WO2019218955A1

WO2019218955A1 - Compound as protease activated receptor 4 (par4) inhibitor for treating platelet aggregation

Info

Publication number: WO2019218955A1
Application number: PCT/CN2019/086556
Authority: WO
Inventors: 吴俊军; 李硕; 温晓明; 阳华; 魏国平; 胡允金; 钱苏
Original assignee: 深圳信立泰药业股份有限公司
Priority date: 2018-05-16
Filing date: 2019-05-13
Publication date: 2019-11-21
Also published as: CN112074523B; CN112074523A

Abstract

Provided is a series of compounds used as protease inhibitory receptor 4 (PAR4) inhibitors for treating platelet aggregation and medical use thereof, relating to the technical field of chemical medicines.

Description

作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物a compound that acts as a protease activated receptor 4 (PAR4) inhibitor for the treatment of platelet aggregation

技术领域Technical field

本发明属于化学药物技术领域，特别提供了一系列作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物及其医药用途。The present invention is in the field of chemical pharmaceutical technology, and particularly provides a series of compounds as protease inhibitory receptor 4 (PAR4) inhibitors for treating platelet aggregation and their medical uses.

背景技术Background technique

血栓栓塞性疾病仍是目前死亡的主要原因之一，尽管有可利用的抗凝血剂如华法林，肝素，和抗血小板剂如阿司匹林和氯吡格雷，替格瑞洛，利伐沙班等等。Thromboembolic disease remains one of the leading causes of death, although available anticoagulants such as warfarin, heparin, and antiplatelet agents such as aspirin and clopidogrel, ticagrelor, rivaroxaban and many more.

血小板的主要生理功能是参与血栓与止血，任何凝血过程都涉及血小板的活化，这是一个复杂的信号级连过程，凝血酶在其中占有核心地位。凝血酶活化血小板主要通过一族G蛋白偶连的蛋白酶活化受体PARs(protease-activated receptors)介导。人类血小板表面表达PAR1与PAR4两种受体，凝血酶能连接并切割PAR1或PAR4，暴露新的N-末端，后者作为一个固定配基与受体进行分子内结合，从而激发跨膜信号传导，引起血小板聚集、释放以及膜糖蛋白的一系列改变。The main physiological function of platelets is to participate in thrombosis and hemostasis. Any blood coagulation process involves the activation of platelets, which is a complex signal cascade process in which thrombin plays a central role. Thrombin-activated platelets are mediated primarily by a family of G-protein-coupled protease-activated receptors (PARs). Human platelets express both PAR1 and PAR4 receptors. Thrombin can bind and cleave PAR1 or PAR4, exposing a new N-terminus, which acts as a binding ligand for intramolecular binding to the receptor, thereby stimulating transmembrane signaling. , causing platelet aggregation, release, and a series of changes in membrane glycoproteins.

PAR1抑制剂已得到广泛研究，包括vorapaxar(沃拉帕沙)和atopaxar(阿托帕沙)的数种化合物已进入后期临床试验。近来，在ACS患者的示踪III期试验中，vorapaxar没有显著减少心血管事件，而是显著增加严重出血的风险(Tricoci,P.等人，N.Eng.J.CH3d.,366(1)：20-33(2012)。因此，仍然需要发现新的具有增加功效和减少出血副作用的抗血小板药。PAR1 inhibitors have been extensively studied, and several compounds including vorapaxar (wolapasa) and atopaxar (attopasa) have entered late clinical trials. Recently, in the Phase III trial of ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of severe bleeding (Tricoci, P. et al., N. Eng. J. CH3d., 366(1) :20-33 (2012). Therefore, there is still a need to discover new antiplatelet drugs with increased efficacy and reduced bleeding side effects.

另外，有一些PAR4抑制剂专利申请公开，如CN104640869A和CN104583218A分别公开了下式I和II的一系列作为蛋白酶活化受体4(PAR4)抑制剂，用于抑制或防止血小板聚集的药物中的用途。In addition, some PAR4 inhibitor patent applications disclose, such as CN104640869A and CN104583218A, respectively, disclose a series of uses of the following formulas I and II as protease activated receptor 4 (PAR4) inhibitors for inhibiting or preventing platelet aggregation. .

所述化合物的研究还处于前期研究阶段，据专利申请公开资料显示，其五元母核中应当含有氧原子才有相应的PAR4活性。The study of the compound is still in the preliminary research stage. According to the patent application disclosure data, the nucleus of the quintuple should contain oxygen atoms to have the corresponding PAR4 activity.

发明内容Summary of the invention

为了寻找具有增加功效和减少出血副作用的抗血小板药，并且本发明提供了一系列作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物，本发明的化合物结构母核不同于已公开的PAR4抑制剂。In order to find anti-platelet drugs with increased efficacy and reduced bleeding side effects, and the present invention provides a series of compounds as protease activated receptor 4 (PAR4) inhibitors for the treatment of platelet aggregation, the structural nucleus of the compound of the present invention is different from A PAR4 inhibitor has been disclosed.

本发明首先提供了一系列化合物，作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物或其药学上可接受的盐，所述化合物的母核如下：所述化合物的母核如下式(I)所示：The present invention first provides a series of compounds as compounds of a protease activated receptor 4 (PAR4) inhibitor for the treatment of platelet aggregation, or a pharmaceutically acceptable salt thereof, the mother nucleus of which is as follows: The nuclear is as shown in the following formula (I):

其中，X选自羰基、硫羰基、亚砜基和砜基；Wherein X is selected from the group consisting of a carbonyl group, a thiocarbonyl group, a sulfoxide group, and a sulfone group;

W、Y和Z分别独立选自CH，N；W, Y and Z are each independently selected from CH, N;

n＝1,2,3,4；n=1, 2, 3, 4;

R ₁选自氢，卤素，C _1-4的烷氧基，C _1-4的烷硫基； R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-4 alkoxy, C _1-4 alkylthio;

R ₂选自取代或非取代的C _1-4的烷氧基，所述取代基选自卤素； R _{2 is} selected from a substituted or unsubstituted C _1-4 alkoxy group, said substituent being selected from halogen;

R ₃选自羟基，C _1-4的烷氧基，取代或者非取代C _6-12的芳基、C _6-10杂芳基、C _3-6杂环烷基、噻唑、噁唑、咪唑，所述取代基选自卤素；以及-NR ₄R ₅，其中，R ₄、R ₅选自氢、羟基，取代或者非取代的C _1-6的烷基、C _1-4的烷氧基、C _3-12的环烷基，所述取代基选自卤素、氰基、C _6-12的芳基、C _6-10杂芳基、C _3-6的杂环烷基、C _3-6的环烷基、C _1-4的氨基，所述C _6-12的芳基、C _6-10杂芳基可进一步C _1-6的烷基、羟基所取代。 R _{3 is} selected from hydroxy, C _1-4 alkoxy, substituted or unsubstituted C _6-12 aryl, C _6-10 heteroaryl, C _3-6 heterocycloalkyl, thiazole, oxazole, imidazole The substituent is selected from a halogen; and -NR ₄ R ₅ , wherein R ₄ , R _{5 are} selected from hydrogen, hydroxy, substituted or unsubstituted C _1-6 alkyl, C _1-4 alkoxy a C _3-12 cycloalkyl group selected from the group consisting of halogen, cyano, C _6-12 aryl, C _6-10 heteroaryl, C _3-6 heterocycloalkyl, C _{3 - The 6} -cycloalkyl group, the C _1-4 amino group, the C _6-12 aryl group and the C _6-10 heteroaryl group may be further substituted with a C _1-6 alkyl group or a hydroxyl group.

作为本发明的一种优选方案，所述C _1-4的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。 As a preferred embodiment of the present invention, the C _1-4 alkoxy group is selected from the group consisting of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, and a sec-butyl group. Oxyl, tert-butoxy.

作为本发明的一种优选方案，所述C _1-4的烷硫基选自甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基。 As a preferred embodiment of the present invention, the C _1-4 alkylthio group is selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, and sec Sulfur-based, tert-butylthio.

作为本发明的一种优选方案，所述卤素选自氟、氯、溴、碘。As a preferred embodiment of the present invention, the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.

作为本发明的一种优选方案，所述C _6-12的芳基选自

C _6-10杂芳基选自

As a preferred embodiment of the present invention, the C _6-12 aryl group is selected from the group consisting of

C _6-10 heteroaryl is selected from

C _3-6杂环烷基选自

C _3-6 heterocycloalkyl is selected from

所述C _1-6的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基环丙烷基、正戊基、异戊基、叔丁基甲基、正己基、异己基、甲基环丁烷基、甲基环戊烷基；所述C _3-12的环烷基选自环丙烷、环丁烷、环戊烷、环己烷、三环[3.3.1.13.7]癸烷、双环[1.1.1]戊烷。 The C _1-6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylcyclopropane, n-pentyl , isoamyl, tert-butylmethyl, n-hexyl, isohexyl, methylcyclobutane, methylcyclopentanyl; said C _3-12 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane Alkane, cyclohexane, tricyclo[3.3.1.13.7] decane, bicyclo[1.1.1]pentane.

作为本发明的一种优选方案，C _1-4的氨基选自甲氨基、乙氨基、二甲氨基、丙氨基、异丙胺基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。 As a preferred embodiment of the present invention, the amino group of C _1-4 is selected from the group consisting of methylamino, ethylamino, dimethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino and tert-butylamino.

作为本发明的一种优选方案，所述化合物的母核如下式(II)所示，As a preferred embodiment of the present invention, the mother nucleus of the compound is represented by the following formula (II).

其中，R ₁、R ₂、R ₄、R ₅、W、Y、Z、n如上定义。 Wherein R ₁ , R ₂ , R ₄ , R ₅ , W, Y, Z, and n are as defined above.

作为本发明的一种优选方案，所述药学上可接受的盐选自无机酸或有机酸成盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、三氟乙酸、单宁酸、酒石酸和对甲苯磺酸。As a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from the group consisting of inorganic acids or organic acid salts selected from the group consisting of 2-acetoxybenzoic acid and 2-hydroxyethanesulfonic acid. Acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid , glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzene Sulfonic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid and p-toluenesulfonic acid.

本发明优选自以下化合物：The invention is preferably derived from the following compounds:

本发明的另一目的在于提供一种药物组合物，其包括前述的化合物或其药学上可接受的盐和一种以上药学上可接受的载体。Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

本发明的另一目的在于提供一种药物用途，所述用途是指前述的化合物或其药学上可接受的盐在制备用于制备治疗血栓相关疾病的药物用途。Another object of the present invention is to provide a pharmaceutical use which is a pharmaceutical use for the preparation of a compound for the treatment of a thrombosis-related disease, or a pharmaceutically acceptable salt thereof.

优选的，所述血栓相关疾病选自动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、脑血管血栓栓塞性病症、和心脏腔室或外周循环中的血栓栓塞性病症。Preferably, the thrombosis-related disease is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a thromboembolic disorder in the heart chamber or peripheral circulation.

除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms 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.

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如甲酸、乙酸、三氟乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, amber Acids, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include amino acids (such as fine Salts of amino acids and the like, and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、三氟乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁酸、酒石酸和对甲苯磺酸。As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, Trifluoroacetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, valley Acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid , nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid , sulfuric acid, tannic acid, tartaric acid and p-toluenesulfonic acid.

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体，以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers, as well as the 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 by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, a compound can be labeled with a radioisotope such as hydrazine (3H), iodine-125 (125I) or C-14 (14C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂载体或介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation carrier or vehicle that is capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient. Representative carriers include water, oil. , vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.

术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a 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 the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

具体实施方式Detailed ways

下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

通式制备路线General formula preparation route

通式合成步骤A:General synthetic step A:

将(A)溶于N,N-二甲基甲酰胺中，加入(B)和碳酸钾。在室温下搅拌4小时。LCMS监测显示原料消失后，过滤除去不溶物。滤液用制备型高效液相色谱纯化。分离条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％的甲酸)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。减压冻干，得目标固体(C)。(A) was dissolved in N,N-dimethylformamide, and (B) and potassium carbonate were added. Stir at room temperature for 4 hours. LCMS monitoring showed disappearance of the starting material and filtration to remove insolubles. The filtrate was purified by preparative high performance liquid chromatography. The separation conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile increased from 50% to 60% in 7 minutes Detection wavelength: 254 nm. Lyophilization under reduced pressure gave the target solid (C).

通式合成步骤B:General synthetic step B:

将(D)溶于乙腈(1.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐。在室温下搅拌15分钟后，向反应液中依次加入(E)和三乙胺。在室温下搅拌2小时。(D) was dissolved in acetonitrile (1.0 mL). Subsequently, 1-propylphosphoric anhydride was added to the above solution. After stirring at room temperature for 15 minutes, (E) and triethylamine were sequentially added to the reaction liquid. Stir at room temperature for 2 hours.

向反应液中加入水淬灭反应。混合液用乙酸乙酯萃取。合并有机相，有机相用饱和食盐水洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)。得目标固体(F)。Water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The residue was purified with EtOAc EtOAc EtOAc EtOAc The target solid (F) was obtained.

实施例1:合成((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酸乙酯Example 1: Synthesis of ((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yl)oxy)acetate

步骤A：合成((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酸乙酯Step A: Synthesis of ((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1, 5-a]pyridin-4-yl)oxy)acetate

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(20毫克，0.060毫摩尔)，N,N-二甲基甲酰胺(8.0毫升)，2-溴乙酸甲酯(18毫克，0.120毫摩尔)和碳酸钾(16毫克，0.120毫摩尔)。得灰色固体((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酸乙酯(8.4毫克，36.0％)。MS(ESI)M/Z：390[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.01(s,1H),7.82(s,1H),7.02(s,1H),6.16(s,1H),4.78(s,2H),4.24(s,3H),3.86(s,3H),3.84(s,3H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (20 mg, 0.060 mmol), N,N-dimethylformamide (8.0 ml), 2-bromoacetic acid methyl ester (18 mg, 0.120 mmol) and potassium carbonate (16 mg, 0.120 mmol) ). Obtained as a gray solid ((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yl)oxy)acetate (8.4 mg, 36.0%). MS (ESI) M/Z: 390 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.01 (s, 1H), 7.82 (s, 1H), 7.02 (s, 1H), 6.16 (s, 1H), 4.78 (s, 2H), 4.24 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H).

实施例2：合成(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸Example 2: Synthesis of (6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1, 5-a]pyridin-4-yloxy)acetic acid

步骤A：合成(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸Step A: Synthesis of (6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yloxy)acetic acid

将(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸甲酯,SAL-162(20毫克，0.05毫摩尔)溶于四氢呋喃(2.0毫升)与水(2.0毫升)的混合溶液中。随后，向上述溶液中加入氢氧化锂(10.8毫克，0.45毫摩尔)。在室温下搅拌2小时。(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a] Methyl pyridin-4-yloxy)acetate, SAL-162 (20 mg, 0.05 mmol) was dissolved in a mixture of tetrahydrofuran (2.0 mL) and water (2.0 mL). Subsequently, lithium hydroxide (10.8 mg, 0.45 mmol) was added to the above solution. Stir at room temperature for 2 hours.

向反应液中加入稀盐酸(1.0摩尔/升)调节PH值约为2，有白色固体析出。过滤，收集滤饼，滤饼烘干得到7.5毫克白色固体(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(收率：40％)。MS(ESI)M/Z：376[M+H ⁺]。 ¹H NMR(300MHz,D ₂O，ppm):δ7.41(s,1H),7.37(s,1H),6.36(s,1H),5.97(s,1H),4.35(s,2H),3.97(s,3H),3.68(s,3H)。 Dilute hydrochloric acid (1.0 mol/liter) was added to the reaction solution to adjust the pH to about 2, and a white solid precipitated. Filtration, collecting the filter cake, and drying the filter cake to give 7.5 mg of a white solid (6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole- 6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetic acid (yield: 40%). MS (ESI) M/Z: 376 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, D 2}} O, ppm): δ7.41 (s, 1H), 7.37 (s, 1H), 6.36 (s, 1H), 5.97 (s, 1H), 4.35 (s, 2H), 3.97 (s, 3H), 3.68 (s, 3H).

实施例3：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Example 3: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N-methylacetamide

步骤A:合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-methylacetamide

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(20毫克，0.063毫摩尔),2-溴-N-甲基乙酰胺(12毫克，0.076毫摩尔)，无水碳酸钾(83毫克，0.601毫摩尔)，N,N-二甲基甲酰胺(2.0毫升)。得到3.0毫克白色固体2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺(收率：12.3％)。MS(ESI)M/Z:389[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.04(s,1H),7.81(s,1H),7.03(s,1H),6.62(s,1H),6.27(s,1H),4.63(s,2H),4.24(s,3H),3.85(s,3H),2.98(s,3H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (20 mg, 0.063 mmol), 2-bromo-N-methylacetamide (12 mg, 0.076 mmol), anhydrous potassium carbonate (83 mg, 0.601 mmol), N, N-dimethyl Carboxamide (2.0 ml). Obtained 3.0 mg of white solid 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N-methylacetamide (yield: 12.3%). MS (ESI) M / Z: 381 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.04 (s, 1H), 7.81 (s, 1H), 7.03 (s, 1H), 6.62 (s, 1H), 6.27 (s, 1H), 4.63 (s, 2H), 4.24 (s, 3H), 3.85 (s, 3H), 2.98 (s, 3H).

实施例4：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 4: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(32毫克，0.10毫摩尔),2-bromoacetamide(28毫克，0.20毫摩尔)，无水碳酸钾(41毫克，0.30毫摩尔)，N,N-二甲基甲酰胺(1.5毫升)。得到2.9毫克白色固体2-(6-甲氧基-2-(2- 甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(收率：7.7％)。MS(ESI)M/Z:375[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.83(s,1H),7.00(s,1H),6.56(s,1H),6.29(s,1H),5.64(s,1H),4.64(s,2H),4.24(s,3H),3.85(s,3H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (32 mg, 0.10 mmol), 2-bromoacetamide (28 mg, 0.20 mmol), anhydrous potassium carbonate (41 mg, 0.30 mmol), N,N-dimethylformamide (1.5 ml) . 2.9 mg of white solid 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)acetamide (yield: 7.7%). MS (ESI) M/Z: 375 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.83 (s, 1H), 7.00 (s, 1H), 6.56 (s, 1H), 6.29 (s, 1H), 5.64 (s, 1H), 4.64 (s, 2H), 4.24 (s, 3H), 3.85 (s, 3H).

实施例5：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N，N-二甲基乙酰胺Example 5: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N,N-dimethylacetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N，N-二甲基乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N,N-dimethylacetamide

详见通式合成步骤A。(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(25毫克，0.08毫摩尔)，2-溴-N，N-二甲基乙酰胺(27毫克，0.16毫摩尔),无水碳酸钾(22毫克，0.16毫摩尔)，N,N-二甲基甲酰胺(3.0毫升)。得到3.1毫克白色固体2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N，N-二甲基乙酰胺(收率：9.6％)。MS(ESI)M/Z：403[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm)δ8.05(s,1H),7.82(s,1H),7.03(s,1H),6.37(s,1H),4.85(s,2H)，4.25(s,3H)，3.84(s,3H),3.15(s,3H),3.02(s,3H)。 See Synthesis Step A for details. (2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-ol (25 mg, 0.08 Methyl), 2-bromo-N,N-dimethylacetamide (27 mg, 0.16 mmol), anhydrous potassium carbonate (22 mg, 0.16 mmol), N,N-dimethylformamide (3.0 ML). Obtained 3.1 mg of white solid 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N,N-dimethylacetamide (yield: 9.6%). MS (ESI) M / Z: 403 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm) δ8.05 (s, 1H), 7.82 (s, 1H), 7.03 (s, 1H), 6.37 (s, 1H), 4.85 (s, 2H), 4.25 ( s, 3H), 3.84 (s, 3H), 3.15 (s, 3H), 3.02 (s, 3H).

实施例6：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-苯乙酮Example 6: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-1-acetophenone

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-苯乙酮Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-1-acetophenone

详见通式合成步骤A。(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(25毫克，0.08毫摩尔)，2-溴-1-苯基乙酮(32毫克，0.16毫摩尔)，无水碳酸钾(22毫克，0.16毫摩尔)，N，N-二甲基甲酰胺(2.0毫升)。得到2.3毫克白色固体2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-苯乙酮(收率：6.6％)。MS(ESI)M/Z：436[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.06-8.03(m,3H),7.81(s,1H),7.66–7.63(m,1H),7.56–7.51(m,2H),7.05(s,1H),6.20(s,1H),5.40(s,2H),4.24(s,3H)，3.82(s,3H)。 See Synthesis Step A for details. (2-Methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-ol (25 mg, 0.08 <RTIgt; mmol), 2-bromo-1-phenylethanone (32 mg, 0.16 mmol), anhydrous potassium carbonate (22 mg, 0.16 mmol) Obtained 2.3 mg of white solid 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-1-acetophenone (yield: 6.6%). MS (ESI) M / Z: 436 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.06-8.03 (m, 3H), 7.81 (s, 1H), 7.66-7.63 (m, 1H), 7.56-7.51 (m, 2H), 7.05 ( s, 1H), 6.20 (s, 1H), 5.40 (s, 2H), 4.24 (s, 3H), 3.82 (s, 3H).

实施例7：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-吗啉代Example 7: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-1-morpholino

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-吗啉代Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-1-morpholino

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(32毫克，0.100毫摩尔)，N,N-二甲基甲酰胺(8毫升)，2-溴-1-吗啉代乙酮(42毫克，0.200毫摩尔)，碳酸钾(28毫克，0.200毫摩尔)。得白色固体2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-1-吗啉代(9.0毫克，20.2％)。MS(ESI)M/Z：445[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.00(s,1H),7.82(s,1H),6.92(s,1H),6.37(s,1H),4.85(s,2H),4.23(s,3H),3.87(s,3H),3.68(br,8H). See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (32 mg, 0.100 mmol), N,N-dimethylformamide (8 ml), 2-bromo-1-morpholinoethyl ketone (42 mg, 0.200 mmol), potassium carbonate (28 Mg, 0.200 mmol). Obtained as a white solid 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1, 5-a]pyridin-4-yloxy)-1-morpholino (9.0 mg, 20.2%). MS (ESI) M/Z: 445 [M+H ⁺ ]. ¹ H NMR (300 MHz, CDCl ₃ , ppm): δ 8.00 (s, 1H), 7.82 (s, 1H), 6.92 (s, 1H), 6.37 (s, 1H), 4.85 (s, 2H), 4.23 (s, 3H), 3.87 (s, 3H), 3.68 (br, 8H).

实施例8：合成N-(2-(二甲基氨基)乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5a]吡啶-4-基氧基)乙酰胺Example 8: Synthesis of N-(2-(dimethylamino)ethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3 ,4]thiadiazole-6-yl)pyrazolo[1,5a]pyridin-4-yloxy)acetamide

步骤A：合成N-(2-(二甲基氨基)乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-(2-(dimethylamino)ethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)pyrazolo[1,5a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，乙腈(1.0毫升)，1-丙基磷酸酐(76毫克，0.12毫摩尔，50％wt)，N,N-二甲基乙烷-1,2-二胺(14毫克，0.16毫摩尔)和三乙胺(0.075毫升)；得到15.6克棕色固体合成N-(2-(二甲基氨基)乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5a]吡啶-4-基氧基)乙酰胺(收率：43.8％)。MS(ESI)M/Z：446[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm)δ8.01(s,1H),7.79(s,1H),7.15(s,1H),6.24(s,1H),4.65(s,2H),4.20(s,3H),3.81(s,3H),3.80-3.76(m,2H),3.65-3.62(m,2H),2.61(s,6H)。 See Synthesis Procedure Step B for details. (6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine -4-yloxy)acetic acid (30 mg, 0.08 mmol), acetonitrile (1.0 mL), 1-propylphosphonic anhydride (76 mg, 0.12 mmol, 50% wt), N,N-dimethyl Alkyl-1,2-diamine (14 mg, 0.16 mmol) and triethylamine (0.075 mL); -Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5a]pyridin-4-yl Oxy)acetamide (yield: 43.8%). MS (ESI) M/Z: 446[M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm) δ8.01 (s, 1H), 7.79 (s, 1H), 7.15 (s, 1H), 6.24 (s, 1H), 4.65 (s, 2H), 4.20 ( s, 3H), 3.81 (s, 3H), 3.80-3.76 (m, 2H), 3.65-3.62 (m, 2H), 2.61 (s, 6H).

实施例9：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(2-吗啉代乙基)乙酰胺Example 9: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)-N-(2-morpholinoethyl)acetamide

步骤A：合成2-溴-N-(2-吗啉代乙基)乙酰胺Step A: Synthesis of 2-bromo-N-(2-morpholinoethyl)acetamide

在冰水浴下，将2-吗啉代乙胺(65毫克，0.50毫摩尔)溶于二氯甲烷(2.0毫升)中。随后，向上述溶液中加入溴乙酰氯(78毫克，0.50毫摩尔)。在常温下搅拌3小时。2-morpholinoethylamine (65 mg, 0.50 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, bromoacetyl chloride (78 mg, 0.50 mmol) was added to the above solution. Stir at room temperature for 3 hours.

将反应液减压浓缩。所得残余物加入乙酸乙酯(5.0毫升)打浆。过滤，收集滤饼，烘干得到123毫克白色固体2-溴-N-(2-吗啉代乙基)乙酰胺(收率：98.0％)。MS(ESI)M/Z：251,253[M+H ⁺]。 The reaction solution was concentrated under reduced pressure. The residue obtained was taken up in ethyl acetate (5 mL). After filtration, the cake was collected and dried to give 123 mg of white solid 2-bromo-N-(2-morpholinoethyl)acetamide (yield: 98.0%). MS (ESI) M / Z: 251, 253 [M+H ⁺ ].

步骤B：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(2-吗啉代乙基)乙酰胺Step B: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-(2-morpholinoethyl)acetamide

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(20毫克，0.063毫摩尔)，2-溴-N-(2-吗啉代乙基)乙酰胺(40毫克，0.160毫摩尔)，无水碳酸钾(40毫克，0.290毫摩尔)，N,N-二甲基甲酰胺(2.0毫升)。得到1.1毫克白色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(2-吗啉代乙基)乙酰胺(收率：3.58％)。MS(ESI)M/Z:488[M+H ⁺]。 ¹H NMR(300MHz,CD ₃CN,ppm):δ8.08(s,1H),7.87(s,1H),7.13(s,1H),6.40(s,1H),4.66(s,2H),4.21(s,3H),3.85(s,3H),3.76-3.66(br,4H),3.52-3.45(br,2H),2.76-2.54(br,6H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (20 mg, 0.063 mmol), 2-bromo-N-(2-morpholinoethyl)acetamide (40 mg, 0.160 mmol), anhydrous potassium carbonate (40 mg, 0.290 mmol) , N,N-dimethylformamide (2.0 ml). Yield 1.1 mg of white solid 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)-N-(2-morpholinoethyl)acetamide (yield: 3.58%). MS (ESI) M / Z: 488 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CD 3}} CN, ppm): δ8.08 (s, 1H), 7.87 (s, 1H), 7.13 (s, 1H), 6.40 (s, 1H), 4.66 (s, 2H), 4.21 (s, 3H), 3.85 (s, 3H), 3.76-3.66 (br, 4H), 3.52-3.45 (br, 2H), 2.76-2.54 (br, 6H).

实施例10：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-4-基)乙-1-酮Example 10: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)-1-(pyridin-4-yl)ethan-1-one

步骤A：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-4-基)乙-1-酮Step A: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-1-(pyridin-4-yl)ethan-1-one

详见通式合成步骤A。6-氯-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(20毫克，0.063毫摩尔),2-溴-1-(吡啶-4-基)乙酮(25毫克，0.126毫摩尔)，无水碳酸钾(61毫克，0.441毫摩尔)，乙腈(2.0毫升)。得到2.2毫克白色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-4-基)乙-1-酮(收率：8.01％)。MS(ESI)M/Z：437[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.89(d,J＝6.0Hz,2H)8.00(s,1H),7.85-7.79(m,3H),6.97(s,1H),6.19(s,1H),5.34(s,2H),4.23(s,3H),3.82(s,3H)。 See Synthesis Step A for details. 6-Chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4- Alcohol (20 mg, 0.063 mmol), 2-bromo-1-(pyridin-4-yl)ethanone (25 mg, 0.126 mmol), anhydrous potassium carbonate (61 mg, 0.441 mmol), acetonitrile (2.0 ML). Obtained 2.2 mg of a white solid 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole) [1,5-a]pyridin-4-yl)oxy)-1-(pyridin-4-yl)ethan-1-one (yield: 8.01%). MS (ESI) M / Z: 437 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.89 (d, J = 6.0Hz, 2H) 8.00 (s, 1H), 7.85-7.79 (m, 3H), 6.97 (s, 1H), 6.19 ( s, 1H), 5.34 (s, 2H), 4.23 (s, 3H), 3.82 (s, 3H).

实施例11：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-2-基)乙-1-酮Example 11: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)-1-(pyridin-2-yl)ethan-1-one

步骤A：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-2-基)乙-1-酮Step A: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-1-(pyridin-2-yl)ethan-1-one

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(50毫克,0.16毫摩尔),2-溴-1-(吡啶-2-基)乙-1-酮(64毫克，0.32毫摩尔),无水碳酸钾(44毫克，0.32毫摩尔),N,N-二甲基甲酰胺(2.0毫升)。得到10.0毫克灰色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡啶-2-基)乙-1-酮(收率：14.3％)。MS(ESI)M/Z437[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.71(d,J＝3.6Hz,1H),8.10(d,J＝8.1Hz,1H),8.01(s,1H),7.91(t,J＝7.8Hz,1H),7.82(s,1H),7.57-7.55(m,1H),7.08(s,1H),6.20(s,1H),5.78(s,2H),4.22(s,3H),3.85(s,3H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (50 mg, 0.16 mmol), 2-bromo-1-(pyridin-2-yl)ethan-1-one (64 mg, 0.32 mmol), anhydrous potassium carbonate (44 mg, 0.32 mmol) ), N,N-dimethylformamide (2.0 ml). 10.0 mg of gray solid 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole was obtained [1,5-a]pyridin-4-yl)oxy)-1-(pyridin-2-yl)ethan-1-one (yield: 14.3%). MS (ESI) M/Z437 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.71 (d, J = 3.6Hz, 1H), 8.10 (d, J = 8.1Hz, 1H), 8.01 (s, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.57-7.55 (m, 1H), 7.08 (s, 1H), 6.20 (s, 1H), 5.78 (s, 2H), 4.22 (s, 3H) , 3.85 (s, 3H).

实施例12：合成1-(2-氟苯基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酮Example 12: Synthesis of 1-(2-fluorophenyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiene Zol-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethanone

步骤A：合成1-(2-氟苯基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酮Step A: Synthesis of 1-(2-fluorophenyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole -6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)ethanone

详见通式合成步骤A。6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(40毫克，0.13毫摩尔),2-溴-1-(2-氟苯基)乙酮(52毫克，0.24毫摩尔)，无水碳酸钾(29毫克，0.24毫摩尔),N,N-二甲基甲酰胺(6.0毫升)。得到1-(2-氟苯基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酮(14.0毫克，25.7％)为白色固体。MS(ESI)M/Z:454[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,2H),7.83(s,1H),7.66-7.61(m,1H),7.36-7.21(m,2H),7.04(s,1H),6.15(s,1H),5.36(d,J＝3.3Hz,2H),4.24(s,3H),3.83(s,3H)。 See Synthesis Step A for details. 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-Alcohol (40 mg, 0.13 mmol), 2-bromo-1-(2-fluorophenyl)ethanone (52 mg, 0.24 mmol), anhydrous potassium carbonate (29 mg, 0.24 mmol), N , N-dimethylformamide (6.0 ml). 1-(2-Fluorophenyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- Pyrazolo[1,5-a]pyridin-4-yloxy)ethanone (14.0 mg, 25.7%) was obtained as a white solid. MS (ESI) M/Z: 454 [M+H ⁺ ]. ¹ H NMR (300 MHz, CDCl ₃ , ppm): δ 8.03 (s, 2H), 7.83 (s, 1H), 7.66-7.61 (m, 1H), 7.36-7.21 (m, 2H), 7.04 (s, 1H), 6.15 (s, 1H), 5.36 (d, J = 3.3 Hz, 2H), 4.24 (s, 3H), 3.83 (s, 3H).

实施例13：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(氧杂环丁烷-3-基甲基)乙酰胺Example 13: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N-(oxetan-3-ylmethyl)acetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(氧杂环丁烷-3-基甲基)乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(oxetan-3-ylmethyl)acetamide

详见通式合成步骤B，步骤A。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.13毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(127毫克，0.20毫摩尔，50％wt)，氧杂环丁烷-3-基甲胺(23毫克，0.26毫摩尔)，三乙胺(0.125毫升)。得到2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(氧杂环丁烷-3-基甲基)乙酰胺(24.8毫克，43.0％)为白色固体。MS(ESI)M/Z:445[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.79(s,1H),7.10(s,1H),6.80(br,1H),6.26(s,1H),4.81(t,J＝6.6Hz,2H),4.62(s,2H),4.46(t,J＝6.9Hz,2H),4.25(s,3H),3.83(s,3H),3.70(s,2H),3.30(s,1H)。 See General Synthesis Step B, Step A for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (30 mg, 0.13 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc (EtOAc) Heterocyclobutane-3-ylmethylamine (23 mg, 0.26 mmol), triethylamine (0.125 mL). 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-yloxy)-N-(oxetan-3-ylmethyl)acetamide (24.8 mg, 43.0%) was obtained as a white solid. MS (ESI) M/Z: 445 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.79 (s, 1H), 7.10 (s, 1H), 6.80 (br, 1H), 6.26 (s, 1H), 4.81 (t, J = 6.6 Hz, 2H), 4.62 (s, 2H), 4.46 (t, J = 6.9 Hz, 2H), 4.25 (s, 3H), 3.83 (s, 3H), 3.70 (s, 2H) , 3.30 (s, 1H).

实施例14：合成N-(2-环丙基乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 14: Synthesis of N-(2-cyclopropylethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4] Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-(2-环丙基乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-(2-cyclopropylethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiophene Diazol-6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(70毫克，0.11毫摩尔，50％wt)，2-环丙基乙胺(54.4毫克，0.64毫摩尔)，三乙胺(0.3 毫升)。得到N-(2-环丙基乙基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(18.8毫克，38.7％)。MS(ESI)M/Z:443[M+H ⁺]。 ¹H NMR(300MHz,CD ₃OD,ppm):δ8.10(s,1H),7.85(s,1H),7.03(s,1H),6.41(d,J＝1.8Hz,1H),4.68(s,2H),4.25(s,3H),3.84(s,3H),3.39(t,J＝7.2Hz,2H),1.45(q,J＝7.2Hz,2H),0.76-0.64(m,2H),0.46-0.40(m,2H),0.08-0.03(m,2H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc (EtOAc,EtOAc) -cyclopropylethylamine (54.4 mg, 0.64 mmol), triethylamine (0.3 mL). N-(2-cyclopropylethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole- 6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide (18.8 mg, 38.7%). MS (ESI) M / Z: 443 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CD 3}} OD, ppm): δ8.10 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 6.41 (d, J = 1.8Hz, 1H), 4.68 ( s, 2H), 4.25 (s, 3H), 3.84 (s, 3H), 3.39 (t, J = 7.2 Hz, 2H), 1.45 (q, J = 7.2 Hz, 2H), 0.76-0.64 (m, 2H) ), 0.46-0.40 (m, 2H), 0.08-0.03 (m, 2H).

实施例15：合成N-(环丙基甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺Example 15: Synthesis of N-(cyclopropylmethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiophene) Diazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

步骤A：合成2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)乙酸Step A: Synthesis of 2-((2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetic acid

将2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)乙酸甲酯(300毫克，1.08毫摩尔)溶于四氢呋喃(12毫升)与水(12毫升)的混合溶液。随后，向上述溶液中加入氢氧化锂(160毫克，6.67毫摩尔)。反应液在室温下搅拌2小时。Methyl 2-((2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetate (300 mg, 1.08 mmol) was dissolved in tetrahydrofuran (12 Mixture of cc) with water (12 ml). Subsequently, lithium hydroxide (160 mg, 6.67 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.

向反应液中加入稀盐酸(1.0摩尔/升)淬灭反应并调节体系的PH值约为4。混合液用乙酸乙酯(25毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。得到2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)乙酸(260毫克)为白色固体，直接用于下步反应，无需纯化。MS(ESI)M/Z:265[M+H ⁺]。 The reaction solution was diluted with hydrochloric acid (1.0 mol/liter) to quench the reaction and the pH of the system was adjusted to about 4. The mixture was extracted with ethyl acetate (25 mL×3×). The combined organic layers were washed with brine (10 mL×3×) and then dried over anhydrous sodium sulfate. 2-((2-Acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetic acid (260 mg) was obtained as a white solid. No purification is required. MS (ESI) M/Z: 265 [M+H ⁺ ].

步骤B：合成2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺Step B: Synthesis of 2-((2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide

将2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)乙酸(260毫克，0.985毫摩尔)，环丙基甲胺(300毫克，4.23毫摩尔)溶于N,N-二甲基甲酰胺(12.0毫升)。随后，向上述溶液中依次加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(1.34克,3.53毫摩尔)和N,N-二异丙基乙基胺(350毫克，2.71毫摩尔)。反应液在室温下搅拌1小时。2-((2-Acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)acetic acid (260 mg, 0.985 mmol), cyclopropylmethylamine ( 300 mg, 4.23 mmol) was dissolved in N,N-dimethylformamide (12.0 mL). Subsequently, 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.34 g, 3.53 mmol) and N, N were sequentially added to the above solution. Diisopropylethylamine (350 mg, 2.71 mmol). The reaction solution was stirred at room temperature for 1 hour.

向反应液中加入水(160毫升)淬灭反应。混合液用乙酸乙酯(80毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(100毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/3)，得到2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(240毫克，76.9％)为白色固体。MS(ESI)M/Z:318[M+H ⁺]。 Water (160 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (80 mL×3×). The combined organic layers were washed with brine (100 mL×3×) then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut Pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide (240 mg, 76.9%) was obtained as a white solid. MS (ESI) M / Z: 318 [M+H ⁺ ].

步骤C：合成2-((2-(2-溴乙酰基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺Step C: Synthesis of 2-((2-(2-bromoacetyl)-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl) Acetamide

将2-((2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(240毫克，0.757毫摩尔)溶于二氯甲烷(10.0毫升)中。在0摄氏度下，向上述溶液中依次加入N,N-二异丙基乙基胺(390毫克，3.02毫摩尔)和三氟甲磺酸三甲基硅酯(500毫克，2.25毫摩尔)。将反应液升至室温，并搅拌30分钟。2-((2-Acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide (240 mg, 0.757 mmol) was dissolved in dichloromethane (10.0 mL). N,N-Diisopropylethylamine (390 mg, 3.02 mmol) and trimethylsilyl trifluoromethanesulfonate (500 mg, 2.25 mmol) were sequentially added to the above solution at 0 °C. The reaction solution was warmed to room temperature and stirred for 30 minutes.

向反应液中加入饱和碳酸氢钠水溶液(5毫升)淬灭反应。混合液用乙酸乙酯(10毫升×3次)萃取。合并有机相，有机相在减压下浓缩。将所得残余物溶于四氢呋喃(6.0毫升)中。在0摄氏度下，向上述溶液中加入N-溴代丁二酰亚胺(593毫克，3.33毫摩尔)的四氢呋喃溶液(4.0毫升)。在0摄氏度下搅拌1小时。The reaction mixture was quenched by aqueous saturated sodium hydrogen sulfate (5 mL). The mixture was extracted with ethyl acetate (10 mL×3×). The organic phases were combined and the organic phase was concentrated. The residue obtained was dissolved in tetrahydrofuran (6.0 mL). To the above solution was added a solution of N-bromosuccinimide (593 mg, 3.33 mmol) in tetrahydrofuran (4.0 mL). Stir at 0 ° C for 1 hour.

向反应液中加入水(10毫升)淬灭反应。混合液用乙酸乙酯(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)，得到2-((2-(2-溴乙酰基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(150毫克，50.2％)为淡黄色固体。MS(ESI)M/Z:396,398[M+H ⁺]。 Water (10 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with brine (10 mL×3×) and then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography eluting elut elut elut , 5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide (150 mg, 50.2%) was obtained as pale yellow solid. MS (ESI) M/Z: 396, 398 [M+H ⁺ ].

步骤D：合成2-((2-(2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺Step D: Synthesis of 2-((2-(2-bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxypyrazolo[1, 5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide

将2-((2-(2-溴乙酰基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(120毫克，0.303毫摩尔)和2-氨基-5-溴-1,3,4-噻二唑(311毫克，1.73毫摩尔)加入异丙醇(6.0毫升)中。反应液在微波反应器中加热至120摄氏度并搅拌30分钟。2-((2-(2-Bromoacetyl)-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)B The amide (120 mg, 0.303 mmol) and 2-amino-5-bromo-1,3,4-thiadiazole (311 mg, 1.73 mmol) were added to isopropyl alcohol (6.0 mL). The reaction solution was heated to 120 ° C in a microwave reactor and stirred for 30 minutes.

将反应液冷却到室温，并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到2-((2-(2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(60毫克，41.5％)为淡黄色固体。MS(ESI)M/Z:477,479[M+H ⁺]。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2/1) to give 2-((2-(2-bromoimidazo[2,1-b][1,3] , 4]thiadiazole-6-yl)-6-methoxypyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide (60 Mg, 41.5%) is a pale yellow solid. MS (ESI) M / Z: 477, 479 [M+H ⁺ ].

步骤E：合成N-(环丙基甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺Step E: Synthesis of N-(cyclopropylmethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiene) Zol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

将2-((2-(2-溴咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基)氧基)-N-(环丙基甲基)乙酰胺(45毫克，0.094毫摩尔)溶于二氯甲烷(1.0毫升)与甲醇(0.2毫升)的混合溶液中。随后，向上述溶液中加入叔丁醇钾(12毫克，0.104毫摩尔)。反应液在室温下搅拌1.5小时。2-((2-(2-Bromoimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-methoxypyrazolo[1,5-a Pyridin-4-yl)oxy)-N-(cyclopropylmethyl)acetamide (45 mg, 0.094 mmol) was dissolved in dichloromethane (1.0 mL) and methanol (0.2 mL). Subsequently, potassium t-butoxide (12 mg, 0.104 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 1.5 hours.

向反应液中加入水(1毫升)淬灭反应。混合液用二氯甲烷(5毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(5毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到N-(环丙基甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(10.0毫克，24.9％)为淡黄色固体产品。MS(ESI)M/Z:429[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.02(s,1H),7.80(s,1H),7.01(s,1H),6.66(br,1H),6.27(s,1H),4.61(s,2H),4.22(s,3H),3.83(s,3H),3.25(t,J＝6.3Hz,2H),1.04-0.99(m,1H)，0.55(d,J＝7.8Hz,2H)，0.26(d,J＝4.5Hz,2H)。 Water (1 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (5 mL×3×). The combined organic layers were washed with brine (5 mL×3×) and dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAcjjjjjjj -Methoxy-imidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide ( 10.0 mg, 24.9%) is a pale yellow solid product. MS (ESI) M / Z: 429 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.02 (s, 1H), 7.80 (s, 1H), 7.01 (s, 1H), 6.66 (br, 1H), 6.27 (s, 1H), 4.61 (s, 2H), 4.22 (s, 3H), 3.83 (s, 3H), 3.25 (t, J = 6.3 Hz, 2H), 1.04-0.99 (m, 1H), 0.55 (d, J = 7.8 Hz, 2H), 0.26 (d, J = 4.5 Hz, 2H).

实施例16：合成N-异丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 16: Synthesis of N-isopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-异丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-isopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(20毫克，0.05毫摩尔)，乙腈(2.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(48毫克，0.075毫摩尔，50％wt)，异丙胺(5.9毫克，0.1毫摩尔)，三乙胺(0.05毫升)。得到N-异丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(9.4毫克，45.2％)为粉红色固体。MS(ESI)M/Z:417[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.05(s,1H),7.82(s,1H),7.04(s,1H),6.34(s,1H)，6.29(s,1H),4.59(s,2H),4.25(s,4H),3.85(s,3H),1.26(d,J＝6.6Hz,6H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (20 mg, 0.05 mmol), acetonitrile (2.0 mL), ethyl acetate solution of 1-propylphosphonic anhydride (48 mg, 0.075 mmol, 50% wt), Propylamine (5.9 mg, 0.1 mmol), triethylamine (0.05 mL). Obtaining N-isopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (9.4 mg, 45.2%) was obtained as a pink solid. MS (ESI) M / Z: 417 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.05 (s, 1H), 7.82 (s, 1H), 7.04 (s, 1H), 6.34 (s, 1H), 6.29 (s, 1H), 4.59 (s, 2H), 4.25 (s, 4H), 3.85 (s, 3H), 1.26 (d, J = 6.6 Hz, 6H).

实施例17：合成N-环丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 17: Synthesis of N-cyclobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-环丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-cyclobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(55毫克，0.15毫摩尔)，乙腈(15毫升)，1-丙基磷酸酐的乙酸乙酯溶液(140毫克，0.22毫摩尔，50％wt)，环丁胺(21毫克，0.30毫摩尔)，三乙胺(0.15毫升)。得到N-环丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(15.3毫克，23.8％)为淡白色固体。MS(ESI)M/Z:429[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm)δ8.03(s,1H),7.80(s,1H),7.04(br,1H),6.63(s,1H),6.25(s,1H),4.55(m,3H),4.23(s,3H),3.83(s,3H),2.46–2.41(m,2H),2.05–1.99(m,2H),1.88–1.80(m,2H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (55 mg, 0.15 mmol), acetonitrile (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) Butylamine (21 mg, 0.30 mmol), triethylamine (0.15 mL). Obtaining N-cyclobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (15.3 mg, 23.8%) was obtained as a pale white solid. MS (ESI) M / Z: 429 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm) δ8.03 (s, 1H), 7.80 (s, 1H), 7.04 (br, 1H), 6.63 (s, 1H), 6.25 (s, 1H), 4.55 ( m, 3H), 4.23 (s, 3H), 3.83 (s, 3H), 2.46 - 2.41 (m, 2H), 2.05 - 1.99 (m, 2H), 1.88 - 1.80 (m, 2H).

实施例18：合成N-苄基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺Example 18: Synthesis of N-benzyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

步骤A：合成N-苄基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺Step A: Synthesis of N-benzyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(83毫克，0.13毫摩尔，50％wt)，乙腈(10.0毫升)，三乙胺(0.125毫升)，苄胺(28.5毫克，0.27毫摩尔)。得到N-苄基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(15.9毫克，26.3％)。MS(ESI)M/Z:465[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ7.99(s,1H),7.79(s,1H),7.33-7.28(m,5H),6.91(m,2H),6.27(s,1H),4.67(s,2H),4.59(s,2H),4.21(s,3H),3.83(s,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (83 mg, 0.13 mmol, 50% wt), acetonitrile (10.0 mL), Ethylamine (0.125 mL), benzylamine (28.5 mg, 0.27 mmol). Obtaining N-benzyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole And [1,5-a]pyridin-4-yl)oxy)acetamide (15.9 mg, 26.3%). MS (ESI) M / Z: 465 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ7.99 (s, 1H), 7.79 (s, 1H), 7.33-7.28 (m, 5H), 6.91 (m, 2H), 6.27 (s, 1H) , 4.67 (s, 2H), 4.59 (s, 2H), 4.21 (s, 3H), 3.83 (s, 3H).

实施例19：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2,2,2-三氟乙基)乙酰胺Example 19: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yloxy)-N-(2,2,2-trifluoroethyl)acetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2,2,2-三氟乙基)乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(2,2,2-trifluoroethyl)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(165毫克，0.26毫摩尔，50％wt)，乙腈(10.0毫升)，三乙胺(0.13毫升)，2,2,2-三氟乙胺(36毫克，0.36毫摩尔)。得到2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2,2,2-三氟乙基)乙酰胺(16.9毫克，28.5％)为白色固体。MS(ESI)M/Z:457[M+H ⁺]。 ¹H NMR(300MHz,DMSO-d ₆,ppm):δ8.84(t,J＝6.3Hz,1H),8.28(s,1H),8.07(s,1H),7.06(s,1H),6.41(d,J＝1.8Hz,1H),4.80(s,2H),4.21(s,3H),4.07-3.94(m,2H),3.80(s,3H)。F NMR(300MHz,DMSO-d ₆,ppm):-70.42。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (165 mg, 0.26 mmol, 50% wt), acetonitrile (10.0 mL), Ethylamine (0.13 ml), 2,2,2-trifluoroethylamine (36 mg, 0.36 mmol). 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-yloxy)-N-(2,2,2-trifluoroethyl)acetamide (16.9 mg, 28.5%) was obtained as a white solid. MS (ESI) M / Z: 467 [M+H ⁺ ]. ^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.84 (t, J = 6.3Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.06 (s, 1H), 6.41 (d, J = 1.8 Hz, 1H), 4.80 (s, 2H), 4.21 (s, 3H), 4.07-3.94 (m, 2H), 3.80 (s, 3H). F NMR (300 MHz, DMSO-d ₆ , ppm): -70.42.

实施例20：合成N-异丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 20: Synthesis of N-isobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-异丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-isobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(51毫克，0.08毫摩尔，50％wt)，乙腈(8.0毫升)，三乙胺(0.075毫升)，异丁胺(11.7毫克，0.16毫摩尔)。得到N-异丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(10.8毫克，31.4％)。MS(ESI)M/Z:431[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.02(s,1H),7.80(s,1H),7.00(s,1H),6.60(s,1H),6.26(d,J＝1.8Hz,1H),4.61(s,2H),4.22(s,3H),3.83(s,3H),3.23-3.18(m,2H),1.92-1.79(m,1H),0.94(m,J＝6.6Hz,6H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (51 mg, 0.08 mmol, 50% wt), acetonitrile (8.0 mL), Ethylamine (0.075 mL), isobutylamine (11.7 mg, 0.16 mmol). Obtaining N-isobutyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole And [1,5-a]pyridin-4-yloxy)acetamide (10.8 mg, 31.4%). MS (ESI) M / Z: 431 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.02 (s, 1H), 7.80 (s, 1H), 7.00 (s, 1H), 6.60 (s, 1H), 6.26 (d, J = 1.8Hz , 1H), 4.61 (s, 2H), 4.22 (s, 3H), 3.83 (s, 3H), 3.23-3.18 (m, 2H), 1.92-1.79 (m, 1H), 0.94 (m, J = 6.6 Hz, 6H).

实施例21：合成N-乙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 21: Synthesis of N-ethyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-乙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-ethyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(83毫克，0.13毫摩尔，50％wt)，乙胺(11.7毫克，0.26毫摩尔)和三乙胺(0.125毫升)，水(5.0毫升)。得到N-乙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(15.0毫克，28.8％)为白色固体。MS(ESI)M/Z:403[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.80(s,1H),7.06(s,1H),6.57(s,1H),6.27(s,1H),4.60(s,2H),4.23(s,3H),3.83(s,3H),3.46(t,J＝6.0Hz,2H),1.23(t,J＝7.2Hz,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc, EtOAc (EtOAc) Amine (11.7 mg, 0.26 mmol) and triethylamine (0.125 mL), water (5.0 mL). Obtaining N-ethyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (15.0 mg, 28.8%) was obtained as a white solid. MS (ESI) M / Z: 403 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.80 (s, 1H), 7.06 (s, 1H), 6.57 (s, 1H), 6.27 (s, 1H), 4.60 (s, 2H), 4.23 (s, 3H), 3.83 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).

实施例22：合成2-(2-(2-(1,1-二氟乙基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Example 22: Synthesis of 2-(2-(2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6- Methoxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide

步骤A：合成5-(1,1-二氟乙基)-1,3,4-噻二唑-2-胺Step A: Synthesis of 5-(1,1-difluoroethyl)-1,3,4-thiadiazol-2-amine

在冰水浴下，将硫代氨基脲(500毫克，5.49毫摩尔)溶于1,4-二氧六环(3.0毫升)中。随后，向上述溶液中依次加入2,2-二氟丙酸(450毫克，4.09毫摩尔)和三氯氧磷(840毫克，5.49毫摩尔)。将反应液加热至90摄氏度，并搅拌5小时。The thiosemicarbazide (500 mg, 5.49 mmol) was dissolved in 1,4-dioxane (3.0 ml) under ice-water bath. Subsequently, 2,2-difluoropropionic acid (450 mg, 4.09 mmol) and phosphorus oxychloride (840 mg, 5.49 mmol) were sequentially added to the above solution. The reaction solution was heated to 90 ° C and stirred for 5 hours.

将反应液冷却到室温，并向反应液中加入水(15毫升)淬灭反应。向反应液中加入氢氧化钠(40％wt)调节体系PH值约为9。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升×3次)洗涤，然后无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到5-(1,1-二氟乙基)-1,3,4-噻二唑-2-胺(290毫克，43.0％)为淡黄色固体。The reaction solution was cooled to room temperature, and water (15 ml) was added to the reaction mixture to quench the reaction. Sodium hydroxide (40% by weight) was added to the reaction solution to adjust the pH of the system to about 9. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (20 mL×3×) and dried over anhydrous sodium sulfate. The obtained residue was purified to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2/1) to give 5-(1,1-difluoroethyl)-1,3,4-thiadiazole- 2-Amine (290 mg, 43.0%) was obtained as a pale yellow solid.

MS(ESI)M/Z:166[M+H ⁺]。 MS (ESI) M / Z: 166 [M+H ⁺ ].

步骤B：合成2-(2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Step B: Synthesis of 2-(2-acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide

将1-(4-羟基-6-甲氧基吡唑[1,5-a]吡啶-2-基)乙酮(500毫克，2.43毫摩尔)溶于乙腈(25毫升)中。随后，向上述溶液中加入2-溴-N-甲基乙酰胺(403毫克，2.67毫摩尔)和无水碳酸钾(1.00克，7.25毫摩尔)。反应液在室温下搅拌3小时。1-(4-Hydroxy-6-methoxypyrazole[1,5-a]pyridin-2-yl)ethanone (500 mg, 2.43 mmol) was dissolved in EtOAc (25 mL). Subsequently, 2-bromo-N-methylacetamide (403 mg, 2.67 mmol) and anhydrous potassium carbonate (1.00 g, 7.25 mmol) were added to the above solution. The reaction solution was stirred at room temperature for 3 hours.

向反应液中加入水(50毫升)淬灭反应。混合液用乙酸乙酯(40毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝3/1),得到2-(2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺(241毫克，35.8％)为粉红色固体。MS(ESI)M/Z:278[M+H ⁺]。 Water (50 ml) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (40 mL×3×). The combined organic layers were washed with brine (20 mL×3×) and then dried over anhydrous sodium sulfate. The obtained residue was purified to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 3/1) to give 2-(2-acetyl-6-methoxypyrazolo[1,5-a] Pyridin-4-yloxy)-N-methylacetamide (241 mg, 35.8%) was obtained as a pink solid. MS (ESI) M / Z: 278 [M+H ⁺ ].

步骤C：合成2-(2-(2-溴乙酰基)-6-甲氧基吡唑[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Step C: Synthesis of 2-(2-(2-bromoacetyl)-6-methoxypyrazole[1,5-a]pyridin-4-yloxy)-N-methylacetamide

详见实施例15，步骤C。2-(2-乙酰基-6-甲氧基吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺(218毫克，0.787毫摩尔)，二氯甲烷(12.0毫升)，N,N-二异丙基乙基胺(406毫克，3.15毫摩尔)和三氟甲磺酸三甲基硅酯(524毫克，2.36毫摩尔)。四氢呋喃(10毫升)，N-溴代丁二酰亚胺(140毫克，0.787毫摩尔)。得到2-(2-(2-溴乙酰基)-6-甲氧基吡唑[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺(123毫克，44.0％)为粉红色固体。MS(ESI)M/Z:356，358[M+H ⁺]。 See Example 15, Step C for details. 2-(2-Acetyl-6-methoxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide (218 mg, 0.787 mmol), methylene chloride (12.0 ml), N,N-diisopropylethylamine (406 mg, 3.15 mmol) and trimethylsilyl trifluoromethanesulfonate (524 mg, 2.36 mmol). Tetrahydrofuran (10 ml), N-bromosuccinimide (140 mg, 0.787 mmol). 2-(2-(2-Bromoacetyl)-6-methoxypyrazole[1,5-a]pyridin-4-yloxy)-N-methylacetamide (123 mg, 44.0%) It is a pink solid. MS (ESI) M/Z: 356, 358 [M+H ⁺ ].

步骤D：合成2-(2-(2-(1,1-二氟乙基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺Step D: Synthesis of 2-(2-(2-(1,1-difluoroethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)-6-A Oxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide

将2-(2-(2-溴乙酰基)-6-甲氧基吡唑[1,5-a]吡啶-4-基氧基)-N-甲基乙酰胺(123毫克，0.346毫摩尔)和2-氨基-5-溴-1,3,4-噻二唑(100毫克，0.606毫摩尔)加入异丙醇(5.0毫升)中。反应液在微波反应器中加热至120摄氏度并搅拌45分钟。2-(2-(2-Bromoacetyl)-6-methoxypyrazole[1,5-a]pyridin-4-yloxy)-N-methylacetamide (123 mg, 0.346 mmol) And 2-amino-5-bromo-1,3,4-thiadiazole (100 mg, 0.606 mmol) was added to isopropanol (5.0 mL). The reaction was heated to 120 ° C in a microwave reactor and stirred for 45 minutes.

将反应液冷却至室温，并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到2-(2-(2-(1,1-二氟乙基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-6-甲氧基吡唑并[1,5-a] 吡啶-4-基氧基)-N-甲基乙酰胺(7.7毫克，5.27％)为白色固体。MS(ESI)M/Z:423[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.33(s,1H),7.87(s,1H),7.12(s,1H),6.63(br,1H),6.31(s,1H),4.61(s,2H),3.87(s,3H),2.98(d,J＝4.8Hz,3H),2.24(t,J＝18.3Hz,3H)。F NMR(300MHz,DMSO-d ₆,ppm):-81.77。 The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut -b][1,3,4]thiadiazole-6-yl)-6-methoxypyrazolo[1,5-a]pyridin-4-yloxy)-N-methylacetamide ( 7.7 mg, 5.27%) is a white solid. MS (ESI) M / Z: 422 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.33 (s, 1H), 7.87 (s, 1H), 7.12 (s, 1H), 6.63 (br, 1H), 6.31 (s, 1H), 4.61 (s, 2H), 3.87 (s, 3H), 2.98 (d, J = 4.8 Hz, 3H), 2.24 (t, J = 18.3 Hz, 3H). F NMR (300 MHz, DMSO-d ₆ , ppm): -81.77.

实施例23：合成N-(环丁基甲基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 23: Synthesis of N-(cyclobutylmethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole- 6-yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-(环丁基甲基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-(cyclobutylmethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6 -yl)pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(76毫克，0.12毫摩尔)，环丁基甲基胺(13.6毫克，0.16毫摩尔)，三乙胺(0.075毫升)。得到N-(环丁基甲基)-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(13毫克，37％)为白色固体。MS(ESI)M/Z:443[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.80(s,1H),7.03(s,1H),6.51(s,1H),6.26(d,J＝1.8Hz,1H),4.60(s,2H),4.23(s,3H),3.83(s,3H),3.43-3.38(m,2H),2.59-2.49(m,1H),2.09-2.02(m,2H),1.92-1.84(m,2H),1.76-1.67(m,2H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc (EtOAc) 13.6 mg, 0.16 mmol, triethylamine (0.075 ml). Obtaining N-(cyclobutylmethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide (13 mg, 37%) was obtained as a white solid. MS (ESI) M / Z: 443 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.80 (s, 1H), 7.03 (s, 1H), 6.51 (s, 1H), 6.26 (d, J = 1.8Hz ,1H), 4.60(s,2H), 4.23(s,3H),3.83(s,3H),3.43-3.38(m,2H),2.59-2.49(m,1H),2.09-2.02(m,2H ), 1.92-1.84 (m, 2H), 1.76-1.67 (m, 2H).

实施例24合成N-丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 24 Synthesis of N-Butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(76毫克，0.12毫摩尔，50％wt)，正丁胺(12毫克，0.16毫摩尔)，三乙胺(0.075毫升)。得到N-丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(10.7毫克，31.1％)为白色固体。MS(ESI)M/Z:431[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.80(s,1H),7.05(s,1H),6.56(s,1H),6.27(s,1H),4.60(s,2H),4.23(s,3H),3.83(s,3H),3.52-3.37(m,2H),1.66-1.54(m,2H),1.46-1.36(m,2H),0.94(t,J＝7.2Hz,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc, EtOAc (EtOAc) Butylamine (12 mg, 0.16 mmol), triethylamine (0.075 mL). Obtaining N-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (10.7 mg, 31.1%) was obtained as a white solid. MS (ESI) M / Z: 431 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.80 (s, 1H), 7.05 (s, 1H), 6.56 (s, 1H), 6.27 (s, 1H), 4.60 (s, 2H), 4.23 (s, 3H), 3.83 (s, 3H), 3.52-3.37 (m, 2H), 1.66-1.54 (m, 2H), 1.46-1.36 (m, 2H), 0.94 (t , J = 7.2 Hz, 3H).

实施例25合成N-叔丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 25 Synthesis of N-tert-Butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-叔丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-tert-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(51毫克，0.08毫摩尔，50％wt)，乙腈(8毫升)，三乙胺(109毫克，1.08毫摩尔)，叔丁胺(23.4毫克，0.32毫摩尔)。得到N-叔丁基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(10.2毫克，29.7％)为白色固体。MS(ESI)M/Z:431[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.04(s,1H),7.80(s,1H),7.04(s,1H),6.34(s,1H),6.27(s,1H),4.48(s,2H),4.24(s,3H),3.83(s,3H),1.43(s,9H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (51 mg, 0.08 mmol, 50% wt), acetonitrile (8 mL), Ethylamine (109 mg, 1.08 mmol), tert-butylamine (23.4 mg, 0.32 mmol). Obtaining N-tert-butyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (10.2 mg, 29.7%) was obtained as a white solid. MS (ESI) M / Z: 431 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.04 (s, 1H), 7.80 (s, 1H), 7.04 (s, 1H), 6.34 (s, 1H), 6.27 (s, 1H), 4.48 (s, 2H), 4.24 (s, 3H), 3.83 (s, 3H), 1.43 (s, 9H).

实施例26合成N-环丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 26 Synthesis of N-cyclopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-环丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-cyclopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，乙腈(5.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(76毫克，0.12毫摩尔，50％wt)，环丙胺(9毫克，0.16毫摩尔)，三乙胺(0.075毫升)。得到N-环丙基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(15.4毫克，46.5％)为白色固体。MS(ESI)M/Z:415[M+H ⁺]。 ¹H NMR(300MHz, CDCl ₃,ppm):δ8.03(s,1H),7.79(s,1H),7.04(s,1H),6.63(s,1H),6.25(s,1H),4.57(s,2H),4.24(s,3H),3.83(s,3H),2.80(s,1H),0.87(d,J＝6.9Hz,2H),0.64(s,2H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), acetonitrile (5.0 mL), EtOAc (EtOAc (EtOAc) Propylamine (9 mg, 0.16 mmol), triethylamine (0.075 mL). Obtaining N-cyclopropyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (15.4 mg, 46.5%) was obtained as a white solid. MS (ESI) M / Z: 415 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.79 (s, 1H), 7.04 (s, 1H), 6.63 (s, 1H), 6.25 (s, 1H), 4.57 (s, 2H), 4.24 (s, 3H), 3.83 (s, 3H), 2.80 (s, 1H), 0.87 (d, J = 6.9 Hz, 2H), 0.64 (s, 2H).

实施例27合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-戊基乙酰胺Example 27 Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-pentylacetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-戊基乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-pentylacetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，乙腈(3.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(102毫克，0.16毫摩尔，50％wt)，正戊胺(28毫克，0.32毫摩尔)，三乙胺(0.15毫升)。得到2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-戊基乙酰胺(13.8毫克，38.8％)。MS(ESI)M/Z：445[M+H ⁺]。 ¹H NMR(300MHz,CD ₃OD,ppm)δ8.10(s,1H),7.85(s,1H),7.03(s,1H),6.40(s,1H),4.68(s,2H),4.24(s,3H),3.84(s,3H),3.30–3.25(m,2H),1.60–1.50(m,2H),1.36–1.28(m,4H),0.89(t,J＝6.3Hz 3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), acetonitrile (3.0 mL), EtOAc (EtOAc, EtOAc (EtOAc) Pentylamine (28 mg, 0.32 mmol), triethylamine (0.15 mL). 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-yloxy)-N-pentylacetamide (13.8 mg, 38.8%). MS (ESI) M/Z: 445 [M+H ⁺ ]. ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.10 (s, 1H), 7.85 (s, 1H), 7.03 (s, 1H), 6.40 (s, 1H), 4.68 (s, 2H), 4.24 (s, 3H), 3.84 (s, 3H), 3.30–3.25 (m, 2H), 1.60–1.50 (m, 2H), 1.36–1.28 (m, 4H), 0.89 (t, J = 6.3 Hz 3H) .

实施例28合成N-环己基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Example 28 Synthesis of N-cyclohexyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

步骤A：合成N-环己基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺Step A: Synthesis of N-cyclohexyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Pyrazolo[1,5-a]pyridin-4-yloxy)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(35毫克，0.09毫摩尔)，二氯甲烷(10.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(369毫克，0.58毫摩尔)，环己胺(45毫克，0.45毫摩尔)，三乙胺(0.87毫升)。得到N-环己基-2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酰胺(10.2毫克，24.8％)为淡黄色固体。MS(ESI)M/Z:457[M+H ⁺]。 ¹H NMR(300MHz,DMSO-d ₆,ppm):δ8.29(s,1H),8.05(s,1H),8.01(d,J＝7.8Hz,1H),6.95(s,1H),6.37(s,1H),4.64(s,2H),4.20(s,3H),3.79(s,3H),3.64(s,1H),1.77–1.67(m,4H),1.57(d,J＝12.3Hz,1H),1.36-1.20(m,5H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridyl-4-yloxy)acetic acid (35 mg, 0.09 mmol), dichloromethane (10.0 mL), EtOAc (EtOAc) (45 mg, 0.45 mmol), triethylamine (0.87 mL). Obtaining N-cyclohexyl-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yloxy)acetamide (10.2 mg, 24.8%) was obtained as a pale yellow solid. MS (ESI) M / Z: 467 [M+H ⁺ ]. ^{1 H NMR (300MHz, DMSO-} d 6, ppm): δ8.29 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 7.8Hz, 1H), 6.95 (s, 1H), 6.37 (s, 1H), 4.64 (s, 2H), 4.20 (s, 3H), 3.79 (s, 3H), 3.64 (s, 1H), 1.77 - 1.67 (m, 4H), 1.57 (d, J = 12.3) Hz, 1H), 1.36-1.20 (m, 5H).

实施例29合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-((四氢-2H-吡喃-4-基)甲基)乙酰胺Example 29 Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

步骤A：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-((四氢-2H-吡喃-4-基)甲基)乙酰胺Step A: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(140毫克，0.22毫摩尔，50％wt)，(四氢-2H-吡喃-4-基)甲胺(48毫克，0.42毫摩尔)，三乙胺(0.2毫升)，乙腈(5毫升)。得到2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-((四氢-2H-吡喃-4-基)甲基)乙酰胺(22.7毫克，43.7％)为白色固体。MS(ESI)M/Z:473[M+H ⁺]。 ¹H NMR(300MHz,CD ₃OD,ppm):δ8.11(s,1H),7.86(s,1H),7.03(s,1H),6.41(s,1H),4.71(s,2H),4.25(s,3H),3.92(d,J＝10.5Hz,2H),3.84(s,3H),3.40–3.39(m,2H),3.19(d,J＝6.9Hz,2H),1.80(br,1H),1.63(d,J＝12.9Hz,2H),1.33–1.21(m,2H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (140 mg, 0.22 mmol, 50% wt), (tetrahydro-2H-pyridin Methylamine (48 mg, 0.42 mmol), triethylamine (0.2 mL), EtOAc (5 mL). 2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yl)oxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (22.7 mg, 43.7%) was obtained as a white solid. MS (ESI) M / Z: 473[M+H ⁺ ]. ¹ H NMR (300 MHz, CD ₃ OD, ppm): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.03 (s, 1H), 6.41 (s, 1H), 4.71 (s, 2H), 4.25 (s, 3H), 3.92 (d, J = 10.5 Hz, 2H), 3.84 (s, 3H), 3.40 - 3.39 (m, 2H), 3.19 (d, J = 6.9 Hz, 2H), 1.80 (br , 1H), 1.63 (d, J = 12.9 Hz, 2H), 1.33 - 1.21 (m, 2H).

实施例30合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(氧杂环丁烷-3-基)乙酰胺Example 30 Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-(oxetan-3-yl)acetamide

步骤A：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(氧杂环丁烷-3-基)乙酰胺Step A: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-(oxetan-3-yl)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并 [1,5-a]吡啶-4-基氧基)乙酸(45毫克，0.12毫摩尔)，乙腈(9.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(153毫克，0.24毫摩尔，50％wt)，氧杂环丁烷-3-胺(44毫克，0.600毫摩尔)，三乙胺(0.113毫升)。得到2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(氧杂环丁烷-3-基)乙酰胺(17.7毫克，34.3％)。MS(ESI)M/Z:431[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.03(s,1H),7.81(s,1H),7.11–7.03(m,2H),6.26(s,1H),5.18–5.14(m,1H),4.96(t,J＝7.2Hz,2H),4.65–4.61(m,4H),4.23(s,3H),3.83(s,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (45 mg, 0.12 mmol), acetonitrile (9.0 mL), EtOAc (EtOAc (EtOAc) Heterocyclobutane-3-amine (44 mg, 0.600 mmol), triethylamine (0.113 mL). 2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yl)oxy)-N-(oxetan-3-yl)acetamide (17.7 mg, 34.3%). MS (ESI) M / Z: 431 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.03 (s, 1H), 7.81 (s, 1H), 7.11-7.03 (m, 2H), 6.26 (s, 1H), 5.18-5.14 (m, 1H), 4.96 (t, J = 7.2 Hz, 2H), 4.65 - 4.61 (m, 4H), 4.23 (s, 3H), 3.83 (s, 3H).

实施例31合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-苯基乙酰胺Example 31 Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-phenylacetamide

步骤A：合成2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-苯基乙酰胺Step A: Synthesis of 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)-N-phenylacetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)，1-丙基磷酸酐的乙酸乙酯溶液(102毫克，0.16毫摩尔，50％wt)，苯胺(15毫克，0.16毫摩尔)，三乙胺(0.075毫升)。得到2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-苯基乙酰胺(15.9毫克，44.2％)为白色固体。MS(ESI)M/Z:451[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.33(s,1H),8.10(s,1H),7.82(s,1H),7.75(d,J＝7.8Hz,2H),7.57(s,1H),7.38(t,J＝7.8Hz,2H),7.16(t,J＝7.8Hz,1H),6.37(s,1H),4.75(s,2H),4.32(s,3H),3.85(s,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a Pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol), ethyl acetate solution of 1-propylphosphonic anhydride (102 mg, 0.16 mmol, 50% wt), aniline (15 mg, 0.16 m Mole), triethylamine (0.075 ml). 2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5 -a]pyridin-4-yl)oxy)-N-phenylacetamide (15.9 mg, 44.2%) was obtained as a white solid. MS (ESI) M / Z: 451 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.33 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.75 (d, J = 7.8Hz, 2H), 7.57 (s , 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.37 (s, 1H), 4.75 (s, 2H), 4.32 (s, 3H), 3.85 (s, 3H).

实施例32合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2-甲基噻唑-5-基)乙酰胺Example 32 Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1 ,5-a]pyridin-4-yloxy)-N-(2-methylthiazol-5-yl)acetamide

步骤A：合成2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2-甲基噻唑-5-基)乙酰胺Step A: Synthesis of 2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] ,5-a]pyridin-4-yloxy)-N-(2-methylthiazol-5-yl)acetamide

详见通式合成步骤B。2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)，乙腈(10.0毫升)，1-丙基磷酸酐的乙酸乙酯溶液(165毫克，0.26毫摩尔，50％wt)，2-甲基噻唑-5-胺(30毫克，0.263毫摩尔)。得到2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)-N-(2-甲基噻唑-5-基)乙酰胺(22.0毫克，35.3％)为白色固体。MS(ESI)M/Z:472[M+H ⁺]。 ¹H NMR(300MHz,CDCl ₃,ppm):δ8.74(s,1H),8.02(s,1H),7.81(s,1H),7.52(s,1H),7.01(s,1H),6.30(s,1H),4.80(s,2H),4.21(s,3H),3.83(s,3H)，2.66(s,3H)。 See Synthesis Procedure Step B for details. 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a ] Pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol), acetonitrile (10.0 mL), EtOAc (EtOAc, EtOAc (EtOAc) Methylthiazole-5-amine (30 mg, 0.263 mmol). 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-yloxy)-N-(2-methylthiazol-5-yl)acetamide (22.0 mg, 35.3%) was obtained as a white solid. MS (ESI) M / Z: 472 [M+H ⁺ ]. ^{_{1 H NMR (300MHz, CDCl 3}} , ppm): δ8.74 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.01 (s, 1H), 6.30 (s, 1H), 4.80 (s, 2H), 4.21 (s, 3H), 3.83 (s, 3H), 2.66 (s, 3H).

实施例33：SAL02-187Example 33: SAL02-187

2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡咯烷-1-基)乙-1-酮2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-1-(pyrrolidin-1-yl)ethan-1-one

反应流程：Reaction process:

实施例33流程：Example 33 process:

步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(50毫克，0.16毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入2-溴-1-(吡咯烷-1-基)乙-1-酮(60毫克，0.32毫摩尔)和无水碳酸钾(43毫克，0.32毫摩尔)。反应液在室温下搅拌2小时。Step A: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, 2-bromo-1-(pyrrolidin-1-yl)ethan-1-one (60 mg, 0.32 mmol) and anhydrous potassium carbonate (43 mg, 0.32 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应体系加入水(20毫升)淬灭。混合液用乙酸乙酯萃取(20毫升×3次)，合并有机相，有机相用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。粗产品经硅胶制备板纯化(展开剂：二氯甲烷/甲醇＝30/1)，收集产品，得到白色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(吡咯烷-1-基)乙-1-酮(17.6毫克，收率26.1％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the reaction system to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The crude product was purified by silica gel chromatography (yield: methylene chloride/methanol = 30/1), and product was obtained to afford 2-((6-methoxy-2-(2-methoxy-imidazo[ , 1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(pyrrolidin-1-yl) Ethyl-1-one (17.6 mg, yield 26.1%).

MS(ESI)M/Z:429[M+H ⁺]。 MS (ESI) M / Z: 429 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.31(s,1H),8.04(s,1H),6.78(s,1H),6.43(s,1H),4.94(s,2H),4.21(s,3H),3.80(s,3H),3.50(t,J＝6.7Hz,2H)3.42-3.35(m,2H),1.97-1.86(m,2H),1.85-1.75(m,2H)。 ^{1 H NMR (300MHz, DMSO-} d 6): δ8.31 (s, 1H), 8.04 (s, 1H), 6.78 (s, 1H), 6.43 (s, 1H), 4.94 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 3.50 (t, J = 6.7 Hz, 2H) 3.42-3.35 (m, 2H), 1.97-1.86 (m, 2H), 1.85-1.75 (m, 2H) .

实施例34：SAL02-211Example 34: SAL02-211

N-(叔丁基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(tert-butyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例34流程：Example 34 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(8.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(75微升，0.08毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向反应液中依次加入三乙胺(109毫克，1.08毫摩尔)和叔丁胺(23毫克，0.32毫摩尔)。反应液在室温下搅拌2小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (75 μL, 0.08 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, triethylamine (109 mg, 1.08 mmol) and tert-butylamine (23 mg, 0.32 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加入水(5毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，最后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/25)，得到白色固体N-(叔丁基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(10.2毫克，收率29.6％)。After LCMS monitoring showed the disappearance of the starting material, water (5 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with brine (10 mL×3×) and then dried over anhydrous sodium sulfate. The residue was purified with EtOAc EtOAc EtOAcjjjjjjjj Methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (10.2 Mg, yield 29.6%).

MS(ESI)M/Z:431[M+H ⁺]。 MS (ESI) M / Z: 431 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.06(s,1H),7.83(s,1H),7.07(s,1H),6.34(s,1H),6.30(s,1H),4.50(s,2H),4.26(s,3H),3.85(s,3H),1.48-1.40(m,9H) ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.06 (s, 1H), 7.83 (s, 1H), 7.07 (s, 1H), 6.34 (s, 1H), 6.30 (s, 1H), 4.50 (s , 2H), 4.26 (s, 3H), 3.85 (s, 3H), 1.48-1.40 (m, 9H)

实施例35：SAL02-238Example 35: SAL02-238

N-乙基-N-羟基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-ethyl-N-hydroxy-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例35流程：Example 35 process:

步骤A：将2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酸(50毫克，0.13毫摩尔)溶于乙腈(10.0毫升)中。随后，向上述溶液中依次加入1-丙基磷酸酐的乙酸乙酯溶液(0.38毫升，0.64毫摩尔，50％wt)，N-乙基羟胺盐酸盐(78毫克，0.79毫摩尔)和三乙胺(0.38毫升)。Step A: 2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ 1,5-a]pyridin-4-yl)oxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.38 ml, 0.64 mmol, 50% by weight), N-ethylhydroxylamine hydrochloride (78 mg, 0.79 mmol) and three were sequentially added to the above solution. Ethylamine (0.38 ml).

LCMS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用二氯甲烷(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/15)，得到类白色固体N-乙基-N-羟基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(15.9毫克，收率28.9％)After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (30 mL×3×). The combined organic layers were washed with brine (30 ml) The residue was purified with EtOAc EtOAcjjjjjjjjjj 2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (15.9 mg, yield 28.9%)

MS(ESI)M/Z:419[M+H ⁺] MS (ESI) M/Z: 419 [M+H ⁺ ]

¹H NMR(300MHz,DMSO-d ₆):δ9.94(s,1H),8.31(s,1H),8.05(s,1H),6.79(s,1H),6.25(s,1H),5.05(s,2H),4.21(s,3H),3.80(s,3H),3.56(q,J＝6.9Hz,2H),1.13(t,J＝6.9Hz,3H). ^{1 H NMR (300MHz, DMSO-} d 6): δ9.94 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 6.79 (s, 1H), 6.25 (s, 1H), 5.05 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 3.56 (q, J = 6.9 Hz, 2H), 1.13 (t, J = 6.9 Hz, 3H).

实施例36：SAL02-227Example 36: SAL02-227

2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(吡啶-3-基甲基)乙酰胺2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-N-(pyridin-3-ylmethyl)acetamide

反应流程：Reaction process:

实施例36流程：Example 36 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(5.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.2毫升，0.33毫摩尔，50％wt))。反应液在室温下搅拌15分钟后，在向其中加入3-氨甲基吡啶(46毫克，0.43毫摩尔)和三乙胺(0.2毫升，1.45毫摩尔)的乙腈溶液(5.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 3-aminomethylpyridine (46 mg, 0.43 mmol) and triethylamine (0.2 ml, 1.45 mmol) in acetonitrile (5.0 ml) was added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后。向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板纯化(展开剂：甲醇/二氯甲烷＝1/30)，得到白色固体2-((6- 甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(吡啶-3-基甲基)乙酰胺(26.1毫克，收率52.6％)。LCMS monitoring showed disappearance of the starting material. Water (20 ml) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 mL) and filtered. The residue was purified by silica gel chromatography eluting eluting elut elut elut elut b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(pyridin-3-ylmethyl)acetamide (26.1 mg, yield 52.6%).

MS(ESI)M/Z:466[M+H ⁺]。 MS (ESI) M / Z: 466 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.82(t,J＝4.8Hz,1H),8.53(s,1H),8.47(s,J＝3.3Hz,1H),8.28(s,1H),8.07(s,1H),7.70(d,J＝7.8Hz,1H),7.42-7.29(m,1H),7.11(s,1H),6.44(s,1H),4.76(s,2H),4.43(d,J＝6.1Hz,2H),4.21(s,3H),3.81(s,3H)。 ^{1 H NMR (300MHz, DMSO-} d 6): δ8.82 (t, J = 4.8Hz, 1H), 8.53 (s, 1H), 8.47 (s, J = 3.3Hz, 1H), 8.28 (s, 1H ), 8.07 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.42 - 7.29 (m, 1H), 7.11 (s, 1H), 6.44 (s, 1H), 4.76 (s, 2H) , 4.43 (d, J = 6.1 Hz, 2H), 4.21 (s, 3H), 3.81 (s, 3H).

实施例37：SAL02-229Example 37: SAL02-229

N-(2,2-二氟乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(2,2-difluoroethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole -6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例37流程：Example 37 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(5.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸酐的乙酸乙酯溶液(0.2毫升，0.29毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入2,2-二氟乙胺(34毫克，0.43毫摩尔)和三乙胺(0.2毫升，1.44毫摩尔)的乙腈溶液(5.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.2 ml, 0.29 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 2,2-difluoroethylamine (34 mg, 0.43 mmol) and triethylamine (0.2 ml, 1.44 mmol) in acetonitrile (5.0 ml) was added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板(展开剂：甲醇/二氯甲烷＝1/30)，得到白色固体N-(2,2-二氟乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(24.4毫克，收率52.2％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut 2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (24.4 mg, yield 52.2%).

MS(ESI)M/Z:439[M+H ⁺]。 MS (ESI) M / Z: 437 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.55(t,J＝5.7Hz,1H),8.29(s,1H),8.07(s,1H),7.09(s,1H),6.44(s,1H),6.29-5.89(m,1H),4.76(s,2H),4.21(s,3H),3.81(s,3H),3.69-3.54(m,2H) ^{1 H NMR (300MHz, DMSO-} d 6): δ8.55 (t, J = 5.7Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.09 (s, 1H), 6.44 (s , 1H), 6.29-5.89 (m, 1H), 4.76 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H), 3.69-3.54 (m, 2H)

¹⁹F NMR(282MHz,DMSO-d ₆)δ-121.84 ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ-121.84

实施例38：SAL02-231Example 38: SAL02-231

4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-甲基丁酰胺4-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] pyridin-4-yl)oxy)-N-methylbutanamide

反应流程：Reaction process:

实施例38流程：Example 38 process:

步骤A：将4-溴丁酸乙酯(194毫克，1.00毫摩尔)溶于丙酮(1.0毫升)中。随后，向上述溶液中加入碘化钠(180毫克，1.20毫摩尔)。将反应液加热至60摄氏度并搅拌1小时。Step A: Ethyl 4-bromobutyrate (194 mg, 1.00 mmol) was dissolved in acetone (1.0 mL). Subsequently, sodium iodide (180 mg, 1.20 mmol) was added to the above solution. The reaction solution was heated to 60 ° C and stirred for 1 hour.

TLC监测显示原料消失后，将反应液冷却至室温。过滤，固体用乙酸乙酯(5毫升)洗涤，所得滤液在减压下浓缩，得到白色固体4-碘丁酸乙酯(220毫克，粗品)。无需纯化，直接用于下一步反应。After TLC monitoring showed disappearance of the starting material, the reaction solution was cooled to room temperature. Filtration and EtOAc (3 mL) It was used directly in the next reaction without purification.

MS(ESI)M/Z:243[M+H ⁺]。 MS (ESI) M / Z: 243 [M+H ⁺ ].

步骤B：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(90毫克，0.28毫摩尔)，4-碘丁酸乙酯(137毫克，0.57毫摩尔)和碳酸钾(117毫克，0.85毫摩尔)加入N,N-二甲基甲酰胺(3.0毫升)中。反应液在室温下搅拌8小时。Step B: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (90 mg, 0.28 mmol), ethyl 4-iodobutanoate (137 mg, 0.57 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added to N,N-dimethyl Formamide (3.0 ml). The reaction solution was stirred at room temperature for 8 hours.

LC-MS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用二氯甲烷(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(20毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用反相制备：制备条件如下：Agela Technologies Flash Column,C18反相柱，40g，20-35um；流动相：水(含有0.05％的碳酸氢铵)和乙腈；流速：60毫升/分钟；梯度：在15分钟内，乙腈从40％升到60％；检测波长：254nm。收集馏分，减压浓缩后低温冻干，得到褐色固体产品4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)丁酸乙酯(60毫克，收率49.6％)。After LC-MS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (30 mL×3×). The combined organic layers were washed with brine (20 ml) The residue was prepared by reverse phase: the preparation conditions were as follows: Agela Technologies Flash Column, C18 reverse phase column, 40 g, 20-35 um; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 60 ml/min; Gradient: Acetonitrile was raised from 40% to 60% in 15 minutes; detection wavelength: 254 nm. The fractions were collected, concentrated under reduced pressure and lyophilized to give 4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4] thiophene) as a brown solid. Ethyl oxazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)butanoate (60 mg, yield 49.6%).

MS(ESI)M/Z:433[M+H ⁺]。 MS (ESI) M / Z: 433 [M+H ⁺ ].

步骤C：将4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4- 基)氧基)丁酸乙酯(60毫克，0.14毫摩尔)溶于四氢呋喃(1.5毫升)中。随后，向上述溶液中加入氢氧化锂(17毫克，0.70毫摩尔)的水溶液(1.5毫升)。反应液在室温下搅拌5小时。Step C: 4-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[ Ethyl 1,5-a]pyridin-4-yloxy)butanoate (60 mg, 0.14 mmol) was dissolved in tetrahydrofurane (1.5 mL). Subsequently, an aqueous solution (1.5 ml) of lithium hydroxide (17 mg, 0.70 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 5 hours.

TLC监测显示原料消失后，向反应液中加入稀盐酸(1.0摩尔/升)调节体系的PH值至3。混合液用乙酸乙酯(15毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩，得到白色固体4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)丁酸(45毫克，粗品)。无需纯化，直接用于下一步反应。After TLC monitoring showed disappearance of the starting material, dilute hydrochloric acid (1.0 mol/L) was added to the reaction solution to adjust the pH of the system to 3. The mixture was extracted with ethyl acetate (15 mL×3×). The combined organic layers were washed with EtOAc EtOAc EtOAc. (2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy) Acid (45 mg, crude). It was used directly in the next reaction without purification.

MS(ESI)M/Z:404[M+H ⁺]。 MS (ESI) M/Z: 404 [M+H ⁺ ].

步骤D：将4-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)丁酸(45毫克，0.11毫摩尔)溶于乙腈(9.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(138毫克，0.22毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，向反应液中加入甲胺盐酸盐(15毫克，0.22毫摩尔)和三乙胺(68毫克，0.67毫摩尔)的乙腈溶液(1.0毫升)。反应液在室温下搅拌1小时。Step D: 4-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)butanoic acid (45 mg, 0.11 mmol) was dissolved in acetonitrile (9.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of methylamine hydrochloride (15 mg, 0.22 mmol) and triethylamine (68 mg, 0.67 mmol) in acetonitrile (1.0 ml) was added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，将反应液在减压下浓缩。残余物经高压制备液相纯化，纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％甲酸)和乙腈；流速:20毫升/分钟；梯度：在7分钟内，乙腈从30％升到50％；检测波长：254nm。收集产品，低温减压冻干，得到白色固体4-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-甲基丁酰胺(6.9毫克，收率14.8％)。After LCMS monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified by high pressure preparative liquid phase. The purification conditions were as follows. Column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% formic acid) and acetonitrile; flow rate: 20 ml/min; gradient: within 7 minutes, Acetonitrile was increased from 30% to 50%; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 4-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-) as a white solid. 6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-N-methylbutanamide (6.9 mg, yield 14.8%).

MS(ESI)M/Z:417[M+H ⁺]。 MS (ESI) M / Z: 417 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.00(s,1H),7.76(s,1H),6.92(s,1H),6.23(s,1H),5.58(s,1H),4.22(s,3H),4.15(t,J＝5.7Hz,2H),3.83(s,3H),2.84(d,J＝4.8Hz,3H),2.45(t,J＝7.1Hz,2H),2.30-2.19(m,2H)。 ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.00 (s, 1H), 7.76 (s, 1H), 6.92 (s, 1H), 6.23 (s, 1H), 5.58 (s, 1H), 4.22 (s , 3H), 4.15 (t, J = 5.7 Hz, 2H), 3.83 (s, 3H), 2.84 (d, J = 4.8 Hz, 3H), 2.45 (t, J = 7.1 Hz, 2H), 2.30-2.19 (m, 2H).

实施例39：SAL02-239Example 39: SAL02-239

N-乙基-N-甲氧基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,5-a]吡啶-4-基)氧基)乙酰胺N-ethyl-N-methoxy-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6 -yl)pyrrolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例39流程：Example 39 Process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)溶于乙腈(10.0毫升)中。随后，向上述溶液依次加入1-丙基磷酸酐的乙酸乙酯溶液(0.13毫升，0.22毫摩尔，50％wt)，N-乙基-O-甲基羟胺盐酸盐(30毫克，0.27毫摩尔)和三乙胺(0.13毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.13 ml, 0.22 mmol, 50% by weight), N-ethyl-O-methylhydroxylamine hydrochloride (30 mg, 0.27 m) was sequentially added to the above solution. Mole) and triethylamine (0.13 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失，向反应液中加入水(30毫升)淬灭，混合液用二氯甲烷(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(30毫升)洗涤，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板纯化(展开剂：甲醇/二氯甲烷＝1/15)，得到白色固体N-乙基-N-甲氧基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,5-a]吡啶-4-基)氧基)乙酰胺(28.1毫克，收率48.8％)The disappearance of the material was observed by LCMS, and water (30 ml) was then evaporated to the mixture, and the mixture was extracted with dichloromethane (30 ml × 3 times). The combined organic layers were washed with brine (30 mL) and filtered and evaporated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc -Methoxy-imidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrrolo[1,5-a]pyridin-4-yl)oxy)acetamide (28.1 Mg, yield 48.8%)

MS(ESI)M/Z：433[M+H ⁺] MS (ESI) M/Z: 433 [M+H ⁺ ]

¹H NMR(300MHz,CDCl ₃)δ8.02(s,1H),7.83(s,1H),7.04(s,1H),6.24(s,1H),4.94(s,2H),4.24(s,3H),3.84(s,3H),3.80(s,3H),3.74(q,J＝7.1Hz,2H),1.26(t,J＝7.2Hz,3H). ^{_{1 H NMR (300MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.83 (s, 1H), 7.04 (s, 1H), 6.24 (s, 1H), 4.94 (s, 2H), 4.24 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.74 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

实施例40：SAL02-228Example 40: SAL02-228

2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(吡啶-4-基甲基)乙酰胺2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-N-(pyridin-4-ylmethyl)acetamide

反应流程：Reaction process:

实施例40流程：Example 40 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(5.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.2毫升，0.33毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入4-氨甲基吡啶(46毫克，0.43毫摩尔)和三乙胺(0.2毫升，1.44毫摩尔)的乙腈(5.0毫升)溶液。反应液在在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (0.2 ml, 0.33 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 4-aminomethylpyridine (46 mg, 0.43 mmol) and triethylamine (0.2 ml, 1.44 mmol) in acetonitrile (5.0 ml) was added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板纯化(展开剂：二氯甲烷/甲醇＝1/30)，收集产品。粗产品进一步经高效液相色谱纯化。纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有0.1％三氟乙酸)和乙腈；流速:25毫升/分钟；梯度：在8分钟内，乙腈从30％升到75％；检测波长：220nm。收集产品，减压冻干得白色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(吡啶-4-基甲基)乙酰胺(3.1毫克，收率6.3％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by silica gel chromatography (yield: methylene chloride / methanol = 1 / 30). The crude product was further purified by high performance liquid chromatography. Purification conditions were as follows, column: X select C18 19 mm * 150 mm; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml / min; gradient: acetonitrile from 30% to 75 in 8 minutes %; detection wavelength: 220 nm. The product was collected and lyophilized to give 2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-) as a white solid. Pyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(pyridin-4-ylmethyl)acetamide (3.1 mg, yield 6.3%).

MS(ESI)M/Z:466[M+H ⁺]。 MS (ESI) M / Z: 466 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.86(s,1H),8.50(d,J＝5.1Hz,2H),8.28(s,1H),8.07(s,1H),7.29(d,J＝5.1Hz,2H),7.13(s,1H),6.47(s,1H),4.80(s,2H),4.42(d,J＝6.0Hz,2H),4.20(s,3H),3.82(s,3H)。 ^{1 H NMR (300MHz, DMSO-} d 6): δ8.86 (s, 1H), 8.50 (d, J = 5.1Hz, 2H), 8.28 (s, 1H), 8.07 (s, 1H), 7.29 (d , J=5.1 Hz, 2H), 7.13 (s, 1H), 6.47 (s, 1H), 4.80 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 4.20 (s, 3H), 3.82 (s, 3H).

实施例41：SAL02-233Example 41: SAL02-233

N-(4-羟基苄基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,5-a]并-4-基)氧基)乙酰胺N-(4-hydroxybenzyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-) Pyrrolo[1,5-a]ind-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例41流程：Example 41 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)和4-(氨基甲基)苯酚(20毫克，0.16毫摩尔)溶于二氯甲烷(2.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(122毫克，0.19毫摩尔，50％wt)和三乙胺(32毫克，0.32毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) and 4-(aminomethyl)phenol (20 mg, 0.16 mmol) were dissolved in dichloromethane (2.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (122 mg, 0.19 mmol, 50% by weight) and triethylamine (32 mg, 0.32 mmol) were added to the above solution. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠水溶液(5毫升)淬灭。混合液用二氯甲烷(5毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/15)，得到粉色固体N-(4-羟基苄基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡咯并[1,5-a]并-4-基)氧基)乙酰胺(6.5毫克，收率12.7％)。After LCMS monitoring showed the disappearance of the material, aq. The mixture was extracted with methylene chloride (5 mL, EtOAc). The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut (2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrrolo[1,5-a]ind-4-yloxy)acetamide (6.5 mg, yield 12.7%).

MS(ESI)M/Z：481[M+H ⁺]。 MS (ESI) M / Z: 481 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆)δ9.28(br,1H),8.66(t,J＝6.1Hz,1H),8.28(s,1H),8.06(s,1H),7.11(s,1H),7.08(d,J＝8.4H,2H),6.71(d,J＝8.4H,2H),6.43(s,1H),4.72(s,2H),4.27(d,J＝6.0Hz,2H),4.21(s,3H),3.81(s,3H). ^{1 H NMR (300MHz, DMSO-} d 6) δ9.28 (br, 1H), 8.66 (t, J = 6.1Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.11 (s, 1H), 7.08 (d, J = 8.4H, 2H), 6.71 (d, J = 8.4H, 2H), 6.43 (s, 1H), 4.72 (s, 2H), 4.27 (d, J = 6.0 Hz, 2H), 4.21 (s, 3H), 3.81 (s, 3H).

实施例42：SAL02-194Example 42: SAL02-194

2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(噻唑-5-基)乙-1-酮2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-1-(thiazol-5-yl)ethan-1-one

反应流程：Reaction process:

实施例42流程：Example 42 process:

步骤A：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(50毫克，0.16毫摩尔)溶于N,N-二甲基甲酰胺(10.0毫升)中。随后，向上述溶液中依次加入2-溴-1-噻唑-5-基-乙酮氢溴酸盐(90毫克，0.32毫摩尔)和无水碳酸钾(65毫克，0.47毫摩尔)。反应液在室温下搅拌2小时。Step A: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] Pyridin-4-ol (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Subsequently, 2-bromo-1-thiazol-5-yl-ethanone hydrobromide (90 mg, 0.32 mmol) and anhydrous potassium carbonate (65 mg, 0.47 mmol) were sequentially added to the above solution. The reaction solution was stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×2次)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经制备硅胶板纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，收集产品，得到黄色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-1-(噻唑-5-基)乙-1-酮(16.7毫克，收率24.0％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 mL×2×) and dried over anhydrous sodium sulfate. The residue was purified by preparative silica gel chromatography (eluent: EtOAc:EtOAc: 2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-1-(thiazol-5-yl) Ethyl-1-one (16.7 mg, yield 24.0%).

MS(ESI)M/Z:442[M+H ⁺]。 MS (ESI) M / Z: 442 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ9.51(s,1H),8.92(s,1H),8.33(s,1H),8.09(s,1H),6.84(s,1H),6.60s,1H),5.71(s,2H),4.21(s,3H),3.80(s,3H)。 ^{1 H NMR (300MHz, DMSO-} d 6): δ9.51 (s, 1H), 8.92 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 6.84 (s, 1H), 6.60 s, 1H), 5.71 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H).

实施例43：SAL02-235Example 43: SAL02-235

N-((1H-咪唑-2-基)甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-((1H-imidazol-2-yl)methyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]] Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例43流程：Example 43 Process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)溶于乙腈(10.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(130毫克，0.20毫摩尔，50％wt)。反应液在室温下搅拌30分钟后，向反应液中依次加入2-乙胺甲基咪唑(65毫克，0.67毫摩尔)和三乙胺(94毫克，0.93毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (130 mg, 0.20 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 30 minutes, 2-ethylaminemethylimidazole (65 mg, 0.67 mmol) and triethylamine (94 mg, 0.93 mmol) were sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(25毫升)淬灭。混合液用乙酸乙酯(25 毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(15毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶制备板纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到黄色固体N-((1H-咪唑-2-基)甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(20.2毫克，收率33.4％)。After LCMS monitoring showed the disappearance of the starting material, water (25 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut Oxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl )oxy)acetamide (20.2 mg, yield 33.4%).

MS(ESI)M/Z:455[M+H ⁺]。 MS (ESI) M/Z: 455 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.42(s,1H),7.96(s,1H),7.69(s,1H),7.09(s,2H),7.02(s,1H),6.05(s,1H),4.82-4.80(m,2H),4.55(s,2H),4.19(s,3H),3.78(s,3H). ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.42 (s, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.09 (s, 2H), 7.02 (s, 1H), 6.05 (s , 1H), 4.82-4.80 (m, 2H), 4.55 (s, 2H), 4.19 (s, 3H), 3.78 (s, 3H).

实施例44：SAL02-241Example 44: SAL02-241

N-((3,3-二氟环丁基)甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-((3,3-difluorocyclobutyl)methyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3, 4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例44流程：Example 44 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于二氯甲烷(2.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(184毫克，0.29毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中依次加入(3,3-二氟环丁基)甲胺盐酸盐(25毫克，0.16毫摩尔)和三乙胺(145毫克，1.44毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (184 mg, 0.29 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, (3,3-difluorocyclobutyl)methylamine hydrochloride (25 mg, 0.16 mmol) and triethylamine (145 mg, 1.44 mmol) were sequentially added thereto. ). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠水溶液(5毫升)淬灭。混合液用二氯甲烷(5毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(5毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/15)，得到白色固体N-((3,3-二氟环丁基)甲基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(26.2毫克，收率49.7％)。After LCMS monitoring showed the disappearance of the material, aq. The mixture was extracted with methylene chloride (5 mL, EtOAc). The obtained residue was purified to silicagel eluting elut elut elut elut elut elut elut elut elut 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-yl)oxy)acetamide (26.2 mg, yield 49.7%).

MS(ESI)M/Z:479[M+H ⁺]。 MS (ESI) M / Z: 495 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.36(t,J＝6.3Hz,1H),8.28(s,1H),8.06(s,1H),7.08(s,1H),6.41(s,1H),4.67(s,2H),4.21(s,3H),3.80(s,3H),3.32(s,2H),2.65-2.55(m,2H),2.42-2.25(m,3H). ^{1 H NMR (300MHz, DMSO-} d 6): δ8.36 (t, J = 6.3Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.08 (s, 1H), 6.41 (s , 1H), 4.67 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 3.32 (s, 2H), 2.65-2.55 (m, 2H), 2.42 - 2.25 (m, 3H).

^19F NMR(300MHz,DMSO-d ₆):-81.50,-91.50. ^19F NMR (300MHz, DMSO-d ₆ ): -81.50, -91.50.

实施例45：SAL02-217Example 45: SAL02-217

N-(2-羟乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶 -4-基)氧基)乙酰胺N-(2-hydroxyethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例45流程：Example 45 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)溶于四氢呋喃(5.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸酐的乙酸乙酯溶液(0.25毫升，0.42毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入乙醇胺(33毫克，0.54毫摩尔)和三乙胺(0.25毫升，1.81毫摩尔)的四氢呋喃(5.0毫升)。将反应液加热至60℃并搅拌12小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in tetrahydrofurane (5.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.25 ml, 0.42 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, ethanolamine (33 mg, 0.54 mmol) and triethylamine (0.25 ml, 1.81 mmol) of tetrahydrofuran (5.0 ml) were added. The reaction solution was heated to 60 ° C and stirred for 12 hours.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭，有白色固体析出。收集滤饼，粗产品高压液相色谱柱制备纯化，纯化条件如下，色谱柱：X select C18 19mm*150mm；流动相：水(含有10毫摩尔/升的碳酸氢铵)和乙腈；流速:60毫升/分钟；梯度：在10分钟内，乙腈保持22％；检测波长：220nm。收集产品，减压冻干得白色固体N-(2-羟乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(11.6毫克，收率20.8％)。After LCMS showed the disappearance of the starting material, water (20 mL) was added to the reaction mixture and quenched to give a white solid. The filter cake was collected and purified by high-pressure liquid chromatography column. The purification conditions were as follows. Column: X select C18 19mm*150mm; mobile phase: water (containing 10 mmol/L ammonium bicarbonate) and acetonitrile; flow rate: 60 ML/min; Gradient: acetonitrile was maintained at 22% in 10 minutes; detection wavelength: 220 nm. The product was collected and lyophilized to give N-(2-hydroxyethyl)-2-(6-methoxy-2-(2-methoxyimidazo[2,1-b][1, 3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (11.6 mg, yield 20.8%).

MS(ESI)M/Z:419[M+H ⁺]。 MS (ESI) M / Z: 418 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆)δ8.27(s,1H),8.15(s,1H),8.04(s,1H),7.05(s,1H),6.43(s,1H),4.80(s,1H),4.67(s,2H),4.20(s,3H),3.80(s,3H),3.27-3.18(m,4H)。 ^{1 H NMR (300MHz, DMSO-} d 6) δ8.27 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.05 (s, 1H), 6.43 (s, 1H), 4.80 ( s, 1H), 4.67 (s, 2H), 4.20 (s, 3H), 3.80 (s, 3H), 3.27-3.18 (m, 4H).

实施例46：SAL02-240Example 46: SAL02-240

N-(双环[1.1.1]戊-2-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(bicyclo[1.1.1]pent-2-yl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4] Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例46流程：Example 46 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(4.0毫升)中。随后，向溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(138毫克，0.22毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中依次加入双环[1.1.1]戊-2-胺(20毫克，0.24毫摩尔)和三乙胺(63毫克，0.62毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (4.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (138 mg, 0.22 mmol, 50% wt) was added to the solution. After the reaction mixture was stirred at room temperature for 15 minutes, bicyclo[1.1.1]pentan-2-amine (20 mg, 0.24 mmol) and triethylamine (63 mg, 0.62 mmol) were sequentially added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/40)，得到白色固体N-(双环[1.1.1]戊-2-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(18.7毫克，收率53.1％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut elut elut elut Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine-4- Ethyloxy)acetamide (18.7 mg, yield 53.1%).

MS(ESI)M/Z:441[M+H ⁺]。 MS (ESI) M / Z: 441 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.05(s,1H),7.82(s,1H),7.02(s,1H),6.87(s,1H),6.27(s,1H),4.54(s,2H),4.25(s,3H),3.85(s,3H),2.53(s,1H),2.21(s,6H)。 ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.05 (s, 1H), 7.82 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 6.27 (s, 1H), 4.54 (s , 2H), 4.25 (s, 3H), 3.85 (s, 3H), 2.53 (s, 1H), 2.21 (s, 6H).

实施例47：SAL02-242Example 47: SAL02-242

2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(3,3,3-三氟丙基)乙酰胺2-((6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a]pyridin-4-yl)oxy)-N-(3,3,3-trifluoropropyl)acetamide

反应流程：Reaction process:

实施例47流程：Example 47 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(100毫克，0.27毫摩尔)溶于二氯甲烷(2.0毫升)中。随后，向溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(305毫克，0.48毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，向反应液中依次加入3,3,3-三氟丙胺盐酸盐(60毫克，0.40毫摩尔)和三乙胺(108毫克，1.07毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (100 mg, 0.27 mmol) was dissolved in dichloromethane (2.0 mL). Subsequently, a solution of 1-propylphosphonic anhydride in ethyl acetate (305 mg, 0.48 mmol, 50% wt) was added to the solution. After the reaction mixture was stirred at room temperature for 15 minutes, 3,3,3-trifluoropropylamine hydrochloride (60 mg, 0.40 mmol) and triethylamine (108 mg, 1.07 mmol) were sequentially added to the mixture. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯(20毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到白色固体2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)-N-(3,3,3-三氟丙基)乙酰胺(30.6毫克，收率24.4％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography eluting eluting elut elut elut elut , 1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-N-(3,3,3-tri Fluoropropyl)acetamide (30.6 mg, yield 24.4%).

MS(ESI)M/Z:471[M+H ⁺]。 MS (ESI) M / Z: 471 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆):δ8.37(t,J＝6.0Hz,1H),8.28(s,1H),8.07(s,1H),7.11(s,1H),6.45(s,1H),4.68(s,2H),4.21(s,3H),3.81(s,3H),3.48-3.38(m,2H)2.49-2.39(m,2H). ^{1 H NMR (300MHz, DMSO-} d 6): δ8.37 (t, J = 6.0Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.11 (s, 1H), 6.45 (s , 1H), 4.68 (s, 2H), 4.21 (s, 3H), 3.81 (s, 3H), 3.48-3.38 (m, 2H) 2.49-2.39 (m, 2H).

¹⁹F NMR(300MHz,DMSO-d ₆)δ-63.94 ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ-63.94

实施例48：SAL02-213Example 48: SAL02-213

N-丁基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-butyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazole [1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例48流程：Example 48 Process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(5.0毫升)中。随后，向上述溶液中加入1-丙基磷酸酐的乙酸乙酯溶液(0.075毫升，0.12毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，向反应液中依次加入正丁胺(12毫克，0.16毫摩尔)和三乙胺(0.075毫升，0.54毫摩尔)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in EtOAc (EtOAc). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.075 ml, 0.12 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, n-butylamine (12 mg, 0.16 mmol) and triethylamine (0.075 ml, 0.54 mmol) were sequentially added to the mixture. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(15毫升)淬灭。混合液用乙酸乙酯(15毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到白色固体N-丁基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(10.7毫克，收率31.1％)。After LCMS monitoring showed the disappearance of the starting material, water (15 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc) (EtOAc) The obtained residue was purified to silicagel elut elut elut elut elut elut elut elut elut elut Imidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (10.7 mg, Yield 31.1%).

MS(ESI)M/Z：431[M+H ⁺]。 MS (ESI) M / Z: 431 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.06(s,1H),7.82(s,1H),7.07(s,1H),6.59(br,1H),6.29(s,1H),4.62(s,2H),4.26(s,3H),3.85(s,3H),3.45-3.37(m,2H),1.66-1.51(m,2H),1.45-1.35(m,2H),1.26(m,3H),0.99-0.96(m,3H)。 ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.06 (s, 1H), 7.82 (s, 1H), 7.07 (s, 1H), 6.59 (br, 1H), 6.29 (s, 1H), 4.62 (s , 2H), 4.26 (s, 3H), 3.85 (s, 3H), 3.45-3.37 (m, 2H), 1.66-1.51 (m, 2H), 1.45-1.35 (m, 2H), 1.26 (m, 3H) ), 0.99-0.96 (m, 3H).

实施例49：SAL02-232Example 49: SAL02-232

N-(4-氟苄基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(4-fluorobenzyl-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl) Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例49流程：Example 49 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)溶于乙腈(10.0毫升)中。随后，向上述溶液中依次加入1-丙基磷酸酐的乙酸乙酯溶液(0.13毫升，0.22毫摩尔,50％wt)，4-氟苄胺(66毫克，0.53毫摩尔)和三乙胺(0.13毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric anhydride (0.13 ml, 0.22 mmol, 50% by weight), 4-fluorobenzylamine (66 mg, 0.53 mmol) and triethylamine (s) were sequentially added to the above solution. 0.13 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(30毫升)淬灭。混合液用二氯甲烷(30毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物用硅胶制备板纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到白色固体N-(4-氟苄基-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(36.9毫克，收率61.4％)。After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (30 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified with EtOAc EtOAc (EtOAc:EtOAc:EtOAc Methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (36.9 Mg, yield 61.4%).

MS(ESI)M/Z:431[M+H ⁺] MS (ESI) M/Z: 431 [M+H ⁺ ]

¹H NMR(300MHz,CDCl ₃):δ8.03(s,1H),7.81(s,1H),7.35-7.30(m,2H),7.09-7.00(m,3H),6.97-6.93(m,1H),6.29(s,1H),4.68(s,2H),4.57(d,J＝6.0Hz,2H),4.26(s,3H),3.85(s,3H). ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.03 (s, 1H), 7.81 (s, 1H), 7.35-7.30 (m, 2H), 7.09-7.00 (m, 3H), 6.97-6.93 (m, 1H), 6.29 (s, 1H), 4.68 (s, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.26 (s, 3H), 3.85 (s, 3H).

实施例50：SAL02-247Example 50: SAL02-247

N-(3-氟双环[1.1.1]戊-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(3-Fluorobicyclo[1.1.1]pent-1-yl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3 , 4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例50流程：Example 50 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(8.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.2毫升，0.33毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入3-氟代环[1.1.1]戊烷-1-胺盐酸盐(59毫克，0.43毫摩尔)和三乙胺(0.3毫升，2.16毫摩尔)的乙腈溶液(2.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, 3-fluorocyclo[1.1.1]pentan-1-amine hydrochloride (59 mg, 0.43 mmol) and triethylamine (0.3 ml, 2.16. Millimol) in acetonitrile (2.0 mL). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯萃取(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水溶液(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经过硅胶板层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得到白色固体N-(3-氟双环[1.1.1]戊-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(25.9毫克，收率51.3％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with aq. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-yl)oxy)acetamide (25.9 mg, yield 51.3%).

MS(ESI)M/Z:459[M+H ⁺]。 MS (ESI) M/Z: 459 [M+H ⁺ ].

¹H NMR(400MHz,DMSO-d ₆):δ8.93(s,1H),8.29(s,1H),8.06(s,1H),7.04(s,1H),6.41(s,1H),4.68(s,2H),4.21(s,3H),3.80(s,3H),2.39(s,6H)。 ^{1 H NMR (400MHz, DMSO-} d 6): δ8.93 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.04 (s, 1H), 6.41 (s, 1H), 4.68 (s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 2.39 (s, 6H).

¹⁹F NMR(282MHz,DMSO-d ₆,)δ-164.43 ¹⁹ F NMR (282 MHz, DMSO-d ₆ ,) δ -164.43

实施例51：SAL02-234Example 51: SAL02-234

N-(2-氟苄基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(2-fluorobenzyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6- Pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例51流程：Example 51 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(5.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.2毫升，0.33毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入2-氟苄胺(54毫克，0.43毫摩尔)和三乙胺(0.2毫升，1.44毫摩尔) 的乙腈溶液(5.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in EtOAc (EtOAc). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 2-fluorobenzylamine (54 mg, 0.43 mmol) and triethylamine (0.2 ml, 1.44 mmol) in acetonitrile (5.0 ml) was added. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(20毫升)淬灭。混合液用乙酸乙酯萃取(20毫升×3次)。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板纯化(展开剂：二氯甲烷/甲醇＝30/1)，得到白色固体N-(2-氟苄基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(20.1毫克，收率37.8％)。After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc Methoxyimidazo[2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (20.1 Mg, yield 37.8%).

MS(ESI)M/Z：483[M+H ⁺]。 MS (ESI) M/Z: 483 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆)δ8.77(t,J＝6.0Hz,1H),8.28(s,1H),8.07(s,1H),7.37-7.29(m,2H),7.24-7.14(m,2H),7.10(s,1H),6.45(s,1H),4.77(s,2H),4.44(d,J＝5.7Hz,2H),4.21(s,3H),3.81(s,3H) ^{1 H NMR (300MHz, DMSO-} d 6) δ8.77 (t, J = 6.0Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.37-7.29 (m, 2H), 7.24- 7.14 (m, 2H), 7.10 (s, 1H), 6.45 (s, 1H), 4.77 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H), 4.21 (s, 3H), 3.81 (s) , 3H)

¹⁹F NMR(282MHz,DMSO-d ₆)δ-119.01 ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ-119.01

实施例52：SAL02-248Example 52: SAL02-248

N-(双环[1.1.1]戊-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(bicyclo[1.1.1]pent-1-yl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]] Thiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例52流程：Example 52 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(50毫克，0.13毫摩尔)溶于乙腈(10.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.25毫升，0.42毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入1-双环[1,1,1]戊胺盐酸盐(64毫克，0.53毫摩尔)和三乙胺(0.25毫升，1.8毫摩尔)的乙腈溶液(2.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (50 mg, 0.13 mmol) was dissolved in EtOAc (10.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (0.25 ml, 0.42 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, 1-dicyclo[1,1,1]pentylamine hydrochloride (64 mg, 0.53 mmol) and triethylamine (0.25 ml, 1.8 mmol) were added thereto. Acetonitrile solution (2.0 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监控显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯萃取(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升×2次)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经硅胶制备板纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得到白色固体N-(双环[1.1.1]戊-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(44.1毫克，收率76.9％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with brine (10 mL×2×) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut elut 2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl) Oxy)acetamide (44.1 mg, yield 76.9%).

MS(ESI)M/Z：441[M+H ⁺]。 MS (ESI) M / Z: 441 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆)δ8.72(s,1H),8.29(s,1H),8.05(s,1H),7.03(s,1H),6.39(s,1H),4.61(s,2H),4.21(s,3H),3.80(s,3H),2.44(s,1H),2.05(s,6H)。 ^{1 H NMR (300MHz, DMSO-} d 6) δ8.72 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.03 (s, 1H), 6.39 (s, 1H), 4.61 ( s, 2H), 4.21 (s, 3H), 3.80 (s, 3H), 2.44 (s, 1H), 2.05 (s, 6H).

实施例53：SAL02-249Example 53: SAL02-249

N-(4,4-二氟环己基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a] 吡啶-4-基)氧基)乙酰胺N-(4,4-difluorocyclohexyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole -6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例53流程：Example 53 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(3.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(138毫克，0.22毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中依次加入4,4-二氟-环己胺盐酸盐(22毫克，0.13毫摩尔)和三乙胺(63毫克，0.62毫摩尔)的乙腈溶液(1.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, 4,4-difluoro-cyclohexylamine hydrochloride (22 mg, 0.13 mmol) and triethylamine (63 mg, 0.62 mmol) of acetonitrile were sequentially added thereto. Solution (1.0 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/25)，得到白色固体N-(4,4-二氟环己基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(27.1毫克，收率68.9％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with EtOAc EtOAc EtOAc. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut -2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy Acetylamine (27.1 mg, yield 68.9%).

MS(ESI)M/Z:493[M+H ⁺]。 MS (ESI) M / Z: 495 [M+H ⁺ ].

¹H NMR(400MHz,CDCl ₃):δ8.04(s,1H),7.83(s,1H),6.95(s,1H),6.43(d,J＝6.0Hz,1H),6.27(s,1H),4.62(s,2H),4.24(s,3H),4.10-3.99(m,1H),3.85(s,3H),2.21-2.12(m,2H),2.11-2.02(m,2H),1.72-1.53(m,4H). ^{_{1 H NMR (400MHz, CDCl 3}} ): δ8.04 (s, 1H), 7.83 (s, 1H), 6.95 (s, 1H), 6.43 (d, J = 6.0Hz, 1H), 6.27 (s, 1H ), 4.62 (s, 2H), 4.24 (s, 3H), 4.10-3.99 (m, 1H), 3.85 (s, 3H), 2.21-2.12 (m, 2H), 2.11-2.02 (m, 2H), 1.72-1.53 (m, 4H).

¹⁹F NMR(376MHz,CDCl ₃,ppm)δ-94.7,-101.6. ¹⁹ F NMR (376 MHz, CDCl ₃ , ppm) δ-94.7, -101.6.

实施例54：SAL02-250Example 54: SAL02-250

N-((3s,5s,7s)-金刚烷-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-((3s,5s,7s)-adamantan-1-yl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3 , 4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例54流程：Example 54 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(4.0毫升)中。随后，向上述溶液中加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(138毫克，0.22毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，向反应液中依次加入4,1-金刚烷胺(24毫克，0.16毫摩尔)和三乙胺(63毫克，0.62毫摩尔)的乙腈溶液(2毫升)，反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] 5-A]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (4.0 mL). Subsequently, an ethyl acetate solution of 1-propylphosphoric acid tricyclic anhydride (138 mg, 0.22 mmol, 50% by weight) was added to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 4,1-adamantamine (24 mg, 0.16 mmol) and triethylamine (63 mg, 0.62 mmol) in acetonitrile (2 ml) was sequentially added to the reaction mixture. The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水(10毫升×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/25)，得到白色固体N-((3s,5s,7s)-金刚烷-1-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(13.1毫克，收率32.2％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The obtained residue was purified to silicagel eluting elut elut elut elut elut elut elut elut (6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine 4-yl)oxy)acetamide (13.1 mg, yield 32.2%).

MS(ESI)M/Z：509[M+H ⁺]。 MS (ESI) M/Z: 495 [M+H ⁺ ].

¹H NMR(400MHz,CDCl ₃)δ8.05(s,1H),7.83(s,1H),6.98(s,1H),6.30(s,1H),6.23(s,1H),4.50(s,2H),4.25(s，3H),3.85(s,3H),2.15(s,3H),2.10(s,6H),1.74(s,6H) ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.05 (s, 1H), 7.83 (s, 1H), 6.98 (s, 1H), 6.30 (s, 1H), 6.23 (s, 1H), 4.50 (s, 2H), 4.25 (s, 3H), 3.85 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.74 (s, 6H)

实施例55：SAL02-251Example 55: SAL02-251

N-((1R,3S,5R,7R)-金刚烷-2-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-((1R,3S,5R,7R)-adamantan-2-yl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1 ,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例55流程：Example 55 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(30毫克，0.08毫摩尔)溶于乙腈(3.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.4毫升，0.67毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入2-金刚烷胺盐酸盐(60毫克，0.32毫摩尔)和三乙胺(0.4毫升，2.88毫摩尔)的乙腈溶液(2.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (30 mg, 0.08 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.4 ml, 0.67 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, a solution of 2-amantaneamine hydrochloride (60 mg, 0.32 mmol) and triethylamine (0.4 ml, 2.88 mmol) in acetonitrile (2.0 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加入水(10毫升)淬灭。有机相用乙酸乙酯萃取(10毫升×3次)萃取。合并有机相，有机相先用饱和食盐水(10毫升)洗涤，然后用无水硫酸钠干燥，过滤，所得滤液在减压下浓缩。残余物经过硅胶制备板纯化(展开剂：二氯甲烷/甲醇＝30/1)，得到白色固体N-((1R,3S,5R,7R)-金刚烷-2-基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(16.6毫克，收率40.8％)After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The organic phase was extracted with ethyl acetate (10 mL×3×). The combined organic layers were washed with brine (10 ml) The residue was purified by silica gel chromatography (yield: methylene chloride/methanol = 30/1) to afford N-((1R,3S,5R,7R)-adamantan-2-yl)-2-(( 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridine- 4-yl)oxy)acetamide (16.6 mg, yield 40.8%)

MS(ESI)M/Z：509[M+H ⁺]。 MS (ESI) M/Z: 495 [M+H ⁺ ].

¹H NMR(300MHz,DMSO-d ₆)δ8.30(s,1H),8.06(s,1H),7.96(d,J＝7.8Hz,1H),6.80(s,1H),6.40(s,1H),4.78(s,2H),4.21(s,3H),3.95-3.87(m,1H),3.80(s,3H),2.01-1.92(m,2H),1.82(m,8H),1.73-1.69(m,2H),1.58-1.50(m,2H). ^{1 H NMR (300MHz, DMSO-} d 6) δ8.30 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 7.8Hz, 1H), 6.80 (s, 1H), 6.40 (s, 1H), 4.78 (s, 2H), 4.21 (s, 3H), 3.95-3.87 (m, 1H), 3.80 (s, 3H), 2.01-1.92 (m, 2H), 1.82 (m, 8H), 1.73 -1.69 (m, 2H), 1.58-1.50 (m, 2H).

实施例56：SAL02-368Example 56: SAL02-368

N-(3-氰基环丁基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺N-(3-cyanocyclobutyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole- 6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例56流程：Example 56 process:

步骤A：将2-(6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基氧基)乙酸(40毫克，0.11毫摩尔)溶于乙腈(3.0毫升)中。随后，向上述溶液中滴加1-丙基磷酸三环酸酐的乙酸乙酯溶液(0.2毫升，0.33毫摩尔，50％wt)。反应液在室温下搅拌15分钟后，再向其中加入3-氨基环丁烷-1-甲腈盐酸盐(57毫克，0.43毫摩尔)和三乙胺(0.3毫升，2.16毫摩尔)的乙腈溶液(2.0毫升)。反应液在室温下搅拌1小时。Step A: 2-(6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1] , 5-a]pyridin-4-yloxy)acetic acid (40 mg, 0.11 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently, a solution of 1-propylphosphoric acid tricyclic anhydride in ethyl acetate (0.2 ml, 0.33 mmol, 50% by weight) was added dropwise to the above solution. After the reaction mixture was stirred at room temperature for 15 minutes, 3-aminocyclobutane-1-carbonitrile hydrochloride (57 mg, 0.43 mmol) and triethylamine (0.3 ml, 2.16 mmol). Solution (2.0 ml). The reaction solution was stirred at room temperature for 1 hour.

LCMS监控显示原料消失后，向反应液中加入水(10毫升)淬灭。混合液用乙酸乙酯(10毫升×3次)萃取，合并有机相，有机相先用饱和食盐水洗涤(10毫升)洗涤，然后有机相用无水硫酸钠干燥后，过滤，所得滤液在减压下浓缩。残余物通过硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/30)，得到白色固体N-(3-氰基环丁基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(11.2毫克，收率23.2％)。After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction mixture to quench. The mixture was extracted with ethyl acetate (10 mL×3×). The organic phase was combined and washed with brine (10 mL). Concentrate under pressure. The residue was purified by EtOAc EtOAcjjjjjjjjjj -(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy) Acetamide (11.2 mg, yield 23.2%).

MS(ESI)M/Z:454[M+H ⁺]。 MS (ESI) M/Z: 454 [M+H ⁺ ].

¹H NMR(400MHz,DMSO-d ₆):δ8.54(d,J＝5.7Hz,1H),8.30(s,1H),8.07(s,1H),7.07(s,1H),6.42(s,1H),4.66(s,2H),4.42-4.35(m,1H),4.21(s,3H),3.81(s,3H),3.10-3.01(m,1H),2.66-2.56(m,2H),2.47-2.39(m,2H) ^{1 H NMR (400MHz, DMSO-} d 6): δ8.54 (d, J = 5.7Hz, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.07 (s, 1H), 6.42 (s , 1H), 4.66 (s, 2H), 4.42-4.35 (m, 1H), 4.21 (s, 3H), 3.81 (s, 3H), 3.10-3.01 (m, 1H), 2.66-2.56 (m, 2H) ), 2.47-2.39 (m, 2H)

实施例57：SAL02-369Example 57: SAL02-369

N-(2-氰基乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶 -4-基)氧基)乙酰胺N-(2-cyanoethyl)-2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazole-6 -yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide

反应流程：Reaction process:

实施例57流程：Example 57 process:

步骤A：在冰水浴下，将3-氨基丙腈(275毫克，3.93毫摩尔)和碳酸钾(530毫克，3.84毫摩尔)加入二氯甲烷(15.0毫升)中。随后，向上述溶液中缓慢滴加溴乙酰溴(392毫克，1.94毫摩尔)的二氯甲烷溶液(5.0毫升)。反应液在室温下搅拌12小时。Step A: 3-Aminopropanenitrile (275 mg, 3.93 mmol) and potassium carbonate (530 mg, 3.84 mmol) were added to dichloromethane (15.0 mL). Subsequently, a solution of bromoacetyl bromide (392 mg, 1.94 mmol) in dichloromethane (5.0 ml) was slowly added dropwise to the above solution. The reaction solution was stirred at room temperature for 12 hours.

TLC监测显示原料消失后，将反应液在减压下浓缩。残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，收集产品，得到白色固体2-溴-N-(2-氰基乙基)乙酰胺(344毫克，收率91.4％)。After TLC monitoring showed disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was purified with EtOAc EtOAc EtOAcjjjjjjj , yield 91.4%).

MS(ESI)M/Z:191,193[M+H ⁺]。 MS (ESI) M / Z: 191, 193 [M+H ⁺ ].

步骤B：将6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-醇(70毫克，0.22毫摩尔)，2-溴-N-(2-氰基乙基)乙酰胺(140毫克，0.73毫摩尔)和无水碳酸钾(210毫克，1.52毫摩尔)加入N,N-二甲基甲酰胺(7.0毫升)中。反应液在室温下搅拌1小时。Step B: 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)pyrazolo[1,5- a] pyridin-4-ol (70 mg, 0.22 mmol), 2-bromo-N-(2-cyanoethyl)acetamide (140 mg, 0.73 mmol) and anhydrous potassium carbonate (210 mg, 1.52) Millimol) was added to N,N-dimethylformamide (7.0 mL). The reaction solution was stirred at room temperature for 1 hour.

TLC监测显示原料消失后，过滤，所得滤液在减压下浓缩。残余物经高压液相色谱制备纯化，制备条件如下：色谱柱：X select C18 19mm*150mm；流动相：水(含有0.05％碳酸氢铵)和乙腈；流速：25毫升/分钟；梯度：在7分钟内，乙腈从50％升到60％；检测波长：254nm。收集产品馏分，减压浓缩后，再减压冻干，得到白色固体N-(2-氰基乙基)-2-((6-甲氧基-2-(2-甲氧基咪唑并[2,1-b][1,3,4]噻二唑-6-基)吡唑并[1,5-a]吡啶-4-基)氧基)乙酰胺(24.5毫克，收率26.0％)。TLC monitoring showed disappearance of the starting material, filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high pressure liquid chromatography, and the preparation conditions were as follows: column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% ammonium hydrogencarbonate) and acetonitrile; flow rate: 25 ml/min; gradient: at 7 Within a minute, acetonitrile rose from 50% to 60%; detection wavelength: 254 nm. The product fractions were collected, concentrated under reduced pressure, and then lyophilized to give a white solid N-(2-cyanoethyl)-2-((6-methoxy-2-(2-methoxy-imidazo[ 2,1-b][1,3,4]thiadiazole-6-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)acetamide (24.5 mg, yield 26.0%) ).

MS(ESI)M/Z：428[M+H ⁺]。 MS (ESI) M / Z: 428 [M+H ⁺ ].

¹H NMR(300MHz,CDCl ₃):δ8.03(s,1H),7.82(s,1H),7.03(br,1H),6.99(s,1H),6.26(s,1H),4.66(s,2H),4.24(s,3H),3.85(s,3H),3.70(q,J＝5.1Hz,2H),2.76(t,J＝5.1Hz,2H). ^{_{1 H NMR (300MHz, CDCl 3}} ): δ8.03 (s, 1H), 7.82 (s, 1H), 7.03 (br, 1H), 6.99 (s, 1H), 6.26 (s, 1H), 4.66 (s , 2H), 4.24 (s, 3H), 3.85 (s, 3H), 3.70 (q, J = 5.1 Hz, 2H), 2.76 (t, J = 5.1 Hz, 2H).

生物活性测试：Biological activity test:

实施例58：Example 58

体外筛选实验-FLIPR方法检测化合物抑制PAR4活性测试In vitro screening test-FLIPR method for detecting compounds inhibiting PAR4 activity test

1、准备试剂：1. Prepare reagents:

实验材料Experimental Materials

1)PAR4的激动剂及抑制剂1) Agonists and inhibitors of PAR4

PAR4的选择性激动剂TFLLR-NH ₂、2-Furoyl-LIGRLO-NH ₂和AYPGKF-NH ₂由Sangon Biotech合成并购买或从Sigma-Aldrich直接购买。在FLIPR钙离子外流试验中它们对PAR4的EC ₅₀分别为2.0μM、0.2μM和1.3μM。SAL02-001-00和SAL02-002-00为高活性的PAR4选择性抑制剂，在FLIPR钙离子外流试验中其对PAR4的IC ₅₀值为5-10nM。 Selective PAR4 agonist _{TFLLR-NH 2, 2-Furoyl} -LIGRLO-NH 2 and AYPGKF-NH ₂ and later synthesized by Sangon Biotech or purchased directly from Sigma-Aldrich. In the FLIPR calcium efflux assay of PAR4 on their EC ₅₀ values of 2.0μM, 0.2μM and 1.3μM. SAL02-001-00 SAL02-002-00 highly active and selective PAR4 inhibitor, calcium ion efflux in the FLIPR assay with an IC ₅₀ value of PAR4 5-10nM.

2)PAR4表达细胞系2) PAR4 expression cell line

利用常规转染的方法将包含人源PAR4cDNA的哺乳动物细胞表达载体分别导入Flp-In-TREx-293细胞，经相应的抗生素筛选获得稳定高表达的Flp-In-TREx-293-PAR4细胞系并利用PAR4FLIPR钙离子外流实验进行功能验证。据文献报道HEK293细胞本身内源性高表达PAR4，因此Flp-In-TREx-293-PAR4细胞系可以用来进行PAR4小分子抑制剂的筛选实验。The mammalian cell expression vector containing human PAR4 cDNA was introduced into Flp-In-TREx-293 cells by conventional transfection method, and the stably high-expression Flp-In-TREx-293-PAR4 cell line was obtained by corresponding antibiotic screening. Functional verification was performed using the PAR4FLIPR calcium ion outflow assay. According to the literature, HEK293 cells express endogenously high expression of PAR4, so Flp-In-TREx-293-PAR4 cell line can be used for screening experiments of PAR4 small molecule inhibitors.

实施例59Example 59

利用FLIPR钙离子外流实验检测化合物对人源PAR4的抑制活性Detection of the inhibitory activity of compounds on human PAR4 by FLIPR calcium ion outflow assay

Flp-In-TREx-293-PAR4细胞培养于DEME高糖(Gibco)、10％胎牛血清、2mM GlutaMAX、1％青霉素-链霉素、15μg/ml blasticidin和200μg/ml潮霉素的培养基中，置于37℃、5％CO2细胞培养箱中培养。细胞接种至经poly-d-lysine处理过的384孔细胞培养板(Corning,3845)中，接种密度为8,000个细胞/孔/25μl细胞接种基质(DMEM高糖、10％胎牛血清、2mM GlutaMAX)于细胞培养箱培养过夜。加入25μl等体积的2X(400ng/ml)四环素诱导基质继续培养24h。实验当天，将培养板中的诱导基质更换为实验缓冲液(HBSS+20mM HEPES)，随后加入20μl等体积的2X Calcium 6dye，于37℃孵育2小时后置于室温待用。利用实验缓冲液将待测化合物和PAR4激动剂稀释至6X浓度，加入10μl 6X待测化合物至384孔细胞培养板，于室温孵育30分钟后，利用FLIPR Tetra将10μl 6X PAR4激动剂加入384孔细胞培养板，进行数据的测定和分析。整个反应体系为60μl，PAR4激动剂的终浓度为1.3μM(EC50)，DMSO的终浓度为0.3％。Flp-In-TREx-293-PAR4 cells cultured in DEME high glucose (Gibco), 10% fetal bovine serum, 2 mM GlutaMAX, 1% penicillin-streptomycin, 15 μg/ml blasticidin and 200 μg/ml hygromycin The medium was cultured in a 37 ° C, 5% CO 2 cell incubator. The cells were seeded into poly-d-lysine-treated 384-well cell culture plates (Corning, 3845) at a seeding density of 8,000 cells/well/25 μl of cell seeding matrix (DMEM high glucose, 10% fetal bovine serum, 2 mM GlutaMAX). ) Incubate overnight in a cell culture incubator. A 25 μl volume of 2X (400 ng/ml) tetracycline was added to induce the substrate to continue to culture for 24 h. On the day of the experiment, the induction matrix in the culture plate was changed to the experimental buffer (HBSS + 20 mM HEPES), followed by the addition of 20 μl of an equal volume of 2X Calcium 6dye, incubated at 37 ° C for 2 hours and then left at room temperature for use. The test compound and the PAR4 agonist were diluted to a 6X concentration using the experimental buffer, 10 μl of the 6X test compound was added to the 384-well cell culture plate, and after incubation for 30 minutes at room temperature, 10 μl of the 6X PAR4 agonist was added to the 384-well cell using FLIPR Tetra. The plates were incubated and the data were measured and analyzed. The entire reaction system was 60 μl, the final concentration of the PAR4 agonist was 1.3 μM (EC50), and the final concentration of DMSO was 0.3%.

实验结果Experimental result

	Compd CodeCompd Code	PAR4IC ₅₀ PAR4IC ₅₀
00	BMS-986120BMS-986120	AA
11	SAL02-162SAL02-162	AA
22	SAL02-166SAL02-166	BB
33	SAL02-175SAL02-175	AA
44	SAL02-202SAL02-202	AA
55	SAL02-215SAL02-215	AA
66	SAL02-191SAL02-191	BB
77	SAL02-206SAL02-206	AA
88	SAL02-207SAL02-207	AA
99	SAL02-209SAL02-209	AA
1010	SAL02-210SAL02-210	AA
1111	SAL02-212SAL02-212	AA

1212	SAL02-190SAL02-190	BB
1313	SAL02-208SAL02-208	AA
1414	SAL02-213SAL02-213	AA
1515	SAL02-211SAL02-211	AA
1616	SAL02-214SAL02-214	BB
1717	SAL02-216SAL02-216	AA
1818	SAL02-218SAL02-218	AA
1919	SAL02-221SAL02-221	BB
2020	SAL02-211SAL02-211	AA
21twenty one	SAL02-227SAL02-227	BB
22twenty two	SAL02-229SAL02-229	AA
23twenty three	SAL02-239SAL02-239	BB
24twenty four	SAL02-194SAL02-194	BB
2525	SAL02-241SAL02-241	BB
2626	SAL02-240SAL02-240	AA
2727	SAL02-242SAL02-242	BB
2828	SAL02-213SAL02-213	AA
2929	SAL02-232SAL02-232	BB
3030	SAL02-247SAL02-247	BB
3131	SAL02-234SAL02-234	AA
3232	SAL02-248SAL02-248	AA
3333	SAL02-250SAL02-250	BB
3434	SAL02-251SAL02-251	BB

(注：A:0.1-20nM；B:20-100nM)(Note: A: 0.1-20nM; B: 20-100nM)

结果显示：本发明所述化合物具有高的PAR4抑制活性。The results show that the compound of the present invention has high PAR4 inhibitory activity.

实施例60血小板凝聚试验Example 60 Platelet Aggregation Test

人洗涤血小板样品的制备：Preparation of human washed platelet samples:

1.健康人全血样品的采集：使用5mL离心管(海门市昊瑞实验器材经营部)，每管加入600uL体积的ACD缓冲液(北京百奥莱博科技有限公司，ACD抗凝剂)。每管采集全血样品至4mL刻度(约采集全血3.4mL)，温和颠倒4-5次混匀，样品采集后20分钟内离心，离心前处于常温保存。1. Collection of whole blood samples from healthy people: Using a 5 mL centrifuge tube (Haimen City Ruirui Experimental Equipment Business Department), 600 uL volume of ACD buffer (Beijing Baiao Laibo Technology Co., Ltd., ACD anticoagulant) was added to each tube. Whole blood samples were taken from each tube to a 4 mL scale (about 3.4 mL of whole blood was collected), gently mixed 4-5 times to mix, centrifuged within 20 minutes after sample collection, and stored at room temperature before centrifugation.

2.富血小板血浆(PRP)的制备：全血样品在170g，常温条件下离心(Eppendorf 5810R型号离心机)14分钟，离心后收集上层较澄清液体至另一洁净空5mL离心管(海门市昊瑞实验器材经营部)，作为富血小板血浆样品。2. Preparation of platelet-rich plasma (PRP): Whole blood samples were centrifuged at 170 g (Eppendorf 5810R centrifuge) for 14 minutes at normal temperature. After centrifugation, the upper clear liquid was collected to another clean empty 5 mL centrifuge tube (Haimen City 昊Rui Experimental Equipment Business Department), as a platelet-rich plasma sample.

3.血小板初次富集及洗涤：富血小板血浆样品在1300g(Eppendorf 5810R型号离心机)，常温条件下离心6分钟；离心后弃去上层澄清液体，使用ACD缓冲液小心缓慢地重悬、洗涤沉淀物一次。3. Primary enrichment and washing of platelets: platelet-rich plasma samples were centrifuged at 1300 g (Eppendorf Model 5810R centrifuge) for 6 minutes at room temperature; after centrifugation, the supernatant liquid was discarded and carefully resuspended and washed with ACD buffer. Once again.

4.人洗涤血小板样品的制备：将重悬后的血小板样品在1300g，常温条件下离心6分钟；离心后弃去上层澄清液体，使用台式液(北京百奥莱博科技有限公司)小心缓慢地重悬沉淀，至洗涤后血小板终浓度为2-4X10 ⁸/mL，常温保存待当天用。 4. Preparation of human washed platelet samples: The resuspended platelet samples were centrifuged at 1300 g for 6 minutes at room temperature; after centrifugation, the supernatant liquid was discarded, using a benchtop liquid (Beijing Biolebo Technology Co., Ltd.) carefully and slowly Resuspend the pellet until the final concentration of platelets after washing is 2-4× ^{10 8} /mL, and store at room temperature for use on the same day.

5.(选做)乏血小板血浆(PPP)的制备：#2步骤后的下层血液样品，在1800g(Eppendorf5810R型号离心机)、常温条件下离心10分钟；离心后，收集上清至另一洁净空5mL离心管(海门市昊瑞实验器材经营部)，作为乏血小板血浆样品，常温保存待用。5. (Optional) Preparation of platelet-poor plasma (PPP): The lower blood sample after step #2 was centrifuged at 1800 g (Eppendorf 5810R centrifuge) at room temperature for 10 minutes; after centrifugation, the supernatant was collected to another cleansing Empty 5mL centrifuge tube (Haimen City, Rui Rui experimental equipment business department), as a sample of platelet-poor plasma, stored at room temperature for use.

受试物与人洗涤血小板样品的孵育：Incubation of test substance with human washed platelet samples:

1.孵育前准备：37℃水浴锅(常州国华电器有限公司，HH-4数显恒温水浴锅)，血小板聚集分析仪(北京世帝科学仪器有限责任公司，LG-PABER-I半自动凝血分析仪)开机预热。1. Preparation before incubation: 37 ° C water bath (Changzhou Guohua Electric Co., Ltd., HH-4 digital thermostat water bath), platelet aggregation analyzer (Beijing Shidi Scientific Instrument Co., Ltd., LG-PABER-I semi-automatic coagulation analysis Instrument) start warm up.

2.受试物与人洗涤血小板样品的孵育：取一洁净500uL规格的离心管，标明待测受试物名称及浓度；取276uL人洗涤血小板样品加入其中，再加入60uL待测受试物，温和混匀4-6次后，放置于水浴锅内孵育，并开始计时。水浴孵育20分钟。2. Incubation of the test substance with the human washed platelet sample: Take a clean 500uL centrifuge tube to indicate the name and concentration of the test object to be tested; take 276uL of human washed platelet sample and add 60uL of the test object to be tested. After gently mixing for 4-6 times, place in a water bath and incubate and start timing. Incubate for 20 minutes in a water bath.

血小板最大聚集率(MAR％)的测定：Determination of maximum platelet aggregation rate (MAR%):

1.测定基线：使用台式液或乏血小板血浆(PPP)作为基线物质，取300uL，加入比色杯(北京世帝科学仪器有限责任公司)进行基线值的测定，该数值仅用于仪器自动计算最大聚集率的测定。1. Determination of baseline: using benchtop fluid or platelet-poor plasma (PPP) as the baseline material, take 300uL, add cuvette (Beijing Shidi Scientific Instrument Co., Ltd.) to determine the baseline value, which is only used for automatic calculation of the instrument. Determination of the maximum aggregation rate.

2.孵育后的目标洗涤血小板的测定：测定时间设定为600s，测定模式为Aggr模式；取280uL孵育后的洗涤血小板样品，加入至比色杯(北京世帝科学仪器有限责任公司)中，加入一枚震荡珠(北京世帝科学仪器有限责任公司)并预热1分钟。预热完成后，将比色杯置于测试通道，按开始按钮10秒中后，缓缓加入20uL的PAR4-AP激动剂或20ul先导化合物，加入过程中枪头不进入液面下很深的位置，得到MAR值。2. Determination of target washed platelets after incubation: the measurement time was set to 600 s, and the measurement mode was Aggr mode; the washed platelet samples after 280 uL incubation were added to a cuvette (Beijing Shidi Scientific Instrument Co., Ltd.). Join a shocking bead (Beijing Shidi Scientific Instrument Co., Ltd.) and warm up for 1 minute. After the preheating is completed, place the cuvette in the test channel. After pressing the start button for 10 seconds, slowly add 20uL of PAR4-AP agonist or 20ul of lead compound. During the addition process, the tip does not enter the deep surface. Position, get the MAR value.

3.阴性激动剂对照：如2的操作，仅将最后加入的PARP-AP激动剂更换为激动剂所用的溶媒(15％HBSS+20mM HEPES的生理盐水溶液)，试验结果作用为阴性激动剂对照。3. Negative agonist control: As in the operation of 2, only the last added PARP-AP agonist was replaced with the vehicle used for the agonist (15% HBSS + 20 mM HEPES physiological saline solution), and the test result was a negative agonist control. .

4.血小板最大聚集率及抑制率的计算：4. Calculation of the maximum aggregation rate and inhibition rate of platelets:

1)血小板最大聚集率＝(600s时比浊度值-基线值)/(10s内比浊度值-基线值)1) Maximum aggregation rate of platelets = (turbidity value at baseline - baseline value at 600s) / (turbidity value within 10s - baseline value)

2)血小板聚集抑制率(％)＝1-(待测化合物MAR％-阴性激动剂MAR％)/(阴性对照MAR％-阴性激动剂MAR％)*100％2) Platelet aggregation inhibition rate (%) = 1 - (test compound MAR% - negative agonist MAR%) / (negative control MAR% - negative agonist MAR%) * 100%

体外血小板凝聚试验数据如下：The data of in vitro platelet aggregation test are as follows:

化合物编号Compound number	IC50 in PAgT(nM)IC50 in PAgT(nM)
BMS-986120BMS-986120	2.6,n＝112.6, n=11

SAL02-211SAL02-211	1.6,n＝11.6, n=1
SAL02-216SAL02-216	3.0.,n＝13.0., n=1
SAL02-218SAL02-218	0.11,n＝10.11, n=1

结果显示：本发明所述化合物比参比化合物BMS986120有更优秀的抗血小板凝聚作用。The results show that the compound of the present invention has superior anti-platelet aggregation effect than the reference compound BMS986120.

实施例61Example 61

血浆蛋白结合率试验Plasma protein binding rate test

1.试验材料Test material

1.1.待测化合物由委托方提供。对照化合物酮康唑购自Sigma公司。1.1. The test compound is provided by the client. The control compound ketoconazole was purchased from Sigma.

1.2.Na ₂HPO ₄，NaH2PO ₄和NaCl购自Sigma公司。 1.2. Na ₂ HPO ₄ , NaH ₂ PO ₄ and NaCl were purchased from Sigma.

1.3.96孔平衡透析板(HTDialysis LLC,Gales Ferry,CT)和平衡透析膜MWCO 12-14K(Cat.#1101)。1.3.96 well balanced dialysis plate (HTDialysis LLC, Gales Ferry, CT) and balanced dialysis membrane MWCO 12-14K (Cat. #1101).

1.4.血浆(EDTA-K ₂抗凝)保存于-80℃，具体信息如下： 1.4. Plasma (EDTA-K ₂ anticoagulation) was stored at -80 ° C, the specific information is as follows:

2.试验方案2. Test plan

采用平衡透析法，将含有浓度分别为1μM的受试物在人、猴、犬、大鼠和小鼠血浆样品和磷酸盐缓冲液分别加入HTDialysis装置中的平衡透析膜两侧，在37℃、5％的CO ₂环境中约100转/分钟转速下透析6小时后取样，测定不同浓度受试物在人、猴、犬、大鼠以及小鼠血浆中的游离百分数。根据实验需求，会使用经磷酸盐缓冲液稀释的血浆进行实验。 Using a balanced dialysis method, the test substance containing the concentration of 1 μM was separately added to the balanced dialysis membrane of the HTDialysis apparatus in human, monkey, canine, rat and mouse plasma samples and phosphate buffer, respectively, at 37 ° C, Samples were taken after dialysis for 6 hours at a speed of about 100 rpm in a 5% CO ₂ atmosphere, and the percentage of free concentration of the test substances in human, monkey, dog, rat, and mouse plasma at different concentrations was determined. According to the experimental requirements, the experiment was performed using plasma diluted with phosphate buffer.

3.试验步骤3. Test procedure

3.1.化合物工作液的制备3.1. Preparation of compound working fluid

将受试粉末和对照药酮康唑制备成高浓度的DMSO储备液，并用DMSO稀释到200μM工作液。The test powder and the control drug ketoconazole were prepared into a high concentration of DMSO stock solution and diluted to 200 μM working solution in DMSO.

3.2.磷酸盐缓冲液的制备(100mM，pH 7.4)3.2. Preparation of phosphate buffer (100 mM, pH 7.4)

用超纯水配置14.2g/L的Na ₂HPO ₄和8.77g/L的NaCl的碱性溶液以及12.0g/L NaH ₂PO ₄和8.77g/L的NaCl的酸性溶液，两种溶液保存在4℃冰箱，有效期7天。用酸碱两种溶液调配pH7.4的缓冲液，调配好的缓冲液保存在4℃冰箱，有效期7天。 An alkaline solution of 14.2 g/L of Na ₂ HPO ₄ and 8.77 g/L of NaCl and an acidic solution of 12.0 g/L of NaH ₂ PO ₄ and 8.77 g/L of NaCl were placed in ultrapure water, and the two solutions were stored in 4 ° C refrigerator, valid for 7 days. The buffer solution of pH 7.4 was prepared by using two kinds of solutions of acid and alkali, and the prepared buffer was stored in a refrigerator at 4 ° C for 7 days.

3.3血浆的准备3.3 Preparation of plasma

预先把水浴和孵箱温度调到37℃。将血浆从-80℃取出，在室温水环境中融化，在3220g的离心力和4℃的温度条件下离心10分钟，移除凝块并将上清转移至新的离心管。测试并记录血浆的pH。(备注：a.仅使用pH范围在7-8之间的血浆。b.仅使用在到货后融化次数不超过两次的血浆。)The water bath and incubator temperature were adjusted to 37 °C in advance. The plasma was taken out from -80 ° C, thawed in a room temperature water environment, centrifuged at a temperature of 3220 g and a temperature of 4 ° C for 10 minutes, the clot was removed and the supernatant was transferred to a new centrifuge tube. Test and record the pH of the plasma. (Remarks: a. Use only plasma with a pH range between 7 and 8. b. Use only plasma that does not melt more than twice after arrival.)

3.4.试验装置的制备3.4. Preparation of test device

将平衡透析膜置于纯水中浸泡60分钟，然后在20％乙醇中浸泡20分钟，最后在透析缓冲液中浸泡20分钟。然后将浸泡后的透析膜平铺在洁净的HTDialysis夹板装置上，参照产品手册完成透析装置的安装。The equilibrated dialysis membrane was immersed in pure water for 60 minutes, then immersed in 20% ethanol for 20 minutes, and finally immersed in dialysis buffer for 20 minutes. The soaked dialysis membrane is then plated onto a clean HTDialysis splint device and the dialysis device is installed according to the product manual.

3.5.孵育体系的制备3.5. Preparation of incubation system

取4μL测试药和对照药的工作液，加入796μL预孵育过的血浆中，充分混合，孵育体系最终的有机溶剂含量为0.5％。混匀后立即转移50μL孵育体系到新的96孔板中，作为0点样品，其处理方式同孵育后的样品。Take 4 μL of the test drug and the control drug working solution, add 796 μL of pre-incubated plasma, mix well, and incubate the final organic solvent content of 0.5%. Immediately after mixing, 50 μL of the incubation system was transferred to a new 96-well plate as a 0-point sample, which was treated in the same manner as the sample after incubation.

3.6.透析方法3.6. Dialysis method

在透析装置中每孔加入796μL孵育体系，另一侧放入等体积的透析缓冲液(PBS)，实验为双平行。将透析板封好，置于37℃、5％CO ₂的孵箱中，在约100rpm条件下平衡6小时。孵育结束后，从透析膜上下两侧各取50μL样品进行处理。 796 μL of incubation system was added to each well in the dialysis apparatus, and an equal volume of dialysis buffer (PBS) was placed on the other side. The experiment was double parallel. The dialysis plates were sealed, placed in an incubator at 37 ° C, 5% CO ₂ , and equilibrated for 6 hours at about 100 rpm. After the incubation, 50 μL of the sample was taken from the upper and lower sides of the dialysis membrane for treatment.

3.7.受试物的血浆稳定性测试3.7. Plasma stability test of the test substance

剩余孵育体系也在同等条件下孵育6小时，孵育结束后，转移50μL孵育体系进行处理。用于测试药的稳定性检测。稳定性样品处理方式同透析孵育样品一样。The remaining incubation system was also incubated for 6 hours under the same conditions. After the incubation, 50 μL of the incubation system was transferred for treatment. For the stability test of test drugs. The stable sample is processed in the same manner as the dialysis incubation sample.

3.8.透析样品的处理3.8. Treatment of dialysis samples

向已取出的缓冲液样品中加入50μL空白血浆，同样向已取出的血浆样品中加入等体积的空白缓冲液。混合均匀，加入300μL的终止液(乙腈，含500nM拉贝洛尔，100nM阿普***，2μM酮洛芬)。所有样品涡旋5分钟，之后于3220g条件下离心30分钟进行蛋白沉淀。转移100μL上清液到进样板，加入100μL纯水混匀，用于LC-MS/MS分析。50 μL of blank plasma was added to the removed buffer sample, and an equal volume of blank buffer was also added to the removed plasma sample. Mix well and add 300 μL of stop solution (acetonitrile, containing 500 nM labetalol, 100 nM alprazolam, 2 μM ketoprofen). All samples were vortexed for 5 minutes and then centrifuged for 30 minutes at 3220 g for protein precipitation. Transfer 100 μL of the supernatant to the sample plate, add 100 μL of pure water, and mix for LC-MS/MS analysis.

结果显示：本发明所述化合物蛋白结合率与参考化合物BMS-986120相比，明显降低。The results showed that the protein binding rate of the compound of the present invention was significantly lower than that of the reference compound BMS-986120.

实施例62Example 62

本发明专利部分化合物的药代动力学测试Pharmacokinetic test of some compounds of the patent of the invention

1、以大鼠为受试动物，应用LC/MS/MS法测定了大鼠静脉注射给予SAL02-208化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。1. Using rat as the test animal, the concentration of drug in plasma at different time after intravenous administration of SAL02-208 compound was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2、试验方案2, the test plan

2.1试验药品2.1 test drugs

SAL02-208SAL02-208

2.2试验动物2.2 Test animals

健康SD大鼠8只，雌雄各半。There were 8 healthy SD rats, half male and half female.

2.3药物配制2.3 drug preparation

称取适量药物，加入5％DMSO和5％吐温80使溶解，后加生理盐水至终体积，配成溶液。Weigh the appropriate amount of the drug, add 5% DMSO and 5% Tween 80 to dissolve, then add physiological saline to the final volume, and prepare a solution.

2.4给药2.4 administration

大鼠8只，雌雄各半，分成相同两组；禁食一夜后静脉注射8 rats, male and female, divided into the same two groups; intravenous injection after fasting overnight

3、操作3, operation

静脉注射给药组于给药前及给药后0.5、1.0、2.0、4.0、6.0、8.0、12.0、24.0h采血0.1ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。用LC/MS/MS法测定不同化合物静脉注射给药后大鼠血浆中的待测化合物含量。In the intravenous administration group, 0.1 ml of blood was collected before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 h after administration, placed in heparinized tubes, and centrifuged at 3500 rpm for 10 min to separate plasma at -20 ° C. save. The content of the test compound in the plasma of rats after intravenous administration of different compounds was determined by LC/MS/MS method.

4、药代动力学参数结果4, pharmacokinetic parameters results

本发明部分化合物及参比化合物BMS-986120药代动力学参数如下：The pharmacokinetic parameters of some of the compounds of the present invention and the reference compound BMS-986120 are as follows:

结果显示：本发明所述化合物在血浆最高浓度，静脉给药产生的暴露量方面性质明显优于参考化合物BMS-986120。The results show that the compound of the present invention is superior in nature to the reference compound BMS-986120 in the highest concentration of plasma and the exposure by intravenous administration.

实施例63Example 63

溶解性实验测试：Solubility test:

1.摘要：以化合物在磷酸盐缓冲溶液pH＝7.4的溶解度考察专利化合物溶解性是否有显著改善。1. Abstract: The solubility of the compound in the phosphate buffer solution at pH=7.4 was investigated to see if there was a significant improvement in the solubility of the patented compound.

2.实验方法：2. Experimental method:

1)配制pH＝7.4磷酸盐缓冲溶液1) Prepare pH=7.4 phosphate buffer solution

2)对照品溶液的配制：各化合物精密称定，置于5mL具塞玻璃试管中，用少量DMSO溶解，并用pH＝7.4磷酸盐缓冲溶液稀释到0.5mg/mL,作为各化合物的自身对照品溶液。2) Preparation of reference solution: Each compound was accurately weighed, placed in a 5 mL stoppered glass test tube, dissolved in a small amount of DMSO, and diluted to 0.5 mg/mL with a pH=7.4 phosphate buffer solution as a self-control for each compound. Solution.

3)化合物的溶解度的测定：各化合物精密称定，置于5mL具塞玻璃试管中，加入pH＝7.4磷酸盐缓冲溶液1mL,超声至药物不再溶解(若完全溶解，继续称定加入化合物)，放入恒温振荡器中温度保持在37±1℃，振摇24h,将饱和溶液用0.45μm微孔滤膜过滤，并取0.1mL用pH＝7.4磷酸盐缓冲溶液稀释到1mL，即为待测化合物的溶解度溶液。3) Determination of solubility of the compound: Each compound was accurately weighed, placed in a 5 mL stoppered glass test tube, and added with a pH=7.4 phosphate buffer solution 1 mL, sonicated until the drug no longer dissolved (if completely dissolved, continue to be added to the compound) Put in a constant temperature oscillator and keep the temperature at 37±1°C, shake for 24h, filter the saturated solution with 0.45μm microporous membrane, and take 0.1mL diluted to 1mL with pH=7.4 phosphate buffer solution. The solubility solution of the compound is measured.

4)取自身对照品溶液及该待测化合物的溶解度溶液进入液相色谱，以外表峰面积法计算化合物在pH＝7.4磷酸盐缓冲溶液的溶解度，相关测定结果见下表。4) Take the self-control solution and the solubility solution of the test compound into the liquid chromatography, and calculate the solubility of the compound in the phosphate buffer solution at pH=7.4 by the peak area method. The relevant measurement results are shown in the following table.

实验结果Experimental result

	Compd CodeCompd Code	Solubility in PBS(pH＝7.4)Solubility in PBS (pH=7.4)
00	BMS-986120BMS-986120	0.04μM0.04μM
11	SAL02-166SAL02-166	39.24μM39.24μM
22	SAL02-191SAL02-191	2.11μM2.11μM
33	SAL02-206SAL02-206	0.98μM0.98μM
44	SAL02-207SAL02-207	0.28μM0.28μM
55	SAL02-208SAL02-208	0.20μM0.20μM
66	SAL02-210SAL02-210	2.75μM2.75μM
77	SAL02-211SAL02-211	0.69μM0.69μM
88	SAL02-212SAL02-212	0.21μM0.21μM
99	SAL02-216SAL02-216	0.25μM0.25μM
1010	SAL02-218SAL02-218	0.21μM0.21μM

结果显示：本发明所述化合物相比参考化合物BMS-986120溶解性有明显改善。The results show that the compound of the present invention has a significant improvement in solubility compared to the reference compound BMS-986120.

Claims

作为用于治疗血小板聚集的蛋白酶激活受体4(PAR4)抑制剂的化合物或其药学上可接受的盐，其特征在于，所述化合物的母核如下式(I)所示：A compound or a pharmaceutically acceptable salt thereof, which is a protease activated receptor 4 (PAR4) inhibitor for treating platelet aggregation, characterized in that the mother nucleus of the compound is represented by the following formula (I):

其中，X选自羰基、硫羰基、亚砜基和砜基；Wherein X is selected from the group consisting of a carbonyl group, a thiocarbonyl group, a sulfoxide group, and a sulfone group;

W、Y和Z分别独立选自CH，N；W, Y and Z are each independently selected from CH, N;

n＝1,2,3,4；n=1, 2, 3, 4;

R ₁选自氢，卤素，C _1-4的烷氧基，C _1-4的烷硫基； R _{1 is} selected from the group consisting of hydrogen, halogen, C _1-4 alkoxy, C _1-4 alkylthio;

R ₂选自取代或非取代的C _1-4的烷氧基，所述取代基选自卤素； R _{2 is} selected from a substituted or unsubstituted C _1-4 alkoxy group, said substituent being selected from halogen;

R ₃选自羟基，C _1-4的烷氧基，取代或者非取代C _6-12的芳基、C _6-10杂芳基、C _3-6杂环烷基、噻唑、噁唑、咪唑，所述取代基选自卤素；以及-NR ₄R ₅，其中，R ₄、R ₅选自氢、羟基，取代或者非取代的C _1-6的烷基、C _1-4的烷氧基、C _3-12的环烷基，所述取代基选自卤素、氰基、C _6-12的芳基、C _6-10杂芳基、C _3-6的杂环烷基、C _3-6的环烷基、C _1-4的氨基，所述C _6-12的芳基、C _6-10杂芳基可进一步C _1-6的烷基、羟基所取代。 R _{3 is} selected from hydroxy, C _1-4 alkoxy, substituted or unsubstituted C _6-12 aryl, C _6-10 heteroaryl, C _3-6 heterocycloalkyl, thiazole, oxazole, imidazole The substituent is selected from a halogen; and -NR ₄ R ₅ , wherein R ₄ , R _{5 are} selected from hydrogen, hydroxy, substituted or unsubstituted C _1-6 alkyl, C _1-4 alkoxy a C _3-12 cycloalkyl group selected from the group consisting of halogen, cyano, C _6-12 aryl, C _6-10 heteroaryl, C _3-6 heterocycloalkyl, C _{3 - The 6} -cycloalkyl group, the C _1-4 amino group, the C _6-12 aryl group and the C _6-10 heteroaryl group may be further substituted with a C _1-6 alkyl group or a hydroxyl group.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述C _1-4的烷氧基选自甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C _1-4 alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, and Butoxy, isobutoxy, sec-butoxy, tert-butoxy.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述C _1-4的烷硫基选自甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the C _1-4 alkylthio group is selected from the group consisting of methylthio, ethylthio, propylthio, isopropylthio, and Butylthio, isobutylthio, sec-butylthio, tert-butylthio.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述卤素选自氟、氯、溴、碘。The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述C _6-12的芳基选自

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the C _6-12 aryl group is selected from

C _6-10杂芳基选自

C _6-10 heteroaryl is selected from

C _3-6杂环烷基选自

C _3-6 heterocycloalkyl is selected from

所述C _1-6的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲基环丙烷基、正戊基、异戊基、叔丁基甲基、正己基、异己基、甲基环丁烷基、甲基环戊烷基；所述C _3-12的环烷基选自环丙烷、环丁烷、环戊烷、环己烷、三环[3.3.1.13.7]癸烷、双环[1.1.1]戊烷。 The C _1-6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methylcyclopropane, n-pentyl , isoamyl, tert-butylmethyl, n-hexyl, isohexyl, methylcyclobutane, methylcyclopentanyl; said C _3-12 cycloalkyl is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane Alkane, cyclohexane, tricyclo[3.3.1.13.7] decane, bicyclo[1.1.1]pentane.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，C _1-4的氨基选自甲氨基、乙氨基、二甲氨基、丙氨基、异丙胺基、正丁氨基、异丁氨基、仲丁氨基和叔丁氨基。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the amino group of C _1-4 is selected from the group consisting of methylamino, ethylamino, dimethylamino, propylamino, isopropylamino, n-butylamino, and iso Butylamino, sec-butylamino and tert-butylamino.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述化合物的母核如下式(II)所示，The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the mother nucleus of the compound is represented by the following formula (II),

其中，R ₁、R ₂、R ₄、R ₅、W、Y、Z、n如上定义。 Wherein R ₁ , R ₂ , R ₄ , R ₅ , W, Y, Z, and n are as defined above.
根据权利要求1所述化合物或其药学上可接受的盐，其特征在于，所述药学上可接受的盐选自无机酸或有机酸成盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、甲酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、氢碳酸、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、三氟乙酸、单宁酸、酒石酸和对甲苯磺酸。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic or organic acid salts, and the inorganic or organic acid is selected from the group consisting of 2- Acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrogen carbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, rich Horse acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, Maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid Succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid and p-toluenesulfonic acid.
根据权利要求1所述化合物，其特征在于，选自以下化合物：A compound according to claim 1 which is selected from the group consisting of:
一种药物组合物，其特征在于，包括如权利要求1-9任一项中定义的化合物或其药学上可接受的盐和药学上可接受的载体。A pharmaceutical composition comprising a compound as defined in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
如权利要求1-9任一项中定义的化合物或其药学上可接受的盐在制备用于制备治疗血栓相关疾病的药物用途。A pharmaceutical use as defined in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a thrombosis-related disease.
根据权利要求11的用途，其特征在于，所述血栓相关疾病选自动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、脑血管血栓栓塞性病症、和心脏腔室或外周循环中的血栓栓塞性病症。The use according to claim 11, wherein said thrombotic-related disease is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, an intravenous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a cardiac chamber or peripheral circulation. A thromboembolic disorder.