10c (0.8 g, 2.7 mmol), 2,5- dichloropyrazine (1.2 g, 8.1 mmol), potassium carbonate (1.1 g, 8.1 mmol) were added to acetonitrile (10 mL), and the temperature was raised to 80 °C to react overnight. Cooled to room temperature, added water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10d (300 mg, yield 27.1%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (dd, 1H), 8.30 (d, 1H), 8.11 (m, 2H), 7.74 (d, 1H), 7.59 (t, 1H), 7.51 (d, 1H), 6.81 (d, 1H), 6.68 (dd, 1H).
Figure 02_image204

向反應瓶中加入10d （100.0 mg，0.24 mmol），Int-1 （83.5 mg，0.5 mmol），1,8- 二氮雜二環十一碳 -7- 烯 （186.8 mg，1.23 mmol），乙腈（2 mL），回流反應過夜。反應完全後，減壓濃縮，粗品經製備，得到10 （10.0 mg，產率7.5%）。MSm/z [M+H]+ : 542.2; 1 H NMR (400 MHz, CDCl3 )δ (ppm) 8.96 (d,1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.22 (d, 1H), 7.53 (t, 1H) , 7.36 (m, 2H), 7.04 (d, 1H), 6.71 (d, 1H), 4.30 (m, 1H), 4.23 (d, 1H), 3.97 (d, 1H), 3.85 (d, 1H), 3.61 (d, 1H), 3.55 (t, 1H), 3.35 (m, 1H), 3.23 (m, 1H), 2.05(m, 1H), 1.86(m, 1H), 1.81 (m, 1H), 1.73 (m, 1H), 1.30 (d, 3H).To the reaction flask was added 10d (100.0 mg, 0.24 mmol), Int-1 (83.5 mg, 0.5 mmol), 1,8 -diazabicycloundec- 7- ene (186.8 mg, 1.23 mmol), acetonitrile (2 mL), the reaction was refluxed overnight. After the reaction was complete, it was concentrated under reduced pressure and the crude product was prepared to give 10 (10.0 mg, 7.5% yield). MS m/z [M+H] + : 542.2; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.96 (d, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.22 ( d, 1H), 7.53 (t, 1H), 7.36 (m, 2H), 7.04 (d, 1H), 6.71 (d, 1H), 4.30 (m, 1H), 4.23 (d, 1H), 3.97 (d , 1H), 3.85 (d, 1H), 3.61 (d, 1H), 3.55 (t, 1H), 3.35 (m, 1H), 3.23 (m, 1H), 2.05(m, 1H), 1.86(m, 1H), 1.81 (m, 1H), 1.73 (m, 1H), 1.30 (d, 3H).

實施例 11

Figure 02_image206
Figure 02_image208
Figure 02_image210
Example 11
Figure 02_image206
Figure 02_image208
Figure 02_image210

向100 mL單口瓶中依次加入2- 胺基吡啶 （500 mg，5.31 mmol），甲烷三羧酸三乙酯 （2.5 g，11.68 mmol）和二甲苯（500 mg，0.18 mmol），在140 ℃下反應3h。後處理，分別用***、乙酸乙酯、甲醇打漿，得11a （1 g，收率74%）。1 H NMR (400 MHz, DMSO-d6 )δ 8.93-8.91 (m, 1H), 8.20-8.15 (m, 1H),7.70-7.37 (m, 2H), 4.16-4.11 (m, 2H),1.24-1.20 (m, 3H).

Figure 02_image212
2 -aminopyridine (500 mg, 5.31 mmol), triethyl methanetricarboxylate (2.5 g, 11.68 mmol) and xylene (500 mg, 0.18 mmol) were sequentially added to a 100 mL single-neck flask, and the mixture was heated at 140 °C. The reaction was carried out for 3 hours. After post-treatment, 11a (1 g, yield 74%) was obtained by beating with ether, ethyl acetate and methanol respectively. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.93-8.91 (m, 1H), 8.20-8.15 (m, 1H), 7.70-7.37 (m, 2H), 4.16-4.11 (m, 2H), 1.24 -1.20 (m, 3H).
Figure 02_image212

將11b （3.0g，16.75 mmol）加入N-N二甲基甲醯胺（30 mL）中，然後加入第三丁基硫醇（3.0g，33.50 mmol），碳酸銫(10.9 g，33.50 mmol），氮氣保護下，升溫至130℃反應24小時。冷卻到室溫，加入水，乙酸乙酯萃取，有機相用飽和食鹽水洗2次，無水硫酸鈉乾燥，過濾乾燥劑，減壓濃縮，過柱得到粗品11c （4.2 g，收率100%）。1 H NMR (400 MHz, DMSO)δ 7.24 (d,J = 8.0 Hz, 1H), 6.93-6.88 (m,2 H).

Figure 02_image214
11b (3.0 g, 16.75 mmol) was added to NN dimethylformamide (30 mL), followed by tert-butyl mercaptan (3.0 g, 33.50 mmol), cesium carbonate (10.9 g, 33.50 mmol), nitrogen Under the protection, the temperature was raised to 130 °C for 24 hours. It was cooled to room temperature, water was added, extracted with ethyl acetate, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered with a drying agent, concentrated under reduced pressure, and passed through a column to obtain crude product 11c (4.2 g, yield 100%). 1 H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.0 Hz, 1H), 6.93-6.88 (m, 2 H).
Figure 02_image214

將11c ( 4.2 g，16.75 mmol )分散在濃鹽酸(30 mL )中，氮氣保護，升溫至85℃攪拌反應1.5小時，冷卻到室溫，繼續攪拌1.5小時。過濾，濾餅用正己烷洗滌2次，得到粗品11d (1.6 g，收率50% )，直接用於下一步反應。

Figure 02_image216
11c (4.2 g, 16.75 mmol) was dispersed in concentrated hydrochloric acid (30 mL), under nitrogen protection, heated to 85 °C and stirred for 1.5 hours, cooled to room temperature, and continued to be stirred for 1.5 hours. After filtration, the filter cake was washed twice with n-hexane to obtain crude product 11d (1.6 g, yield 50%), which was directly used in the next reaction.
Figure 02_image216

將11d ( 1.3 g，6.67 mmol )溶解在二氧六環(15 mL )中，然後加入N-二異丙基乙胺(1.4 g，11.1 mmol），三[二亞苄基丙酮]二鈀 (512 mg，0.56 mmol），4,5-雙二苯基膦-9,9-二甲基氧雜蒽(642 mg，1.11 mmol），氮氣保護下，升溫至100℃反應16小時。冷卻至室溫，減壓濃縮，管柱層析純化得11e （1.1 g，收率54%）。1 H NMR (400 MHz, CDCl3 )δ 8.39 (s, 1H), 7.98 (s, 1H), 7.34-7.30 (m, 1H), 7.08 (d,J = 8.0 Hz, 1H), 6.86 (d,J = 8.0 Hz, 1H).

Figure 02_image218
11d (1.3 g, 6.67 mmol) was dissolved in dioxane (15 mL), followed by the addition of N-diisopropylethylamine (1.4 g, 11.1 mmol), tris[dibenzylideneacetone]dipalladium ( 512 mg, 0.56 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (642 mg, 1.11 mmol), under nitrogen protection, the temperature was raised to 100 °C for 16 hours. It was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain 11e (1.1 g, yield 54%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.34-7.30 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H).
Figure 02_image218

向氯苯（5 mL）中加入11e （210 mg，0.69 mmol），11a (150 mg，0.63 mmol），氮氣置換，升溫135℃攪拌24小時。加石油醚析出固體，過濾得到固體11f （240 mg，收率76%），直接用於下一步反應。

Figure 02_image220
To chlorobenzene (5 mL) were added 11e (210 mg, 0.69 mmol), 11a (150 mg, 0.63 mmol), nitrogen was replaced, and the temperature was increased to 135 °C and stirred for 24 hours. Add petroleum ether to precipitate a solid, and filter to obtain a solid 11f (240 mg, yield 76%), which is directly used in the next reaction.
Figure 02_image220

向二甲基亞碸（13 mL）中加入11f （240 mg，0.49 mmol），Int-1 (132 mg，0.54 mmol），磷酸鉀（612 mg，2.89 mmol），氮氣置換，升溫85℃攪拌16小時。加水析出固體，過濾得到固體，經矽膠管柱層析得目標產物11 （110 mg，收率36%）。MS m/z [M+H]+ 628.1;1 H NMR (400 MHz, DMSO)δ 12.61(s, 1H), 8.87 (d,J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.89 (d,J = 8.0 Hz, 2H), 7.45 (t,J = 8.0 Hz, 2H), 7.33 (d,J = 8.0 Hz, 2H), 7. 7.17 (s, 1H), 6.85 (d,J = 8.0 Hz, 2H), 4.15-4.02 (m, 3H), 3.80 (d,J = 4.0 Hz, 1H), 3.61 (d,J = 8.0 Hz, 1H), 3.36-3.30 (m, 2H), 3.18 (s, 1H), 1.78-1.55 (m, 4H), 1.26 (s, 2H), 1.17 (d,J = 8.0 Hz, 3H).To dimethylsulfoxide (13 mL) was added 11f (240 mg, 0.49 mmol), Int-1 (132 mg, 0.54 mmol), potassium phosphate (612 mg, 2.89 mmol), nitrogen was replaced, the temperature was increased to 85 °C and stirred for 16 Hour. Water was added to separate out the solid, and the solid was obtained by filtration. The target product 11 (110 mg, yield 36%) was obtained by silica gel column chromatography. MS m/z [M+H] + 628.1; 1 H NMR (400 MHz, DMSO) δ 12.61(s, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.27 ( s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7. 7.17 (s, 1H), 6.85 (d, J = 8.0 Hz, 2H), 4.15-4.02 (m, 3H), 3.80 (d, J = 4.0 Hz, 1H), 3.61 (d, J = 8.0 Hz, 1H) ), 3.36-3.30 (m, 2H), 3.18 (s, 1H), 1.78-1.55 (m, 4H), 1.26 (s, 2H), 1.17 (d, J = 8.0 Hz, 3H).

實施例 12

Figure 02_image222
Figure 02_image224
Figure 02_image226
Example 12
Figure 02_image222
Figure 02_image224
Figure 02_image226

50 mL單口瓶中加入嘧啶-2-羧酸（400 mg，3.2 mmol）和二氯亞碸（2 mL）。在80 ℃下反應3小時。後處理，減壓濃縮得12a ， 直接用於下一步。

Figure 02_image228
Pyrimidine-2-carboxylic acid (400 mg, 3.2 mmol) and dichlorosulfite (2 mL) were added to a 50 mL single-neck flask. The reaction was carried out at 80°C for 3 hours. After post-treatment, concentrated under reduced pressure to obtain 12a , which was directly used in the next step.
Figure 02_image228

將11e (100 mg，0.37 mmol )溶解於無水四氫呋喃(5 mL )中，將12a 的四氫呋喃滴加入反應液中，室溫過夜反應。減壓濃縮，過柱得12b （90 mg，收率60%）。1 H NMR (400 MHz, CDCl3 )δ 10.80 (s, 1H), 8.98 (d,J = 4.8 Hz, 2H), 8.67 (d,J = 8.4 Hz, 1H), 8.33 (d,J = 1.2 Hz, 1H), 8.11 (d,J = 1.2 Hz, 1H), 7.64 (t,J = 8.0 Hz, 1H), 7.59 – 7.47 (m, 2H).

Figure 02_image222
11e (100 mg, 0.37 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the tetrahydrofuran of 12a was added dropwise to the reaction solution, and the reaction was carried out at room temperature overnight. Concentrated under reduced pressure, passed through column to obtain 12b (90 mg, yield 60%). 1 H NMR (400 MHz, CDCl 3 ) δ 10.80 (s, 1H), 8.98 (d, J = 4.8 Hz, 2H), 8.67 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 1.2 Hz , 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.59 – 7.47 (m, 2H).
Figure 02_image222

100 mL單口瓶中加入化合物12b （90 mg，0.22 mmol），再加入Int-1 （41 mg，0.24 mmol），N,N-二甲基甲醯胺（3 mL），再加入磷酸鉀（280 mg，1.32 mmol），加熱至80 ℃，反應3小時。反應液冷卻至室溫，加入20 mL水，乙酸乙酯萃取2次，飽和食鹽水洗三次， 有機相硫酸鈉乾燥，旋乾，刮板，得到12 （20 mg，收率18%）。MSm/z [M+H]+ : 546.1;1 H NMR (400 MHz, CDCl3 )δ 10.65 (s, 1H), 8.98 (d,J = 4.8 Hz, 2H), 8.28 (d,J = 8.4Hz, 1H), 8.18 (s, 2H), 7.53 (t,J = 4.8 Hz, 1H), 7.38 (t,J = 8.4 Hz, 1H), 6.93 (d,J = 8.0 Hz, 1H), 4.32 – 3.98 (m, 4H), 3.76 (d,J = 9.2 Hz, 1H), 3.24 – 3.03 (m, 2H), 2.11 – 2.04 (m, 1H), 1.95 – 1.73 (m, 3H), 1.44 (d,J = 6.4 Hz, 3H)。Compound 12b (90 mg, 0.22 mmol) was added to a 100 mL single-neck flask, then Int-1 (41 mg, 0.24 mmol), N,N-dimethylformamide (3 mL), and potassium phosphate (280 mmol) were added. mg, 1.32 mmol), heated to 80 °C, and reacted for 3 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, extracted with ethyl acetate twice, washed with saturated brine three times, the organic phase was dried over sodium sulfate, spin-dried, and scraped to obtain 12 (20 mg, yield 18%). MS m/z [M+H] + : 546.1; 1 H NMR (400 MHz, CDCl 3 ) δ 10.65 (s, 1H), 8.98 (d, J = 4.8 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.18 (s, 2H), 7.53 (t, J = 4.8 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.32 – 3.98 (m, 4H), 3.76 (d, J = 9.2 Hz, 1H), 3.24 – 3.03 (m, 2H), 2.11 – 2.04 (m, 1H), 1.95 – 1.73 (m, 3H), 1.44 (d, J = 6.4 Hz, 3H).

實施例 13

Figure 02_image230
Figure 02_image232
Figure 02_image234
Example 13
Figure 02_image230
Figure 02_image232
Figure 02_image234

氮氣保護下，將11a (240 mg，1.0 mmol)和鈀碳（50 mg）加入至甲醇（5 mL）中，氫氣置換，常溫常壓下反應16小時。過濾，減壓濃縮得13b （240 mg，產率100%）。 1 H NMR (400 MHz, DMSO):δ 12.29 (br, 1H), 4.06 (q,J = 8.0 Hz, 2H), 3.64 (t,J = 8.0 Hz, 2H), 2.76 (t,J = 8.0 Hz, 2H), 1.71-1.83 (m, 4H), 1.17 (t,J = 8.0 Hz, 3H).

Figure 02_image236
Under nitrogen protection, 11a (240 mg, 1.0 mmol) and palladium on carbon (50 mg) were added to methanol (5 mL), replaced with hydrogen, and reacted at room temperature and pressure for 16 hours. Filtration and concentration under reduced pressure gave 13b (240 mg, 100% yield). 1 H NMR (400 MHz, DMSO): δ 12.29 (br, 1H), 4.06 (q, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 2.76 (t, J = 8.0 Hz) , 2H), 1.71-1.83 (m, 4H), 1.17 (t, J = 8.0 Hz, 3H).
Figure 02_image236

向氯苯（6 mL）中加入13b （240 mg，1.0 mmol），11e (305 mg，1.0mmol），氮氣置換，升溫135℃攪拌24小時。加石油醚析出固體，過濾得到固體，過柱得到白色固體13c （300 mg，收率60%）。1 H NMR (400 MHz, DMSO)δ 14.86 (s, 1H), 11.90 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 7.97-7.93 (m, 1H), 7.76-7.71 (m, 2H), 3.89-3.86 (m, 2H), 2.90 (t,J = 8.0 Hz, 2H), 1.95-1.81 (m, 4H).

Figure 02_image238
13b (240 mg, 1.0 mmol) and 11e (305 mg, 1.0 mmol) were added to chlorobenzene (6 mL), nitrogen was replaced, and the temperature was increased to 135° C. and stirred for 24 hours. Petroleum ether was added to separate out the solid, the solid was obtained by filtration, and passed through a column to obtain a white solid 13c (300 mg, yield 60%). 1 H NMR (400 MHz, DMSO) δ 14.86 (s, 1H), 11.90 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 7.97-7.93 (m, 1H), 7.76-7.71 (m, 2H), 3.89-3.86 (m, 2H), 2.90 (t, J = 8.0 Hz, 2H), 1.95-1.81 (m, 4H).
Figure 02_image238

向二甲基亞碸（5 mL）中加入13c （200 mg，0.40 mmol），Int-1 (147 mg，0.60 mmol），磷酸鉀（509 mg，2.40mmol），氮氣置換，升溫85℃攪拌16小時。加水析出固體，過濾得到固體，過柱得到目標產物13 （140 mg，收率55%）。MSm/z [M+H]+ : 632.2;1 H NMR (400 MHz, DMSO)δ 8.49 (s, 1H), 8.29 (s, 1H), 7.68 (m, 1H), 7.49 (m, 1H), 6.93 (m, 1H), 4.17-4.05 (m, 3H), 3.83-3.78 (m, 3H), 3.60 (d,J = 8.0 Hz, 1H), 3.14 (s, 1H), 2.84 (s, 2H), 1.91-1.57 (m, 9H), 1.26 (s, 3H), 1.16 (d,J = 8.0 Hz, 3H).To dimethylsulfoxide (5 mL) was added 13c (200 mg, 0.40 mmol), Int-1 (147 mg, 0.60 mmol), potassium phosphate (509 mg, 2.40 mmol), nitrogen was replaced, the temperature was increased to 85 °C and stirred for 16 Hour. Water was added to separate out the solid, the solid was obtained by filtration, and the target product 13 (140 mg, yield 55%) was obtained by passing through the column. MS m/z [M+H] + : 632.2; 1 H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 8.29 (s, 1H), 7.68 (m, 1H), 7.49 (m, 1H) , 6.93 (m, 1H), 4.17-4.05 (m, 3H), 3.83-3.78 (m, 3H), 3.60 (d, J = 8.0 Hz, 1H), 3.14 (s, 1H), 2.84 (s, 2H) ), 1.91-1.57 (m, 9H), 1.26 (s, 3H), 1.16 (d, J = 8.0 Hz, 3H).

實施例 14

Figure 02_image240
Figure 02_image242
Figure 02_image244
Example 14
Figure 02_image240
Figure 02_image242
Figure 02_image244

14a-1 (290 mg，1.0 mmol)，14a-2 (220 mg，1.0 mmol)，Pd(PPh3 )4 (115 mg，0.1 mmol)，K2 CO3 (238 mg，2.0 mmol)加入至DMF（1 mL），100-105℃下攪拌16小時。反應液倒入乙酸乙酯（100 mL）。10%食鹽水（50 mL）洗三次。有機相濃縮後管柱層析得到14b （190 mg， 產率：81.8%）。MSm/z [M+H]+ : 259.3; 1 H NMR (400 MHz, DMSO)δ 7.55 (s, 1H), 7.46 (s, 1H), 7.45-7.44 (m, 1H), 7.16-7.14 (m, 1H), 7.12-7.09 (m, 1H), 4.22 (q,J = 8.0 Hz,1H), 1.53 (t,J = 8.0 Hz,1H)。

Figure 02_image246
14a-1 (290 mg, 1.0 mmol), 14a-2 (220 mg, 1.0 mmol), Pd( PPh3 ) 4 ( 115 mg, 0.1 mmol), K2CO3 (238 mg, 2.0 mmol) were added to DMF (1 mL), stirred at 100-105 °C for 16 hours. The reaction solution was poured into ethyl acetate (100 mL). 10% saline (50 mL) washed three times. The organic phase was concentrated and column chromatography gave 14b (190 mg, yield: 81.8%). MS m/z [M+H] + : 259.3; 1 H NMR (400 MHz, DMSO) δ 7.55 (s, 1H), 7.46 (s, 1H), 7.45-7.44 (m, 1H), 7.16-7.14 ( m, 1H), 7.12-7.09 (m, 1H), 4.22 (q, J = 8.0 Hz, 1H), 1.53 (t, J = 8.0 Hz, 1H).
Figure 02_image246

14b (190 mg，0.74 mmol)，14b-2 (480 mg，2.2 mmol)，碳酸銫 (715 mg，2.2 mmol)，加入N,N-二甲基甲醯胺（2 mL），130℃條件下攪拌16小時。反應液倒入乙酸乙酯（100 mL）。10%食鹽水（50 mL）洗三次。有機相濃縮後管柱層析得到14c （70 mg， 產率：33.8%）。 1 H NMR (400 MHz, DMSO)δ 7.51 (s, 1H), 7.43 (s, 1H), 7.26-7.25 (m, 2H), 7.11-7.10 (m, 1H), 7.12-7.09 (m, 1H), 4.21 (q,J = 8.0 Hz,1H), 1.52 (t,J = 8.0 Hz,1H)。

Figure 02_image248
14b (190 mg, 0.74 mmol), 14b-2 (480 mg, 2.2 mmol), cesium carbonate (715 mg, 2.2 mmol), N,N-dimethylformamide (2 mL) was added, at 130 °C Stir for 16 hours. The reaction solution was poured into ethyl acetate (100 mL). 10% saline (50 mL) washed three times. The organic phase was concentrated and column chromatography gave 14c (70 mg, yield: 33.8%). 1 H NMR (400 MHz, DMSO) δ 7.51 (s, 1H), 7.43 (s, 1H), 7.26-7.25 (m, 2H), 7.11-7.10 (m, 1H), 7.12-7.09 (m, 1H) , 4.21 (q, J = 8.0 Hz, 1H), 1.52 (t, J = 8.0 Hz, 1H).
Figure 02_image248

14c (70 mg，0.25 mmol)，14c-2 (52 mg，0.28 mmol)，Pd(dba)3 (11 mg，0.01 mmol)，Xantphos (15 mg，0.02 mmol)，二乙基異丙胺 (96 mg，0.75 mmol)加入1,4-二氧六環（5 mL），氮氣保護，100-105℃條件下攪拌16小時。反應液濃縮後管柱層析得到14d （50 mg， 產率：52%）。MSm/z [M+H]+ : 385.0; 1 H NMR (400 MHz, DMSO)δ 8.36 (s, 1H), 8.08 (s, 1H), 7.63 (d,J = 8.0 Hz,1H), 7.55 (s, 1H), 7.51 (t,J = 8.0 Hz,1H), 7.47 (s, 1H), 7.44 (d,J = 8.0 Hz,1H)。

Figure 02_image250
14c (70 mg, 0.25 mmol), 14c-2 (52 mg, 0.28 mmol), Pd(dba) 3 (11 mg, 0.01 mmol), Xantphos (15 mg, 0.02 mmol), diethylisopropylamine (96 mg , 0.75 mmol) was added 1,4-dioxane (5 mL), under nitrogen protection, and stirred at 100-105 °C for 16 hours. After the reaction solution was concentrated, column chromatography gave 14d (50 mg, yield: 52%). MS m/z [M+H] + : 385.0; 1 H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H).
Figure 02_image250

將14d (50 mg，0.13 mmol),Int-1 (38 mg，0.16 mmol)，磷酸鉀 (82 mg，0.39 mmol)，加入二甲基亞碸（5 mL），80-90℃條件下攪拌5小時。反應液倒入乙酸乙酯（100 mL）。10%食鹽水（50 mL）洗三次。有機相濃縮後管柱層析得到14 （60 mg， 產率：88.9 %）, 純度99.1A%  (254 nm)。 1 H NMR (400 MHz, DMSO)δ 8.23 (m, 1H), 8.19 (m, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.29-7.25 (m,1H), 7.15-7.09 (s, 1H), 4.25-4.20 (m, 3H), 3.95-3.92 (m, 1H), 3.84 (d,J = 8.0 Hz,1H), 3.72 (d,J = 12.0 Hz, 1H), 3.49-3.47 (m, 1H), 3.39-3.34 (m, 1H), 3.03 (d,J = 8.0 Hz,1H), 1.93-1.88 (m, 1H), 1.79-1.74 (m, 3H), 1.54 (t,J = 8.0 Hz, 3H), 1.26 (d,J = 4.0 Hz, 3H)。MSm/z [M+H]+ : 519.2。 14d (50 mg, 0.13 mmol), Int-1 (38 mg, 0.16 mmol), potassium phosphate (82 mg, 0.39 mmol), dimethylsulfite (5 mL) were added, and the mixture was stirred at 80-90 °C for 5 Hour. The reaction solution was poured into ethyl acetate (100 mL). 10% saline (50 mL) washed three times. The organic phase was concentrated and column chromatography gave 14 (60 mg, yield: 88.9 %) with a purity of 99.1A% (254 nm). 1 H NMR (400 MHz, DMSO) δ 8.23 (m, 1H), 8.19 (m, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.29-7.25 (m, 1H), 7.15-7.09 (s, 1H), 4.25-4.20 (m, 3H), 3.95-3.92 (m, 1H), 3.84 (d, J = 8.0 Hz, 1H), 3.72 (d, J = 12.0 Hz, 1H), 3.49- 3.47 (m, 1H), 3.39-3.34 (m, 1H), 3.03 (d, J = 8.0 Hz, 1H), 1.93-1.88 (m, 1H), 1.79-1.74 (m, 3H), 1.54 (t, J = 8.0 Hz, 3H), 1.26 (d, J = 4.0 Hz, 3H). MS m/z [M+H] + : 519.2.

實施例 15

Figure 02_image252
Figure 02_image254
Figure 02_image256
Example 15
Figure 02_image252
Figure 02_image254
Figure 02_image256

將15a （92.4 mg，0.4 mmol），4- 溴 -1-( 四氫 -2H - 吡喃 -4- 基 )-1H - 吡唑 （111.0 mg，0.4 mmol），碳酸鈉 （85.0 mg，0.8 mmol），[1,1'- 雙 ( 二苯基膦基 ) 二茂鐵 ] 二氯化鈀 （29 mg，0.04 mmol）加入水（1 mL）和N,N-二甲基甲醯胺（1 mL）中，氮氣置換，100-105℃反應16小時。反應完全後，反應液倒入乙酸乙酯（100 mL），10%食鹽水（50 mL）洗三次。有機相濃縮後管柱層析得到15b （70 mg，產率：45%）。 1 H NMR (400 MHz, CDCl3 )δ 7.74-7.63 (m, 1H), 7.54-7.52 (m, 1H), 7.47-7.44 (m, 1H), 7.40-7.32 (m, 1H), 7.24 (m, 1H), 4.41-4.35 (m, 1H), 4.13-4.10 (m, 2H), 3.60-3.51 (m, 2H), 2.24-2.20 (m, 4H), 1.33 (s, 9H)。MSm/z [M+H]+ : 385.3。

Figure 02_image258
Combine 15a (92.4 mg, 0.4 mmol), 4- bromo - 1-( tetrahydro - 2H - pyran- 4 -yl ) -1H- pyrazole (111.0 mg, 0.4 mmol), sodium carbonate (85.0 mg, 0.8 mmol), [1,1'- bis ( diphenylphosphino ) ferrocene ] palladium dichloride (29 mg, 0.04 mmol) was added to water (1 mL) and N,N-dimethylformamide (1 mL), replaced with nitrogen, and reacted at 100-105 °C for 16 hours. After the reaction was completed, the reaction solution was poured into ethyl acetate (100 mL) and washed three times with 10% saline (50 mL). The organic phase was concentrated and column chromatography gave 15b (70 mg, yield: 45%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.74-7.63 (m, 1H), 7.54-7.52 (m, 1H), 7.47-7.44 (m, 1H), 7.40-7.32 (m, 1H), 7.24 (m , 1H), 4.41-4.35 (m, 1H), 4.13-4.10 (m, 2H), 3.60-3.51 (m, 2H), 2.24-2.20 (m, 4H), 1.33 (s, 9H). MS m/z [M+H] + : 385.3.
Figure 02_image258

15b (40 mg，0.1 mmol) 加入鹽酸（12M，2 mL），80℃ 攪拌兩小時，TLC檢測反應終點，濃縮脫溶，後加入2- 溴 -5- 氯吡嗪 (19 mg，0.1 mmol)，Pd2 (dba)3 (9 mg，0.01 mmol)，Xantphos (12 mg，0.02 mmol)，二乙基異丙胺 (38 mg，0.3 mmol)加入1,4-二氧六環（1 mL），氮氣保護，100-105℃條件下攪拌16小時。反應液濃縮後管柱層析得到15d （20 mg， 產率：45.4%）。 1 H NMR(400 MHz, CDCl3 )δ 8.40(d,J = 4.0 Hz,1H), 8.12(d,J = 4.0 Hz,1H), 7.76(d,J = 8.0 Hz,1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.59-7.39 (m, 2H), 4.45-4.38 (m, 1H), 4.18-4.12 (m, 2H), 3.63-3.55 (m, 2H), 2.20-2.09 (m, 4H)。MSm/z [M+H]+ : 441.1。

Figure 02_image260
15b (40 mg, 0.1 mmol) was added with hydrochloric acid (12M, 2 mL), stirred at 80°C for 2 hours, the reaction end was detected by TLC, concentrated and desolubilized, and then 2- bromo -5 -chloropyrazine (19 mg, 0.1 mmol) was added. , Pd 2 (dba) 3 (9 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), diethylisopropylamine (38 mg, 0.3 mmol) was added 1,4-dioxane (1 mL), Under nitrogen protection, the mixture was stirred at 100-105°C for 16 hours. After the reaction solution was concentrated, column chromatography gave 15d (20 mg, yield: 45.4%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40(d, J = 4.0 Hz, 1H), 8.12(d, J = 4.0 Hz, 1H), 7.76(d, J = 8.0 Hz, 1H), 7.66 (s , 1H), 7.62 (s, 1H), 7.59-7.39 (m, 2H), 4.45-4.38 (m, 1H), 4.18-4.12 (m, 2H), 3.63-3.55 (m, 2H), 2.20-2.09 (m, 4H). MS m/z [M+H] + : 441.1.
Figure 02_image260

向反應瓶中加入15d （50.0 mg，0.11 mmol），Int-1 （30.0 mg，0.12 mmol），磷酸鉀 （70.0 mg，0.33 mmol），二甲基亞碸（1.1 mL），80-90℃反應16小時。反應完全後，倒入乙酸乙酯（100 mL），10%食鹽水（50 mL）洗三次。有機相濃縮後管柱層析得到15 （38 mg，產率：60%）。 1 H NMR (400 MHz, CDCl3 )δ 8.22 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.28-7.24 (m,1H), 7.14-7.09 (m, 2H), 4.39-4.37 (m, 1H), 4.20-4.18 (m, 1H), 4.14-4.11 (m, 3H), 3.92-3.89 (m, 2H), 3.82 (d,J =12.0 Hz,1H), 3.69 (d,J = 8.0 Hz, 1H), 3.59-3.53 (m, 3H), 3.47 (m, 1H), 3.37 (m, 1H), 3.0 (d,J = 4.0 Hz,1H), 2.15-2.09 (m, 4H), 1.89 (m, 1H), 1.78-1.64 (m, 3H), 1.24 (d,J = 8.0 Hz, 3H)。MSm/z [M+H]+ : 575.4。Add 15d (50.0 mg, 0.11 mmol), Int-1 (30.0 mg, 0.12 mmol), potassium phosphate (70.0 mg, 0.33 mmol), dimethylsulfite (1.1 mL) to the reaction flask, react at 80-90 °C 16 hours. After the reaction was completed, pour into ethyl acetate (100 mL) and wash three times with 10% saline (50 mL). The organic phase was concentrated and column chromatography gave 15 (38 mg, yield: 60%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.28-7.24 (m, 1H), 7.14- 7.09 (m, 2H), 4.39-4.37 (m, 1H), 4.20-4.18 (m, 1H), 4.14-4.11 (m, 3H), 3.92-3.89 (m, 2H), 3.82 (d, J =12.0 Hz, 1H), 3.69 (d, J = 8.0 Hz, 1H), 3.59-3.53 (m, 3H), 3.47 (m, 1H), 3.37 (m, 1H), 3.0 (d, J = 4.0 Hz, 1H ), 2.15-2.09 (m, 4H), 1.89 (m, 1H), 1.78-1.64 (m, 3H), 1.24 (d, J = 8.0 Hz, 3H). MS m/z [M+H] + : 575.4.

生物活性評價Biological activity evaluation

評價了本發明的化合物選擇性抑制SHP2活性的能力。本文所述的本發明的化合物的抑制性質可以通過如下任一實驗中的測試來證明。Compounds of the invention were evaluated for their ability to selectively inhibit SHP2 activity. The inhibitory properties of the compounds of the invention described herein can be demonstrated by testing in any of the following experiments.

SHP2變構抑制實驗SHP2 allosteric inhibition assay

SHP2通過雙-酪胺醯基-磷酸化肽與其Src Homology 2(SH2)結構域的激活被變構激活。稍後的激活步驟導致釋放出SHP2的自身抑制界面，這轉而使SHP2蛋白酪胺酸磷酸酶(PTP)活化和可用於受質識別和反應催化。SHP2的催化活性採用替代受質DiFMUP以迅速螢光實驗模式進行監測。SHP2 is allosterically activated by activation of a bis-tyrosinyl-phosphorylated peptide and its Src Homology 2 (SH2) domain. A later activation step results in the release of the autoinhibitory interface of SHP2, which in turn makes SHP2 protein tyrosine phosphatase (PTP) activated and available for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored in a rapid fluorescence experimental mode using the surrogate substrate DiFMUP.

磷酸酶反應在平底、低邊緣、非結合表面的384-孔黑色聚苯乙烯板(Corning，Cat#3575)中採用25 μL的最終反應體積和如下實驗緩衝液條件於室溫進行：60mM HEPES，pH 7.2，75mM NaCl，75 mM KCl，1mM EDTA，0.05% P-20，5mM DTT。Phosphatase reactions were performed in flat-bottom, low-edge, non-binding surface 384-well black polystyrene plates (Corning, Cat#3575) using a final reaction volume of 25 μL and the following experimental buffer conditions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% P-20, 5 mM DTT.

採用如下實驗監測了本發明的化合物(濃度為0.0003-100 μM不等)對SHP2的抑制： 其中，將0.5 nM SHP2與0.5 μM肽IRS1_pY1172(dPEG8) pY1222(序列：H2 N-LN (pY) IDLDLV(dPEG8)LST(pY)ASINFQK-醯胺) (SEQ ID NO:1)（WO2016/203406A1）一起溫育。於25℃溫育30-60分鐘後，將替代受質DiFMUP(Invitrogen，cat#D6567)加入反應物中，於25℃溫育30分鐘。然後通過添加5 μL的 160 μM bpV(Phen)溶液(Enzo Life Sciences cat#ALX-270-204)，將反應物小心稀釋。採用微量板讀數器(VARIOSKAN LUX，Thermo)，採用分別是340 nm和450 nm的激發波長和發射波長，監測了螢光信號。採用基於對照的標準化進行了標準化的IC50 回歸曲線，分析了抑制劑劑量響應曲線。本發明的實施例所列化合物的IC50 列於表2中。Inhibition of SHP2 by compounds of the invention (concentrations ranging from 0.0003-100 μM) was monitored using the following experiments: wherein 0.5 nM SHP2 was combined with 0.5 μM peptide IRS1_pY1172(dPEG8) pY1222 (sequence: H 2 N-LN (pY) IDLDLV(dPEG8)LST(pY)ASINFQK-amide) (SEQ ID NO: 1) (WO2016/203406A1) were incubated together. After 30-60 minutes of incubation at 25°C, the surrogate substrate DiFMUP (Invitrogen, cat#D6567) was added to the reaction and incubated at 25°C for 30 minutes. The reaction was then carefully diluted by adding 5 μL of 160 μM bpV(Phen) solution (Enzo Life Sciences cat#ALX-270-204). Fluorescent signals were monitored using a microplate reader (VARIOSKAN LUX, Thermo) with excitation and emission wavelengths of 340 nm and 450 nm, respectively. Inhibitor dose-response curves were analyzed using control-based normalization normalized IC50 regression curves. The IC50s of the compounds listed in the Examples of the present invention are listed in Table 2.

表2 化合物抑制SHP2的IC50 值 實施例 化學結構 IC50 （nM） 1

Figure 02_image014
A 2
Figure 02_image016
 A 3
Figure 02_image018
 A 4
Figure 02_image020
 A 5
Figure 02_image022
 A 6
Figure 02_image024
 B 7
Figure 02_image026
 B 8
Figure 02_image028
 B 9
Figure 02_image030
 B 10
Figure 02_image032
 A 11
Figure 02_image034
 A 12
Figure 02_image036
 A 13
Figure 02_image038
 A 14
Figure 02_image040
 A 15
Figure 02_image042
 A 注；A≤10 nM；10 nM＜B≤ 50 nM。Table 2 IC50 values of compounds inhibiting SHP2 Example chemical structure IC50 (nM) 1
Figure 02_image014
 A 2
Figure 02_image016
 A 3
Figure 02_image018
 A 4
Figure 02_image020
 A 5
Figure 02_image022
 A 6
Figure 02_image024
 B 7
Figure 02_image026
 B 8
Figure 02_image028
 B 9
Figure 02_image030
 B 10
Figure 02_image032
 A 11
Figure 02_image034
 A 12
Figure 02_image036
 A 13
Figure 02_image038
 A 14
Figure 02_image040
 A 15
Figure 02_image042
 A Note; A≤10 nM; 10 nM<B≤50 nM.

Figure 110132447-A0101-11-0001-2
Figure 110132447-A0101-11-0001-2

無。without.

Claims (15)

一種式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，所述式（Ⅰ）化合物的結構為：
Figure 03_image001
其中： R1 和R2 各自相同或不同，其各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基；或R1 和R2 形成3-8元環烷基、環烯基或雜環基，任選的，所述3-8元環烷基、環烯基或雜環基被選自由-OH、-NH2 、-CN、NO2 、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、C3 -C12 環烷基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； X選自化學鍵、-NH-、-CONH-；
Figure 03_image005
選自C6 -C10 芳基、5-10元雜芳基、C4 -C12 環烷基、3-12元雜環基、C6 -C14 橋環基或者螺環基、C6 -C14 橋雜環基或者螺雜環基；其中所述5-10元雜芳基、3-12元雜環基、C6 -C14 橋雜環基或者螺雜環基含有1-3個任選自N、NH、O、S、C(O)、S(O) 的雜原子或基團； 每一個R3 各自相同或不同，各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：C1 -C10 烷基、C1 -C10 烷胺基、-C1 -C10 烷基醯胺、C1 -C10 烷氧基、-NH2 、C3 -C12 環烷基、3-12元雜環基、C6 -C10 芳基或5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CONH2 、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基、C6 -C10 芳基或3-12元雜環基中的一個或多個取代基所取代；或任意相鄰的兩個R3 形成3-6元飽和或者不飽和的環，任選的，所述3-6元飽和或者不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C3 -C12 環烷胺基、C1 -C10 烷基胺基、C3 -C12 環烷基、鹵代C1 -C10 烷基胺基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代； R4 、R5 、R6 、R7 、R8 、R9 、R10 、R11 各自獨立地選自H、D、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、取代或未取代的下列基團：-NH2 、C1 -C10 烷基、C1 -C10 烷胺基、C1 -C10 烷氧基、C3 -C12 環烷基、C3 -C12 環烷基氧基、3-12元雜環基、C6 -C10 芳基、5-10元雜芳基，所述取代是被選自C1 -C10 烷基、C3 -C12 環烷基、3-12元雜環基、鹵素原子、-NH2 、-CN、-COOH、-CHO、-OH、-NO2 、羥基-C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、5-10元雜芳基或C6 -C10 芳基中的一個或多個取代基所取代； m為0、1、2、3或4； n為0、1或2。A compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, the structure of the compound of formula (I) is:
Figure 03_image001
wherein: R 1 and R 2 are each the same or different, and are each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkyloxy, 3-12 membered heterocyclyl, C6 - C10 aryl, 5-10 membered heteroaryl; or R 1 and R 2 form 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl, optional , the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group is selected from -OH, -NH 2 , -CN, NO 2 , halogen atom, C 1 -C 10 alkyl, C 1 -C 10 Substituted by any 1-3 of the group consisting of alkoxy, C 1 -C 10 alkylamino, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl and 5-10 membered heteroaryl; X Selected from chemical bond, -NH-, -CONH-;
Figure 03_image005
Selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 4 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 14 bridged cyclyl or spirocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclyl, C 6 -C 14 -bridged heterocyclyl or spiro heterocyclyl contains 1-3 a heteroatom or group optionally selected from N, NH, O, S, C(O), S(O); each R is the same or different, independently selected from H, D, halogen atoms, - CN, -COOH, -CHO, -OH, -NO 2 , substituted or unsubstituted following groups: C 1 -C 10 alkyl, C 1 -C 10 alkylamino, -C 1 -C 10 alkyl amide Amine, C 1 -C 10 alkoxy, -NH 2 , C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -C 10 membered aryl or 5-10 membered heteroaryl, said The substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclyl, halogen atom, -NH 2 , -CN, -COOH, -CONH 2 , -CHO, -OH, -NO 2 , hydroxy-C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, 5-10 membered heteroaryl, C 6 -C 10 aryl Or substituted by one or more substituents in the 3-12-membered heterocyclic group; or any adjacent two R 3 form a 3-6-membered saturated or unsaturated ring, optionally, the 3-6-membered ring The saturated or unsaturated ring is selected from -OH, -NH 2 , -CN, halogen atom, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkylamino, C 1 -C 10 alkylamine group, C 3 -C 12 cycloalkyl group, halogenated C 1 -C 10 alkylamine group, C 6 -C 10 aryl group and 5-10 membered heteroaryl group Any 1-3 substituted; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are each independently selected from H, D, halogen atom, -CN, -COOH, -CHO , -OH, -NO 2 , substituted or unsubstituted following groups: -NH 2 , C 1 -C 10 alkyl, C 1 -C 10 alkylamino, C 1 -C 10 alkoxy, C 3 - C 12 cycloalkyl, C 3 -C 12 cycloalkyloxy, 3-12 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, the substitution is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH 2 , -CN, -COOH, -CHO, -OH, -NO 2 , hydroxyl -C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C Substituted by one or more substituents in 1 -C 10 alkylamino group, 5-10-membered heteroaryl group or C 6 -C 10 aryl group; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2. 如請求項1所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中， R1 和R2 形成3-8元環烷基、環烯基或雜環基，任選的，所述3-8元環烷基、環烯基或雜環基被選自由-OH、-NH2 、-CN、NO2 、鹵素原子、C1 -C10 烷基、C1 -C10 烷氧基、C1 -C10 烷胺基、C3 -C12 環烷基、C6 -C10 芳基和5-10元雜芳基組成的組中的任意1-3個所取代；
Figure 03_image005
選自C6 -C10 芳基、5-10元雜芳基、3-12元雜環基，優選為C6 -C10 芳基、5-9元雜芳基，其中所述5-10元雜芳基、3-12元雜環基含有1-3個任選自N、NH、O、S、C(O)的雜原子或基團；優選的，所述3-12元雜環基選自氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、丁內醯胺基、戊內醯胺基、己內醯胺基、丁內酯基、戊內酯基、己內酯基、丁二醯亞胺或
Figure 03_image008
中的任一種； 每一個R3 各自相同或不同，各自獨立地選自H、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、C1 -C6 烷基、C1 -C6 烷氧基、3-12元雜環基、-C1 -C10 烷基醯胺、-NH2 ，或任意相鄰的兩個R3 形成5-6元飽和或不飽和的環，任選的，所述5-6元飽和或不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C6 烷基和C1 -C6 烷氧基組成的組中的任意1-3個所取代。The compound of claim 1 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R 1 and R 2 form a 3-8 membered cycloalkyl, ring Alkenyl or heterocyclyl, optionally, the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl is selected from -OH, -NH 2 , -CN, NO 2 , halogen atom, C 1 - The group consisting of C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, C 3 -C 12 cycloalkyl, C 6 -C 10 aryl and 5-10 membered heteroaryl Any 1-3 of them are replaced;
Figure 03_image005
Selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic, preferably C 6 -C 10 aryl, 5-9 membered heteroaryl, wherein the 5-10 The membered heteroaryl group and the 3-12 membered heterocyclic group contain 1-3 heteroatoms or groups optionally selected from N, NH, O, S, C(O); preferably, the 3-12 membered heterocyclic ring group is selected from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, Tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactone, valerolactone, caprolactone, butyrolactone, valerolactone, caprolactone , butanediimide or
Figure 03_image008
any one; each R 3 is the same or different, each independently selected from H, halogen atom, -CN, -COOH, -CHO, -OH, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-12 membered heterocyclyl, -C 1 -C 10 alkylamide, -NH 2 , or any adjacent two R 3 form a 5-6 membered saturated or unsaturated ring , optionally, the 5-6 membered saturated or unsaturated ring is selected from -OH, -NH 2 , -CN, halogen atom, C 1 -C 6 alkyl group and C 1 -C 6 alkoxy group Replaced by any 1-3 of the group. 如請求項1或2所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中， R1 和R2 形成環戊烷、四氫呋喃環、四氫吡咯環、四氫噻吩環，任選地，所述環戊烷、四氫呋喃環、四氫吡咯環、四氫噻吩環被選自由-OH、-NH2 、鹵素原子、C1 -C10 烷基和C1 -C10 烷氧基組成的組中的任意1-3個所取代；
Figure 03_image005
選自苯基、萘基、5-10元雜芳基或3-12元雜環基；其中所述5-10元雜芳基、3-12元雜環基含有1-3個任選自N、NH、O、C(O)的雜原子或基團； 每一個R3 各自相同或不同，其各自獨立地選自H、鹵素原子、-C1 -C6 烷基CONH2 、-COOH、-CN、C1 -C6 烷基、羥基取代的C1 -C6 烷基、胺基取代的C1 -C6 烷基、C1 -C6 烷氧基、-NH2 ，或任意相鄰的兩個R3 形成5元或6元環。The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein R 1 and R 2 form a cyclopentane, tetrahydrofuran ring, Tetrahydropyrrole ring, tetrahydrothiophene ring, optionally, the cyclopentane, tetrahydrofuran ring, tetrahydropyrrole ring, tetrahydrothiophene ring is selected from -OH, -NH2 , halogen atom, C1 - C10 substituted by any 1-3 of the group consisting of alkyl and C 1 -C 10 alkoxy;
Figure 03_image005
Selected from phenyl, naphthyl, 5-10-membered heteroaryl or 3-12-membered heterocyclic group; wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclic group contains 1-3 optional from Heteroatoms or groups of N, NH, O, C(O); each R 3 is the same or different, each independently selected from H, halogen atoms, -C 1 -C 6 alkyl CONH 2 , -COOH , -CN, C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , or any Adjacent two R 3 form a 5- or 6-membered ring. 如請求項1或2所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中，
Figure 03_image005
選自苯基、萘基、5-10元雜芳基或3-12元雜環基； 所述5-10元雜芳環選自噻吩基、吡啶基、嘧啶基、吡嗪基、噠嗪基、吡咯基、吡唑基、噻唑基、1,2,3-***基、1,2,4-***基、咪唑基、四氮唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、異喹啉基、喹唑啉基、吲唑基、吲哚[1,2-a]吡嗪基、4,7-二氮雜吲哚、吡唑并嘧啶基、咪唑并嘧啶基、噁唑并嘧啶基、異噁唑并嘧啶基、咪唑并吡嗪基、吡唑并吡嗪、吡咯并吡嗪基、呋喃并吡嗪基、噻吩并吡嗪基、吡啶并嘧啶酮基、苯并噁唑基、苯并噻唑基中的任一種；所述3-12元雜環基選自氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、丁內醯胺基、戊內醯胺基、己內醯胺基、丁內酯基、戊內酯基、己內酯基、丁二醯亞胺或
Figure 03_image008
中的任一種；所述3-12元雜環基選自丁內醯胺基、吡咯烷基、丁二醯亞胺基或
Figure 03_image008
中的任一種； 每一個R3 各自相同或不同，其各自獨立地選自H、鹵素原子、-C1 -C6 烷基CONH2 、-COOH、-CN、C1 -C6 烷基、羥基取代的C1 -C6 烷基、胺基取代的C1 -C6 烷基、C1 -C6 烷氧基、-NH2 ，或任意相鄰的兩個R3 形成5元或6元環。The compound of claim 1 or 2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein,
Figure 03_image005
is selected from phenyl, naphthyl, 5-10-membered heteroaryl or 3-12-membered heterocyclic group; the 5-10-membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazine base, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxalyl azolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl , indazolyl, indole[1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazolopyrimidyl, oxazolopyrimidyl, isoxazolopyrimidine of pyrazinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl, benzothiazolyl Any; the 3-12-membered heterocyclic group is selected from aziridinyl, azetidine, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl , piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactone, butyrolactone group, valerolactone group, caprolactone group, succinimide or
Figure 03_image008
Any one of; the 3-12-membered heterocyclic group is selected from butyrolactone, pyrrolidinyl, butanediimide or
Figure 03_image008
any one; each R 3 is the same or different, each independently selected from H, halogen atom, -C 1 -C 6 alkyl CONH 2 , -COOH, -CN, C 1 -C 6 alkyl, Hydroxy substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , or any adjacent two R 3 form a 5-membered or 6-membered yuan ring. 如請求項1所述的式（Ⅰ）化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中，所述式（Ⅰ）化合物具有式(Ⅰ-1)所示的結構：
Figure 03_image012
其中，R3 、X和
Figure 03_image005
的定義如請求項1所示。The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula (I) has the formula (I) -1) The structure shown:
Figure 03_image012
where R 3 , X and
Figure 03_image005
is defined as in Request Item 1. 如請求項5所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中，
Figure 03_image005
選自C6 -C10 芳基、5-10元雜芳基或3-12元雜環基，其中所述5-10元雜芳基或3-12元雜環基含有1-3個任選自N、NH、O、S、C(O)、S(O) 的雜原子或基團； 每一個R3 各自相同或不同，各自獨立地選自H、鹵素原子、-CN、-COOH、-CHO、-OH、-NO2 、C1 -C6 烷基、C1 -C6 烷氧基、3-12元雜環基、-C1 -C10 烷基醯胺、-NH2 ，或任意相鄰的兩個R3 形成5-6元飽和或不飽和的環，任選的，所述5-6元飽和或不飽和的環被選自由-OH、-NH2 、-CN、鹵素原子、C1 -C6 烷基和C1 -C6 烷氧基組成的組中的任意1-3個所取代。The compound of claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein,
Figure 03_image005
Selected from C 6 -C 10 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclic group, wherein the 5-10-membered heteroaryl or 3-12-membered heterocyclic group contains 1-3 arbitrary A heteroatom or group selected from N, NH, O, S, C(O), S(O); each R 3 is the same or different, and is independently selected from H, halogen atom, -CN, -COOH , -CHO, -OH, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-12-membered heterocyclic group, -C 1 -C 10 alkylamide, -NH 2 , or any adjacent two R 3 form a 5-6 membered saturated or unsaturated ring, optionally, the 5-6 membered saturated or unsaturated ring is selected from -OH, -NH 2 , -CN , halogen atom, C 1 -C 6 alkyl group and C 1 -C 6 alkoxy group consisting of any 1-3 substituted. 如請求項5所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中，
Figure 03_image005
選自C6 -C10 芳基、5-6元雜芳基或5-12元雜環基，其中所述5-6元雜芳基或5-12元雜環基含有1-3個任選自N、NH、O、C(O)的雜原子或基團； 每一個R3 各自相同或不同，其各自獨立地選自H、鹵素原子、5-6元雜環基、-C1 -C6 烷基CONH2 、-COOH、-CN、C1 -C6 烷基、羥基取代的C1 -C6 烷基、胺基取代的C1 -C6 烷基、C1 -C6 烷氧基、-NH2 ，或任意相鄰的兩個R3 形成5元或6元環。The compound of claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein,
Figure 03_image005
Selected from C 6 -C 10 aryl, 5-6-membered heteroaryl or 5-12-membered heterocyclic group, wherein the 5-6-membered heteroaryl or 5-12-membered heterocyclic group contains 1-3 arbitrary A heteroatom or group selected from N, NH, O, C(O); each R 3 is the same or different, each independently selected from H, halogen atom, 5-6 membered heterocyclic group, -C 1 -C 6 alkyl CONH 2 , -COOH, -CN, C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, -NH 2 , or any two adjacent R 3 s form a 5- or 6-membered ring. 如請求項5所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，其中，
Figure 03_image005
為苯基、萘基；或者選自噻吩基、吡啶基、嘧啶基、吡嗪基、噠嗪基、吡咯基、吡唑基、噻唑基、1,2,3-***基、1,2,4-***基、咪唑基、四氮唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、異喹啉基、喹唑啉基、吲唑基、吲哚[1,2-a]吡嗪基、4,7-二氮雜吲哚、吡唑并嘧啶基、咪唑并嘧啶基、噁唑并嘧啶基、異噁唑并嘧啶基、咪唑并吡嗪基、吡唑并吡嗪、吡咯并吡嗪基、呋喃并吡嗪基、噻吩并吡嗪基、吡啶并嘧啶酮基、苯并噁唑基中的任一種的雜芳基；或者選自氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、哌啶基、嗎啉基、哌嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、丁內醯胺基、戊內醯胺基、己內醯胺基、丁內酯基、戊內酯基、己內酯基、丁二醯亞胺或
Figure 03_image008
中的任一種的雜環基； 每一個R3 各自相同或不同，其各自獨立地選自H、鹵素原子、-C1 -C6 烷基CONH2 、-COOH、-CN、C1 -C6 烷基、6元含氧雜環基、羥基取代的C1 -C6 烷基、胺基取代的C1 -C6 烷基、C1 -C6 烷氧基、-NH2 ，或任意相鄰的兩個R3 形成5元或6元環； 式(Ⅰ-1)所示結構中，四氫呋喃環上取代的甲基和胺基處於四氫呋喃環的同一側。The compound of claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein,
Figure 03_image005
is phenyl, naphthyl; or selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2 ,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazole base, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole[1,2-a]pyrazinyl, 4,7-diaza Indole, pyrazolopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, isoxazolopyrimidyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furanopyrazinyl , a heteroaryl group of any one of thienopyrazinyl, pyridopyrimidinonyl, benzoxazolyl; or selected from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl , tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamide , valerolactone, caprolactone, butyrolactone, valerolactone, caprolactone, butanediimide or
Figure 03_image008
any one of the heterocyclyl groups; each R 3 is the same or different, each independently selected from H, halogen atom, -C 1 -C 6 alkyl CONH 2 , -COOH, -CN, C 1 -C 6 -alkyl, 6-membered oxygen-containing heterocyclic group, hydroxy-substituted C 1 -C 6 alkyl, amino-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , or any Two adjacent R 3s form a 5-membered or 6-membered ring; in the structure shown in formula (I-1), the methyl and amine groups substituted on the tetrahydrofuran ring are on the same side of the tetrahydrofuran ring. 一種選自如下的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物：
Figure 03_image014
Figure 03_image016
Figure 03_image018
Figure 03_image020
Figure 03_image022
Figure 03_image024
Figure 03_image026
Figure 03_image028
Figure 03_image030
Figure 03_image032
Figure 03_image034
Figure 03_image036
Figure 03_image038
Figure 03_image040
Figure 03_image042
Figure 03_image026
Figure 03_image028
Figure 03_image030
Figure 03_image046
Figure 03_image048
Figure 03_image050
。A compound selected from the group consisting of: a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:
Figure 03_image014
Figure 03_image016
Figure 03_image018
Figure 03_image020
Figure 03_image022
Figure 03_image024
Figure 03_image026
Figure 03_image028
Figure 03_image030
Figure 03_image032
Figure 03_image034
Figure 03_image036
Figure 03_image038
Figure 03_image040
Figure 03_image042
Figure 03_image026
Figure 03_image028
Figure 03_image030
Figure 03_image046
Figure 03_image048
Figure 03_image050
. 一種藥物組合物，其包含如請求項1-9任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物。A pharmaceutical composition comprising the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof. 一種藥物製劑，其包括如請求項1-9中任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物或者如請求項10所述的藥物組合物，所述製劑為片劑、膠囊劑、注射劑、顆粒劑、粉劑、栓劑、丸劑、乳膏劑、糊劑、凝膠劑、散劑、口服溶液、吸入劑、混懸劑、乾懸劑、貼劑、洗劑中的任一種。A pharmaceutical preparation comprising a compound as described in any one of claims 1-9 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof or as claimed in claim 10 Described pharmaceutical composition, described preparation is tablet, capsule, injection, granule, powder, suppository, pill, cream, paste, gel, powder, oral solution, inhalation, suspension, dry Any of suspensions, patches, and lotions. 一種如請求項1-9中任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者如請求項10所述的藥物組合物，或者如請求項11所述的藥物製劑，其用作預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的用途。A compound as described in any one of claim 1-9 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical combination as described in claim 10 or a pharmaceutical preparation as claimed in claim 11 for use in the prevention and/or treatment of non-receptor protein tyrosine phosphatase mediated or dependent diseases or conditions. 一種如請求項1-9中任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者如請求項10所述的藥物組合物，或者如請求項11所述的藥物製劑，在製備預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的藥物中的應用。A compound as described in any one of claim 1-9 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical combination as described in claim 10 Use of the substance, or the pharmaceutical preparation according to claim 11, in the preparation of a medicament for preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions. 一種預防和/或治療非受體蛋白酪胺酸磷酸酶媒介的或依賴的疾病或病症的方法，其包括：將治療有效量的如請求項1-9中任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者如請求項10所述的藥物組合物，或者如請求項11所述的藥物製劑施用於對其有需求的患者。A method of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions, comprising: treating a therapeutically effective amount of a compound according to any one of claims 1-9 or the same A pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label, or a pharmaceutical composition as claimed in claim 10, or a pharmaceutical formulation as claimed in claim 11 for administration to patients in need. 一種醫藥品，其包含至少一種額外的治療劑，以及如請求項1-9中任一項所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物，或者如請求項10所述的藥物組合物，或者如請求項11所述的藥物製劑。A medicinal product comprising at least one additional therapeutic agent, and a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope thereof A marker, or a pharmaceutical composition as claimed in claim 10, or a pharmaceutical preparation as claimed in claim 11.
TW110132447A 2020-09-02 2021-09-01 Pyrazine derivative and applications in SHP2 inhibition thereof capable of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions. TW202210488A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010910913.2A CN114195799A (en) 2020-09-02 2020-09-02 Pyrazine derivative and application thereof in inhibition of SHP2
CN202010910913.2 2020-09-02

Publications (1)

Publication Number Publication Date
TW202210488A true TW202210488A (en) 2022-03-16

Family

ID=80644409

Family Applications (1)

Application Number Title Priority Date Filing Date
TW110132447A TW202210488A (en) 2020-09-02 2021-09-01 Pyrazine derivative and applications in SHP2 inhibition thereof capable of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

Country Status (2)

Country Link
CN (1) CN114195799A (en)
TW (1) TW202210488A (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114716448B (en) * 2021-05-13 2024-01-30 中国科学院上海药物研究所 Heterocyclic compound for inhibiting SHP2 activity, preparation method and application thereof
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors

Also Published As

Publication number Publication date
CN114195799A (en) 2022-03-18

Similar Documents

Publication Publication Date Title
CN111647000B (en) Pyrazine derivative and application thereof in inhibition of SHP2
RU2717577C2 (en) Imidazoisoindole derivative, method for production thereof and medical use
TWI450720B (en) Pyrimidyl cyclopentanes as akt protein kinase inhibitors
TWI662026B (en) Pyridinone derivatives, preparation process and pharmaceutical use thereof
TW202210488A (en) Pyrazine derivative and applications in SHP2 inhibition thereof capable of preventing and/or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.
WO2015055071A1 (en) Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
TW202003495A (en) Benzene and piperidine or heteroaryl group and piperidine derivatives, preparation method thereof and application thereof in medicine
WO2021218939A1 (en) Fused ring compound and application thereof in medicine
WO2022194066A1 (en) Kras g12d inhibitor and applications thereof in medicine
WO2022135590A1 (en) Pyrimido-heterocyclic compounds, and preparation method therefor and use thereof
WO2019062328A1 (en) Aniline-substituted 1,2-dihydropyrrol[3,4-c]pyridin/pyrimidin-3-one derivative and use
JP2017511309A (en) Inhibitors of WNT signaling pathway
WO2022135442A1 (en) Cdk2 inhibitor and preparation method therefor
CN108299420B (en) Pentacyclic compounds as selective estrogen receptor down-regulators and uses thereof
WO2020011220A1 (en) Heteroaryl derivative, preparation method therefor, and medical use thereof
CA3075324A1 (en) Deuterium atom-substituted indole formamide derivative, preparation method therefor, and medical applications thereof
WO2020173417A1 (en) Acryloyl-containing nuclear transport regulator and uses thereof
CN109485595A (en) Indole carboxamides analog derivative, preparation method and its application in medicine that hydrophilic radical replaces
WO2023125708A1 (en) P38 mapk/mk2 pathway modulator, composition thereof, preparation method therefor, and use thereof
CN107428682B (en) Amide derivatives, preparation method and medical application thereof
CN108779100A (en) 3,4- bipyridyls pyrazole derivatives, preparation method and its application in medicine
CN110407839B (en) Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure
CN116239603A (en) 2-aminopyrimidine heterocyclic compound and application thereof
WO2019184919A1 (en) Adamantane-containing compound and use thereof in treating cancer
WO2021110135A1 (en) Crystal form as inhibitor of acc1 and acc2, and preparation method therefor and use thereof