TW201927777A - IDO inhibitor - Google Patents

IDO inhibitor Download PDF

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TW201927777A
TW201927777A TW107145936A TW107145936A TW201927777A TW 201927777 A TW201927777 A TW 201927777A TW 107145936 A TW107145936 A TW 107145936A TW 107145936 A TW107145936 A TW 107145936A TW 201927777 A TW201927777 A TW 201927777A
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Taiwan
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compound
solution
pharmaceutically acceptable
mmol
acceptable salt
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TW107145936A
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Chinese (zh)
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周明
陸劍宇
胡國平
照中 丁
健 黎
曙輝 陳
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大陸商基石藥業（蘇州）有限公司
大陸商拓石藥業（上海）有限公司
大陸商南京明德新藥研發股份有限公司
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Publication of TW201927777A publication Critical patent/TW201927777A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention discloses a novel class of compounds which are IDO inhibitors, and specifically discloses a compound of the formula (I) and a pharmaceutically acceptable salt thereof.

Description

IDO抑制劑IDO inhibitor

本發明涉及新的作為IDO抑制劑的化合物，具體公開了式（I）所示化合物及其藥學上可接受的鹽。本發明還涉及式（I）所示化合物及其藥學上可接受的鹽在製備治療腫瘤藥物中的應用。The present invention relates to a novel compound as an IDO inhibitor, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. The invention also relates to the use of a compound represented by formula (I) and a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors.

本申請主張如下優先權：CN201711375318.8，申請日2017年12月19日。This application claims the following priority: CN201711375318.8, the filing date of December 19, 2017.

惡性腫瘤是現如今危害人類生命安全的主要疾病之一。近百年來，人類為了對抗惡性腫瘤，發展出了多種包括最常用的化療，手術，放療以及靶向療法在內的診療手段與治療方法。這些療法在一定程度上延緩的腫瘤的發展，延長了患者生命。但是由於惡性腫瘤的無限制生長，浸潤與轉移的特性，以上療法依舊無法達到理想的抑制效果。同時，以上的療法的毒副作用也是限制其應用的關鍵因素。Malignant tumors are one of the main diseases that endanger human life. In the past century, in order to combat malignant tumors, humans have developed a variety of diagnostic methods and treatment methods, including the most commonly used chemotherapy, surgery, radiotherapy and targeted therapy. These therapies to some extent delay the development of tumors and prolong patient life. However, due to the unrestricted growth, invasion and metastasis of malignant tumors, the above therapies still cannot achieve the desired inhibitory effect. At the same time, the toxic and side effects of the above therapies are also the key factors limiting their application.

近年來，免疫療法作為惡性腫瘤治療的新興療法被發展起來，其特點是通過調動宿主的天然防禦機制來抵抗腫瘤的生長。其主要途徑主要通過激活宿主原有的免疫系統，增強宿主集體對腫瘤細胞的免疫反應，利用免疫系統能力達到精準有效的殺傷腫瘤，遏制其發展。In recent years, immunotherapy has been developed as a new treatment for malignant tumors, which is characterized by resisting tumor growth by mobilizing the host's natural defense mechanism. The main way is to activate the host's original immune system, enhance the host's collective immune response to tumor cells, and use the ability of the immune system to achieve accurate and effective killing of tumors and curb their development.

吲哚胺-吡咯-2,3-雙加氧酶（Indoleeamine-pyrrole-2,3-dioxygenase，IDO）是一種含鐵紅素的單體蛋白，其功能在於催化了色胺酸向犬尿胺酸轉變的決速步驟。IDO在多種腫瘤細胞內有過表達。過度表達的IDO可以迅速消耗腫瘤微環境內色胺酸，使得浸潤至腫瘤內部的T細胞由於缺乏色胺酸而停滯於G1期中期，從而抑制了T細胞增殖並使T細胞信號傳導受阻，功能喪失。因此，抑制腫瘤內部過表達的IDO功能有助於激活集體免疫系統，抵制腫瘤生長。Indoleeamine-pyrrole-2,3-dioxygenase (IDO) is a monomeric protein containing ferritin, and its function is to catalyze tryptamine to kynuria The decisive step in acid conversion. IDO is overexpressed in a variety of tumor cells. Overexpressed IDO can quickly consume tryptophan in the tumor microenvironment, making T cells infiltrated inside the tumor stagnate in the middle stage of G1 due to lack of tryptophan, thereby inhibiting T cell proliferation and blocking T cell signaling, function Lost. Therefore, inhibiting IDO function that is overexpressed inside the tumor helps to activate the collective immune system and resist tumor growth.

IDO抑制劑作為藥物在醫藥行業具有良好的應用前景，但是目前尚無IDO抑制劑上市。處於臨床的IDO抑制劑只有NewLinkGenetics公司開發的NLG-0919與Incyte公司的INCB-24360及百時美施貴寶的BMS-985205。但是，現有臨床IDO抑制劑存在諸如CYP抑制（NLG0919）、給藥劑量大、半衰期短、給藥次數多(INCB-24360)等問題。因此，無上述缺點的IDO抑制劑依舊是未被滿足的醫療需求。IDO inhibitors have good application prospects as pharmaceuticals in the pharmaceutical industry, but no IDO inhibitors are currently on the market. The only clinical IDO inhibitors are NLG-0919 developed by NewLink Genetics, INCB-24360 of Incyte, and BMS-985205 of Bristol-Myers Squibb. However, the existing clinical IDO inhibitors have problems such as CYP inhibition (NLG0919), large doses, short half-life, and frequent dosing (INCB-24360). Therefore, IDO inhibitors without the aforementioned disadvantages remain unmet medical needs.

NLG-0919，INCB-24360及BMS-986205的具體結構如下：
The specific structures of NLG-0919, INCB-24360 and BMS-986205 are as follows:

本發明提供式（I）化合物或其藥學上可接受的鹽，

其中，
為單鍵或雙鍵；
環A選自5元雜芳基，所述5元雜芳基上至少含有1個N原子；
Y選自C和N；
R1 選自H、C1-6 烷基、C1-6 雜烷基，所述C1-6 烷基、C1-6 雜烷基任選被1、2或3個R取代；
R2 、R3 、R4 和R5 分別獨立地選自H和C1-6 烷基；
或者R4 和R5 連接在一起，形成3~4元環烷基，所述3~4元環烷基任選被1、2或3個R取代；
R6 、R7 和R8 分別獨立地選自H、鹵素、OH、CN、NH2 和C1~3 烷基，所述C1~3 烷基任選被1、2或3個R9 取代；
R9 分別獨立地選自CN、F、Cl、Br和I；
R分別獨立地選自鹵素、OH、CN、NH2 、C1-4 烷基、C1-4 雜烷基、C3-6 環烷基、3~6元雜環烷基、苯基和5~6元雜芳基，所述C1-4 烷基、C1-4 雜烷基、C3~6 環烷基、3~6元雜環烷基、苯基和5~6元雜芳基任選被1、2或3個R’取代；
R’分別獨立地選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 O、CH3 CH2 、CH3 CH2 O、CH(CH3 )2 、N(CH3 )2 、CF3 、CH2 F和CHF2 ；
所述5元雜芳基、5~6元雜芳基、3~6元雜環烷基、C1-6 雜烷基和C1-4 雜烷基分別包含1、2、獨立地選自-C(=O)-、N、-NH-、-O-、-S-；
以上任何一種情況下，雜原子或雜原子團的數目分別獨立地選自1、2或3。The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

among them,
Single or double bond;
Ring A is selected from a 5-membered heteroaryl group, which contains at least one N atom;
Y is selected from C and N;
R 1 is selected from H, C 1-6 alkyl, and C 1-6 heteroalkyl, and the C 1-6 alkyl and C 1-6 heteroalkyl are optionally substituted with 1, 2 or 3 R;
R 2 , R 3 , R 4 and R 5 are each independently selected from H and C 1-6 alkyl;
Or R 4 and R 5 are linked together to form a 3- to 4-membered cycloalkyl group, which is optionally substituted with 1, 2 or 3 R;
R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, OH, CN, NH 2 and C 1 to 3 alkyl groups, and the C 1 to 3 alkyl groups are optionally substituted by 1, 2 or 3 R 9 Replace
R 9 is independently selected from CN, F, Cl, Br, and I;
R is independently selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, the C 1-4 alkyl, C 1-4 heteroalkyl, C 3 to 6 cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, and 5 to 6 membered heteroaryl Aryl is optionally substituted with 1, 2 or 3 R ';
R 'are independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O, CH (CH 3 ) 2 , N (CH 3 ) 2 , CF 3 , CH 2 F and CHF 2 ;
The 5-membered heteroaryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl, C 1-6 heteroalkyl, and C 1-4 heteroalkyl each include 1, 2, and are independently selected from -C (= O)-, N, -NH-, -O-, -S-;
In any of the above cases, the number of heteroatoms or heteroatomic groups is independently selected from 1, 2, or 3.

在本發明的一些方案中，上述R選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 O、CH3 CH2 、CH3 CH2 O、CH(CH3 )2 、N(CH3 )2 、CF3 、CH2 F、CHF2 、。In some embodiments of the present invention, the R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O, and CH (CH 3 ). 2 , N (CH 3 ) 2 , CF 3 , CH 2 F, CHF 2 , .

在本發明的一些方案中，上述R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 ，所述CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 任選被1、2或3個R取代。In some aspects of the present invention, the R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, and N (CH 3 ) 2. The CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, and N (CH 3 ) 2 are optionally substituted with 1, 2 or 3 R.

在本發明的一些方案中，上述R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O、N(CH3 )2 、CH2 OH、CF3 、CH2 F、CHF2 和。In some embodiments of the present invention, R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, N (CH 3 ) 2 , and CH 2 OH. , CF 3 , CH 2 F, CHF 2 and .

在本發明的一些方案中，上述R2 、R3 、R4 和R5 分別獨立地選自H、CH3 、CH3 CH2 和CH(CH3 )2 。In some aspects of the invention, the aforementioned R 2 , R 3 , R 4 and R 5 are independently selected from H, CH 3 , CH 3 CH 2 and CH (CH 3 ) 2 .

在本發明的一些方案中，上述R6 、R7 和R8 分別獨立地選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 CH2 、CH(CH3 )2 、CF3 、CH2 F和CHF2 。In some aspects of the present invention, the aforementioned R 6 , R 7 and R 8 are each independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CF 3 , CH 2 F and CHF 2 .

在本發明的一些方案中，上述結構單元選自、、、和。In some aspects of the present invention, the aforementioned structural unit From , , , with .

在本發明的一些方案中，上述結構單元選自、、、、、、、、、、、、、、、、、、、、、、、、、和。In some aspects of the present invention, the aforementioned structural unit From , , , , , , , , , , , , , , , , , , , , , , , , , with .

在本發明的一些方案中，上述環A選自吡咯基、吡唑基、咪唑基、三唑基、唑基、異唑基、噻唑基和異噻唑基。In some embodiments of the present invention, the ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Oxazolyl, iso Oxazolyl, thiazolyl, and isothiazolyl.

在本發明的一些方案中，上述結構單元選自和。In some aspects of the present invention, the aforementioned structural unit From with .

在本發明的一些方案中，上述結構單元選自、、、、、和。In some aspects of the present invention, the aforementioned structural unit From , , , , , with .

在本發明的一些方案中，上述R選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 O、CH3 CH2 、CH3 CH2 O、CH(CH3 )2 、N(CH3 )2 、CF3 、CH2 F、CHF2 、，其他變量如上述所定義。In some embodiments of the present invention, the R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O, and CH (CH 3 ). 2 , N (CH 3 ) 2 , CF 3 , CH 2 F, CHF 2 , The other variables are as defined above.

在本發明的一些方案中，上述R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 ，所述CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 任選被1、2或3個R取代，其他變量如上述所定義。In some aspects of the present invention, the R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, and N (CH 3 ) 2. The CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, and N (CH 3 ) 2 are optionally substituted by 1, 2 or 3 R, other variables are as defined above.

在本發明的一些方案中，上述R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O、N(CH3 )2 、CH2 OH、CF3 、CH2 F、CHF2 和，其他變量如上述所定義。In some embodiments of the present invention, R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, N (CH 3 ) 2 , and CH 2 OH. , CF 3 , CH 2 F, CHF 2 and The other variables are as defined above.

在本發明的一些方案中，上述R2 、R3 、R4 和R5 分別獨立地選自H、CH3 、CH3 CH2 和CH(CH3 )2 ，其他變量如上述所定義。In some aspects of the present invention, the aforementioned R 2 , R 3 , R 4 and R 5 are independently selected from H, CH 3 , CH 3 CH 2 and CH (CH 3 ) 2 , and other variables are as defined above.

在本發明的一些方案中，上述R6 、R7 和R8 分別獨立地選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 CH2 、CH(CH3 )2 、CF3 、CH2 F和CHF2 ，其他變量如上述所定義。In some aspects of the present invention, the aforementioned R 6 , R 7 and R 8 are each independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CF 3 , CH 2 F and CHF 2 , other variables are as defined above.

在本發明的一些方案中，上述結構單元選自、、、和，其他變量如上述所定義。In some aspects of the present invention, the aforementioned structural unit From , , , with The other variables are as defined above.

在本發明的一些方案中，上述結構單元選自、、、、、、、、、、、、、、、、、、、、、、、、、和，其他變量如上述所定義。In some aspects of the present invention, the aforementioned structural unit From , , , , , , , , , , , , , , , , , , , , , , , , , with The other variables are as defined above.

在本發明的一些方案中，上述環A選自吡咯基、吡唑基、咪唑基、三唑基、唑基、異唑基、噻唑基和異噻唑基，其他變量如上述所定義。In some embodiments of the present invention, the ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Oxazolyl, iso Oxazolyl, thiazolyl, and isothiazolyl, other variables are as defined above.

在本發明的一些方案中，上述結構單元選自和，其他變量如上述所定義。In some aspects of the present invention, the aforementioned structural unit From with The other variables are as defined above.

在本發明的一些方案中，上述結構單元選自、、、、、和，其他變量如上述所定義。In some aspects of the present invention, the aforementioned structural unit From , , , , , with The other variables are as defined above.

在本發明的一些方案中，上述化合物選自
和，
其中，R1 、R2 、R3 、R4 、R5 、R6 、R7 和R8 如上述所定義。In some embodiments of the present invention, the above compound is selected from
with ,
Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.

本發明還提供化合物或其藥學上可接受的鹽，選自



。The invention also provides a compound or a pharmaceutically acceptable salt thereof, selected from



.

本發明還提供上述化合物或其藥學上可接受的鹽在製備治療癌症藥物中的應用。The invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

本發明還有一些方案是由上述各變量任意組合而來。

技術效果Some solutions of the present invention are obtained by arbitrarily combining the above variables.

Technical effect

本發明提供一種新型結構的選擇性IDO抑制劑，具有此優異的體外IDO酶活性；由於分子量較小，預計會有更好的溶解度和滲透性，從而成藥性更強。本發明化合物小鼠體內代謝穩定性好，具有較好的口服生物利用度，藥代動力學性質優良。

定義和說明The present invention provides a novel structure-selective IDO inhibitor with this excellent in vitro IDO enzyme activity; due to its smaller molecular weight, it is expected to have better solubility and permeability, and thus stronger drug-making properties. The compound of the present invention has good metabolic stability in mice, good oral bioavailability, and excellent pharmacokinetic properties.

Definition and description

除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。當本文中出現商品名時，意在指代其對應的商品或其活性成分。這裡所採用的術語“藥學上可接受的”，是針對那些化合物、材料、組合物和/或劑型而言，它們在可靠的醫學判斷的範圍之內，適用於與人類和動物的組織接觸使用，而沒有過多的毒性、刺激性、過敏性反應或其它問題或併發症，與合理的利益/風險比相稱。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

術語“藥學上可接受的鹽”是指本發明化合物的鹽，由本發明發現的具有特定取代基的化合物與相對無毒的酸或鹼製備。當本發明的化合物中含有相對酸性的功能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的鹼與這類化合物的中性形式接觸的方式獲得鹼加成鹽。藥學上可接受的鹼加成鹽包括鈉、鉀、鈣、銨、有機胺或鎂鹽或類似的鹽。當本發明的化合物中含有相對鹼性的官能團時，可以通過在純的溶液或合適的惰性溶劑中用足夠量的酸與這類化合物的中性形式接觸的方式獲得酸加成鹽。藥學上可接受的酸加成鹽的實例包括無機酸鹽，所述無機酸包括例如鹽酸、氫溴酸、硝酸、碳酸，碳酸氫根，磷酸、磷酸一氫根、磷酸二氫根、硫酸、硫酸氫根、氫碘酸、亞磷酸等；以及有機酸鹽，所述有機酸包括如乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸和甲磺酸等類似的酸；還包括胺基酸（如精胺酸等）的鹽，以及如葡糖醛酸等有機酸的鹽。本發明的某些特定的化合物含有鹼性和酸性的官能團，從而可以被轉換成任一鹼或酸加成鹽。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; similar acids; also amino acids (such as arginine) And organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

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

除了鹽的形式，本發明所提供的化合物還存在前藥形式。本文所​​描述的化合物的前藥容易地在生理條件下發生化學變化從而轉化成本發明的化合物。此外，前體藥物可以在體內環境中通過化學或生化方法被轉換到本發明的化合物。In addition to the salt form, the compounds provided by the present invention also exist in prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.

本發明的某些化合物可以以非溶劑化形式或者溶劑化形式存在，包括水合物形式。一般而言，溶劑化形式與非溶劑化的形式相當，都包含在本發明的範圍之內。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are included in the scope of the present invention.

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

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

除非另有說明，術語“順反異構體”或者“幾何異構體”係由因雙鍵或者成環碳原子單鍵不能自由旋轉而引起。Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.

除非另有說明，術語“非對映異構體”是指分子具有兩個或多個手性中心，並且分子間為非鏡像的關係的立體異構體。Unless otherwise stated, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.

除非另有說明，“(D )”或者“(+)”表示右旋，“(L )”或者“(-) ”表示左旋，“（DL ）”或者“(±)”表示外消旋。Unless otherwise stated, "( D )" or "(+)" means right-handed, "( L )" or "(-)" means left-handed, and "( DL )" or "(±)" means racemic.

除非另有說明，用楔形實線鍵（）和楔形虛線鍵（）表示一個立體中心的絕對構型，用直形實線鍵（）和直形虛線鍵（）表示立體中心的相對構型，用波浪線（）表示楔形實線鍵（）或楔形虛線鍵（），或用波浪線（）表示直形實線鍵（）和直形虛線鍵（）。Unless otherwise specified, use a wedge solid line key ( ) And wedge-shaped dashed keys ( ) Represents the absolute configuration of a solid center, using straight solid line keys ( ) And a straight dashed key ( ) Indicates the relative configuration of the three-dimensional center, using wavy lines ( ) Represents a wedge solid line key ( ) Or wedge dashed key ( ) Or use a wavy line ( ) Represents a straight solid line key ( ) And a straight dashed key ( ).

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

除非另有說明，術語“富含一種異構體”、“異構體富集”、“富含一種對映體”或者“對映體富集”指其中一種異構體或對映體的含量小於100%，並且，該異構體或對映體的含量大於等於60%，或者大於等於70%，或者大於等於80%，或者大於等於90%，或者大於等於95%，或者大於等於96%，或者大於等於97%，或者大於等於98%，或者大於等於99%，或者大於等於99.5%，或者大於等於99.6%，或者大於等於99.7%，或者大於等於99.8%，或者大於等於99.9%。Unless otherwise stated, the terms "enriched with one isomer", "enriched with isomers", "enriched with one enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96 or more %, Or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

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

可以通過的手性合成或手性試劑或者其他常規技術製備光學活性的(R )-和(S )-異構體以及D 和L 異構體。如果想得到本發明某化合物的一種對映體，可以通過不對稱合成或者具有手性助劑的衍生作用來製備，其中將所得非對映體混合物分離，並且輔助基團裂開以提供純的所需對映異構體。或者，當分子中含有鹼性官能團（如氨基）或酸性官能團（如羧基）時，與適當的光學活性的酸或鹼形成非對映異構體的鹽，然後通過本領域所公知的常規方法進行非對映異構體拆分，然後回收得到純的對映體。此外，對映異構體和非對映異構體的分離通常是通過使用色譜法完成的，所述色譜法採用手性固定相，並任選地與化學衍生法相結合（例如由胺生成氨基甲酸鹽）。本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚（3 H），碘-125（125 I）或C-14（14 C）。又例如，可用重氫取代氫形成氘代藥物，氘與碳構成的鍵比普通氫與碳構成的鍵更堅固，相比於未氘化藥物，氘代藥物有降低毒副作用、增加藥物穩定性、增強療效、延長藥物生物半衰期等優勢。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包括在本發明的範圍之內。術語“藥學上可接受的載體”是指能夠遞送本發明有效量活性物質、不干擾活性物質的生物活性並且對宿主或者患者無毒副作用的任何製劑或載體介質代表性的載體包括水、油、蔬菜和礦物質、膏基、洗劑基質、軟膏基質等。這些基質包括懸浮劑、增粘劑、透皮促進劑等。它們的製劑為化妝品領域或局部藥物領域的技術人員所周知。Optically active ( R )-and ( S ) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure Enantiomers required. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (such as the generation of amino groups from amines) Formate). The compounds of the invention may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). As another example, deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have reduced side effects and increased drug stability. , Enhance efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic or side effects to the host or patient. Representative carriers include water, oil, vegetables And minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.

術語“賦形劑”通常是指配製有效的藥物組合物所需要載體、稀釋劑和/或介質。The term "excipient" generally refers to a carrier, diluent, and / or vehicle required to formulate an effective pharmaceutical composition.

針對藥物或藥理學活性劑而言，術語“有效量”或“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。對於本發明中的口服劑型，組合物中一種活性物質的“有效量”是指與該組合物中另一種活性物質聯用時為了達到預期效果所需要的用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由本領域技術人員根據常規試驗確定。For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. For an oral dosage form in the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depends on the age and general situation of the recipient, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine tests.

術語“活性成分”、“治療劑”，“活性物質”或“活性劑”是指一種化學實體，它可以有效地治療目標紊亂、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

“任選”或“任選地”指的是隨後描述的事件或狀況可能但不是必需出現的，並且該描述包括其中所述事件或狀況發生的情況以及所述事件或狀況不發生的情況。"Optional" or "optionally" refers to events or conditions described later that may, but need not, occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.

術語“被取代的”是指特定原子上的任意一個或多個氫原子被取代基取代，可以包括重氫和氫的變體，只要特定原子的價態是正常的並且取代後的化合物是穩定的。當取代基為氧（即=O）時，意味著兩個氫原子被取代。氧取代不會發生在芳香基上。The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (= O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.

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

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

當一個連接基團的數量為0時，比如-(CRR)0 -，表示該連接基團為單鍵。When the number of a linking group is 0, such as-(CRR) 0- , the linking group is a single bond.

當其中一個變量選自單鍵時，表示其連接的兩個基團直接相連，比如A-L-Z中L代表單鍵時表示該結構實際上是A-Z。When one of the variables is selected from a single bond, the two groups connected to it are directly connected. For example, in A-L-Z, when L represents a single bond, the structure is actually A-Z.

當一個取代基為空缺時，表示該取代基是不存在的，比如A-X中X為空缺時表示該結構實際上是A。When a substituent is vacant, it means that the substituent does not exist. For example, X in A-X indicates that the structure is actually A.

除非另有規定，術語“雜”表示雜原子或雜原子團(即含有雜原子的原子團)，包括碳（C）和氫（H）以外的原子以及含有這些雜原子的原子團，例如包括氧（O）、氮（N）、硫（S）、矽（Si）、鍺（Ge）、鋁（Al）、硼（B）、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2 -，以及任選被取代的-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-或-S(=O)N(H)-。Unless otherwise specified, the term "hetero" means heteroatoms or heteroatomic groups (ie, groups containing heteroatoms), including atoms other than carbon (C) and hydrogen (H), and groups containing these heteroatoms, such as oxygen (O ), Nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -C (= O) O-,- C (= O)-, -C (= S)-, -S (= O), -S (= O) 2- , and optionally substituted -C (= O) N (H)-,- N (H)-, -C (= NH)-, -S (= O) 2 N (H)-or -S (= O) N (H)-.

除非另有規定，“環”表示被取代或未被取代的環烷基、雜環烷基、環烯基、雜環烯基、環炔基、雜環炔基、芳基或雜芳基。所述的環包括單環、雙環和多環體系，其中雙環和多環體系包括聯環、螺環、并環和橋環。環上原子的數目通常被定義為環的元數，例如，“5～7元環”是指環繞排列5～7個原子。除非另有規定，該環任選地包含1～3個雜原子。因此，“5～7元環”包括例如苯基、吡啶和哌啶基；另一方面，術語“5～7元雜環基”包括吡啶基和哌啶基，但不包括苯基。術語“環”還包括含有至少一個環的環系，其中的每一個“環”均獨立地符合上述定義。Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The rings include monocyclic, bicyclic and polycyclic ring systems, wherein the bicyclic and polycyclic ring systems include linked rings, spiral rings, parallel rings and bridge rings. The number of atoms on a ring is usually defined as the number of rings. For example, a "5- to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, a "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocyclic group" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently meets the above definition.

除非另有規定，術語“烷基”用於表示直鏈或支鏈的飽和的碳氫基團，在一些實施方案中，所述烷基為C1-12 烷基；在另一些實施方案中，所述烷基為C1-6 烷基；在另一些實施方案中，所述烷基為C1-3 烷基。其可以是單取代（如-CH2 F）或多取代的（如-CF3 ），可以是一價（如甲基）、二價（如亞甲基）或者多價（如次甲基）。烷基的實例包括但不限於甲基(Me)，乙基(Et)，丙基(包括n -丙基和異丙基)，丁基(包括n -丁基，異丁基，s -丁基和t -丁基)，戊基 (包括n -戊基，異戊基和新戊基)、己基等。Unless otherwise specified, the term "alkyl" is used to indicate a straight or branched chain saturated hydrocarbon group. In some embodiments, the alkyl group is a C 1-12 alkyl group; in other embodiments , The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It can be mono-substituted (such as -CH 2 F) or poly-substituted (such as -CF 3 ), and can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). . Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n -propyl and isopropyl), butyl (including n -butyl, isobutyl, s -butyl And t -butyl), pentyl (including n -pentyl, isopentyl and neopentyl), hexyl and the like.

除非另有規定，“烯基”用於表示直鏈或支鏈的包含一個或多個碳-碳雙鍵的碳氫基團，碳-碳雙鍵可以位於該基團的任何位置上。在一些實施方案中，所述烯基為C2-8 烯基；在另一些實施方案中，所述烯基為C2-6 烯基；在另一些實施方案中，所述烯基為C2-4 烯基。其可以是單取代或多取代的，可以是一價、二價或者多價。烯基的實例包括但不限於乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁間二烯基，戊間二烯基，己間二烯基等。Unless otherwise specified, "alkenyl" is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bonds may be located at any position of the group. In some embodiments, the alkenyl is C 2-8 alkenyl; in other embodiments, the alkenyl is C 2-6 alkenyl; in other embodiments, the alkenyl is C 2-4 alkenyl. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent. Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

除非另有規定，“炔基”用於表示直鏈或支鏈的包含一個或多個碳-碳三鍵的碳氫基團，碳-碳三鍵可以位於該基團的任何位置上。在一些實施方案中，所述炔基為C2-8 炔基；在另一些實施方案中，所述炔基為C2-6 炔基；在另一些實施方案中，所述炔基為C2-4 炔基。其可以是單取代或多取代的，可以是一價、二價或者多價。炔基的實例包括但不限於乙炔基，丙炔基，丁炔基，戊炔基等。Unless otherwise specified, "alkynyl" is used to indicate a straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bond may be located at any position of the group. In some embodiments, the alkynyl is C 2-8 alkynyl; in other embodiments, the alkynyl is C 2-6 alkynyl; in other embodiments, the alkynyl is C 2-4 alkynyl. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and the like.

除非另有規定，術語“雜烷基”本身或者與另一術語聯合，表示由一定數目碳原子和至少一個雜原子或雜原子團組成的，穩定的直鏈或支鏈的烷基原子團或其組合物。在一些實施方案中，雜原子選自B、O、N和S，其中氮和硫原子任選地被氧化，氮雜原子任選地被季銨化。在另一些實施方案中，雜原子團選自-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2 -、-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-和-S(=O)N(H)-。在一些實施方案中，所述雜烷基為C1-6 雜烷基；在另一些實施方案中，所述雜烷基為C1-3 雜烷基。雜原子或雜原子團可以位於雜烷基的任何內部位置，包括該烷基與分子其餘部分的連接位置，但術語“烷氧基”、“烷氨基”和“烷硫基”（或硫代烷氧基）屬於慣用表達，是指分別通過一個氧原子、氨基或硫原子連接到分子的其餘部分的那些烷基基團。雜烷基的實例包括但不限於-OCH3 、-OCH2 CH3 、-OCH2 CH2 CH3 、-OCH2 (CH3 )2 、-CH2 -CH2 -O-CH3 、-NHCH3 、-N(CH3 )2 、-NHCH2 CH3 、-N(CH3 )(CH2 CH3 )、-CH2 -CH2 -NH-CH3 、-CH2 -CH2 -N(CH3 )-CH3 、-SCH3 、-SCH2 CH3 、-SCH2 CH2 CH3 、-SCH2 (CH3 )2 、-CH2 -S-CH2 -CH3 、-CH2 -CH2 、-S(=O)-CH3 、-CH2 -CH2 -S(=O)2 -CH3 、-CH=CH-O-CH3 、-CH2 -CH=N-OCH3 和–CH=CH-N(CH3 )-CH3 。至多兩個雜原子可以是連續的，例如-CH2 -NH-OCH3 。Unless otherwise specified, the term "heteroalkyl" itself or in combination with another term means a stable straight or branched chain alkyl radical group or a combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group Thing. In some embodiments, the heteroatoms are selected from B, O, N, and S, where nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatomic group is selected from -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O), -S (= O) 2 -, -C (= O) N (H)-, -N (H)-, -C (= NH)-, -S (= O) 2 N (H)-, and -S (= O) N ( H)-. In some embodiments, the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl. A heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkane (Oxy) is a customary expression and refers to those alkyl groups which are each connected to the rest of the molecule through an oxygen, amino or sulfur atom. Examples of heteroalkyl include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3 ) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -N (CH 3 ) (CH 2 CH 3 ), -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N ( CH 3 ) -CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2- CH 2 , -S (= O) -CH 3 , -CH 2 -CH 2 -S (= O) 2 -CH 3 , -CH = CH-O-CH 3 , -CH 2 -CH = N-OCH 3 And -CH = CH-N (CH 3 ) -CH 3 . Up to two heteroatoms may be continuous, such as -CH 2 -NH-OCH 3 .

“烷氧基”代表通過氧橋連接的具有特定數目碳原子的上述烷基，除非另有規定，C1-6 烷氧基包括C1 、C2 、C3 、C4 、C5 和C6 的烷氧基。在一些實施方案中，所述烷氧基為C1-3 烷氧基。烷氧基的實例包括但不限於：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、三級丁氧基、正戊氧基和S -戊氧基。"Alkoxy" represents the above-mentioned alkyl group having a specific number of carbon atoms connected through an oxygen bridge. Unless otherwise specified, C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy. In some embodiments, the alkoxy group is a C 1-3 alkoxy group. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, n-pentoxy and S -pentyloxy.

除非另有規定，術語“雜烯基”本身或者與另一術語聯合，表示由一定數目碳原子和至少一個雜原子或雜原子團組成的，穩定的直鏈或支鏈的烯基原子團或其組合物。在一些實施方案中，雜原子選自B、O、N和S，其中氮和硫原子任選地被氧化，氮雜原子任選地被季銨化。在另一些實施方案中，雜原子團選自-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2 -、-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-和-S(=O)N(H)-。在一些實施方案中，所述雜烯基為C2-6 雜烯基；在另一些實施方案中，所述雜烷基為C2-4 雜烯基。雜原子或雜原子團可以位於雜烯基的任何內部位置，包括該烯基與分子其餘部分的連接位置，但術語“烯基氧基”、“烯基氨基”和“烯基硫基”屬於慣用表達，是指分別通過一個氧原子、氨基或硫原子連接到分子的其餘部分的那些烯基基團。雜烯基的實例包括但不限於-O-CH=CH2 、-O-CH=CHCH3 、-O-CH=C(CH3 )2 、-CH=CH-O-CH3 、-O-CH=CHCH2 CH3 、-CH2 -CH=CH-OCH3 、-NH-CH=CH2 、-N(CH=CH2 )-CH3 、-CH=CH-NH-CH3 、-CH=CH-N(CH3 )2 、-S-CH=CH2 、-S-CH=CHCH3 、-S-CH=C(CH3 )2 、-CH2 -S-CH=CH2 、-S(=O)-CH=CH2 和-CH=CH-S(=O)2 -CH3 。至多兩個雜原子可以是連續的，例如-CH=CH-NH-OCH3 。Unless otherwise specified, the term "heteroalkenyl" itself or in combination with another term means a stable straight or branched chain alkenyl radical or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group Thing. In some embodiments, the heteroatoms are selected from B, O, N, and S, where nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatomic group is selected from -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O), -S (= O) 2 -, -C (= O) N (H)-, -N (H)-, -C (= NH)-, -S (= O) 2 N (H)-, and -S (= O) N ( H)-. In some embodiments, the heteroalkenyl is C 2-6 heteroalkenyl; in other embodiments, the heteroalkyl is C 2-4 heteroalkenyl. A heteroatom or heteroatom group can be located at any internal position of the heteroalkenyl group, including the position where the alkenyl group is attached to the rest of the molecule, but the terms "alkenyloxy", "alkenylamino" and "alkenylthio" are customary Expression refers to those alkenyl groups that are connected to the rest of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkenyl include, but are not limited to, -O-CH = CH 2 , -O-CH = CHCH 3 , -O-CH = C (CH 3 ) 2 , -CH = CH-O-CH 3 , -O- CH = CHCH 2 CH 3 , -CH 2 -CH = CH-OCH 3 , -NH-CH = CH 2 , -N (CH = CH 2 ) -CH 3 , -CH = CH-NH-CH 3 , -CH = CH-N (CH 3 ) 2 , -S-CH = CH 2 , -S-CH = CHCH 3 , -S-CH = C (CH 3 ) 2 , -CH 2 -S-CH = CH 2 ,- S (= O) -CH = CH 2 and -CH = CH-S (= O) 2 -CH 3 . Up to two heteroatoms may be consecutive, such as -CH = CH-NH-OCH 3 .

除非另有規定，術語“雜炔基”本身或者與另一術語聯合，表示由一定數目碳原子和至少一個雜原子或雜原子團組成的，穩定的直鏈或支鏈的炔基原子團或其組合物。在一些實施方案中，雜原子選自B、O、N和S，其中氮和硫原子任選地被氧化，氮雜原子任選地被季銨化。在另一些實施方案中，雜原子團選自-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2 -、-C(=O)N(H)-、-N(H)-、-C(=NH)-、-S(=O)2 N(H)-和-S(=O)N(H)-。在一些實施方案中，所述雜炔基為C2-6 雜炔基；在另一些實施方案中，所述雜烷基為C2-4 雜炔基。雜原子或雜原子團可以位於雜炔基的任何內部位置，包括該炔基與分子其餘部分的連接位置，但術語“炔基氧基”、“炔基氨基”和“炔基硫基”屬於慣用表達，是指分別通過一個氧原子、氨基或硫原子連接到分子的其餘部分的那些炔基基團。雜炔基的實例包括但不限於、、、、、、、、、、、、和。至多兩個雜原子可以是連續的，例如。Unless otherwise specified, the term "heteroalkynyl" itself or in combination with another term means a stable straight or branched chain alkynyl radical or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group Thing. In some embodiments, the heteroatoms are selected from B, O, N, and S, where nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatomic group is selected from -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O), -S (= O) 2 -, -C (= O) N (H)-, -N (H)-, -C (= NH)-, -S (= O) 2 N (H)-, and -S (= O) N ( H)-. In some embodiments, the heteroalkynyl is a C 2-6 heteroalkynyl; in other embodiments, the heteroalkyl is a C 2-4 heteroalkynyl. A heteroatom or heteroatom group can be located at any internal position of the heteroalkynyl group, including the position where the alkynyl group is attached to the rest of the molecule, but the terms "alkynyloxy", "alkynylamino" and "alkynylthio" are customary Expression refers to those alkynyl groups that are connected to the rest of the molecule through an oxygen, amino, or sulfur atom, respectively. Examples of heteroalkynyl include, but are not limited to , , , , , , , , , , , , with . Up to two heteroatoms can be continuous, for example .

除非另有規定，“環烷基”包括任何穩定的環狀烷基，其包括單環、雙環或者三環體系，其中雙環和三環體系包括螺環、并環和橋環。在一些實施方案中，所述環烷基為C3-8 環烷基；在另一些實施方案中，所述環烷基為C3-6 環烷基；在另一些實施方案中，所述環烷基為C5-6 環烷基。其可以是單取代或多取代的，可以是一價、二價或者多價。這些環烷基的實例包括，但不限於，環丙基、環丁基、環戊基、環己基、環庚基、雙環[2.2.1]庚烷基、[2.2.2]二環辛烷、[4.4.0]二環癸烷等。Unless otherwise specified, "cycloalkyl" includes any stable cyclic alkyl group including monocyclic, bicyclic, or tricyclic systems, where bicyclic and tricyclic systems include spiro, paracyclic, and bridged rings. In some embodiments, the cycloalkyl is C 3-8 cycloalkyl; in other embodiments, the cycloalkyl is C 3-6 cycloalkyl; in other embodiments, the cycloalkyl Cycloalkyl is C 5-6 cycloalkyl. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent. Examples of these cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, [2.2.2] bicyclooctane , [4.4.0] dicyclodecane, etc.

除非另有規定，“環烯基”包括任何穩定的環狀烯基，在該基團的任何位點含有一個或多個碳-碳雙鍵，其包括單環、雙環或者三環體系，其中雙環和三環體系包括螺環、并環和橋環，但是此體系的任意環都是非芳香性的。在一些實施方案中，所述環烯基為C3-8 環烯基；在另一些實施方案中，所述環烯基為C3-6 環烯基；在另一些實施方案中，所述環烯基為C5-6 環烯基。其可以是單取代或多取代的，可以是一價、二價或者多價。這些環烯基的實例包括，但不限於，環戊烯基、環己烯基等。Unless otherwise specified, "cycloalkenyl" includes any stable cyclic alkenyl group containing one or more carbon-carbon double bonds at any position in the group, including monocyclic, bicyclic, or tricyclic systems, where Bicyclic and tricyclic systems include spiro, parallel and bridged rings, but any ring in this system is non-aromatic. In some embodiments, the cycloalkenyl is C 3-8 cycloalkenyl; in other embodiments, the cycloalkenyl is C 3-6 cycloalkenyl; in other embodiments, the cycloalkenyl The cycloalkenyl is a C 5-6 cycloalkenyl. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent. Examples of these cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

除非另有規定，“環炔基”包括任何穩定的環狀炔基，在該基團的任何位點含有一個或多個碳-碳三鍵，其包含單環、雙環或者三環體系，其中雙環和三環體系包括螺環、并環和橋環。其可以是單取代或多取代的，可以是一價、二價或者多價。Unless otherwise specified, "cycloalkynyl" includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position in the group, which includes monocyclic, bicyclic, or tricyclic systems, where Bicyclic and tricyclic systems include spiro, parallel and bridge rings. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent.

除非另有規定，術語“雜環烷基”本身或者與其他術語聯合分別表示環化的“雜烷基”，其包括單環、雙環和三環體系，其中雙環和三環體系包括螺環、并環和橋環。此外，就該“雜環烷基”而言，雜原子可以佔據雜環烷基與分子其餘部分的連接位置。在一些實施方案中，所述雜環烷基為4~6元雜環烷基；在另一些實施方案中，所述雜環烷基為5~6元雜環烷基。雜環烷基的實例包括但不限於氮雜環丁基、氧雜環丁基、硫雜環丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基 (包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基 (包括四氫呋喃-2-基等)、四氫吡喃基、哌啶基 (包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌基 (包括1-哌基和2-哌基等)、嗎福林基 (包括3-嗎福林基和4-嗎福林基等)、二烷基、二噻烷基、異唑烷基、異噻唑烷基、1,2- 基、1,2-噻基、六氫嗒基、高哌基、高哌啶基或氧雜環庚烷基。Unless otherwise specified, the term "heterocycloalkyl" itself or in combination with other terms respectively represents a cyclic "heteroalkyl", which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, Parallel ring and bridge ring. In addition, with regard to the "heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene 2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperidine (Including 1-piperidine 2-piperyl Base, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), two Alkyl, dithioalkyl, iso Oxazolidinyl, isothiazolidinyl, 1,2- Base, 1,2-thia Hexahydro Base Radical, homopiperidinyl or oxecanyl.

除非另有規定，術語“雜環烯基”本身或者與其他術語聯合分別表示環化的“雜烯基”，其包括單環、雙環和三環體系，其中雙環和三環體系包括螺環、并環和橋環，但是此體系的任意環都是非芳香性的。此外，就該“雜環烯基”而言，雜原子可以佔據雜環烯基與分子其餘部分的連接位置。在一些實施方案中，所述雜環烯基為4~6元雜環烯基；在另一些實施方案中，所述雜環烯基為5~6元雜環烯基。雜環烯基的實例包括但不限於、、、、、、、、、、、、或。Unless otherwise specified, the term "heterocycloalkenyl" itself or in combination with other terms respectively represents a cyclic "heteroalkenyl", which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, Parallel and bridged rings, but any ring in this system is non-aromatic. In addition, as far as the "heterocyclic alkenyl group" is concerned, a heteroatom may occupy a connection position of the heterocyclic alkenyl group with the rest of the molecule. In some embodiments, the heterocycloalkenyl is a 4- to 6-membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is a 5- to 6-membered heterocycloalkenyl. Examples of heterocyclenyl include, but are not limited to , , , , , , , , , , , , or .

除非另有規定，術語“雜環炔基”本身或者與其他術語聯合分別表示環化的“雜炔基”，其包括單環、雙環和三環體系，其中雙環和三環體系包括螺環、并環和橋環。此外，就該“雜環炔基”而言，雜原子可以佔據雜環炔基與分子其餘部分的連接位置。在一些實施方案中，所述雜環炔基為4~6元雜環炔基；在另一些實施方案中，所述雜環炔基為5~6元雜環炔基。除非另有規定，術語“鹵代素”或“鹵素”本身或作為另一取代基的一部分表示氟、氯、溴或碘原子。此外，術語“鹵代烷基”意在包括單鹵代烷基和多鹵代烷基。例如，術語“鹵代（C1 -C4 ）烷基”意在包括但不僅限於三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有規定，鹵代烷基的實例包括但不僅限於：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。Unless otherwise specified, the term "heterocycloalkynyl" itself or in combination with other terms respectively represents a cyclic "heteroalkynyl", which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, Parallel ring and bridge ring. In addition, as far as the "heterocyclic alkynyl group" is concerned, a heteroatom may occupy a connection position of the heterocyclic alkynyl group with the rest of the molecule. In some embodiments, the heterocycloalkynyl is a 4- to 6-membered heterocycloalkynyl; in other embodiments, the heterocycloalkynyl is a 5- to 6-membered heterocycloalkynyl. Unless otherwise specified, the term "halogen" or "halogen" refers to a fluorine, chlorine, bromine or iodine atom by itself or as part of another substituent. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C 1 -C 4) alkyl" is meant to include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl and the like Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

除非另有規定，本發明術語“芳環”和“芳基”可以互換使用，術語“芳環”或“芳基”表示多不飽和的碳環體系，它可以是單環、雙環或多環體系，其中至少一個環是芳香性的，所述雙環和多環體系中的各個環稠合在一起或共價連接。其可以是單取代或多取代的，可以是一價、二價或者多價，在一些實施方案中，所述芳基為C6-12 芳基；在另一些實施方案中，所述芳基為C6-10 芳基。芳基的非限制性實施例包括苯基、萘基 (包括1-萘基和2-萘基等)、聯苯基 (包括4-聯苯基等)。、上述任意一個芳基環系的取代基選自本發明所述的可接受的取代基。Unless otherwise specified, the terms "aryl ring" and "aryl" in the present invention are used interchangeably. The term "aryl ring" or "aryl" means a polyunsaturated carbocyclic ring system, which may be monocyclic, bicyclic, or polycyclic Systems in which at least one ring is aromatic, and the individual rings in the bicyclic and polycyclic systems are fused together or covalently linked. It may be mono- or poly-substituted, and may be monovalent, divalent, or polyvalent. In some embodiments, the aryl is a C 6-12 aryl; in other embodiments, the aryl C 6-10 aryl. Non-limiting examples of aryl include phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.), biphenyl (including 4-biphenyl, etc.). The substituent of any one of the above aryl ring systems is selected from the acceptable substituents described in the present invention.

除非另有規定，本發明術語“雜芳環”和“雜芳基”可以互換使用，術語“雜芳基”是指含有1、2、3或4個獨立選自B、N、O和S的雜原子的芳基（或芳環），其可以是單環、雙環或三環體系，其中氮原子可以是被取代的或未取代的（即N或NR，其中R是H或本文已經定義過的其他取代基），且任選地被季銨化，氮和硫雜原子可任選被氧化（即NO和S(O)p ，p是1或2）。雜芳基可通過雜原子連接到分子的其餘部分。在一些實施方案中，所述雜芳基為5-10元雜芳基；在另一些實施方案中，所述雜芳基為5-6元雜芳基。所述雜芳基的非限制性實施例包括吡咯基 (包括N -吡咯基、2-吡咯基和3-吡咯基等)、吡唑基 (包括2-吡唑基和3-吡唑基等)、咪唑基 (包括N -咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、唑基 (包括2-唑基、4-唑基和5-唑基等)、三唑基 (1H -1,2,3-三唑基、2H -1,2,3-三唑基、1H -1,2,4-三唑基和4H -1,2,4-三唑基等)、四唑基、異唑基 (3-異唑基、4-異唑基和5-異唑基等)、噻唑基 (包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基 (包括2-呋喃基和3-呋喃基等)、噻吩基 (包括2-噻吩基和3-噻吩基等)、吡啶基 (包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡基、嘧啶基 (包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基 (包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基 (包括2-苯并咪唑基等)、吲哚基 (包括5-吲哚基等)、異喹啉基 (包括1-異喹啉基和5-異喹啉基等)、喹啉基 (包括2-喹啉基和5-喹啉基等)、喹啉基 (包括3-喹啉基和6-喹啉基等)、吡基、2-苯基-4-唑基、嘌呤基、苯基并唑基。上述任意一個雜芳基環系的取代基選自本發明所述的可接受的取代基。Unless otherwise specified, the terms "heteroaryl ring" and "heteroaryl" in the present invention are used interchangeably, and the term "heteroaryl" means containing 1, 2, 3 or 4 independently selected from B, N, O and S Aryl (or aromatic ring) of a heteroatom, which may be a monocyclic, bicyclic, or tricyclic system, where the nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or as defined herein) Other substituents), and optionally quaternized, nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S (O) p , p is 1 or 2). Heteroaryl groups can be attached to the rest of the molecule through heteroatoms. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group; in other embodiments, the heteroaryl group is a 5-6 membered heteroaryl group. Non-limiting examples of the heteroaryl group include pyrrolyl (including N -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) ), Imidazolyl (including N -imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), Azolyl (including 2- Oxazolyl, 4- Oxazolyl and 5- Oxazolyl, etc.), triazolyl (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl, and 4 H -1,2,4-triazolyl, etc.), tetrazolyl, iso Azolyl (3-iso Oxazolyl, 4-iso Oxazolyl and 5-iso Oxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl And 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyridine Base, pyrimidyl (including 2-pyrimidyl and 4-pyrimidyl), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.) , Indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinol Phenyl (including 2-quinine And quinoline Quinolyl, etc.), quinolyl (including 3-quinolyl and 6-quinolyl, etc.), pyridine Base, 2-phenyl-4- Oxazolyl, purinyl, phenyl Azole. The substituent of any of the above heteroaryl ring systems is selected from the acceptable substituents described in the present invention.

除非另有規定，術語“芳烷基”意在包括芳基附著於烷基的那些基團，在一些實施方案中，所述芳烷基為C6-10 芳基-C1-4 烷基；在另一些實施方案中，所述芳烷基為C6-10 芳基-C1-2 烷基。芳烷基的實例包括但不限於苄基、苯乙基、萘甲基等。“芳氧基”和“芳硫基”分別表示芳烷基中的碳原子（如亞甲基）已經被氧或硫原子代替的那些基團，在一些實施方案中，所述芳氧基為C6-10 芳基-O-C1-2 烷基；在另一些實施方案中，芳氧基為C6-10 芳基-C1-2 亞烷基-O-。在一些實施方案中，所述芳硫基為C6-10 芳基-S-C1-2 烷基；在另一些實施方案中，芳硫基為C6-10 芳基-C1-2 亞烷基-S-。芳氧基和芳硫基的實例包括但不限於苯氧基甲基、3-(1-萘氧基)丙基，苯硫基甲基等。Unless otherwise specified, the term "aralkyl" is intended to include those groups in which an aryl group is attached to an alkyl group. In some embodiments, the aralkyl group is a C 6-10 aryl-C 1-4 alkyl group. In other embodiments, the aralkyl is a C 6-10 aryl-C 1-2 alkyl. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. "Aryloxy" and "arylthio" refer to those groups in which the carbon atom (such as methylene) in the aralkyl group has been replaced by an oxygen or sulfur atom. In some embodiments, the aryloxy group is C 6-10 aryl-OC 1-2 alkyl; in other embodiments, aryloxy is C 6-10 aryl-C 1-2 alkylene-O-. In some embodiments, the arylthio group is C 6-10 aryl-SC 1-2 alkyl; in other embodiments, the arylthio group is C 6-10 aryl-C 1-2 alkylene Radical -S-. Examples of aryloxy and arylthio include, but are not limited to, phenoxymethyl, 3- (1-naphthyloxy) propyl, phenylthiomethyl, and the like.

除非另有規定，術語“雜芳烷基”意在包括雜芳基附著於烷基的那些基團，在一些實施方案中，所述雜芳烷基為5-8元雜芳基-C1-4 烷基；在另一些實施方案中，所述雜芳烷基為5-6元雜芳基-C1-2 烷基。雜芳烷基的實例包括但不限於吡咯基甲基、吡唑基甲基、吡啶基甲基、嘧啶基甲基等。“雜芳氧基”和“雜芳硫基”分別表示雜芳烷基中的碳原子（如亞甲基）已經被氧或硫原子代替的那些基團，在一些實施方案中，所述雜芳氧基為5-8元雜芳基-O-C1-2 烷基；在另一些實施方案中，雜芳氧基為5-6元雜芳基-C1-2 亞烷基-O-。在一些實施方案中，所述雜芳硫基為5-8元雜芳基-S-C1-2 烷基；在另一些實施方案中，雜芳硫基為5-6元雜芳基-C1-2 亞烷基-S-。雜芳氧基和雜芳硫基的實例包括但不限於吡咯氧甲基、吡唑氧甲基、2-吡啶氧甲基、吡咯硫甲基、吡唑硫甲基、2-吡啶硫甲基等。Unless otherwise specified, the term "heteroaralkyl" is intended to include those groups in which a heteroaryl group is attached to an alkyl group. In some embodiments, the heteroaralkyl group is a 5-8 membered heteroaryl-C 1 -4 alkyl; in other embodiments, the heteroaralkyl is a 5-6 membered heteroaryl-C 1-2 alkyl. Examples of heteroaralkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like. "Heteroaryloxy" and "heteroarylthio" refer to those groups in which a carbon atom (such as methylene) in a heteroaralkyl group has been replaced by an oxygen or sulfur atom, and in some embodiments, the hetero Aryloxy is a 5-8 membered heteroaryl-OC 1-2 alkyl; in other embodiments, heteroaryloxy is a 5-6 membered heteroaryl-C 1-2 alkylene-O-. In some embodiments, the heteroarylthio group is a 5-8 membered heteroaryl-SC 1-2 alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C 1 -2 alkylene-S-. Examples of heteroaryloxy and heteroarylthio include, but are not limited to, pyrrolyloxymethyl, pyrazolylmethyl, 2-pyridyloxymethyl, pyrrolylthio, pyrazolethiomethyl, 2-pyridylthiomethyl Wait.

術語“離去基團”是指可以被另一種官能團或原子通過取代反應（例如親和取代反應）所取代的官能團或原子。例如，代表性的離去基團包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、對溴苯磺酸酯、對甲苯磺酸酯等；醯氧基，如乙醯氧基、三氟乙醯氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonic acid. Esters, etc .; ethoxy, such as ethoxy, trifluoroethoxy and the like.

本發明採用下述縮略詞：eq代表當量、等量；DCM代表二氯甲烷；PE代表石油醚；DMF代表N，N-二甲基甲醯胺；DMSO代表二甲亞碸；EtOAc代表乙酸乙酯；MeOH代表甲醇；BOC代表三級丁氧羰基是一種胺保護基團；THF代表四氫呋喃；Boc2 O代表二-三級丁基二碳酸酯；NCS代表N-氯代丁二醯亞胺；PMB代表對甲氧基苄胺；THP代表2-四氫呋喃基；Pd(t-Bu3 P)2 代表二（三三級丁基膦）鈀；Na2 SO4 代表無水硫酸鈉；T3 P代表丙基磷酸酐；LiOH.H2 O代表水合氫氧化鋰；BH3-Me2S代表硼烷二甲硫醚溶液；t-BuONa代表三級丁醇鈉；TEA代表三乙胺；MeCN代表乙腈；K2 CO3 代表碳酸鉀；NH4 Cl代表氯化銨；H2 O代表水；NaOH代表氫氧化鈉；BH3 -Me2 S代表硼烷二甲硫醚溶液；Pd(OH)2 /C代表氫氧化鈀/碳；N2 代表氮氣；HCl代表鹽酸；FA代表甲酸；n-BμLi代表正丁基鋰；MeI代表碘甲烷；LiHMDS代表六甲基二矽基胺基鋰的四氫呋喃溶液。The following abbreviations are used in the present invention: eq stands for equivalent weight, equivalent amount; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N, N-dimethylformamide; DMSO stands for dimethylarsine; EtOAc stands for acetic acid Ethyl ester; MeOH for methanol; BOC for tertiary butoxycarbonyl is an amine protecting group; THF for tetrahydrofuran; Boc 2 O for di-tertiary butyl dicarbonate; NCS for N-chlorobutanediimine ; PMB stands for p-methoxybenzylamine; THP stands for 2-tetrahydrofuranyl; Pd (t-Bu 3 P) 2 stands for bis (tri-tertiary-butylphosphine) palladium; Na 2 SO 4 stands for anhydrous sodium sulfate; T 3 P Represents propyl phosphoric anhydride; LiOH.H 2 O represents hydrated lithium hydroxide; BH3-Me2S represents borane dimethyl sulfide solution; t-BuONa represents tertiary butanolate; TEA represents triethylamine; MeCN represents acetonitrile; K 2 CO 3 stands for potassium carbonate; NH 4 Cl stands for ammonium chloride; H 2 O stands for water; NaOH stands for sodium hydroxide; BH 3 -Me 2 S stands for borane dimethyl sulfide solution; Pd (OH) 2 / C stands for palladium hydroxide / carbon; N 2 Representative nitrogen; HCI Representative hydrochloride; the FA on behalf acid; n-BμLi represents n-butyl lithium; representatives of MeI methyl iodide; of LiHMDS representative of hexamethyldisilazane silicon based amine Tetrahydrofuran solution of lithium.

為讓本發明之上述和其他目的、特徵和優點能更明顯易懂，下文特舉實施例，並配合所附圖式，作詳細說明如下。In order to make the above and other objects, features, and advantages of the present invention more comprehensible, embodiments are described below in detail with reference to the accompanying drawings, as follows.

下面通過實施例對本發明進行詳細描述，但並不意味著對本發明任何不利限制。本發明的化合物可以通過本領域技術人員所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。對本領域的技術人員而言，在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。The following describes the present invention in detail through examples, but it does not imply any disadvantageous limitation to the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

實施例1

Example 1

化合物1-c的合成
將化合物1-a(10g, 59.88mmol, 6.62mL)溶解在MeCN(100mL)中，並在20℃下分批加入1-b(10.80g, 239.52mmol, 15.67mL) ，K2 CO3 (24.83g, 179.64mmol)。所得混合物在氮氣保護下，20℃下攪拌12小時。將反應物過濾後，濾液減壓濃縮，得到化合物1-c。Synthesis of compound 1-c Compound 1-a (10 g, 59.88 mmol, 6.62 mL) was dissolved in MeCN (100 mL), and 1-b (10.80 g, 239.52 mmol, 15.67 mL) was added in portions at 20 ° C. K 2 CO 3 (24.83 g, 179.64 mmol). The resulting mixture was stirred at 20 ° C for 12 hours under the protection of nitrogen. After the reaction was filtered, the filtrate was concentrated under reduced pressure to obtain compound 1-c.

化合物1-e的合成
將化合物1-c(6g, 45.74mmol)溶解於DCM(60mL)中，並在20℃下往溶液中加入TEA(13.89g, 137.22mmol, 19.10mL)，並在0℃下加入1-d(7.46g, 45.74mmol, 4.78mL)，所得混合物在20℃下氮氣保護下攪拌1小時。將反應液用DCM(75mL×2)萃取除去有機雜質.將所得有機相混合並用飽和NH4 Cl(50mL×3)，洗滌Na2 SO4 乾燥,過濾旋幹後得到粗品產物1-e。Synthesis of compound 1-e Compound 1-c (6 g, 45.74 mmol) was dissolved in DCM (60 mL), and TEA (13.89 g, 137.22 mmol, 19.10 mL) was added to the solution at 20 ° C, and the temperature was 0 ° C. Next, 1-d (7.46 g, 45.74 mmol, 4.78 mL) was added, and the resulting mixture was stirred at 20 ° C for 1 hour under nitrogen protection. The reaction solution was extracted with DCM (75 mL × 2) to remove organic impurities. The obtained organic phases were mixed and washed with saturated NH 4 Cl (50 mL × 3), washed with Na 2 SO 4 and dried, and filtered to spin-dry to obtain the crude product 1-e.

化合物1-f的合成
將化合物1-e(8.49g, 38.37mmol)溶解於THF(90mL)中，並在20℃下往溶液中加入TEA(11.65g, 115.11mmol, 16.02mL)和1-m(5.26g, 38.37mmol, 4.97mL)。所得混合物在70℃下攪拌12小時。通過液相質譜檢測至反應完成。將反應液用EtOAc(135mL)萃取除去有機雜質。將所得有機相混合並用飽和NH4 Cl (45mL×3)，洗滌Na2 SO4 乾燥，將粗品通過柱層析(石油醚/乙酸乙酯=1:0到0:1)純化得到1-f。Synthesis of compound 1-f Compound 1-e (8.49 g, 38.37 mmol) was dissolved in THF (90 mL), and TEA (11.65 g, 115.11 mmol, 16.02 mL) and 1-m were added to the solution at 20 ° C. (5.26 g, 38.37 mmol, 4.97 mL). The resulting mixture was stirred at 70 ° C for 12 hours. The reaction was detected to be complete by liquid mass spectrometry. The reaction was extracted with EtOAc (135 mL) to remove organic impurities. The obtained organic phases were mixed and washed with saturated NH 4 Cl (45 mL × 3), washed with Na 2 SO 4 and dried, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1: 0 to 0: 1) to obtain 1-f .

化合物1-g的合成
將化合物1-f (3g, 8.37mmol)溶解於H2 O(30mL)和MeOH(30mL)中，並在20℃下往溶液中加入LiOH.H2 O(3.51g, 83.69mmol)。所得混合物在20℃下攪拌12小時。將反應物減壓濃縮後，用EtOAc(30mL×3)萃取，分液，水相冷卻到0℃加入2MHCl調節pH=7，過濾得到粗品1-g。Synthesis of compound 1-g Compound 1-f (3 g, 8.37 mmol) was dissolved in H 2 O (30 mL) and MeOH (30 mL), and LiOH.H 2 O (3.51 g, 83.69 mmol). The resulting mixture was stirred at 20 ° C for 12 hours. The reaction was concentrated under reduced pressure, extracted with EtOAc (30 mL × 3), and the layers were separated. The aqueous phase was cooled to 0 ° C and 2M HCl was added to adjust the pH = 7. The crude product was 1-g by filtration.

化合物1-h的合成
將化合物1-g(4.6g, 13.92mmol)溶解於DMF(50mL)中，並在20℃下往溶液中加入T3 P(13.29g, 20.88mmol, 12.42mL)和TEA(4.23g, 41.77mmol, 5.81mL)。所得混合物在氮氣保護下20℃攪拌12小時。將反應物加入水(100ml)後，用EtOAc(50mL×3)萃取。合併有機相用飽和食鹽水洗(50mL×3)，Na2 SO4 乾燥，過濾濃縮後得到粗品1-h。Synthesis of Compound 1-h Compound 1-g (4.6 g, 13.92 mmol) was dissolved in DMF (50 mL), and T 3 P (13.29 g, 20.88 mmol, 12.42 mL) and TEA were added to the solution at 20 ° C. (4.23 g, 41.77 mmol, 5.81 mL). The resulting mixture was stirred under a nitrogen atmosphere at 20 ° C for 12 hours. After the reaction was added to water (100 ml), it was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to give the crude product 1-h.

化合物1-i的合成
將化合物1-h(637mg, 2.04mmol)溶解於THF(10mL)中，並在0℃下往溶液中加入BH3 -Me2 S(10M, 1.02mL)。所得混合物在氮氣保護下25℃攪拌2小時。將反應物加入水(20ml)後加入1MHCl調節pH=1，用EtOAc(10mL×3)萃取，分液，水相加入2MNaOH調節pH=10，用EtOAc(10mL×3)萃取，合併有機相用飽和食鹽水洗(10mL×3)，Na2 SO4 乾燥，過濾濃縮後得到粗品1-i。Synthesis of compound 1-i Compound 1-h (637 mg, 2.04 mmol) was dissolved in THF (10 mL), and BH 3 -Me 2 S (10M, 1.02 mL) was added to the solution at 0 ° C. The resulting mixture was stirred under a nitrogen atmosphere at 25 ° C for 2 hours. The reaction was added with water (20ml), and then 1M HCl was added to adjust the pH = 1, and the mixture was extracted with EtOAc (10mL × 3). The layers were separated. The aqueous phase was added with 2M NaOH to adjust the pH = 10. It was washed with saturated brine (10 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to obtain crude 1-i.

化合1-j的合成
將化合物1-i(170mg, 569.70μmol)溶解於MeOH(5mL)中，並在20℃下往溶液中加入Pd(OH)2 /C(40.00mg,純度20%)，所得混合物在氫氣保護下45℃攪拌1小時。將反應物過濾濃縮後得到粗品1-j。Synthesis of compound 1-j Compound 1-i (170 mg, 569.70 μmol) was dissolved in MeOH (5 mL), and Pd (OH) 2 / C (40.00 mg, purity 20%) was added to the solution at 20 ° C. The resulting mixture was stirred at 45 ° C for 1 hour under the protection of hydrogen. The reaction was filtered and concentrated to obtain crude 1-j.

化合物1-l的合成
將化合物1-k(200mg, 633.73μmol)，化合物1-j(112.96mg, 633.73μmol)，Pd(PtBu3 )2 (32.38mg, 63.37μmol, 0.1eq)和tBuONa(182.70mg, 1.90mmol, 3eq)溶於THF(5mL)，用N2 置換三次，所得棕色混合物在N2 氛圍70℃攪拌2小時。將混合物倒入水30mL和EtOAc(30mL)30mL中。有機相分離後用水30mL洗滌，Na2 SO4 乾燥，過濾濃縮得到化合物1-l。Synthesis of compound 1-l Compound 1-k (200 mg, 633.73 μmol), compound 1-j (112.96 mg, 633.73 μmol), Pd (PtBu 3 ) 2 (32.38 mg, 63.37 μmol, 0.1eq) and tBuONa (182.70 mg, 1.90 mmol, 3 eq) was dissolved in THF (5 mL) and replaced with N 2 three times, and the resulting brown mixture was stirred at 70 ° C. for 2 hours in a N 2 atmosphere. The mixture was poured into 30 mL of water and 30 mL of EtOAc (30 mL). The organic phase was separated, washed with 30 mL of water, dried over Na 2 SO 4 , filtered and concentrated to obtain compound 1-1.

化合物1的合成
將化合物1-l(280mg, 678.07μmol)溶於MeOH(10mL)後加入HCl/MeOH(4M,847.59μL)。所得混合物在25℃下攪拌3小時。將混合物倒入水30mL和EtOAc(30mL)中，分離得到有機相用水30mL洗滌，Na2 SO4 乾燥，過濾濃縮後得到粗品，粗品通過製備色譜純化(甲酸體系)得到化合物1。
1 HNMR(400MHz,氘代氯仿)δ=7.99(s,1H), 6.96(s,1H), 6.26(d,J =1.3Hz,1H), 4.07(m,4H), 3.70-3.59(m,2H), 3.57-3.46(m,2H), 3.10(q,J =7.2Hz,2H), 1.06(t,J =7.1Hz,3H)。Synthesis of Compound 1 Compound 1-1 (280 mg, 678.07 μmol) was dissolved in MeOH (10 mL), and then HCl / MeOH (4M, 847.59 μL) was added. The resulting mixture was stirred at 25 ° C for 3 hours. The mixture was poured into 30 mL of water and EtOAc (30 mL). The organic phase was separated and washed with 30 mL of water, dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product. The crude product was purified by preparative chromatography (formic acid system) to obtain compound 1.
1 HNMR (400MHz, deuterated chloroform) δ = 7.99 (s, 1H), 6.96 (s, 1H), 6.26 (d, J = 1.3Hz, 1H), 4.07 (m, 4H), 3.70-3.59 (m, 2H), 3.57-3.46 (m, 2H), 3.10 (q, J = 7.2Hz, 2H), 1.06 (t, J = 7.1Hz, 3H).

實施例2

Example 2

化合物2-a的合成
將化合物1-j(500mg, 2.81mmol)溶解於THF(10mL)中，並在25℃下往溶液中加入TEA(851.52mg, 8.42mmol, 1.17mL)和Boc2 O(642.80mg, 2.95mmol, 676.63μL)。所得混合物在25℃下氮氣保護下攪拌12小時。向溶液中加入飽和NH4 Cl(15mL)，將混合液用EtOAc(15mL×3)萃取除去有機雜質。將所得有機相混合並用飽和NH4 Cl(15mL×3)洗滌Na2 SO4 乾燥，過濾旋幹後得到粗品產物2-a。Synthesis of compound 2-a Compound 1-j (500 mg, 2.81 mmol) was dissolved in THF (10 mL), and TEA (851.52 mg, 8.42 mmol, 1.17 mL) and Boc 2 O ( 642.80 mg, 2.95 mmol, 676.63 μL). The resulting mixture was stirred under a nitrogen blanket at 25 ° C for 12 hours. To the solution was added saturated NH 4 Cl (15 mL), and the mixture was extracted with EtOAc (15 mL × 3) to remove organic impurities. The obtained organic phases were mixed and washed with saturated NH 4 Cl (15 mL × 3) to dry Na 2 SO 4 , and filtered and spin-dried to obtain a crude product 2-a.

化合物2-b的合成
將化合物2-a(500mg, 1.80mmol)溶解於THF(5mL)中，用氮氣置換三次，並在-70℃下往溶液中緩慢加入n-BμLi(2.5M, 3.59mL)。所得混合物在-70℃下攪拌1小時，然後在此溫度下加入MeI(5.10g, 35.92mmol, 2.24mL)。所得混合溶液在氮氣保護下，25℃下反應11小時。將反應液加入H2 O(15ml)，用EtOAc(15mL×3)萃取除去有機雜質。將所得有機相混合並用飽和食鹽水(15mL×3)，洗滌Na2 SO4 乾燥，將粗品通過製備色譜(甲酸體系)。純化，得到2-b。Synthesis of compound 2-b Compound 2-a (500mg, 1.80mmol) was dissolved in THF (5mL), replaced with nitrogen three times, and n-BμLi (2.5M, 3.59mL) was slowly added to the solution at -70 ° C. ). The resulting mixture was stirred at -70 ° C for 1 hour, and then MeI (5.10 g, 35.92 mmol, 2.24 mL) was added at this temperature. The resulting mixed solution was reacted at 25 ° C for 11 hours under the protection of nitrogen. The reaction solution was added with H 2 O (15 ml), and extracted with EtOAc (15 mL × 3) to remove organic impurities. The obtained organic phases were mixed and saturated brine (15 mL × 3), washed with Na 2 SO 4 and dried, and the crude product was subjected to preparative chromatography (formic acid system). Purified to give 2-b.

化合物2-c的合成
將化合物2-b(100mg, 326.35μmol)溶解於MeOH(5mL)中，並在25℃下往溶液中加入HCl/MeOH(4M, 5mL)。所得混合物在25℃下攪拌1小時。將反應物減壓濃縮後，得到粗品2-c。Synthesis of compound 2-c Compound 2-b (100 mg, 326.35 μmol) was dissolved in MeOH (5 mL), and HCl / MeOH (4M, 5 mL) was added to the solution at 25 ° C. The resulting mixture was stirred at 25 ° C for 1 hour. The reaction was concentrated under reduced pressure to obtain crude 2-c.

化合物2-d的合成
將化合物2-c(50mg, 242.36μml)，1-k(69.53mg, 220.33μmol)，t-BuONa(63.52mg, 660.98μmol)溶解於THF(5mL)中，氮氣置換三次後，往溶液中加入Pd(t-Bu3 P)2 (11.26mg, 22.03μmol, 0.1eq )。所得混合物在氮氣保護下70℃攪拌3小時。向反應物中加入EtOAc(15ml)。過濾，濾液用飽和食鹽水洗(10mL×2),Na2 SO4 乾燥，過濾濃縮後得到粗品2-d。Synthesis of compound 2-d Compound 2-c (50 mg, 242.36 μml), 1-k (69.53 mg, 220.33 μmol), t-BuONa (63.52 mg, 660.98 μmol) were dissolved in THF (5 mL), and replaced with nitrogen three times Then, Pd (t-Bu 3 P) 2 (11.26 mg, 22.03 μmol, 0.1 eq ) was added to the solution. The resulting mixture was stirred at 70 ° C for 3 hours under a nitrogen atmosphere. To the reaction was added EtOAc (15 ml). It was filtered, and the filtrate was washed with saturated brine (10 mL × 2), dried over Na 2 SO 4 , filtered and concentrated to obtain crude 2-d.

化合物2的合成
向化合物2-d(77mg, 174.61μmol)中加入HCl/MeOH(4M, 2mL)。所得混合溶液在25℃攪拌1小時。通過液相質譜檢測至反應完成。減壓濃縮後得到粗品。粗品通過製備色譜純化後，得到化合物2。
1 HNMR(400MHz,DMSO-d6 )δ=13.05(brs,1H), 8.25(s,1H), 6.87(s,1H), 6.43(s,1H), 3.95(t,J =6.1Hz,2H), 3.88(s,2H), 3.58-3.45(m,2H), 3.32-3.23(m,2H), 1.32-1.17(m,6H), 1.08(t,J =7.0Hz,3H)。Synthesis of compound 2 To compound 2-d (77 mg, 174.61 μmol) was added HCl / MeOH (4M, 2 mL). The obtained mixed solution was stirred at 25 ° C for 1 hour. The reaction was detected to be complete by liquid mass spectrometry. The crude product was obtained after concentration under reduced pressure. After the crude product was purified by preparative chromatography, compound 2 was obtained.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.05 (brs, 1H), 8.25 (s, 1H), 6.87 (s, 1H), 6.43 (s, 1H), 3.95 (t, J = 6.1Hz, 2H ), 3.88 (s, 2H), 3.58-3.45 (m, 2H), 3.32-3.23 (m, 2H), 1.32-1.17 (m, 6H), 1.08 (t, J = 7.0Hz, 3H).

實施例3

Example 3

化合物3-b的合成
向化合物1-a(10g, 59.88mmol, 6.62mL)的乙腈溶液(100mL)中加入碳酸鉀(24.83g, 179.64mmol)和化合物3-a(10.62g, 179.64mmol, 15.43mL)，在25℃下反應12小時，懸濁液一直保持無色。加入200毫升乙酸乙酯後過濾，濾液濃縮得到化合物3-b。Synthesis of compound 3-b To a solution (100 mL) of compound 1-a (10 g, 59.88 mmol, 6.62 mL) in acetonitrile were added potassium carbonate (24.83 g, 179.64 mmol) and compound 3-a (10.62 g, 179.64 mmol, 15.43 mL), and reacted at 25 ° C for 12 hours. The suspension remained colorless. 200 ml of ethyl acetate was added, followed by filtration, and the filtrate was concentrated to obtain compound 3-b.

化合物物3-c的合成
向化合物3-b(8.2g, 56.47mmol)的二氯甲烷溶液(100mL)中加入三乙胺(17.14g, 169.42mmol, 23.58mL)。將溶液冷卻到0℃後滴加化合物1-d(9.21g, 56.47mmol, 5.90mL)，滴加完後在25℃下反應12小時，混合物的顏色從無色變為棕色。加入100毫升二氯甲烷，混合物用飽和的氯化銨水溶液洗滌3次，每次200毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物3-c。Synthesis of compound 3-c To a solution of compound 3-b (8.2 g, 56.47 mmol) in dichloromethane (100 mL) was added triethylamine (17.14 g, 169.42 mmol, 23.58 mL). After the solution was cooled to 0 ° C, compound 1-d (9.21g, 56.47mmol, 5.90mL) was added dropwise. After the dropwise addition, the reaction was performed at 25 ° C for 12 hours, and the color of the mixture changed from colorless to brown. 100 ml of dichloromethane was added, and the mixture was washed three times with 200 ml of saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-c.

化合物物3-d的合成
向化合物3-c(11.6g, 49.30mmol)的四氫呋喃溶液(110mL)中加入三乙胺(9.98g, 98.60mmol, 13.72mL)和對甲氧基苄胺(6.76g, 49.30mmol, 6.38mL)，在70℃下反應12小時後，溶液的顏色保持棕色。加入300毫升乙酸乙酯稀釋，用飽和食鹽水洗3次，每次200毫升，無水硫酸鈉乾燥，過濾，濃縮得到的粗品通過快速矽膠柱（洗脫液：石油醚/乙酸乙酯=1：1）分離純化得到產品3-d。Synthesis of compound 3-d To a solution of compound 3-c (11.6 g, 49.30 mmol) in tetrahydrofuran (110 mL) was added triethylamine (9.98 g, 98.60 mmol, 13.72 mL) and p-methoxybenzylamine (6.76 g , 49.30 mmol, 6.38 mL). After 12 hours of reaction at 70 ° C, the color of the solution remained brown. Add 300 ml of ethyl acetate to dilute, wash with saturated brine 3 times, 200 ml each time, dry with anhydrous sodium sulfate, filter, and concentrate the obtained crude product through a fast silica gel column (eluent: petroleum ether / ethyl acetate = 1: 1) ) Isolation and purification to obtain product 3-d.

化合物物3-e的合成
向化合物3-d(13.5g, 36.24mmol)的甲醇(70mL)和水(70mL)的溶液中加入一水合氫氧化鋰(15.21g, 362.44mmol)，在25℃下反應12小時後，混合物的顏色保持黃色。加入140毫升水後用乙酸乙酯萃取兩次，每次100mL，用1M的鹽酸溶液將水層pH調到7，過濾，濾餅用30 mL水洗滌一次，然後真空乾燥得到化合物3-e。Synthesis of compound 3-e To a solution of compound 3-d (13.5 g, 36.24 mmol) in methanol (70 mL) and water (70 mL) was added lithium hydroxide monohydrate (15.21 g, 362.44 mmol) at 25 ° C. After 12 hours of reaction, the color of the mixture remained yellow. After adding 140 ml of water and extracting twice with 100 mL of ethyl acetate, the pH of the aqueous layer was adjusted to 7 with 1M hydrochloric acid solution, filtered, the filter cake was washed once with 30 mL of water, and then dried under vacuum to obtain compound 3-e.

化合物物3-f的合成
向化合物3-e(4g, 11.61mmol)的N,N-二甲基甲醯胺(60mL)溶液中加入三乙胺(3.53g, 34.84mmol, 4.85mL)和三正丙基磷酸酐(11.09g, 17.42mmol, 10.36mL)，在氮氣保護和25℃下反應12小時後，溶液的顏色保持黃色。加入150毫升乙酸乙酯稀釋，用飽和氯化銨溶液洗3次，每次150毫升，再用飽和食鹽水溶液洗滌（2次，每次150毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物3-f。Synthesis of compound 3-f To a solution of compound 3-e (4 g, 11.61 mmol) in N, N-dimethylformamide (60 mL) were added triethylamine (3.53 g, 34.84 mmol, 4.85 mL) and three After n-propyl phosphoric anhydride (11.09 g, 17.42 mmol, 10.36 mL) was reacted for 12 hours at 25 ° C under a nitrogen atmosphere, the color of the solution remained yellow. Add 150 ml of ethyl acetate to dilute, wash 3 times with saturated ammonium chloride solution, 150 ml each time, and then wash with saturated common salt solution (2 times, 150 ml each time, dry with anhydrous sodium sulfate, filter, and concentrate to obtain compound 3- f.

化合物物3-g的合成
在0℃下，向化合物3-f(3.7g, 11.34mmol)的四氫呋喃(50mL)溶液中加入硼烷二甲硫醚(10M, 5.67mL)，在25℃下反應12小時後，溶液的顏色保持黃色。慢慢加入50毫升水淬滅反應，然後用1M的鹽酸溶液將混合物pH調到3，用乙酸乙酯萃取兩次，每次50mL。水層用飽和的碳酸鈉溶液將pH調到9，然後用乙酸乙酯萃取兩次，每次50mL，聯合的有機層用50mL飽和食鹽水溶液洗滌一次，無水硫酸鈉乾燥、過濾，濃縮得到化合物3-g。Synthesis of 3-g of compound compound Boron dimethyl sulfide (10M, 5.67mL) was added to a solution of compound 3-f (3.7g, 11.34mmol) in tetrahydrofuran (50mL) at 0 ° C, and reacted at 25 ° C After 12 hours, the color of the solution remained yellow. 50 ml of water was slowly added to quench the reaction, and then the pH of the mixture was adjusted to 3 with a 1 M hydrochloric acid solution, and extracted twice with 50 mL of ethyl acetate. The aqueous layer was adjusted to pH 9 with a saturated sodium carbonate solution, and then extracted twice with 50 mL each of ethyl acetate. The combined organic layer was washed once with 50 mL of a saturated common salt solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3. -g.

化合物物3-h的合成
向化合物3-g(2.45g, 7.84mmol)的甲醇(30mL)溶液中加入Pd(OH)2 /C(250mg, 純度20%)，經三次氫氣置換後，在氫氣氛圍（15psi）、25℃下反應12小時後，經矽藻土過濾，濾液濃縮得到化合物3-h。Synthesis of compound 3-h To a solution of compound 3-g (2.45g, 7.84mmol) in methanol (30mL) was added Pd (OH) 2 / C (250mg, purity 20%). After three hydrogen replacements, After 12 hours of reaction at 25 ° C. in an atmosphere (15 psi), it was filtered through celite, and the filtrate was concentrated to obtain compound 3-h.

化合物物3-i的合成
向化合物1-k(300mg, 950.59μmol)和3-h(201.06mg, 1.05mmol)的四氫呋喃(10mL)溶液中加入三級丁醇鈉(274.07mg, 2.85mmol)和二（三三級丁基磷）鈀(48.58mg, 95.06μmol)，在氮氣氛圍、70℃下反應2小時後，溶液顏色從紅色變為黑色。加入20毫升乙酸乙酯稀釋，經矽藻土過濾，濾液用飽和氯化鈉溶液洗2次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物3-i(500mg, 粗品)。產品直接用於下一步。Synthesis of compound 3-i To a solution of compound 1-k (300 mg, 950.59 μmol) and 3-h (201.06 mg, 1.05 mmol) in tetrahydrofuran (10 mL) were added sodium tert-butoxide (274.07 mg, 2.85 mmol) and The color of the solution changed from red to black after reacting at 70 ° C for 2 hours in di (tri-tertiary butyl phosphorus) palladium (48.58 mg, 95.06 μmol). 20 ml of ethyl acetate was added for dilution, and the mixture was filtered through celite, and the filtrate was washed twice with saturated sodium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-i (500 mg, crude product). The product is used directly in the next step.

化合物3的合成
將化合物3-i(450mg, 1.05mmol)溶於鹽酸甲醇溶液(4M, 15mL)中，在25℃下反應1小時後，溶液顏色保持黃色。濃縮得到的粗品通過製備級高效液相色譜（甲酸體系）製備純化得到化合物3。
1 HNMR(400MHz,DMSO-d6 )δ=13.01(s,1H), 8.15(s,1H), 6.84(s,1H), 6.24(s,1H), 4.04-3.94(m,5H), 3.49-3.40(m,2H), 3.39-3.35(m,2H), 0.84(d,J =6.8Hz,6H)。Synthesis of Compound 3 Compound 3-i (450 mg, 1.05 mmol) was dissolved in a methanolic hydrochloric acid solution (4M, 15 mL), and the reaction solution remained at a color of yellow after reacting at 25 ° C for 1 hour. The concentrated crude product was purified by preparative high performance liquid chromatography (formic acid system) to obtain compound 3.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.01 (s, 1H), 8.15 (s, 1H), 6.84 (s, 1H), 6.24 (s, 1H), 4.04-3.94 (m, 5H), 3.49 -3.40 (m, 2H), 3.39-3.35 (m, 2H), 0.84 (d, J = 6.8Hz, 6H).

實施例4

Example 4

化合物物4-b的合成
在25℃下向化合物1-a(10g, 59.88mmol, 6.62mL)的乙腈溶液(100mL)中加入碳酸鉀(24.83g, 179.64mmol)。然後化合物4-a(10.62g, 179.64mmol, 15.43mL)加入混合液中，在25℃下反應12小時，懸濁液一直保持無色。加入200毫升二氯甲烷後過濾，濾液加入飽和氯化銨洗滌萃取，然後加入無水硫酸鈉乾燥，濃縮得到化合物4-b。Synthesis of compound 4-b To a solution of compound 1-a (10 g, 59.88 mmol, 6.62 mL) in acetonitrile (100 mL) at 25 ° C was added potassium carbonate (24.83 g, 179.64 mmol). Then compound 4-a (10.62 g, 179.64 mmol, 15.43 mL) was added to the mixture and reacted at 25 ° C for 12 hours. The suspension remained colorless. After adding 200 ml of dichloromethane and filtering, the filtrate was washed with saturated ammonium chloride and extracted, and then dried by adding anhydrous sodium sulfate and concentrated to obtain compound 4-b.

化合物物4-c的合成
向化合物4-b(12.07g, 62.46mmol)的二氯甲烷溶液(100mL)中加入三乙胺(18.96g, 187.38mmol, 26.08mL)。將溶液冷卻到0℃後滴加化合物1-d(10.18g, 62.46mmol, 6.53mL)，滴加完後在25℃下反應12小時，混合物的顏色從無色變為黑色。加入30毫升二氯甲烷稀釋，混合物用飽和的氯化銨水溶液洗滌（20 mL×3），無水硫酸鈉乾燥，過濾，濃縮得到化合物4-c。Synthesis of compound 4-c To a solution of compound 4-b (12.07 g, 62.46 mmol) in dichloromethane (100 mL) was added triethylamine (18.96 g, 187.38 mmol, 26.08 mL). After the solution was cooled to 0 ° C, compound 1-d (10.18g, 62.46mmol, 6.53mL) was added dropwise. After the dropwise addition, the reaction was performed at 25 ° C for 12 hours, and the color of the mixture changed from colorless to black. 30 ml of dichloromethane was added for dilution, and the mixture was washed with a saturated aqueous ammonium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-c.

化合物物4-d的合成
向化合物4-c(10.31g, 36.39mmol)的四氫呋喃溶液(100mL)中加入三乙胺(7.36g, 72.77mmol, 10.13mL)和對甲氧基苄胺(4.99g, 36.39mmol, 4.71mL)，在70℃下反應12小時後，溶液的顏色保持黑色。直接濃縮得到的粗品通過快速矽膠柱（洗脫液：石油醚/乙酸乙酯=0：1）分離純化得到產品4-d。Synthesis of compound 4-d To a solution of compound 4-c (10.31 g, 36.39 mmol) in tetrahydrofuran (100 mL) was added triethylamine (7.36 g, 72.77 mmol, 10.13 mL) and p-methoxybenzylamine (4.99 g). , 36.39 mmol, 4.71 mL). After 12 hours of reaction at 70 ° C, the color of the solution remained black. The crude product directly concentrated was separated and purified through a fast silica gel column (eluent: petroleum ether / ethyl acetate = 0: 1) to obtain the product 4-d.

化合物物4-e的合成
向化合物4-d(11.34g, 26.97mmol)的甲醇(50mL)和水(50mL)的溶液中加入一水合氫氧化鋰(11.32g, 269.67mmol, 10eq)，在25℃下反應12小時後，混合物的顏色保持無色。用乙酸乙酯萃取（30 mL×3），用1M的鹽酸溶液將水層pH調到7，過濾，然後將濾餅真空乾燥得到化合物4-e。Synthesis of compound 4-e To a solution of compound 4-d (11.34 g, 26.97 mmol) in methanol (50 mL) and water (50 mL) was added lithium hydroxide monohydrate (11.32 g, 269.67 mmol, 10 eq) at 25 After 12 hours of reaction at ° C, the color of the mixture remained colorless. Extract with ethyl acetate (30 mL × 3), adjust the pH of the aqueous layer to 7 with 1M hydrochloric acid solution, filter, and dry the filter cake under vacuum to obtain compound 4-e.

化合物物4-f的合成
向化合物4-e(6.69g, 17.05mmol)的N,N-二甲基甲醯胺(50mL)溶液中加入三乙胺(5.17g, 51.14mmol, 7.12mL)和三正丙基磷酸酐(16.27g, 25.57mmol, 15.21mL)，在氮氣保護和25℃下反應12小時後，溶液的顏色保持黃色。加入30毫升乙酸乙酯稀釋萃取，用飽和食鹽水溶液洗滌（60 mL×3），無水硫酸鈉乾燥，過濾，濃縮得到化合物4-f。Synthesis of compound 4-f To a solution of compound 4-e (6.69 g, 17.05 mmol) in N, N-dimethylformamide (50 mL) were added triethylamine (5.17 g, 51.14 mmol, 7.12 mL) and Tri-n-propyl phosphoric anhydride (16.27 g, 25.57 mmol, 15.21 mL), after 12 hours of reaction under nitrogen protection at 25 ° C, the color of the solution remained yellow. 30 ml of ethyl acetate was added to dilute the extract, washed with a saturated saline solution (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-f.

化合物物4-g的合成
在0℃下，向化合物4-f(5.19g, 13.87mmol)的四氫呋喃(60mL)溶液中加入硼烷二甲硫醚((10M, 6.93mL)，在25℃下反應12小時後，溶液的顏色保持黃色。慢慢加入60毫升水淬滅反應，然後用1M的鹽酸溶液將混合物pH調到3，用甲基三級丁基醚萃取兩次，每次20mL。水層用飽和的碳酸鈉溶液將pH調到10，然後用乙酸乙酯萃取（20 mL×2），合併有機層用20mL飽和食鹽水溶液洗1次，無水硫酸鈉乾燥，過濾，濃縮得到化合物4-g。Synthesis of 4-g of compound compound To a solution of compound 4-f (5.19 g, 13.87 mmol) in tetrahydrofuran (60 mL) at 0 ° C was added borane dimethyl sulfide ((10M, 6.93mL), and the temperature was at 25 ° C. After 12 hours of reaction, the color of the solution remained yellow. 60 ml of water was slowly added to quench the reaction, and then the pH of the mixture was adjusted to 3 with a 1M hydrochloric acid solution, and extracted twice with 20 mL of methyltributyl ether. The aqueous layer was adjusted to pH 10 with a saturated sodium carbonate solution, and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed once with 20 mL of a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4 -g.

化合物物4-h的合成
向化合物4-g(200mg, 554.83μmol)的甲醇(10mL)溶液中加入氫氧化鈀(38.96mg, 277.42μmol)，經三次氫氣置換後，在氫氣環境下（15psi）和50℃下反應2小時後，用20M甲醇稀釋後經矽藻土過濾，濾液濃縮得到4-h。Synthesis of compound 4-h To a solution of compound 4-g (200mg, 554.83μmol) in methanol (10mL) was added palladium hydroxide (38.96mg, 277.42μmol), and after three hydrogen replacements, under a hydrogen environment (15psi) After reacting at 50 ° C for 2 hours, it was diluted with 20M methanol and filtered through celite. The filtrate was concentrated to give 4-h.

化合物物4-i的合成
向化合物1-k(130.13mg, 412.33μmol)和4-h(109.00mg, 453.56μmol)的四氫呋喃(10mL)溶液中加入三級丁醇鈉(118.88mg, 1.24mmol)和二（三三級丁基磷）鈀(21.07mg, 41.23μmol)，在氮氣保護和70℃下反應3小時後，溶液顏色變為黑色。加入20毫升乙酸乙酯稀釋，經矽藻土過濾，濾液用飽和氯化鈉溶液洗2次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物4-i。Synthesis of compound 4-i To a solution of compound 1-k (130.13 mg, 412.33 μmol) and 4-h (109.00 mg, 453.56 μmol) in tetrahydrofuran (10 mL) was added tertiary sodium butoxide (118.88 mg, 1.24 mmol) And di (tri-tertiary butyl phosphorus) palladium (21.07 mg, 41.23 μmol), after reacting for 3 hours at 70 ° C. under nitrogen protection, the color of the solution turned black. 20 ml of ethyl acetate was added for dilution, and the mixture was filtered through celite. The filtrate was washed twice with saturated sodium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-i.

化合物物4的合成
將化合物4-i(177.00mg, 372.63μmol)溶於鹽酸甲醇溶液(4M, 5mL)中，在25℃下反應2小時後，濃縮得到的粗品通過製備級高效液相色譜（甲酸體系）製備純化得到產品4。
1 HNMR(400MHz,DMSO-d6 )δ=13.04(s,1H), 8.13(s,1H), 7.34-7.24(m,3H), 7.17(d,J =6.5Hz,2H), 6.90(s,1H), 6.26(s,1H), 4.17(s,2H), 4.06(t,J =5.2Hz,2H), 3.97(t,J =5.7Hz,2H), 3.76-3.63(m,2H), 3.39(t,J =5.6Hz,2H) 。Synthesis of compound 4 Compound 4-i (177.00 mg, 372.63 μmol) was dissolved in methanolic hydrochloric acid solution (4M, 5 mL), and after reacting at 25 ° C for 2 hours, the crude product obtained after concentration was subjected to preparative high-performance liquid chromatography ( Formic acid system) preparation and purification to obtain product 4.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.04 (s, 1H), 8.13 (s, 1H), 7.34-7.24 (m, 3H), 7.17 (d, J = 6.5Hz, 2H), 6.90 (s , 1H), 6.26 (s, 1H), 4.17 (s, 2H), 4.06 (t, J = 5.2Hz, 2H), 3.97 (t, J = 5.7Hz, 2H), 3.76-3.63 (m, 2H) , 3.39 (t, J = 5.6Hz, 2H).

實施例5

Example 5

化合物物5-c的合成
在25℃下向化合物5-b(7.16g, 106.08mmol)的乙腈溶液(10mL)中加入碳酸鉀(33.83g, 244.80mmol)。然後化合物5-a(10g, 81.60mmol, 8.70mL)加入混合液中，在25℃下反應12小時，懸濁液一直保持無色。濃縮得到5-c。Synthesis of compound 5-c To a solution of compound 5-b (7.16 g, 106.08 mmol) in acetonitrile (10 mL) at 25 ° C was added potassium carbonate (33.83 g, 244.80 mmol). Then compound 5-a (10 g, 81.60 mmol, 8.70 mL) was added to the mixture and reacted at 25 ° C for 12 hours. The suspension remained colorless. Concentration gave 5-c.

化合物物5-d的合成
向化合物5-c(6.92g, 59.07mmol)的二氯甲烷溶液(20mL)中加入三乙胺(17.93g, 177.21mmol, 24.67mL)。將溶液冷卻到0℃後滴加化合物1-d(9.63g, 59.07mmol, 6.17mL)，滴加完後在25℃下反應12小時，混合物的顏色從無色變為黑色。加入20毫升二氯甲烷稀釋，混合物用飽和的氯化銨溶液洗3次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到物5-d。Synthesis of compound 5-d To a solution of compound 5-c (6.92 g, 59.07 mmol) in dichloromethane (20 mL) was added triethylamine (17.93 g, 177.21 mmol, 24.67 mL). After the solution was cooled to 0 ° C, compound 1-d (9.63g, 59.07mmol, 6.17mL) was added dropwise. After the dropwise addition, the reaction was performed at 25 ° C for 12 hours, and the color of the mixture changed from colorless to black. 20 ml of dichloromethane was added for dilution, and the mixture was washed 3 times with saturated ammonium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-d.

化合物物5-e的合成
向化合物5-d(9.96g, 48.06mmol)的四氫呋喃溶液(100mL)中加入三乙胺(9.73g, 96.12mmol, 13.38mL)和對甲氧基苄胺(6.59g, 48.06mmol, 6.22mL)，在氮氣氛圍、70℃下反應12小時後，溶液的顏色保持黑色。直接濃縮得到的粗品通過快速矽膠柱（洗脫液：石油醚/乙酸乙酯=0：1）分離純化得到5-e。Synthesis of compound 5-e To a solution of compound 5-d (9.96 g, 48.06 mmol) in tetrahydrofuran (100 mL) were added triethylamine (9.73 g, 96.12 mmol, 13.38 mL) and p-methoxybenzylamine (6.59 g). , 48.06 mmol, 6.22 mL). After 12 hours of reaction at 70 ° C in a nitrogen atmosphere, the color of the solution remained black. The crude product directly concentrated was separated and purified through a fast silica gel column (eluent: petroleum ether / ethyl acetate = 0: 1) to obtain 5-e.

化合物物5-f的合成
向化合物5-e(4.72g, 13.70mmol)的甲醇(50mL)和水(50mL)的溶液中加入一水合氫氧化鋰(5.75g, 137.04mmol)，在25℃下反應12小時後，混合物的顏色保持無色。用乙酸乙酯萃取2次，每次20mL，在0℃下用1M的鹽酸溶液將水層pH調到7，過濾，然後將濾餅真空乾燥得到化合物5-f。Synthesis of compound 5-f To a solution of compound 5-e (4.72 g, 13.70 mmol) in methanol (50 mL) and water (50 mL) was added lithium hydroxide monohydrate (5.75 g, 137.04 mmol), at 25 ° C. After 12 hours of reaction, the color of the mixture remained colorless. Extract twice with 20 mL of ethyl acetate, adjust the pH of the aqueous layer to 7 with 1M hydrochloric acid solution at 0 ° C, filter, and then dry the filter cake under vacuum to obtain compound 5-f.

化合物物5-g的合成
向化合物5-f(1.5g, 4.74mmol)的N,N-二甲基甲醯胺(10mL)溶液中加入三乙胺(1.44g, 14.22mmol, 1.98mL,)和三正丙基磷酸酐(4.53g, 7.11mmol, 4.23mL)，在氮氣氛圍、25℃下反應12小時後，溶液的顏色保持黃色。加入20毫升乙酸乙酯稀釋萃取，用飽和氯化鈉溶液洗2次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物5-g。Synthesis of Compound 5-g To a solution of Compound 5-f (1.5 g, 4.74 mmol) in N, N-dimethylformamide (10 mL) was added triethylamine (1.44 g, 14.22 mmol, 1.98 mL,) After the reaction with tri-n-propyl phosphoric anhydride (4.53 g, 7.11 mmol, 4.23 mL) under a nitrogen atmosphere at 25 ° C. for 12 hours, the color of the solution remained yellow. 20 ml of ethyl acetate was added to dilute the extract, washed twice with saturated sodium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-g of compound.

化合物物5-h的合成
在0℃下，向化合物5-g(1.17g, 3.92mmol)的四氫呋喃(10mL)溶液中加入硼烷二甲硫醚(10M, 1.96mL)，在25℃下反應12小時後，溶液的顏色保持黃色。慢慢加入10毫升水淬滅反應，然後用1M的5mL鹽酸溶液將混合物pH調到3，用甲基三級丁基醚萃取兩次，每次10mL。水層用飽和的碳酸鈉溶液將pH調到10，然後用乙酸乙酯萃取(20 mL×2），合併有機層用20mL飽和的氯化鈉溶液洗1次，無水硫酸鈉乾燥，過濾，濃縮得到化合物5-h。Synthesis of compound 5-h At 0 ° C, to a solution of compound 5-g (1.17g, 3.92mmol) in tetrahydrofuran (10mL) was added borane dimethylsulfide (10M, 1.96mL), and the reaction was performed at 25 ° C. After 12 hours, the color of the solution remained yellow. 10 ml of water was slowly added to quench the reaction, and then the pH of the mixture was adjusted to 3 with 1 M of 5 mL of a hydrochloric acid solution, and extracted twice with 10 mL of methyltributyl ether. The aqueous layer was adjusted to pH 10 with a saturated sodium carbonate solution, and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed once with 20 mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 5-h was obtained.

化合物物5-i的合成
向化合物5-h(552mg, 1.94mmol)的甲醇(10mL)溶液中加入氫氧化鈀(136.30mg, 純度25%)，經三次氫氣置換後，在氫氣氛圍（15psi）、50℃下反應2小時後，經矽藻土過濾，將濾液濃縮得到化合物5-i。Synthesis of compound 5-i To a solution of compound 5-h (552 mg, 1.94 mmol) in methanol (10 mL) was added palladium hydroxide (136.30 mg, purity 25%). After three hydrogen replacements, the mixture was placed in a hydrogen atmosphere (15 psi). After reacting at 50 ° C for 2 hours, it was filtered through celite, and the filtrate was concentrated to obtain compound 5-i.

化合物物5-j的合成
向化合物5-j(310mg, 1.89mmol)和1-k(541.57mg, 1.72mmol)的四氫呋喃(10mL)溶液中加入三級丁醇鈉(494.75mg, 5.15mmol)和二（三三級丁基磷）鈀(87.70mg,171.60μmol)，在氮氣氛圍、70℃下反應3小時後，溶液顏色保持紅色。加入20毫升乙酸乙酯稀釋，經矽藻土過濾，濾液用飽和氯化鈉溶液洗2次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物5-j。Synthesis of compound 5-j To a solution of compound 5-j (310 mg, 1.89 mmol) and 1-k (541.57 mg, 1.72 mmol) in tetrahydrofuran (10 mL) were added sodium tert-butoxide (494.75 mg, 5.15 mmol) and The color of the solution remained red after reaction for 3 hours at 70 ° C in a nitrogen atmosphere at 87.70 mg, 171.60 μmol. 20 ml of ethyl acetate was added to dilute, filtered through celite, and the filtrate was washed twice with saturated sodium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5-j.

化合物物5的合成
將化合物5-j(358mg, 897.45μmol)溶於鹽酸甲醇溶液(4M)和甲醇溶液(10mL)中，在25℃下反應1小時後，溶液顏色保持無色。濃縮得到的粗品通過製備級高效液相色譜（甲酸體系）製備純化得到化合物5。
1 HNMR(400MHz,DMSO-d6 )δ=13.06(s,1H), 8.11(s,1H), 6.88(s,1H), 6.22(s,1H), 3.99(t,J =4.8Hz,2H), 3.90(t,J =5.8Hz,2H), 3.70-3.45(m,4H), 2.71(s,3H)。Synthesis of compound 5 Compound 5-j (358 mg, 897.45 μmol) was dissolved in a methanolic hydrochloric acid solution (4M) and a methanolic solution (10 mL), and after reacting at 25 ° C. for 1 hour, the color of the solution remained colorless. The crude product obtained by concentration was prepared and purified by preparative high-performance liquid chromatography (formic acid system) to obtain compound 5.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.06 (s, 1H), 8.11 (s, 1H), 6.88 (s, 1H), 6.22 (s, 1H), 3.99 (t, J = 4.8Hz, 2H ), 3.90 (t, J = 5.8Hz, 2H), 3.70-3.45 (m, 4H), 2.71 (s, 3H).

實施例6

Example 6

化合物物6-b的合成
向化合物6-a(50g, 312.08mmol, 49.02mL)的二氯甲烷溶液(500mL)中加入三乙胺(63.16g,624.17mmol,86.88mL)。將溶液冷卻到0℃後滴加化合物1-d(50.88g, 312.08mmol, 32.61mL)，滴加完後在25℃下反應12小時，混合物的顏色為黃色。加入30毫升二氯甲烷萃取，混合物用飽和的氯化銨溶液洗2次，每次20毫升，無水硫酸鈉乾燥，過濾，濃縮得到化合物6-b。Synthesis of compound 6-b To a solution of compound 6-a (50 g, 312.08 mmol, 49.02 mL) in dichloromethane (500 mL) was added triethylamine (63.16 g, 624.17 mmol, 86.88 mL). After the solution was cooled to 0 ° C, compound 1-d (50.88g, 312.08mmol, 32.61mL) was added dropwise. After the dropwise addition, the reaction was performed at 25 ° C for 12 hours. The color of the mixture was yellow. 30 ml of dichloromethane was added for extraction, and the mixture was washed twice with saturated ammonium chloride solution, 20 ml each time, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6-b.

化合物物6-c的合成
把化合物6-b(67g, 267.66mmol)加入4M鹽酸二氧六環溶液(600mL)中，在25℃下反應1小時後，溶液的顏色保持黃色。直接濃縮得到的粗品產品6-c。Synthesis of compound 6-c Compound 6-b (67 g, 267.66 mmol) was added to a 4M solution of dioxane hydrochloride (600 mL), and after reacting at 25 ° C for 1 hour, the color of the solution remained yellow. The resulting crude product 6-c was directly concentrated.

化合物物6-d的合成
向化合物6-c(58.82g, 391.61mmol)（粗品）的甲醇(50mL)的溶液中加入三乙胺(118.88g, 1.17mol, 163.52mL)，在25℃下反應24小時後，混合物的顏色保持黃色。直接濃縮得到的產品6-d。Synthesis of compound 6-d To a solution of compound 6-c (58.82g, 391.61mmol) (crude) in methanol (50mL) was added triethylamine (118.88g, 1.17mol, 163.52mL), and the reaction was performed at 25 ° C. After 24 hours, the color of the mixture remained yellow. The resulting product 6-d was directly concentrated.

化合物物6-e的合成
向化合物6-d(47.59mg, 316.86μmol)，化合物1-k(50mg, 158.43μmol)混合的N,N-二甲基甲醯胺(5mL)溶液中加入三級丁醇鈉(45.68mg, 475.30μmol)和二（三三級丁基磷）鈀(8.10mg, 15.84μmol)，在氮氣氛圍、70℃下反應3小時後，溶液的顏色保持紅色。加入20毫升乙酸乙酯萃取，經矽藻土過濾，濾液用飽和氯化鈉溶液洗2次，每次10毫升，飽和氯化銨溶液洗2次，每次10毫升，無水硫酸鈉乾燥，過濾，濃縮得到的粗品通過製備級高效液相色譜（甲酸體系）製備純化得到產品6-e。Synthesis of compound 6-e To a solution of compound 6-d (47.59mg, 316.86μmol) and compound 1-k (50mg, 158.43μmol) in N, N-dimethylformamide (5mL) was added to the third stage After reacting with sodium butoxide (45.68mg, 475.30μmol) and bis (tri-tertiarybutylphosphorus) palladium (8.10mg, 15.84μmol) in a nitrogen atmosphere at 70 ° C for 3 hours, the color of the solution remained red. Add 20 ml of ethyl acetate for extraction, filter through diatomaceous earth, wash the filtrate twice with saturated sodium chloride solution, 10 ml each time, wash twice with saturated ammonium chloride solution, 10 ml each time, dry over anhydrous sodium sulfate, filter The concentrated crude product was prepared and purified by preparative high-performance liquid chromatography (formic acid system) to obtain product 6-e.

化合物物6的合成
將化合物6-e(38mg, 98.73μmol)溶於鹽酸甲醇溶液(4M, 5mL)和甲醇溶液(5mL)中，在25℃下反應1小時後，溶液顏色保持無色。濃縮得到的粗品通過製備級高效液相色譜（甲酸體系）製備純化得到化合物6.
1 HNMR(400MHz,DMSO-d6 )δ=13.01(s,1H), 8.12(s,1H), 7.38(s,1H), 6.84(s,1H), 6.20(s,1H), 4.02(t,J =5.2Hz,2H), 3.92(t,J =5.7Hz,2H), 3.49(t,J =5.2Hz,2H), 3.30-3.24(m,2H)。Synthesis of Compound 6: Compound 6-e (38 mg, 98.73 μmol) was dissolved in a hydrochloric acid methanol solution (4M, 5 mL) and a methanol solution (5 mL). After reacting at 25 ° C. for 1 hour, the color of the solution remained colorless. The concentrated crude product was purified by preparative high-performance liquid chromatography (formic acid system) to obtain compound 6.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.01 (s, 1H), 8.12 (s, 1H), 7.38 (s, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 4.02 (t , J = 5.2Hz, 2H), 3.92 (t, J = 5.7Hz, 2H), 3.49 (t, J = 5.2Hz, 2H), 3.30-3.24 (m, 2H).

實施例7

Example 7

化合物7-b的合成
將化合物7-a(1g, 3.35mmol)溶解在THF(10mL)中，氮氣置換三次，並在-70℃下緩慢加入LiHMDS(1M, 16.76mL),在此溫度下反應一小時後，依然在此溫度下緩慢加入MeI(9.51g, 67.02mmol, 4.17mL,)。所得混合物在氮氣保護下，25℃下攪拌11小時。將反應物加入水(20ml)後，用EtOAc(15mL×3)萃取。合併有機相用飽和食鹽水洗(15mL×3)，Na2 SO4 乾燥，過濾濃縮後得到粗品7-b.Synthesis of compound 7-b Compound 7-a (1g, 3.35mmol) was dissolved in THF (10mL), replaced with nitrogen three times, and LiHMDS (1M, 16.76mL) was slowly added at -70 ° C, and the reaction was performed at this temperature After one hour, MeI (9.51 g, 67.02 mmol, 4.17 mL,) was slowly added at this temperature. The resulting mixture was stirred at 25 ° C for 11 hours under the protection of nitrogen. After the reaction was added to water (20 ml), it was extracted with EtOAc (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to give the crude 7-b.

化合物物7-c的合成
將化合物7-b(500mg, 1.60mmol)溶解於MeOH(10mL)中，並在25℃下往溶液中加入氫氧化鈀/C(50mg)。氫氣置換三次，所得混合物在50℃下氫氣保護下攪拌12小時。通過液相質譜檢測至反應完成。將反應物過濾濃縮後得到粗品7-c。Synthesis of compound 7-c Compound 7-b (500 mg, 1.60 mmol) was dissolved in MeOH (10 mL), and palladium hydroxide / C (50 mg) was added to the solution at 25 ° C. Hydrogen was replaced three times, and the resulting mixture was stirred under hydrogen protection at 50 ° C for 12 hours. The reaction was detected to be complete by liquid mass spectrometry. The reaction was filtered and concentrated to obtain crude 7-c.

化合物物7-d的合成
將化合物7-c(120mg，624.09μmol)，1-d(179.05mg, 567.36μmol, 1eq )，t-BuONa(163.58mg, 1.70mmol)溶解於THF(5mL)中，氮氣置換三次，並在25℃下往溶液中加入Pd(t-Bu3 P)2 (29.00mg, 56.74μmol)。所得混合物在70℃下攪拌3小時。通過質譜檢測至反應完成。將反應液加入EtOAc(15ml)，過濾，濾液用飽和食鹽水洗(10mL×2)，Na2 SO4 乾燥，過濾濃縮後得到粗品7-d。Synthesis of compound 7-d Compound 7-c (120 mg, 624.09 μmol), 1-d (179.05 mg, 567.36 μmol, 1 eq ), t-BuONa (163.58 mg, 1.70 mmol) were dissolved in THF (5 mL) , Nitrogen was replaced three times, and Pd (t-Bu 3 P) 2 (29.00 mg, 56.74 μmol) was added to the solution at 25 ° C. The resulting mixture was stirred at 70 ° C for 3 hours. The reaction was detected to be complete by mass spectrometry. The reaction solution was added to EtOAc (15 ml), filtered, and the filtrate was washed with saturated brine (10 mL × 2), dried over Na 2 SO 4 , filtered and concentrated to obtain the crude product 7-d.

化合物7的合成
將化合物(140mg, 327.90μmol)溶解於HCl/MeOH(4M, 5mL)中，所得混合物在25℃下攪拌1小時。通過質譜檢測至反應完成。將反應物減壓濃縮後，粗品通過製備色譜(甲酸體系)純化得到化合物7。
1 HNMR(400MHz,DMSO-d6 )δ=13.06(brs,1H), 8.09(s,1H), 6.88(s,1H), 6.26-6.20(m,1H), 4.28-4.16(m,1H), 4.10-3.99(m,1H), 3.68-3.41(m,2H), 3.30-3.13(m,2H), 2.72(qd,J =6.9,13.9Hz,1H), 2.59-2.52(m,1H), 1.35(d,J =6.2Hz,3H), 0.92(t,J =7.1Hz,3H)。Synthesis of compound 7 The compound (140 mg, 327.90 μmol) was dissolved in HCl / MeOH (4M, 5 mL), and the resulting mixture was stirred at 25 ° C. for 1 hour. The reaction was detected to be complete by mass spectrometry. After the reaction was concentrated under reduced pressure, the crude product was purified by preparative chromatography (formic acid system) to obtain compound 7.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.06 (brs, 1H), 8.09 (s, 1H), 6.88 (s, 1H), 6.26-6.20 (m, 1H), 4.28-4.16 (m, 1H) , 4.10-3.99 (m, 1H), 3.68-3.41 (m, 2H), 3.30-3.13 (m, 2H), 2.72 (qd, J = 6.9,13.9Hz, 1H), 2.59-2.52 (m, 1H) , 1.35 (d, J = 6.2Hz, 3H), 0.92 (t, J = 7.1Hz, 3H).

實施例8

Example 8

化合物8-b的合成
將化合物8-a(5g, 32.55mmol, HCl)和TEA(11.53g, 113.93mmol, 15.86mL)溶解於DCM(50mL)中，然後在氮氣氛圍0℃下，於30分鐘之內逐滴加入1-d(5.31g, 32.55mmol, 3.40mL)，所得混合物在25℃攪拌5.5小時。通過加入飽和氯化銨溶液(80mL)淬滅反應，然後用DCM(2×80mL)萃取。合併有機相用飽和食鹽水洗滌(70mL×3)，Na2 SO4 乾燥，過濾濃縮後得到粗品，即為8-b。Synthesis of compound 8-b Compound 8-a (5g, 32.55mmol, HCl) and TEA (11.53g, 113.93mmol, 15.86mL) were dissolved in DCM (50mL), and then under a nitrogen atmosphere at 0 ° C for 30 minutes 1-d (5.31 g, 32.55 mmol, 3.40 mL) was added dropwise thereto, and the resulting mixture was stirred at 25 ° C for 5.5 hours. The reaction was quenched by the addition of a saturated ammonium chloride solution (80 mL) and then extracted with DCM (2 x 80 mL). The combined organic phases were washed with saturated brine (70 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product, which was 8-b.

化合物8-c的合成
將化合物8-b(5.4g, 26.06mmol)和1-m(3.57g, 26.06mmol, 3.37mL, 1eq)溶解於THF(40mL)中，然後加入TEA(5.27g, 52.11mmol, 7.25mL, 2eq)。將反應液加熱至70℃攪拌6小時。往反應液中加入水(40mL)，濃縮反應液除去大部分THF。將混合液用乙酸乙酯(150mL)稀釋，分液。有機相用氯化銨洗滌(80mL×3)、Na2 SO4 乾燥，過濾濃縮後得到粗品。所得粗品用柱層析(洗脫液,石油醚/乙酸乙酯=5/1至 0/1)純化得到8-c。Synthesis of compound 8-c Compound 8-b (5.4g, 26.06mmol) and 1-m (3.57g, 26.06mmol, 3.37mL, 1eq) were dissolved in THF (40mL), and then TEA (5.27g, 52.11) was added mmol, 7.25mL, 2eq). The reaction solution was heated to 70 ° C and stirred for 6 hours. Water (40 mL) was added to the reaction solution, and the reaction solution was concentrated to remove most of THF. The mixture was diluted with ethyl acetate (150 mL) and the layers were separated. The organic phase was washed with ammonium chloride (80 mL × 3), dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product. The obtained crude product was purified by column chromatography (eluent, petroleum ether / ethyl acetate = 5/1 to 0/1) to obtain 8-c.

化合物8-d的合成
將化合物8-c(6.16g, 17.88mmol)溶解於MeOH(60mL)和H2 O(60mL)中，然後加入LiOH.H2 O(3.00g, 71.54mmol, 4eq)。將反應液在25℃下攪拌12小時。通過液相質譜檢測顯示反應結束。將反應液濃縮除去MeOH。使用3MHCl調節溶液的pH至8，此時大量固體析出，過濾並用冰水(10mL)洗滌濾餅，將其真空乾燥即得8-d。Synthesis of compound 8-d Compound 8-c (6.16 g, 17.88 mmol) was dissolved in MeOH (60 mL) and H 2 O (60 mL), and then LiOH.H 2 O (3.00 g, 71.54 mmol, 4 eq) was added. The reaction solution was stirred at 25 ° C for 12 hours. Detection by liquid mass spectrometry showed that the reaction was complete. The reaction was concentrated to remove MeOH. 3M HCl was used to adjust the pH of the solution to 8. At this time, a large amount of solids were precipitated, filtered, and the filter cake was washed with ice water (10 mL) and dried under vacuum to obtain 8-d.

化合物8-e的合成
將化合物8-d(4.8g, 14.53mmol)溶解於DMF(30mL)中，然後在氮氣氛圍下加入T3 P(13.87g, 21.79mmol, 12.96mL)和TEA(4.41g, 43.58mmol, 6.07mL, 3eq)。將反應液在50℃攪拌2小時。通過液相質譜檢測顯示目標產物形成。向反應液中加入水(70mL)，用EtOAc(70mL×3)萃取,合併有機相用飽和食鹽水(50mL×3)洗滌，用Na2 SO4 乾燥，濃縮得粗產品8-e。Synthesis of compound 8-e. Compound 8-d (4.8 g, 14.53 mmol) was dissolved in DMF (30 mL), and then T 3 P (13.87 g, 21.79 mmol, 12.96 mL) and TEA (4.41 g) were added under a nitrogen atmosphere. , 43.58 mmol, 6.07 mL, 3 eq). The reaction solution was stirred at 50 ° C for 2 hours. Detection by liquid mass spectrometry showed the formation of the target product. Water (70 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (70 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over Na 2 SO 4 , and concentrated to obtain the crude product 8-e.

化合物8-f的合成
將化合物8-e(3.9g, 12.48mmol)溶解於THF(12.48mL)中，然後在0℃、氮氣氛圍下，於30分鐘內逐滴加入BH3 -Me2 S(10M, 12.48mL)。將反應液在25℃攪拌9.5小時。通過液相質譜檢測顯示目標產物形成。向反應液中加入水(70mL)，用3MHCl調節反應液pH=1，用EtOAc(70mL×3)萃取；然後使用4M氫氧化鈉調節水相pH=10，用EtOAc(70mL×3)萃取，將合併有機相用飽和食鹽水(60mL×3)洗滌、Na2 SO4 乾燥，濃縮得粗產品8-f。Synthesis of compound 8-f Compound 8-e (3.9 g, 12.48 mmol) was dissolved in THF (12.48 mL), and then BH 3 -Me 2 S ( 10M, 12.48mL). The reaction solution was stirred at 25 ° C for 9.5 hours. Detection by liquid mass spectrometry showed the formation of the target product. Water (70 mL) was added to the reaction solution, the reaction solution was adjusted to pH = 1 with 3M HCl, and extracted with EtOAc (70 mL × 3); then the aqueous phase was adjusted to pH = 10 with 4 M sodium hydroxide, and extracted with EtOAc (70 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over Na 2 SO 4 , and concentrated to obtain a crude product 8-f.

化合物8-g的合成
將化合物8-f(1.3g, 4.36mmol)溶解於MeOH(10mL)中，然後在氮氣氛圍下加入鈀/碳(200mg, 4.36mmol)和乙酸(315.00mg, 5.25mmol,0.3mL)，將混合液使用氫氣置換三次，所得混合液在氫氣氛圍(50psi)、25℃攪拌3小時。通過液相質譜檢測顯示目標產物形成。將混合液過濾濃縮得粗產品8-g。Synthesis of compound 8-g Compound 8-f (1.3 g, 4.36 mmol) was dissolved in MeOH (10 mL), and then palladium / carbon (200 mg, 4.36 mmol) and acetic acid (315.00 mg, 5.25 mmol, 0.3 mL), the mixture was replaced with hydrogen three times, and the obtained mixture was stirred in a hydrogen atmosphere (50 psi) at 25 ° C for 3 hours. Detection by liquid mass spectrometry showed the formation of the target product. The mixture was filtered and concentrated to obtain 8-g of crude product.

化合物8-h的合成
將化合物8-g(100mg, 419.63μmol, CH3COOH)和1-k(120.15mg, 377.67μmol)溶解於THF(4mL)中，然後在氮氣氛圍下加入t-BuONa(80.65mg, 839.26μmol)和Pd(t-Bu3P)2(21.45mg, 41.96μmol)，用氮氣置換三次，將混合液在70℃攪拌4小時。通過液相質譜檢測顯示目標產物形成。將混合液濃縮除去溶劑，加入飽和食鹽水（10mL），並用乙酸乙酯(10mL×2)萃取。將合併的有機相用飽和食鹽水(10mL×3)洗滌，用Na2 SO4 乾燥、過濾，濃縮得殘留物，其用製備色譜純化得8-h。Synthesis of compound 8-h Compound 8-g (100 mg, 419.63 μmol, CH3COOH) and 1-k (120.15 mg, 377.67 μmol) were dissolved in THF (4 mL), and then t-BuONa (80.65 mg) was added under a nitrogen atmosphere. , 839.26 μmol) and Pd (t-Bu3P) 2 (21.45 mg, 41.96 μmol), replaced with nitrogen three times, and the mixture was stirred at 70 ° C. for 4 hours. Detection by liquid mass spectrometry showed the formation of the target product. The mixture was concentrated to remove the solvent, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated to give a residue, which was purified by preparative chromatography to give 8-h.

化合物8的合成
將化合物8-h(110mg, 266.39μmol)溶解於HCl/MeOH(2mL)中，之後將反應液在25℃攪拌2小時。將混合液濃縮獲得粗產品。將粗品用飽和食鹽水(20 mL) 稀釋，之後用飽和Na2 CO3 溶液調節溶液pH=10。用乙酸乙酯( 40mL×2)萃取。將有機相用飽和食鹽水(40mL×2)洗滌，Na2 SO4 乾燥，過濾，濃縮得粗產品。將粗產品使用大板純化(PE:EtOAc=3:1)得化合物8。
1 HNMR(400MHz,DMSO-d6 )δ=8.11(s,1H), 6.89(s,1H), 6.51(d,J =1.3Hz,1H), 3.97-3.90(m,4H), 3.54(brd,J =5.4Hz,2H), 1.09(s,6H)。Synthesis of Compound 8 Compound 8-h (110 mg, 266.39 μmol) was dissolved in HCl / MeOH (2 mL), and then the reaction solution was stirred at 25 ° C. for 2 hours. The mixture was concentrated to obtain a crude product. The crude product was diluted with saturated brine (20 mL), and then the solution was adjusted to pH = 10 with a saturated Na 2 CO 3 solution. Extract with ethyl acetate ( 40 mL x 2). The organic phase was washed with saturated brine (40 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated to obtain a crude product. The crude product was purified using a large plate (PE: EtOAc = 3: 1) to give compound 8.
1 HNMR (400MHz, DMSO-d 6 ) δ = 8.11 (s, 1H), 6.89 (s, 1H), 6.51 (d, J = 1.3Hz, 1H), 3.97-3.90 (m, 4H), 3.54 (brd , J = 5.4Hz, 2H), 1.09 (s, 6H).

實施例9

Example 9

化合物9-b的合成
將化合物9-a(800mg, 2.68mmol)溶解在THF(10mL)中，氮氣置換三次，並在-70℃下緩慢加入n-BμLi(2.5M, 5.36mL),在此溫度下反應一小時後，依然在此溫度下緩慢加入9-e(5.04g, 26.81mmol, 2.02mL)，將所得混合物在氮氣保護下，25℃下攪拌11小時。將反應物加入水(30mL)後，用EtOAc(15mL×3)萃取，將有機相合併，用飽和食鹽水(15mL×3)洗滌，Na2 SO4 乾燥，過濾濃縮後得到粗品，粗品通過製備色譜(甲酸體系)純化，純化回來的溶液直接用EtOAc(20mL×3)萃取，合併有機相用飽和食鹽水(3×20mL)洗滌，Na2 SO4 乾燥,過濾濃縮後得到產品9-b。Synthesis of compound 9-b Compound 9-a (800mg, 2.68mmol) was dissolved in THF (10mL), replaced with nitrogen three times, and n-BμLi (2.5M, 5.36mL) was slowly added at -70 ° C, here After reacting at the temperature for one hour, 9-e (5.04 g, 26.81 mmol, 2.02 mL) was slowly added at the same temperature, and the resulting mixture was stirred at 25 ° C. for 11 hours under the protection of nitrogen. The reaction was added to water (30 mL), and extracted with EtOAc (15 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over Na 2 SO 4 and filtered to obtain a crude product. The crude product was prepared by Purified by chromatography (formic acid system). The purified solution was directly extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated brine (3 × 20 mL), dried over Na 2 SO 4 , filtered and concentrated to obtain product 9-b.

化合物9-c的合成
將化合物9-b(180mg, 554.81μmol, 1eq )溶解於MeOH(5mL)中，並在25℃下往溶液中加入氫氧化鈀/碳(20mg，純度20%)，氫氣置換三次，所得混合物在50℃下氫氣保護下攪拌12小時。將反應物過濾濃縮後得到粗品9-c。Synthesis of compound 9-c Compound 9-b (180 mg, 554.81 μmol, 1 eq ) was dissolved in MeOH (5 mL), and palladium hydroxide / carbon (20 mg, purity 20%) was added to the solution at 25 ° C. Hydrogen was replaced three times, and the resulting mixture was stirred under hydrogen protection at 50 ° C for 12 hours. The reaction was filtered and concentrated to obtain crude 9-c.

化合物9-d的合成
將化合物9-c(73mg, 357.34μmol)，1-d(102.52mg, 324.85μmol)，t-BuONa(93.66mg, 974.55μmol)溶解於THF(5mL)中，氮氣置換三次，並在25℃下往溶液中加入Pd(t-Bu3 P)2 (16.60mg, 32.49μmol)，所得混合物在70℃下攪拌12小時。向反應液中加入EtOAc(15mL，過濾，濾液用飽和食鹽水(10mL×2)洗滌，Na2 SO4 乾燥,過濾濃縮得粗品9-d。Synthesis of compound 9-d Compound 9-c (73 mg, 357.34 μmol), 1-d (102.52 mg, 324.85 μmol), t-BuONa (93.66 mg, 974.55 μmol) were dissolved in THF (5 mL), and replaced with nitrogen three times Then, Pd (t-Bu 3 P) 2 (16.60 mg, 32.49 μmol) was added to the solution at 25 ° C., and the resulting mixture was stirred at 70 ° C. for 12 hours. To the reaction solution was added EtOAc (15 mL, filtered, and the filtrate was washed with saturated brine (10 mL × 2), dried over Na 2 SO 4 , and concentrated by filtration to obtain the crude 9-d.

化合物9的合成
將化合物9-d(120mg, 273.37μmol)溶解於HCl/MeOH(4M, 3mL)中，所得混合物在25℃下攪拌1小時。通過液相質譜檢測至反應完成，將反應物減壓濃縮後，粗品通過製備色譜純化得到化合物9。
1 HNMR(400MHz,DMSO-d6 )δ=13.02(brs,1H), 8.17(s,1H), 6.85(s,1H), 6.26(s,1H), 4.13-3.97(m,2H), 3.89(s,2H), 3.62-3.47(m,2H), 3.29-3.15(m,2H), 2.08(s,1H), 1.31-1.15(m,4H), 1.07(t,J =7.0Hz,3H)。Synthesis of Compound 9 Compound 9-d (120 mg, 273.37 μmol) was dissolved in HCl / MeOH (4M, 3 mL), and the resulting mixture was stirred at 25 ° C. for 1 hour. Liquid chromatography mass spectrometry was used to detect the completion of the reaction. After the reaction was concentrated under reduced pressure, the crude product was purified by preparative chromatography to obtain compound 9.
1 HNMR (400MHz, DMSO-d 6 ) δ = 13.02 (brs, 1H), 8.17 (s, 1H), 6.85 (s, 1H), 6.26 (s, 1H), 4.13-3.97 (m, 2H), 3.89 (s, 2H), 3.62-3.47 (m, 2H), 3.29-3.15 (m, 2H), 2.08 (s, 1H), 1.31-1.15 (m, 4H), 1.07 (t, J = 7.0Hz, 3H ).

實施例10

Example 10

化合物10的合成
將化合物10-a(100mg, 432.01μmol)和1-j(115.51mg, 648.01μmol)溶於THF(5.00mL)中，再加入Pd(t-Bu3 P)2 (22.08mg, 43.20μmol)和t-BuONa(83.04mg, 864.02μmol)，所得混合物用氮氣置換後，加熱至70℃攪拌3小時。向反應液中加入水(50mL)中並攪拌3分鐘，水相用EtOAc(50mL×3)萃取，合併有機相用飽和食鹽水(50mL)洗滌，Na2 SO4乾燥，過濾後減壓濃縮得到粗品，粗品通過製備色譜純化得到10。
1 HNMR(400MHz,DMSO-d 6 )δppm8.31(s,1H), 8.06(s,1H)7.52(s,1H), 5.83(s,1H), 3.94-3.91(m,2H), 3.83-3.80(m,2H), 3.58-3.56(m,4H), 3.14-3.08(m,2H), 1.02(t,J =7.2Hz,3H)。Synthesis of compound 10 Compound 10-a (100 mg, 432.01 μmol) and 1-j (115.51 mg, 648.01 μmol) were dissolved in THF (5.00 mL), and Pd (t-Bu 3 P) 2 (22.08 mg, 43.20 μmol) and t-BuONa (83.04 mg, 864.02 μmol). After the resulting mixture was replaced with nitrogen, the mixture was heated to 70 ° C. and stirred for 3 hours. Water (50 mL) was added to the reaction solution and stirred for 3 minutes. The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over Na 2 SO 4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative chromatography to obtain 10.
1 HNMR (400MHz, DMSO- d 6 ) δppm8.31 (s, 1H), 8.06 (s, 1H) 7.52 (s, 1H), 5.83 (s, 1H), 3.94-3.91 (m, 2H), 3.83- 3.80 (m, 2H), 3.58-3.56 (m, 4H), 3.14-3.08 (m, 2H), 1.02 (t, J = 7.2Hz, 3H).

實施例11
Example 11

化合物11的合成
將化合物1(20mg, 60.82μmol)溶於DCM(5mL)後加入NCS(8.12mg, 60.82μmol)，所得白色懸濁液在30℃攪拌3小時。在25℃下將混合用水(30mL)淬滅反應，然後用DCM(30mL)萃取，合併有機相用水(30mL)洗滌，Na2 SO4 乾燥，過濾濃縮得到粗品，粗品通過高效液相色譜製備純化得化合物11。
1 HNMR(400MHz,CHLOROFORM-d)δ=8.03(s,1H),　6.35(s,1H),　6.51-6.17(m,1H),　4.05(s,4H),　3.68-3.56(m,2H),　3.55-3.44(m,2H),　3.10(d,J =7.2Hz,2H),　1.08(t,J =7.1Hz,3H)Synthesis of Compound 11 Compound 1 (20 mg, 60.82 μmol) was dissolved in DCM (5 mL), and NCS (8.12 mg, 60.82 μmol) was added. The obtained white suspension was stirred at 30 ° C. for 3 hours. The mixture was quenched with water (30 mL) at 25 ° C, and then extracted with DCM (30 mL). The combined organic phases were washed with water (30 mL), dried over Na 2 SO 4 , and concentrated by filtration to obtain a crude product. The crude product was purified by high-performance liquid chromatography. Obtained compound 11.
1 HNMR (400MHz, CHLOROFORM-d) δ = 8.03 (s, 1H), 6.35 (s, 1H), 6.51-6.17 (m, 1H), 4.05 (s, 4H), 3.68-3.56 (m, 2H), 3.55-3.44 (m, 2H), 3.10 (d, J = 7.2Hz, 2H), 1.08 (t, J = 7.1Hz, 3H)

實施例12
Example 12

化合物12的合成
將化合物1(20mg, 60.82μmol)溶於DCM(5mL)後加入NCS(8.12mg, 60.82μmol)，將所得白色懸濁液在30℃攪拌3小時。在25℃下用水(30mL)淬滅反應，然後用DCM(30mL)萃取，合併有機相用水(30mL)洗滌，Na2 SO4 乾燥，過濾濃縮得到粗品，粗品通過高效液相色譜製備純化得到化合物12。
1 HNMR(400MHz,CHLOROFORM-d)δ=8.22-8.04(m,1H), 7.55(d,J =1.0Hz,1H), 3.76-3.67(m,1H), 3.74-3.66(m,3H), 3.66-3.56(m,4H), 3.46-3.41(m,2H), 1.31(t,J =7.2Hz,3H)

實驗例1化合物對IDO1酶抑制活性的評價Synthesis of compound 12: Compound 1 (20 mg, 60.82 μmol) was dissolved in DCM (5 mL), NCS (8.12 mg, 60.82 μmol) was added, and the obtained white suspension was stirred at 30 ° C. for 3 hours. The reaction was quenched with water (30 mL) at 25 ° C, then extracted with DCM (30 mL), the combined organic phases were washed with water (30 mL), dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product, and the crude product was purified by HPLC to obtain a compound. 12.
1 HNMR (400MHz, CHLOROFORM-d) δ = 8.22-8.04 (m, 1H), 7.55 (d, J = 1.0Hz, 1H), 3.76-3.67 (m, 1H), 3.74-3.66 (m, 3H), 3.66-3.56 (m, 4H), 3.46-3.41 (m, 2H), 1.31 (t, J = 7.2Hz, 3H)

Evaluation of Compound of Experimental Example 1 on IDO1 Enzyme Inhibitory Activity

實驗目的：
檢測本發明化合物對IDO1酶活性的抑制效應。Purpose:
The inhibitory effect of the compound of the present invention on the activity of IDO1 was detected.

實驗方法：
I. 化合物溶液配製
1) 待測化合物加DMSO配成高濃度儲存溶液。
2) 用DMSO稀釋陽性化合物儲存液，配成100倍液。
3) 在工作板中第一列加入8µL上述溶液為最高濃度，3倍稀釋11個濃度，配成100倍溶液。
4) 取以上板中溶液0.5µL到檢測板。
II. 所用試劑配製
1) 2倍IDO1酶溶液，包含的組分有：50mM磷酸鹽緩衝溶液，0.1%吐溫20,2%甘油，20mML-抗壞血酸，,200U/ml過氧化氫酶（catalase，sigma），20µM亞甲藍，120nMIDO1酶；
2) 2倍受質（L-色胺酸）溶液：終濃度為0.1mM，用水將受質稀釋至2倍(0.2mM)。
III. IDO1酶反應
1) 按表1每孔加入0.5µL100倍化合物溶液。所有對照孔加入0.5µL100%DMSO。
2) 按表1每孔加入25µL2倍IDO1酶溶液。 100%效果對照孔加入25µL不含有IDO1酶的反應液。
3) 將檢測板1000rpm離心1min以混勻。
4) 將檢測板放置室溫下培育30min。
5) 按表1每孔加入25µL上述-受質（L-色胺酸）溶液。
6) 將檢測板1000rpm離心1分鐘以混勻。
7) 將檢測板置於酶標儀，設置溫度為25℃，分別在10min，60min讀OD320 。experimental method:
I. Compound solution preparation
1) Test compound plus DMSO to prepare a high concentration storage solution.
2) Dilute the positive compound stock solution with DMSO to make a 100-fold solution.
3) Add 8µL of the above solution to the first column of the working plate as the highest concentration, dilute it 11 times to make a 100-fold solution.
4) Take 0.5µL of the solution from the above plate to the detection plate.
II. Preparation of reagents used
1) 2x IDO1 enzyme solution, including: 50mM phosphate buffer solution, 0.1% Tween 20, 2% glycerol, 20mML-ascorbic acid, 200U / ml catalase (sigma), 20µM sub Methyl blue, 120nMIDO1 enzyme;
2) 2-fold substrate (L-tryptophan) solution: The final concentration is 0.1 mM. Dilute the substrate to 2-fold (0.2 mM) with water.
III. IDO1 enzyme reaction
1) Add 0.5 µL of 100-fold compound solution to each well according to Table 1. Add 0.5 µL of 100% DMSO to all control wells.
2) Add 25 µL of 2-fold IDO1 enzyme solution to each well according to Table 1. Add 100µL reaction solution without IDO1 enzyme to 100% control wells.
3) Centrifuge the test plate at 1000 rpm for 1 min to mix.
4) Incubate the test plate at room temperature for 30 minutes.
5) Add 25µL of the above-substance (L-tryptophan) solution to each well according to Table 1.
6) Centrifuge the test plate at 1000 rpm for 1 minute to mix.
7) Place the detection plate in the microplate reader, set the temperature to 25 ° C, and read the OD 320 at 10min and 60min respectively.

實驗數據分析結果：見表1。
表1體外篩選試驗結果
結論：本發明的化合物對Hela細胞內的IDO蛋白酶活性具有明顯的抑制作用。

實驗例2：化合物藥代動力學的評價Experimental data analysis results: see Table 1.
Table 1 In vitro screening test results
Conclusion: The compounds of the present invention have a significant inhibitory effect on IDO protease activity in Hela cells.

Experimental Example 2: Evaluation of Compound Pharmacokinetics

試驗動物
本研究使用的健康的成年雌性Balb/c小鼠，均購自上海靈暢生物科技有限公司。Experimental animals Healthy adult female Balb / c mice used in this study were purchased from Shanghai Lingchang Biotechnology Co., Ltd.

藥物的配製
靜脈注射組給藥溶液的配製
精確稱量適量化合物，加入一定量的PEG400超聲2分鐘後得到澄清溶液，然後加入適量的純水。得到終濃度為1mg/mL的澄清溶液，給藥溶媒為60%PEG400+40%純水。靜脈注射組溶液在給藥前用2um的濾膜進行過濾。
口服給組給藥溶液的配製
精確稱量適量化合物，加入一定量的PEG400超聲2分鐘後得到澄清溶液，然後加入適量的純水。得到終濃度為10mg/mL的混懸溶液，給藥溶媒為60%PEG400+40%純水Formulation of the drug The formulation of the solution for the intravenous injection group is accurately weighed to the right amount of the compound, adding a certain amount of PEG400 for 2 minutes to obtain a clear solution, and then adding the right amount of pure water. A clear solution with a final concentration of 1 mg / mL was obtained, and the administration vehicle was 60% PEG400 + 40% pure water. The intravenous injection group solution was filtered through a 2um filter before administration.
Formulation of the oral administration solution accurately weighed the appropriate amount of compound, added a certain amount of PEG400 to the ultrasound for 2 minutes to obtain a clear solution, and then added an appropriate amount of pure water. A suspension solution with a final concentration of 10 mg / mL was obtained, and the administration vehicle was 60% PEG400 + 40% pure water.

給藥
12只雌性Balb/c小鼠，按照每組6只，分為2組。
第一組，靜脈注射給予2mg/kg的化合物1；第二組，灌胃給予50mg/kg化合物1。Dosing
Twelve female Balb / c mice were divided into two groups according to six mice in each group.
In the first group, Compound 1 was administered intravenously at 2 mg / kg; in the second group, Compound 1 was administered intragastrically at 50 mg / kg.

樣品採集
採用交叉採血方式，每個時間點採集三隻動物的血液。分別於給藥前及給藥後0.0833（僅靜注組）、0.25、0.5、1、2、4、8、24小時採集40μL全血。將全血置於抗凝管中，在4℃條件先，3000g離心15分鐘，製備血漿並保存於-80℃。應用LC/MS-MS測定血漿中的藥物濃度。The samples were collected by cross-blood collection, and the blood of three animals was collected at each time point. 40 μL of whole blood was collected before and after 0.0833 (intravenous injection only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The whole blood was placed in an anticoagulation tube, and centrifuged at 3000 g for 15 minutes at 4 ° C to prepare plasma and stored at -80 ° C. LC / MS-MS was used to determine the drug concentration in plasma.

實驗結果：見表2。
表2化合物藥代動力學的評價實驗結果
結論：本發明化合物小鼠體內代謝穩定性好，具有較好的口服生物利用度，綜合藥代動力學性質優。Experimental results: see Table 2.
Table 2 Evaluation results of compound pharmacokinetics
Conclusion: The compound of the present invention has good metabolic stability in mice, has good oral bioavailability, and has excellent comprehensive pharmacokinetic properties.

雖然本發明已以實施例揭露如上，然其並非用以限定本發明，本發明所屬技術領域中具有通常知識者，在不脫離本發明之精神和範圍內，當可作些許之更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。Although the present invention has been disclosed as above with the examples, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention pertains may make some modifications and retouching without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be determined by the scope of the appended patent application.

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Claims (14)

式（I）化合物或其藥學上可接受的鹽， 其中，為單鍵或雙鍵； 環A選自5元雜芳基，所述5元雜芳基上至少含有1個N原子； Y選自C和N； R1 選自H、C1-6 烷基、C1-6 雜烷基，所述C1-6 烷基、C1-6 雜烷基任選被1、2或3個R取代； R2 、R3 、R4 和R5 分別獨立地選自H和C1-6 烷基； 或者R4 和R5 連接在一起，形成3~4元環烷基，所述3~4元環烷基任選被1、2或3個R取代； R6 、R7 和R8 分別獨立地選自H、鹵素、OH、CN、NH2 和C1~3 烷基，所述C1~3 烷基任選被1、2或3個R9 取代； R9 分別獨立地選自CN、F、Cl、Br和I； R分別獨立地選自鹵素、OH、CN、NH2 、C1-4 烷基、C1-4 雜烷基、C3-6 環烷基、3~6元雜環烷基、苯基和5~6元雜芳基，所述C1-4 烷基、C1-4 雜烷基、C3~6 環烷基、3~6元雜環烷基、苯基和5~6元雜芳基任選被1、2或3個R’取代； R’分別獨立地選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 O、CH3 CH2 、CH3 CH2 O、CH(CH3 )2 、N(CH3 )2 、CF3 、CH2 F和CHF2 ； 所述5元雜芳基、5~6元雜芳基、3~6元雜環烷基、C1-6 雜烷基和C1-4 雜烷基分別包含1、2、獨立地選自-C(=O)-、N、-NH-、-O-、-S-； 以上任何一種情況下，雜原子或雜原子團的數目分別獨立地選自1、2或3。A compound of formula (I) or a pharmaceutically acceptable salt thereof, among them, Is a single or double bond; ring A is selected from a 5-membered heteroaryl group, which contains at least one N atom; Y is selected from C and N; R 1 is selected from H, C 1-6 alkane , C 1-6 heteroalkyl, said C 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R; R 2 , R 3 , R 4 and R 5 respectively Independently selected from H and C 1-6 alkyl; or R 4 and R 5 are joined together to form a 3- to 4-membered cycloalkyl, which is optionally 1, 2, or 3 R is substituted; R 6 , R 7 and R 8 are each independently selected from H, halogen, OH, CN, NH 2 and C 1-3 alkyl, said C 1-3 alkyl is optionally 1, 2, or 3 R 9 is substituted; R 9 is independently selected from CN, F, Cl, Br and I; R is independently selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 heteroalkane Group, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, the C 1-4 alkyl, C 1-4 heteroalkyl, C 3 ~ 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted with 1, 2 or 3 R ';R' are each independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3, CH 3 O, CH 3 CH 2, CH 3 CH 2 O, CH (CH 3) 2, N (CH 3) 2, CF 3, CH 2 F CHF 2; the 5-membered heteroaryl, 5 to 6 membered heteroaryl, 3-6 membered heterocycloalkyl, C 1-6 alkyl and heteroaryl C 1-4 heteroalkyl comprising 1, 2, respectively, independent Ground is selected from -C (= O)-, N, -NH-, -O-, -S-; in any of the above cases, the number of heteroatoms or heteroatomic groups is independently selected from 1, 2, or 3. 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽，其中，R選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 O、CH3 CH2 、CH3 CH2 O、CH(CH3 )2 、N(CH3 )2 、CF3 、CH2 F、CHF2 、。The compound or pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 O, and CH 3 CH 2 , CH 3 CH 2 O, CH (CH 3 ) 2 , N (CH 3 ) 2 , CF 3 , CH 2 F, CHF 2 , . 如申請專利範圍第1或2項所述的化合物或其藥學上可接受的鹽，其中，R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 ，所述CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O和N(CH3 )2 任選被1、2或3個R取代。The compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 of the scope of patent application, wherein R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O and N (CH 3 ) 2 , wherein CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, and N (CH 3 ) 2 are optionally 1, 2 or 3 R substitutions. 如申請專利範圍第3項所述的化合物或其藥學上可接受的鹽，其中，R1 選自H、CH3 、CH3 CH2 、CH(CH3 )2 、CH3 O、CH3 CH2 O、N(CH3 )2 、CH2 OH、CF3 、CH2 F、CHF2 和。The compound or pharmaceutically acceptable salt thereof according to item 3 of the scope of patent application, wherein R 1 is selected from H, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CH 3 O, CH 3 CH 2 O, N (CH 3 ) 2 , CH 2 OH, CF 3 , CH 2 F, CHF 2 and . 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽，其中，R2 、R3 、R4 和R5 分別獨立地選自H、CH3 、CH3 CH2 和CH(CH3 )2 。The compound or a pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein R 2 , R 3 , R 4 and R 5 are each independently selected from H, CH 3 , CH 3 CH 2 and CH ( CH 3 ) 2 . 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽，其中，R6 、R7 和R8 分別獨立地選自F、Cl、Br、I、OH、CN、NH2 、CH3 、CH3 CH2 、CH(CH3 )2 、CF3 、CH2 F和CHF2 。The compound or pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein R 6 , R 7 and R 8 are each independently selected from F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 , CF 3 , CH 2 F, and CHF 2 . 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽，其中，結構單元選自、、、和。The compound or a pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein the structural unit From , , , with . 如申請專利範圍第7項所述的化合物或其藥學上可接受的鹽，其中，結構單元選自、、、、、、、、、、、、、、、、、、、、、、、、、和。The compound or a pharmaceutically acceptable salt thereof according to item 7 of the scope of patent application, wherein the structural unit From , , , , , , , , , , , , , , , , , , , , , , , , , with . 如申請專利範圍第1項所述的化合物或其藥學上可接受的鹽，其中，環A選自吡咯基、吡唑基、咪唑基、三唑基、唑基、異唑基、噻唑基和異噻唑基。The compound or a pharmaceutically acceptable salt thereof according to item 1 of the scope of patent application, wherein ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Oxazolyl, iso Oxazolyl, thiazolyl, and isothiazolyl. 如申請專利範圍第9項所述的化合物或其藥學上可接受的鹽，其中，結構單元選自和。The compound or a pharmaceutically acceptable salt thereof according to item 9 of the scope of patent application, wherein the structural unit From with . 如申請專利範圍第9項所述的化合物或其藥學上可接受的鹽，其中，結構單元選自、、、、、和。The compound or a pharmaceutically acceptable salt thereof according to item 9 of the scope of patent application, wherein the structural unit From , , , , , with . 如申請專利範圍第1~6任意一項或如申請專利範圍第9項所述的化合物或藥學上可接受的鹽，化合物選自和， 其中，R1 、R2 、R3 、R4 、R5 、R6 、R7 和R8 如申請專利範圍第1~6或9項所定義。A compound or a pharmaceutically acceptable salt as described in any one of the scope of claims 1 to 6 or in the scope of claims 9 with Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in items 1 to 6 or 9 of the scope of patent application. 化合物或其藥學上可接受的鹽，選自 。Compound or pharmaceutically acceptable salt thereof, selected from . 如申請專利範圍第1~13任意一項所述的化合物或其藥學上可接受的鹽在製備治療癌症藥物中的應用。Application of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.
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