技术领域technical field
本发明属于药物学领域，具体涉及一种含氮杂环链接的苯丙酸类化合物、其药物学上可接受的盐、立体异构体或其前药分子，其药物组合物，制备方法，以及其在制备治疗糖尿病及糖脂代谢紊乱的药物中的用途，尤其是在制备治疗Ⅱ型糖尿病的药物的用途。上述化合物具有显著的降血糖及调节糖脂代谢活性的功能。The invention belongs to the field of pharmacy, and specifically relates to a phenylpropionic acid compound with a nitrogen-containing heterocyclic link, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule, its pharmaceutical composition, and its preparation method. And its use in the preparation of medicines for treating diabetes and glucose and lipid metabolism disorders, especially the use in the preparation of medicines for treating type II diabetes. The above-mentioned compound has obvious functions of lowering blood sugar and regulating glucose and lipid metabolism activity.
背景技术Background technique
众所周知，糖尿病是继肿瘤、心脑血管疾病后位列第三的严重威胁人类健康的慢性疾病。2011年世界卫生组织的报告指出全世界有3.66亿人罹患糖尿病。在我国，糖尿病患者总人数已超过9000万，并且每年还以350万至400万人的幅度递增。鉴于目前严峻的形势，开发新型治疗糖尿病的药物是非常有必要的。As we all know, diabetes is the third chronic disease that seriously threatens human health after tumors and cardiovascular and cerebrovascular diseases. According to the World Health Organization report in 2011, 366 million people worldwide suffer from diabetes. In my country, the total number of diabetic patients has exceeded 90 million, and the number is increasing by 3.5 million to 4 million every year. In view of the current severe situation, it is very necessary to develop new drugs for the treatment of diabetes.
糖尿病按照病因、临床表现和并发症的不同分为Ⅰ型和Ⅱ型糖尿病。Ⅰ型糖尿病的特征是缺乏胰岛素分泌能力，称为胰岛素依赖型糖尿病（IDDM），Ⅱ型糖尿病则是由于自身无法有效利用胰岛素造成，称为非胰岛素依赖型糖尿病（NIDDM）。Ⅱ型糖尿病患者占全球糖尿病总数的90%以上。Ⅱ型糖尿病的糖尿病的发病机制复杂，其基本特征是骨骼肌、肝脏、脂肪等组织对胰岛素产生抵抗。病程早期患者胰岛β细胞可代偿性分泌胰岛素以抵消胰岛素作用的缺陷，从而维持机体正常的血糖水平。然而，随着病程的发展，胰岛β细胞胰岛素分泌功能不足，患者的代偿机制崩溃，导致机体血糖水平异常升高，进而产生体内糖脂代谢紊乱发生Ⅱ型糖尿病。Diabetes is divided into type Ⅰ and type Ⅱ diabetes according to the etiology, clinical manifestations and complications. Type 1 diabetes is characterized by a lack of insulin secretion, known as insulin-dependent diabetes mellitus (IDDM), and type 2 diabetes is caused by the inability to effectively use insulin itself, known as non-insulin-dependent diabetes mellitus (NIDDM). Type Ⅱ diabetes patients account for more than 90% of the total number of diabetes in the world. The pathogenesis of type Ⅱ diabetes is complex, and its basic feature is that skeletal muscle, liver, fat and other tissues are resistant to insulin. In the early stage of the disease, the pancreatic β cells can compensatoryly secrete insulin to counteract the defect of insulin action, so as to maintain the body's normal blood sugar level. However, as the course of the disease progresses, the insulin secretion function of the pancreatic β cells is insufficient, and the patient's compensatory mechanism collapses, resulting in an abnormal increase in the body's blood sugar level, which in turn leads to a disorder of glucose and lipid metabolism in the body and type Ⅱ diabetes.
鉴于目前糖尿病的发病形势严峻，开发治疗糖尿病的药物迫在眉睫。目前针对糖尿病的新药研发主要集中在两方面。一方面，药物开发者期待在现有作用靶点的基础上寻找更加有效和低毒的新一代药物；另一方面是积极研究糖尿病的发病机制，寻找与糖尿病有关的新型靶点，并针对这些新靶点设计具有全新作用机制的、具有自主知识产权的新药。In view of the severe situation of diabetes at present, it is imminent to develop drugs for the treatment of diabetes. At present, the research and development of new drugs for diabetes mainly focuses on two aspects. On the one hand, drug developers look forward to finding a new generation of drugs that are more effective and less toxic based on existing targets; on the other hand, they are actively studying the pathogenesis of diabetes, looking for new targets related to diabetes, and targeting these New targets design new drugs with brand-new mechanism of action and independent intellectual property rights.
GTP蛋白耦联受体40（GTP-binding protein coupling receptor40,GPR40)是一个七次跨膜受体。在胰岛中表达丰富，另外在肠道系统中也有所表达。现有的研究结果显示，这种跨膜受体可能与某些癌症、神经类疾病和代谢性疾病有关，尤其是糖尿病。研究发现，各种形式的游离脂肪酸（free fatty acid,FFA）是GPR40的天然配体。FFA可以通过激活胰岛β细胞膜上的GPR40放大葡萄糖刺激的胰岛素分泌。鉴于GPR40受体激动剂具有葡萄糖依赖性的促进胰岛素分泌的优势，使其成为治疗糖尿病的潜在靶点。GTP protein coupling receptor 40 (GTP-binding protein coupling receptor40, GPR40) is a seven transmembrane receptor. It is abundantly expressed in pancreatic islets and is also expressed in the intestinal system. Existing research results show that this transmembrane receptor may be related to certain cancers, neurological diseases and metabolic diseases, especially diabetes. Studies have found that various forms of free fatty acid (FFA) are natural ligands of GPR40. FFA can amplify glucose-stimulated insulin secretion by activating GPR40 on the islet β-cell membrane. Given that GPR40 receptor agonists have the advantage of promoting insulin secretion in a glucose-dependent manner, they become potential targets for the treatment of diabetes.
针对此靶标各大制药公司以及研究机构研究开发了多个系列的化合物。目前，已经报道进入临床的化合物有三个，其中日本TAKEDA公司的化合物TAK-875已经进入III期临床实验，Aiming at this target, major pharmaceutical companies and research institutions have researched and developed multiple series of compounds. At present, there are three compounds that have been reported to enter the clinic, among which the compound TAK-875 of Japan’s TAKEDA company has entered phase III clinical trials.
美国礼来公司的LY-2881835则在新加坡进入了I期临床实验，而日本tobacco公司的JTT-851也在日本进入了II期临床实验，但目前并没有公布所选取化合物的具体结构，而该公司的专利WO2009054479A1保护的化合物通式如下所示：LY-2881835 of Eli Lilly and Company of the United States has entered phase I clinical trial in Singapore, while JTT-851 of Japanese tobacco company has also entered phase II clinical trial in Japan, but the specific structure of the selected compound has not been announced at present, and this The general formula of the compound protected by the company's patent WO2009054479A1 is as follows:
根据文献（Expert Opin.Ther.Pat.2009,19,237-264;Bioorg.Med.Chem.Lett.2006,16,1840-1845;Bioorg.Med.Chem.Lett.2010,20,1298-1301;J.Med.Chem.2007,50,2807-2817.;Org.Process Res.Dev.2011,15,104-111.;ACSMed.Chem.Lett.2010,1,345-349.;J.Med.Chem.2008,51,7061-7064.;J.Med.Chem.2011,54,6691-6703.）报道，目前处于临床前研究阶段并且公布具体结构式的化合物如下所示：According to literature (Expert Opin.Ther.Pat.2009,19,237-264; Bioorg.Med.Chem.Lett.2006,16,1840-1845; Bioorg.Med.Chem.Lett.2010,20,1298-1301; J. Med.Chem.2007,50,2807-2817.;Org.Process Res.Dev.2011,15,104-111.;ACSMed.Chem.Lett.2010,1,345-349.;J.Med.Chem.2008,51, 7061-7064.; J.Med.Chem.2011, 54, 6691-6703.) reported that the compounds currently in the preclinical research stage and published specific structural formulas are as follows:
发明内容Contents of the invention
本发明涉及具有下面通式I所示结构的化合物，其与已报道化合物的结构明显不同。本发明的化合物具有显著的降血糖及调节糖脂代谢活性的功能，是一类新型GPR40激动剂。The present invention relates to compounds having the structure shown in the following general formula I, which is obviously different from the structures of the reported compounds. The compound of the present invention has significant functions of lowering blood sugar and regulating glucose and lipid metabolism activity, and is a new type of GPR40 agonist.
本发明的一个目的是提供如下通式I所示的苯丙酸类化合物、或者其药学上可接受的盐、或其对映异构体、外消旋体及其混合物、或其立体异构体，或其前药分子。One object of the present invention is to provide the phenylpropionic acid compound shown in the following general formula I, or its pharmaceutically acceptable salt, or its enantiomer, racemate and mixture thereof, or its stereoisomer body, or its prodrug molecule.
本发明的另一个目的是提供了通式I所示的苯丙酸类化合物的制备方法。Another object of the present invention is to provide the preparation method of the phenylpropionic acid compound shown in general formula I.
本发明的另一目的是提供一种药物组合物，其包含治疗有效量的选自通式I所示的苯丙酸类化合物、其药学上可接受的盐、其对映异构体、外消旋体及其混合物、其立体异构体和其前药分子中的一种或多种和药学上可接受的辅料。Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of phenylpropionic acid compounds represented by general formula I, its pharmaceutically acceptable salts, its enantiomers, exogenous One or more of the racemate and its mixture, its stereoisomer and its prodrug molecule, and pharmaceutically acceptable auxiliary materials.
本发明的又一个目的是提供了选自通式I所示的苯丙酸类化合物、其药学上可接受的盐、其对映异构体、外消旋体及其混合物、其立体异构体和其前药分子中的一种或多种在制备治疗糖尿病及糖脂代谢紊乱的药物中的用途。Another object of the present invention is to provide phenylpropionic acid compounds selected from general formula I, its pharmaceutically acceptable salts, its enantiomers, racemates and mixtures thereof, and its stereoisomers Use of one or more of the body and its prodrug molecules in the preparation of drugs for treating diabetes and glucose and lipid metabolism disorders.
本发明的再一目的是提供一种治疗糖尿病及糖脂代谢紊乱的方法，其包括向需要该治疗的对象给药选自通式I所示的苯丙酸类化合物或者其药学上可接受的盐、其对映异构体、外消旋体及其混合物、立体异构体和其前药分子中的一种或多种。Another object of the present invention is to provide a method for treating diabetes and disorders of glucose and lipid metabolism, which includes administering a phenylpropionic acid compound selected from general formula I or a pharmaceutically acceptable compound thereof to a subject in need of the treatment. One or more of salts, enantiomers, racemates and mixtures thereof, stereoisomers and prodrug molecules thereof.
本发明的一个方面提供了通式I所示的苯丙酸类化合物：One aspect of the present invention provides phenylpropionic acid compounds shown in general formula I:
（I）(I)
其中，in,
X为H、D或F；X is H, D or F;
R1和R2各自独立选自H、羟基、卤素、硝基、C1-C20烷基、卤代C1-C20烷基、C1-C20烷氧基、卤代C1-C20烷氧基、C3-C10环烷基和含有选自S、O和N中的1至3个杂原子的3至10元杂环基；优选选自H、羟基、卤素、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基和含有至少一个氮原子的3至10元杂环基；更优选地各自独立地选自H、羟基、卤素、硝基、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C8环烷基和氮杂环丙烷-1-基；R1 and R2 are each independently selected from H, hydroxyl, halogen, nitro, C1 -C20 alkyl, halogenated C1 -C20 alkyl, C1 -C20 alkoxy, halogenated C1 - C20 alkoxy, C3 -C10 cycloalkyl and 3 to 10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from S, O and N; preferably selected from H, hydroxyl, halogen, nitric acid group, C1 -C6 alkyl, halogenated C1 -C6 alkyl, C1 -C6 alkoxy, halogenated C1 -C6 alkoxy, C3 -C8 cycloalkyl and containing 3 to 10 membered heterocyclic group with at least one nitrogen atom; more preferably each independently selected from H, hydroxyl, halogen, nitro, C1 -C4 alkyl, halogenated C1 -C4 alkyl, C1 -C4 alkoxy, halogenated C1 -C4 alkoxy, C3 -C8 cycloalkyl and aziridine-1-yl;
R3选自H；卤素；羧基；C1-C20烷基；卤代C1-C20烷基；-ORa；-N(Ra)SO2Rb、-NRaRb；-N(Ra)C(O)Rb；-C(O)NRaRb；-SO2Ra；-SRb；用选自C1-C10烷氧基、C3-C10环烷基、-SRc、-SO2Rc、-NRcRd或未取代或者被C1-C6烷基、羟基或氧代基团取代的含有选自O、S和N中的1～3个杂原子的3-8元杂环基中的取代基取代的C1-C20烷氧基；和用C1-C10烷氧基、C3-C10环烷基、-SRc、-SO2Rc或-NRcRd取代的C1-C20烷基；R3 isselected from H; halogen; carboxyl; C1-C20 alkyl;halogenated C1 -C20alkyl; N(Ra )C(O)Rb ; -C(O)NRa Rb ;-SO2 Ra ;-SRb; Alkyl, -SRc , -SO2 Rc , -NRc Rd or unsubstituted or substituted by C1 -C6 alkyl, hydroxyl or oxo group containing 1 selected from O, S and N C1 -C20 alkoxy substituted by substituents in a 3-8 membered heterocyclic group of ~ 3 heteroatoms; and C1 -C10 alkoxy, C3 -C10 cycloalkyl, -SRc , -SO2 Rc or -NRc Rd substituted C1 -C20 alkyl;
R3优选选自H；卤素；羧基；C1-C6烷基；卤代C1-C6烷基；-ORa；-N(Ra)SO2Rb；-NRaRb；-N(Ra)C(O)Rb；-C(O)NRaRb；-SO2Ra；-SRb；用选自C1-C4烷氧基、C3-C8环烷基、-SRc、-SO2Rc、-NRcRd或未取代或者被C1-C4烷基、羟基或氧代基团取代的含有选自O、S和N中的1～3个杂原子的3-6元杂环基中的取代基取代的C1-C6烷氧基；和用C1-C4烷氧基、C3-C8环烷基、-SRc、-SO2Rc或-NRcRd取代的C1-C6烷基；R3 is preferably selected from H; halogen; carboxyl; C1 -C6 alkyl; halogenated C1 -C6 alkyl; -ORa ; -N(Ra) SO2 Rb; -N(Ra )C(O)Rb ; -C(O)NRa Rb ;-SO2 Ra ;-SRb; Cycloalkyl, -SRc , -SO2 Rc , -NRc Rd or unsubstituted or substituted by C1 -C4 alkyl, hydroxyl or oxo group containing a group selected from O, S and N A C1 -C6 alkoxy group substituted by a substituent in a 3-6 membered heterocyclic group with 1 to 3 heteroatoms; and a C1 -C4 alkoxy group, a C3 -C8 cycloalkyl group, - C1 -C6 alkyl substituted by SRc , -SO2 Rc or -NRc Rd ;
R3进一步优选选自H；卤素；羧基；C1-C6烷基；卤代C1-C6烷基；-ORa；-N(Ra)SO2Rb；-NRaRb；-N(Ra)C(O)Rb；-C(O)NRaRb；-SO2Ra；-SRb；用选自C1-C4烷氧基、C3-C6环烷基、-SRc、-SO2Rc、-NRcRd或未取代或者被C1-C4烷基、羟基或氧代基团取代的含有选自O、S和N中的1～3个杂原子的3-6元杂环基中的取代基取代的C1-C4烷氧基；和用C1-C4烷氧基、C3-C6环烷基、-SRc、SO2Rc或NRcRd取代的C1-C4烷基；R3 is further preferably selected from H; halogen; carboxyl; C1 -C6 alkyl; halogenated C1 -C6 alkyl; -ORa ; -N(Ra) SO2 Rb; ;-N(Ra )C(O)Rb ;-C(O)NRa Rb ;-SO2 Ra ;-SRb;6 Cycloalkyl, -SRc , -SO2 Rc , -NRc Rd or unsubstituted or substituted by C1 -C4 alkyl, hydroxyl or oxo group containing selected from O, S and N A C1 -C4 alkoxy group substituted by a substituent in a 3-6 membered heterocyclic group with 1 to 3 heteroatoms; and a C1 -C4 alkoxy group, a C3 -C6 cycloalkyl group, C1 -C4 alkyl substituted by -SRc , SO2 Rc or NRc Rd ;
其中，in,
Ra和Rb各自独立选自H、C1-C6烷基、C3-C8环烷基和未取代或者被C1-C6烷基或氧代基团取代的含有选自O、S和N中的1～3个杂原子的3-8元杂环基；优选各自独立选自H、C1-C4烷基、C3-C6环烷基和未取代或者被C1-C3烷基或氧代基团取代的含有选自O、S和N中的1～3个杂原子的3-6元杂环基；Ra and Rb are each independently selected from H, C1 -C6 alkyl, C3 -C8 cycloalkyl, and unsubstituted or substituted by C1 -C6 alkyl or oxo groups containing selected from O , 3-8 membered heterocyclic groups with 1 to 3 heteroatoms in S and N; preferably each independently selected from H, C1 -C4 alkyl, C3 -C6 cycloalkyl and unsubstituted or replaced by C A 3-6 membered heterocyclic group containing 1 to3 heteroatoms selected from O, S and N substituted by a1 -C3 alkyl or oxo group;
Rc和Rd各自独立地选自H、C1-C6烷基和未取代或者被C1-C3烷基取代的含有选自O、S和N中的1～3个杂原子的3-8元杂环基；优选各自独立地选自H、C1-C3烷基和未取代或者被C1-C3烷基取代的含有选自O、S和N中的1～3个杂原子的3-6元杂环基；Rc and Rd are each independently selected from H, C1 -C6 alkyl and unsubstituted or substituted by C1 -C3 alkyl containing 1 to 3 heteroatoms selected from O, S and N 3-8 membered heterocyclic group; preferably each independently selected from H, C1 -C3 alkyl and unsubstituted or substituted by C1 -C3 alkyl containing 1 to 3 selected from O, S and N 3-6 membered heterocyclic groups of heteroatoms;
R4选自H、羟基、卤素、C1-C20烷基和卤代C1-C20烷基；优选选自H、羟基、卤素、C1-C6烷基和卤代C1-C6烷基，R4 is selected from H, hydroxyl, halogen, C1 -C20 alkyl and halogenated C1 -C20 alkyl; preferably selected from H, hydroxyl, halogen, C1 -C6 alkyl and halogenated C1 - C6 alkyl,
R5选自H、卤素和C1-C20烷基；优选选自H、卤素和C1-C6烷基；R is selected from H, halogen and C1 -C20 alkyl; preferably selected from H, halogen and C1 -C6 alkyl;
或者R4和R5连同和其相连的碳原子与苯环一起形成苯并5-8元杂环基，所述杂环上含有选自O、N和S中的1～3个杂原子，且所述杂环基未被取代或者被C1-C6烷基取代；优选R4和R5连同和其相连的碳原子与苯环一起形成苯并5元杂环基，该5元杂环基含有选自O、N和S中的1～2个杂原子，且未被取代或者被C1-C3烷基取代；进一步优选地，R4和R5连同和其相连的碳原子与苯环一起形成Or R4 and R5 together with the carbon atom connected to it and the benzene ring form a benzo 5-8 membered heterocyclic group, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, N and S, And the heterocyclic group is unsubstituted or substituted by C1 -C6 alkyl; preferably R4 and R5 together with the carbon atom connected to it and the benzene ring form a benzo 5-membered heterocyclic group, the 5-membered heterocyclic group The ring group contains 1 to 2 heteroatoms selected from O, N and S, and is unsubstituted or substituted by C1 -C3 alkyl; more preferably, R4 and R5 together with the carbon atoms connected to them form with benzene ring
进一步地，本发明的通式I所示的苯丙酸类化合物具有如下通式II或通式III所示的结构：Further, the phenylpropionic acid compound represented by the general formula I of the present invention has the structure shown in the following general formula II or general formula III:
其中，X、R1～R5的定义与上述相同；R6为H或C1-C6烷基，以及在通式III中，当Z为O或S时，R6不存在。Wherein, the definitions of X, R1 to R5 are the same as above; R6 is H or C1 -C6 alkyl, and in the general formula III, when Z is O or S, R6 does not exist.
在本发明中，术语“卤素”包括氟、氯、溴和碘。术语“卤代”指的是用单个或多个选自氟、氯、溴和碘中的卤素原子取代。In the present invention, the term "halogen" includes fluorine, chlorine, bromine and iodine. The term "halo" refers to substitution with one or more halogen atoms selected from fluorine, chlorine, bromine and iodine.
术语“C1-C20烷基”是指主链上具有1至20个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、已基、辛基、癸基、十一烷基、十二烷基、十四烷基、十六烷基、十七烷基、十八烷基、二十烷基等。术语“C1-C6烷基”和“C1-C4烷基”具有类似的含义。The term "C1 -C20 alkyl" refers to a straight chain or branched chain alkyl group having 1 to 20 carbon atoms in the main chain, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, heptadecyl Alkyl, octadecyl, eicosyl, etc. The terms "C1 -C6 alkyl" and "C1 -C4 alkyl" have similar meanings.
术语“C1-C20烷氧基”是指主链上具有1至20个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、戊氧基、已氧基、辛氧基、癸氧基、十一烷氧基、十二烷氧基、十四烷氧基、十六烷氧基、十七烷氧基、十八烷氧基、二十烷氧基等。术语“C1-C10烷氧基”、“C1-C6烷氧基”和“C1-C4烷氧基”具有类似的含义。The term "C1 -C20 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 20 carbon atoms in the main chain, including without limitation methoxy, ethoxy, n-propoxy , isopropoxy, butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, hexadecyloxy, Heptadecyloxy, octadecyloxy, eicosyloxy, etc. The terms "C1 -C10 alkoxy", "C1 -C6 alkoxy" and "C1 -C4 alkoxy" have similar meanings.
术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基和环庚基；术语“C3-C8环烷基”和“C3-C6环烷基”具有类似的含义。The term "C3 -C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo Heptyl; the terms "C3 -C8 cycloalkyl" and "C3 -C6 cycloalkyl" have similar meanings.
术语“3-8元杂环基”是指环上具有3-8个原子的含有选自N、O和S原子中的至少一个原子的非芳香族环基，如环氧基、吡咯烷基、吗啉基等；术语“5-8元杂环基”和“3-6元杂环基”具有类似的含义。The term "3-8 membered heterocyclic group" refers to a non-aromatic ring group containing at least one atom selected from N, O and S atoms with 3-8 atoms on the ring, such as epoxy group, pyrrolidinyl group, Morpholinyl, etc.; the terms "5-8 membered heterocyclic group" and "3-6 membered heterocyclic group" have similar meanings.
本发明中的术语“药学上可接受的盐”是指根据本发明的通式I所示的化合物与磷酸、硫酸、盐酸等无机酸，或醋酸、酒石酸、柠檬酸、苹果酸、富马酸等有机酸，或天冬氨酸、谷氨酸等酸性氨基酸形成的盐，或与上述酸成酯或酰胺后再与无机碱形成的盐，如钠、钾、钙、铝盐和铵盐。The term "pharmaceutically acceptable salt" in the present invention refers to the compounds shown in general formula I according to the present invention and inorganic acids such as phosphoric acid, sulfuric acid, hydrochloric acid, or acetic acid, tartaric acid, citric acid, malic acid, fumaric acid Such as organic acids, or salts of acidic amino acids such as aspartic acid and glutamic acid, or salts formed with inorganic bases after forming esters or amides with the above acids, such as sodium, potassium, calcium, aluminum salts and ammonium salts.
本发明所述化合物优选选自下列化合物：The compounds according to the invention are preferably selected from the following compounds:
本发明的另一个方面公开了根据本发明的通式I所示的苯丙酸类化合物的制备方法，其为下列方法之一。Another aspect of the present invention discloses the preparation method of the phenylpropionic acid compound represented by the general formula I according to the present invention, which is one of the following methods.
方法一：如下面反应式1所示：Method 1: As shown in Reaction Formula 1 below:
反应式1Reaction 1
步骤1：将R4取代的对溴苄醇1和丙烯酸乙酯2经过Heck反应得到中间体3，将双键还原得到中间体4，再经过溴化反应把苄醇变成苄溴得到中间体5；所述Heck反应可以在例如醋酸钯、四（三苯基膦）钯或二（三苯基膦）二氯化钯等钯金属催化剂存在下在例如N,N-二甲基甲酰胺或三乙胺等溶剂中进行；所述双键还原反应可以在例如钯碳复合物催化剂存在下在例如乙酸乙酯、乙酸丁酯、甲醇、乙醇或正丙醇等溶剂中使用例如氢气作为还原剂进行；所述溴化反应可以使用例如三溴化磷，五溴化磷，三溴氧磷或二溴亚砜等溴化剂在例如乙腈、二氯甲烷或乙醚等溶剂中进行；Step1 : R4 substituted p-bromobenzyl alcohol 1 and ethyl acrylate 2 undergo Heck reaction to obtain intermediate 3, reduce the double bond to obtain intermediate 4, and then undergo bromination reaction to change benzyl alcohol into benzyl bromide to obtain intermediate 5; the Heck reaction can be in the presence of palladium metal catalysts such as palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride in the presence of, for example, N,N-dimethylformamide or Carry out in solvents such as triethylamine; The double bond reduction reaction can use such as hydrogen as a reducing agent in solvents such as ethyl acetate, butyl acetate, methanol, ethanol or n-propanol in the presence of a palladium carbon composite catalyst Carry out; The bromination reaction can use bromination agents such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or thionyl bromide in solvents such as acetonitrile, dichloromethane or ether;
步骤2：将中间体5和底物6经过亲核取代反应得到中间体7；所述亲核取代反应可以在例如碳酸钾、碳酸铯、氢化钠、氢化钾、叔丁醇钾、叔丁醇钠或氢氧化钠等碱存在下在例如乙腈、N,N-二甲基甲酰胺或四氢呋喃的溶剂中进行；Step 2: intermediate 5 and substrate 6 are subjected to nucleophilic substitution reaction to obtain intermediate 7; In the presence of a base such as sodium or sodium hydroxide in a solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran;
步骤3：中间体7和经过Suzuki反应偶联得到中间体8，再将中间体8经过水解反应得到产物9；Step 3: Intermediate 7 and Intermediate 8 was obtained through Suzuki reaction coupling, and then intermediate 8 was hydrolyzed to obtain product 9;
所述Suzuki反应可以在例如四（三苯基膦）钯、二（三苯基膦）二氯化钯、醋酸钯或钯碳复合物等催化剂存在下在例如甲苯/乙腈/水的混合溶剂、甲苯/乙醇/水的混合溶剂、乙腈/水的混合溶剂或乙醇/水的混合溶剂中进行；以及所述中间8的水解反应可以在例如氢氧化钾、氢氧化钠或氢氧化锂等碱的存在下在例如乙腈/水混合溶剂、甲醇/水混合溶剂或乙醇/水混合溶剂的溶剂中；The Suzuki reaction can be in the mixed solvent such as toluene/acetonitrile/water, Carry out in the mixed solvent of toluene/ethanol/water, the mixed solvent of acetonitrile/water or the mixed solvent of ethanol/water; In the presence of solvents such as acetonitrile/water mixed solvents, methanol/water mixed solvents or ethanol/water mixed solvents;
在上述步骤1～步骤3中，各个步骤的反应均在本领域普通技术人员公知的反应条件下进行。In the above steps 1 to 3, the reactions in each step are carried out under reaction conditions known to those skilled in the art.
方法二：如下面反应式2所示：Method 2: As shown in the following reaction formula 2:
反应式2Reaction 2
步骤1：化合物17（其中，Z为O或S，R6不存在）或20（其中，Z为N，R6为H或C1-C6烷基）和底物6经过亲核取代反应得到化合物21，所述亲核取代反应可以在例如碳酸钾、碳酸铯、氢化钠、叔丁醇钾或叔丁醇钠的催化剂的存在下在例如乙腈、丙酮、乙酸乙酯、四氢呋喃或N,N-二甲基甲酰胺的溶剂中进行；Step 1: Nucleophilic substitution reaction between compound 17 (where Z is O or S, and R6 does not exist) or 20 (where Z is N, R6 is H or C1 -C6 alkyl) and substrate 6 To obtain compound 21, the nucleophilic substitution reaction can be carried out in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or N, in the presence of a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium tert-butoxide or sodium tert-butoxide Carry out in the solvent of N-dimethylformamide;
步骤2：化合物21和经过Suzuki反应偶联得到中间体22，再将中间体22经过水解反应得到产物23；所述Suzuki反应可以在例如四（三苯基膦）钯、二（三苯基膦）二氯化钯、醋酸钯或钯碳复合物等催化剂存在下在例如甲苯/乙腈/水的混合溶剂、甲苯/乙醇/水的混合溶剂、乙腈/水的混合溶剂或乙醇/水的混合溶剂中进行；所述水解反应可以在例如氢氧化钾、氢氧化钠或氢氧化锂等碱的存在下在例如乙腈/水混合溶剂、甲醇/水混合溶剂或乙醇/水混合溶剂的溶剂中。Step 2: Compound 21 and Intermediate 22 is obtained through Suzuki reaction coupling, and then intermediate 22 is subjected to a hydrolysis reaction to obtain product 23; the Suzuki reaction can be, for example, tetrakis (triphenylphosphine) palladium, two (triphenylphosphine) palladium dichloride, In the presence of catalysts such as palladium acetate or palladium-carbon complexes, carry out in the mixed solvent of for example toluene/acetonitrile/water, the mixed solvent of toluene/ethanol/water, the mixed solvent of acetonitrile/water or the mixed solvent of ethanol/water; The hydrolysis The reaction can be performed in a solvent such as an acetonitrile/water mixed solvent, methanol/water mixed solvent or ethanol/water mixed solvent in the presence of a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide.
在上述步骤1～步骤2中，各个步骤的反应均在本领域普通技术人员公知的反应条件下进行。In the above steps 1 to 2, the reactions in each step are carried out under reaction conditions known to those skilled in the art.
作为一个实例，所述化合物17和20可以通过如下方法制备：As an example, the compounds 17 and 20 can be prepared by the following method:
反应式3Reaction 3
步骤1：将化合物10的羟基用保护剂保护得到化合物11，然后和氯乙酰氯经过傅克反应得到化合物12；Step 1: protect the hydroxyl group of compound 10 with a protecting agent to obtain compound 11, and then react with chloroacetyl chloride to obtain compound 12 through Friedel-Crafts reaction;
所述保护剂可以为乙酸酐、乙酰氯或乙酰溴，所述保护羟基的反应可以在例如三乙胺、二异丙基乙基胺或4-二甲氨基吡啶等催化剂存在下在例如二氯甲烷、三氯甲烷、乙腈、丙酮或乙酸乙酯等溶剂中进行；所述傅克反应可以在例如三氯化铝、二氯化锌或三氟化硼乙醚溶液等催化剂存在下在例如二氯甲烷、三氯甲烷或乙醚等溶剂中进行；The protecting agent can be acetic anhydride, acetyl chloride or acetyl bromide, and the reaction of protecting the hydroxyl group can be in the presence of catalysts such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, such as dichloro Carry out in solvents such as methane, chloroform, acetonitrile, acetone or ethyl acetate; The Friedel-Crafts reaction can be in the presence of catalysts such as aluminum trichloride, zinc dichloride or boron trifluoride ether solution, for example in dichloro Carried out in solvents such as methane, chloroform or ether;
步骤2：化合物12经过分子内亲核取代反应得到化合物13，然后和witting试剂经过witting反应得到化合物14；所述分子内亲核取代反应可以在例如醋酸钠、醋酸钾、碳酸钾、叔丁醇钾或叔丁醇钠等碱存在下在例如甲醇、乙醇或乙腈等溶剂中进行；所述witting反应可以在例如甲苯、苯或二甲苯等溶剂中进行Step 2: compound 12 obtains compound 13 through intramolecular nucleophilic substitution reaction, and then obtains compound 14 through witting reaction with witting reagent; described intramolecular nucleophilic substitution reaction can be in for example sodium acetate, potassium acetate, potassium carbonate, tert-butanol In the presence of bases such as potassium or sodium tert-butoxide, carry out in solvents such as methanol, ethanol or acetonitrile; the witting reaction can be carried out in solvents such as toluene, benzene or xylene
步骤3：化合物14经氢化还原反应得到化合物15，当Z=O或S时，化合物15经水解反应得到化合物16，化合物16经过溴化反应，然后再滴加入无水乙醇经过酯化反应得到化合物17；所述还原反应可以在例如钯碳的催化剂存在下在例如甲醇、乙醇或乙酸乙酯的溶剂中进行；所述水解反应可以在例如氢氧化钠、氢氧化钾或氢氧化锂的催化剂存在下在例如乙醇/水、甲醇/水或乙腈/水的溶剂中进行；所述溴化反应可以在例如三溴化磷，五溴化磷，三溴氧磷或二溴亚砜等溴化剂存在下在例如乙腈或乙酸乙酯的溶剂中进行；Step 3: Compound 14 is hydrogenated and reduced to obtain compound 15. When Z=O or S, compound 15 is hydrolyzed to obtain compound 16, compound 16 is subjected to bromination reaction, and then added dropwise to absolute ethanol to undergo esterification reaction to obtain compound 17; the reduction reaction can be carried out in a solvent such as methanol, ethanol or ethyl acetate in the presence of a catalyst such as palladium carbon; the hydrolysis reaction can be carried out in a catalyst such as sodium hydroxide, potassium hydroxide or lithium hydroxide Carried out in a solvent such as ethanol/water, methanol/water or acetonitrile/water; the bromination reaction can be carried out in brominating agents such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or thionyl bromide in the presence of a solvent such as acetonitrile or ethyl acetate;
步骤4：当Z=NH时，化合物15和R7I经烷基化反应得到化合物18，化合物18经水解反应得到化合物19，化合物19经过溴化反应，然后再滴加入无水乙醇经过酯化反应得到化合物20；所述烷基化反应可以在例如氢化钠、氢化钾、叔丁醇钾或叔丁醇钠等催化剂存在下在例如乙腈、丙酮或四氢呋喃N,N-二甲基甲酰胺等溶剂中进行；所述水解反应可以在例如氢氧化钠、氢氧化钾或氢氧化锂的催化剂存在下在例如乙醇/水、甲醇/水或乙腈/水的溶剂中进行；所述溴化反应可以在例如三溴化磷，五溴化磷，三溴氧磷或二溴亚砜等溴化剂存在下在例如乙腈或乙酸乙酯的溶剂中进行；Step 4: When Z=NH, compound 15 and R7 I undergo alkylation reaction to obtain compound 18, compound 18 undergoes hydrolysis reaction to obtain compound 19, compound 19 undergoes bromination reaction, and then adds absolute ethanol dropwise for esterification The reaction obtains compound 20; the alkylation reaction can be in the presence of catalysts such as sodium hydride, potassium hydride, potassium tert-butoxide or sodium tert-butoxide in for example acetonitrile, acetone or tetrahydrofuran N,N-dimethylformamide etc. Carry out in solvent; Said hydrolysis reaction can carry out in the solvent such as ethanol/water, methanol/water or acetonitrile/water under the catalyst presence of such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Described bromination reaction can be in a solvent such as acetonitrile or ethyl acetate in the presence of a brominating agent such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or thionyl bromide;
其中，Z为O、S或N，R7为C1-C6烷基；Wherein, Z is O, S or N, R7 is C1 -C6 alkyl;
在上述步骤1～步骤4中，各个步骤的反应均在本领域普通技术人员公知的反应条件下进行。In the above steps 1 to 4, the reactions in each step are carried out under the reaction conditions known to those skilled in the art.
在反应式1～3中，X，R1～R5的定义与上述X，R1～R5的定义相同。In Reaction Formulas 1 to 3, the definitions of X, R1 to R5 are the same as the definitions of X, R1 to R5 described above.
本发明的又一方面是提供了一种药物组合物，该药物组合物包含治疗有效量的选自上述通式I所示的苯丙酸类化合物、其对映异构体、外消旋体及其混合物和其药学上可接受的盐中一种或多种，及任选的药学上可接受的辅料。所述药物组合物可以用于治疗糖尿病或糖脂代谢紊乱。Another aspect of the present invention is to provide a pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of phenylpropionic acid compounds shown in the above general formula I, its enantiomers, racemates One or more of mixtures thereof and pharmaceutically acceptable salts thereof, and optional pharmaceutically acceptable auxiliary materials. The pharmaceutical composition can be used for treating diabetes or glucose and lipid metabolism disorder.
本发明的又一方面是提供了选自通式I所示的苯丙酸类化合物、其对映异构体、外消旋体及其混合物、其立体异构体、其前药分子以及其药学上可接受的盐中的一种或多种在制备治疗糖尿病或糖脂代谢紊乱的药物中的用途。Another aspect of the present invention provides phenylpropionic acid compounds selected from general formula I, its enantiomers, racemates and mixtures thereof, its stereoisomers, its prodrug molecules and its Use of one or more pharmaceutically acceptable salts in the preparation of medicines for treating diabetes or glucose and lipid metabolism disorders.
在本发明的又一个方面，提供了一种治疗糖尿病或糖脂代谢紊乱的方法，其包括向具有该需要的患者施用治疗有效量的选自根据本发明的苯丙酸类化合物、其对映异构体、外消旋体及其混合物、其立体异构体、其前药分子和其药学上可接受的盐中一种或多种，或者根据本发明的药物组合物。In yet another aspect of the present invention, there is provided a method for treating diabetes or disorders of glucose and lipid metabolism, which comprises administering to a patient in need a therapeutically effective amount of a phenylpropionic acid compound selected from the present invention, its enantiomer One or more of isomers, racemates and mixtures thereof, stereoisomers thereof, prodrug molecules thereof and pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to the present invention.
附图说明Description of drawings
图1为HYH-013单次给药对ob/ob小鼠血糖的影响(mM，n=8)*，P<0.05，与对照组相比；**，P<0.01，与对照组相比。Fig. 1 is the influence (mM, mM, n=8)*, P<0.05, compared with the control group; **, P<0.01, compared with the control group.
具体实施方式detailed description
以下通过实施例进一步说明本发明，但所述实施例并不限制本发明的范围。The present invention is further illustrated by the following examples, but the examples do not limit the scope of the present invention.
核磁共振氢谱用BrukerAMX-400型、Gemini-300型或AMX–600型核磁共振仪记录，化学位移δ的单位为ppm。比旋光由Perkin-Elmer241型自动旋光仪测定，所用微波为CEM-discovery微波反应器。所有反应溶剂均按照常规方法进行纯化。柱层析用硅胶(200-300目)为青岛海洋化工分厂生产。薄层层析使用GF254高效板，为烟台化工研究所生产。制备型薄层层析板由自己制备，固定相采用GF254(HG/T2354-92)硅胶和羧甲基纤维素钠(800-1200)制备，分别为青岛海洋化工有限公司和中国医药（集团）上海化学试剂公司生产。所有溶剂均为分析纯试剂，所用试剂均购自国药集团化学试剂有限公司。采用碘、紫外荧光等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。Proton NMR spectra were recorded with Bruker AMX-400, Gemini-300 or AMX-600 NMR instruments, and the unit of chemical shift δ was ppm. The specific rotation was measured by a Perkin-Elmer241 automatic polarimeter, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to conventional methods. Silica gel (200-300 mesh) for column chromatography was produced by Qingdao Ocean Chemical Branch Factory. Thin-layer chromatography uses GF254 high-efficiency plate, which is produced by Yantai Chemical Research Institute. The preparative thin-layer chromatography plate was prepared by ourselves, and the stationary phase was prepared by GF254 (HG/T2354-92) silica gel and sodium carboxymethyl cellulose (800-1200), respectively provided by Qingdao Ocean Chemical Co., Ltd. and China Pharmaceutical (Group) Co., Ltd. Produced by Shanghai Chemical Reagent Company. All solvents were analytical reagents, and the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Use iodine, ultraviolet fluorescence and other methods to develop color. The organic solvent was evaporated under reduced pressure in a rotary evaporator.
实施例1：3-(4-溴甲基苯基)丙酸乙酯的制备Embodiment 1: the preparation of 3-(4-bromomethylphenyl) ethyl propionate
称取4-溴苯甲醇1a（购自韶远化学科技（上海）有限公司，10.50g，56.0mmol，）溶于100mL三乙胺中，加入20.0mL丙烯酸乙酯2，醋酸钯（0.50g，2.2mmol），三苯基膦（0.50g，1.9mmol）。反应体系用氮气置换三次，然后置于油浴中95℃反应72小时，反应液冷却至室温，过滤，滤液浓缩后，硅胶柱层析(石油醚/乙酸乙酯=4/1)分离得到白色固体3a10.8g，产率93%。1H NMR(300MHz,CDCl3)：δ=7.67(d,J=16.0Hz,1H),7.51(d,J=8.1Hz,2H),7.38(d,J=8.1Hz,2H),6.42(d,J=16.0Hz,1H),4.72(d,J=5.4Hz,2H),4.26(q,J=7.2Hz,2H),1.33(t,J=7.1Hz,3H)。Weigh 4-bromobenzyl alcohol 1a (purchased from Shaoyuan Chemical Technology (Shanghai) Co., Ltd., 10.50 g, 56.0 mmol,) and dissolve it in 100 mL of triethylamine, add 20.0 mL of ethyl acrylate 2, palladium acetate (0.50 g, 2.2mmol), triphenylphosphine (0.50g, 1.9mmol). The reaction system was replaced with nitrogen three times, then placed in an oil bath at 95°C for 72 hours, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated, then separated by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a white Solid 3a 10.8 g, 93% yield.1 H NMR (300MHz, CDCl3 ): δ=7.67(d, J=16.0Hz, 1H), 7.51(d, J=8.1Hz, 2H), 7.38(d, J=8.1Hz, 2H), 6.42( d, J=16.0Hz, 1H), 4.72(d, J=5.4Hz, 2H), 4.26(q, J=7.2Hz, 2H), 1.33(t, J=7.1Hz, 3H).
将10.8g中间体3a溶解于100mL乙酸乙酯中，加入10%钯碳200mg，氢气置换三次后，室温下反应4小时，反应液垫硅藻土过滤，滤液浓缩后硅胶柱层析分离（乙酸乙酯/石油醚=1/8），得白色固体4a10.1g，产率93%。1H NMR(300MHz,CDCl3)：δ=7.29(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.65(s,2H),4.18–4.05(m,2H),2.94(t,J=7.8Hz,2H),2.61(dd,J=9.2,6.2Hz,3H),1.29–1.16(m,3H).Dissolve 10.8g of intermediate 3a in 100mL of ethyl acetate, add 200mg of 10% palladium carbon, replace with hydrogen three times, react at room temperature for 4 hours, filter the reaction solution with diatomaceous earth, concentrate the filtrate, and then separate it by silica gel column chromatography (acetic acid Ethyl ester/petroleum ether=1/8) to obtain 10.1 g of white solid 4a with a yield of 93%.1 H NMR (300MHz, CDCl3 ): δ=7.29(d, J=8.0Hz, 2H), 7.20(d, J=8.0Hz, 2H), 4.65(s, 2H), 4.18–4.05(m, 2H ),2.94(t,J=7.8Hz,2H),2.61(dd,J=9.2,6.2Hz,3H),1.29–1.16(m,3H).
将10.2g中间体4a溶解于200mL无水乙醚中，冰水浴下滴加入20.0g三溴化磷，然后保温反应1小时，加入水洗涤，有机层用无水硫酸钠干燥，浓缩后硅胶柱层析分离（乙酸乙酯/石油醚=1/15），得白色固体5a12.2g，产率92%。1H NMR(300MHz,CDCl3)：δ=7.31(d,J=8.1Hz,2H),7.18(d,J=8.1Hz,2H),4.48(s,2H),4.12(q,J=7.1Hz,2H),2.94(t,J=7.8Hz,2H),2.61(t,J=7.8Hz,2H),1.23(t,J=7.1Hz,3H)。Dissolve 10.2g of intermediate 4a in 200mL of anhydrous ether, add 20.0g of phosphorus tribromide dropwise in an ice-water bath, then keep the temperature for 1 hour, add water to wash, and dry the organic layer with anhydrous sodium sulfate. After concentration, the silica gel column layer Analysis and separation (ethyl acetate/petroleum ether=1/15) gave 12.2 g of white solid 5a with a yield of 92%.1 H NMR (300MHz, CDCl3 ): δ=7.31(d, J=8.1Hz, 2H), 7.18(d, J=8.1Hz, 2H), 4.48(s, 2H), 4.12(q, J=7.1 Hz, 2H), 2.94(t, J=7.8Hz, 2H), 2.61(t, J=7.8Hz, 2H), 1.23(t, J=7.1Hz, 3H).
实施例2：3-(4-溴甲基-2-氟苯基)丙酸乙酯的制备Embodiment 2: Preparation of 3-(4-bromomethyl-2-fluorophenyl) ethyl propionate
按照与实施例1所示类似的方法，用化合物1b代替化合物1a，制备得到化合物3-(4-溴甲基-2-氟苯基)丙酸乙酯(化合物5b)。1H NMR(300MHz,CDCl3)δ7.19(t,J=7.8Hz,1H),7.11–7.03(m,2H),4.43(s,2H),4.12(q,J=7.1Hz,2H),2.96(t,J=7.6Hz,2H),2.61(t,J=7.6Hz,2H),1.23(t,J=7.1Hz,3H).Compound 3-(4-bromomethyl-2-fluorophenyl) ethyl propionate (compound 5b) was prepared according to a method similar to that shown in Example 1, substituting compound 1b for compound 1a.1 H NMR (300MHz, CDCl3 )δ7.19(t, J=7.8Hz, 1H), 7.11–7.03(m, 2H), 4.43(s, 2H), 4.12(q, J=7.1Hz, 2H) ,2.96(t,J=7.6Hz,2H),2.61(t,J=7.6Hz,2H),1.23(t,J=7.1Hz,3H).
实施例3：3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯的制备Embodiment 3: Preparation of ethyl 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)phenyl)propionate
称取2.50g化合物6a，3.90g化合物5a，4.0g碳酸钾加入到100mL圆底烧瓶中，加入无水乙腈50mL，50℃反应5小时。将反应液降至室温，过滤，滤液浓缩硅胶柱层析分离（乙酸乙酯/石油醚=1/10），得3.63g白色固体化合物7a，产率69%。1H NMR(300MHz,CDCl3)：δ=7.41(dd,J=15.1,7.5Hz,3H),7.22(d,J=8.0Hz,2H),7.07(d,J=7.4Hz,1H),6.72(d,J=8.2Hz,1H),5.31(s,2H),4.13(q,J=7.1Hz,2H),2.96(t,J=7.8Hz,2H),2.62(t,J=7.8Hz,2H),1.23(dd,J=8.3,6.0Hz,3H).Weigh 2.50g of compound 6a, 3.90g of compound 5a, and 4.0g of potassium carbonate into a 100mL round bottom flask, add 50mL of anhydrous acetonitrile, and react at 50°C for 5 hours. The reaction solution was lowered to room temperature, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (ethyl acetate/petroleum ether=1/10) to obtain 3.63 g of white solid compound 7a with a yield of 69%.1 H NMR (300MHz, CDCl3 ): δ=7.41(dd, J=15.1,7.5Hz,3H),7.22(d,J=8.0Hz,2H),7.07(d,J=7.4Hz,1H), 6.72(d, J=8.2Hz, 1H), 5.31(s, 2H), 4.13(q, J=7.1Hz, 2H), 2.96(t, J=7.8Hz, 2H), 2.62(t, J=7.8 Hz,2H),1.23(dd,J=8.3,6.0Hz,3H).
实施例4：3-(4-(((6-苯基吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-001)的制备Example 4: Preparation of 3-(4-(((6-phenylpyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-001)
称取100.0mg化合物7a，45.0mg苯硼酸，15.0mg四（三苯基膦）钯和75.0mg碳酸钾加入到10mL微波反应器专用管中，加入2.0mL甲苯，0.4mL乙醇和0.4mL水，用氮气置换3次，然后置于CEM微波反应器中120℃反应30分钟，反应液浓缩后硅胶柱层析分离，得到3-(4-(((6-苯基吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯97.0mg，为无色油状物。1H NMR(300MHz,CDCl3)δ8.09-8.00(m,2H),7.69-7.59(m,1H),7.51-7.36(m,5H),7.28-7.18(m,3H),6.73(dd,J=8.1,5.6Hz,1H),5.49(s,2H),4.13(q,J=7.1Hz,2H),2.97(t,J=7.8Hz,2H),2.63(t,J=7.8Hz,2H),1.24(t,J=7.1Hz,3H).Weigh 100.0mg of compound 7a, 45.0mg of phenylboronic acid, 15.0mg of tetrakis(triphenylphosphine)palladium and 75.0mg of potassium carbonate into a 10mL microwave reactor dedicated tube, add 2.0mL of toluene, 0.4mL of ethanol and 0.4mL of water, Replaced with nitrogen for 3 times, then placed in a CEM microwave reactor at 120 ° C for 30 minutes, the reaction solution was concentrated and separated by silica gel column chromatography to obtain 3-(4-(((6-phenylpyridin-2-yl)oxy ) methylene) phenyl) ethyl propionate 97.0 mg, a colorless oil.1 H NMR (300MHz, CDCl3 )δ8.09-8.00(m,2H),7.69-7.59(m,1H),7.51-7.36(m,5H),7.28-7.18(m,3H),6.73(dd ,J=8.1,5.6Hz,1H),5.49(s,2H),4.13(q,J=7.1Hz,2H),2.97(t,J=7.8Hz,2H),2.63(t,J=7.8Hz ,2H),1.24(t,J=7.1Hz,3H).
将上述得到的油状物溶于5.0mL乙腈中，加入1.0mL水，加入氢氧化锂10.0mg，置于40℃油浴中反应12小时，TLC检测反应结束。用2M盐酸溶液调pH=2-3，加入水，用乙酸乙酯萃取3次，合并有机层用饱和食盐水洗涤，有机层用无水硫酸钠干燥，过滤浓缩得3-(4-(((6-苯基吡啶-2-基)氧)亚甲基)苯基)丙酸90mg，为白色固体。1H NMR(400MHz,CDCl3)δ8.04(dd,J=8.3,1.3Hz,2H),7.69-7.60(m,1H),7.51-7.33(m,6H),7.24(d,J=8.0Hz,2H),6.76-6.72(m,1H),5.49(s,2H),2.97(t,J=7.8Hz,2H),2.69(t,J=7.8Hz,2H).The oil obtained above was dissolved in 5.0 mL of acetonitrile, 1.0 mL of water was added, 10.0 mg of lithium hydroxide was added, and the mixture was placed in an oil bath at 40° C. for 12 hours. TLC detected that the reaction was complete. Use 2M hydrochloric acid solution to adjust the pH=2-3, add water, extract 3 times with ethyl acetate, combine the organic layers and wash with saturated brine, dry the organic layer with anhydrous sodium sulfate, filter and concentrate to obtain 3-(4-(( (6-Phenylpyridin-2-yl)oxy)methylene)phenyl)propanoic acid 90 mg as a white solid.1 H NMR (400MHz, CDCl3 )δ8.04(dd, J=8.3,1.3Hz,2H),7.69-7.60(m,1H),7.51-7.33(m,6H),7.24(d,J=8.0 Hz,2H),6.76-6.72(m,1H),5.49(s,2H),2.97(t,J=7.8Hz,2H),2.69(t,J=7.8Hz,2H).
实施例5：3-(4-(((6-(2-甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-002)的制备Example 5: Preparation of 3-(4-(((6-(2-methylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-002)
除了使用2-甲基苯硼酸代替苯硼酸之外，以按照与实施例4类似的方法制得化合物3-(4-(((6-(2-甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.65(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.41(d,J=7.9Hz,2H),7.34-7.27(m,3H),7.23(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H),2.41(s,3H).Except using 2-methylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-methylphenyl)pyridin-2-yl) oxy)methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.65(t, J=7.8Hz, 1H), 7.44(d, J=7.6Hz, 1H), 7.41(d, J=7.9Hz, 2H), 7.34-7.27 (m,3H),7.23(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98 (t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H),2.41(s,3H).
实施例6：3-(4-(((6-(4-甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-003)的制备Example 6: Preparation of 3-(4-(((6-(4-methylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-003)
除了使用对甲基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=8.18(d,J=8.2Hz,2H),7.64-7.60(m,2H),7.59-7.55(m,1H),7.40(d,J=8.2Hz,1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,2H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J=7.7Hz,2H),2.73-.66(m,2H),1.42(s,3H).Except using p-methylphenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(4-methylphenyl)pyridin-2-yl)oxygen) was obtained in a similar manner to Example 4 methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=8.18(d,J=8.2Hz,2H),7.64-7.60(m,2H),7.59-7.55(m,1H),7.40(d,J=8.2Hz, 1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,2H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J =7.7Hz,2H),2.73-.66(m,2H),1.42(s,3H).
实施例7：3-(4-(((6-(2-乙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-004)的制备Example 7: Preparation of 3-(4-(((6-(2-ethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-004)
除了使用2-乙基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-乙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.65(t,J=7.8Hz,1H),7.41(dd,J=14.6,7.7Hz,3H),7.31-.24(m,3H),7.23(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H),2.51(q,J=7.1Hz,1H,2H),1.30(d,J=8.2,6.1Hz,3H).Except using 2-ethylphenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(2-ethylphenyl)pyridin-2-yl)oxygen ) methylene) phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.65(t, J=7.8Hz, 1H), 7.41(dd, J=14.6, 7.7Hz, 3H), 7.31-.24(m, 3H), 7.23(d ,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H ),2.70(t,J=7.8Hz,2H),2.51(q,J=7.1Hz,1H,2H),1.30(d,J=8.2,6.1Hz,3H).
实施例8：3-(4-(((6-(2-异丙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-005)的制备Example 8: Preparation of 3-(4-(((6-(2-isopropylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-005)
除了使用2-异丙基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-异丙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CD3Cl)δ=7.65(t,J=7.7Hz,1H),7.46-7.30(m,5H),7.28-7.19(m,3H),6.97(d,J=7.2Hz,1H),6.78(d,J=8.1Hz,1H),5.38(s,2H),3.30(m,1H),2.97(t,J=7.6Hz,2H),2.69(t,J=7.8Hz,2H),1.21(d,J=6.8Hz,6H).Except using 2-isopropylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-isopropylphenyl)pyridin-2-yl) was obtained in a similar manner to Example 4 )oxy)methylene)phenyl)propionic acid.1 H NMR(300MHz,CD3 Cl)δ=7.65(t,J=7.7Hz,1H),7.46-7.30(m,5H),7.28-7.19(m,3H),6.97(d,J=7.2Hz ,1H),6.78(d,J=8.1Hz,1H),5.38(s,2H),3.30(m,1H),2.97(t,J=7.6Hz,2H),2.69(t,J=7.8Hz ,2H),1.21(d,J=6.8Hz,6H).
实施例9：3-(4-(((6-(2-叔丁基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-006)的制备Example 9: Preparation of 3-(4-(((6-(2-tert-butylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-006)
除了使用2-异丁基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-叔丁基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CDCl3)δ=7.69(t,J=7.7Hz,1H),7.49-7.33(m,4H),7.29-7.22(m,4H),6.99(d,J=7.2Hz,1H),6.79(d,J=8.1Hz,1H),5.38(s,2H),2.96(t,J=7.6Hz,2H),2.68(t,J=7.8Hz,2H),1.19(s,9H).Except using 2-isobutylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-tert-butylphenyl)pyridin-2-yl) was obtained in a similar manner to Example 4 )oxy)methylene)phenyl)propionic acid.1 H NMR (300MHz, CDCl3 )δ=7.69(t, J=7.7Hz, 1H), 7.49-7.33(m, 4H), 7.29-7.22(m, 4H), 6.99(d, J=7.2Hz, 1H),6.79(d,J=8.1Hz,1H),5.38(s,2H),2.96(t,J=7.6Hz,2H),2.68(t,J=7.8Hz,2H),1.19(s, 9H).
实施例10：3-(4-(((6-(2-硝基苯基)吡啶-2-基)氧基亚甲基)苯基)丙酸(化合物HYH-007)的制备Example 10: Preparation of 3-(4-(((6-(2-nitrophenyl)pyridin-2-yl)oxymethylene)phenyl)propionic acid (compound HYH-007)
除了使用2-硝基苯硼酸代替苯硼酸之外，按照与实施例4所示类似的方法制得化合物3-(4-(((6-(2-硝基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=8.25(t,J=7.8Hz,1H),7.84(d,J=7.6Hz,1H),7.51(d,J=7.9Hz,2H),7.34-7.27(m,3H),7.25(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).Except using 2-nitrophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-nitrophenyl)pyridin-2-yl) was obtained according to a method similar to that shown in Example 4 )oxy)methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 ) δ=8.25(t, J=7.8Hz, 1H), 7.84(d, J=7.6Hz, 1H), 7.51(d, J=7.9Hz, 2H), 7.34-7.27 (m,3H),7.25(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=8.1Hz,1H),5.40(s,2H),2.98 (t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
实施例11：3-(4-(((6-(2-氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-008)的制备Example 11: Preparation of 3-(4-(((6-(2-aminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-008)
除了使用2-氨基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=8.76(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H),7.25(d,J=7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.88-6.95(m,2H),6.57(d,J=8.1Hz,1H),6.08(brs,2H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).In addition to using 2-aminophenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(2-aminophenyl)pyridin-2-yl)oxy)oxide was obtained in a similar manner to Example 4. Methyl)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=8.76(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H),7.25(d,J= 7.9Hz,2H),7.02(d,J=7.3Hz,1H),6.88-6.95(m,2H),6.57(d,J=8.1Hz,1H),6.08(brs,2H),5.40(s, 2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
实施例12：3-(4-(((6-(2-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-009)的制备Example 12: Preparation of 3-(4-(((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-009)
除了使用2-羟基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=11.2(s,1H),8.65(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H),7.21(d,J=7.9Hz,2H),6.09(d,J=7.3Hz,1H),6.81(m,2H),6.57(d,J=8.1Hz,1H),5.40(s,2H),2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).Except using 2-hydroxyphenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)oxygenide was prepared according to a method similar to that of Example 4. Methyl)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=11.2(s,1H),8.65(t,J=7.8Hz,1H),7.44(d,J=7.6Hz,1H),7.34-7.27(m,3H) ,7.21(d,J=7.9Hz,2H),6.09(d,J=7.3Hz,1H),6.81(m,2H),6.57(d,J=8.1Hz,1H),5.40(s,2H) ,2.98(t,J=7.7Hz,2H),2.70(t,J=7.8Hz,2H).
实施例13：3-(4-(((6-(2-(三氟甲基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-010)的制备Example 13: 3-(4-(((6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH-010) preparation
除了使用2-三氟甲基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-(三氟甲基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CD3Cl)δ=7.78(d,J=7.5Hz,1H),7.69–7.57(m,2H),7.52(t,J=7.3Hz,2H),7.39(d,J=8.1Hz,2H),7.22(d,J=8.1Hz,2H),7.02(d,J=7.3Hz,1H),6.81(dd,J=8.3,0.6Hz,1H),5.36(s,2H),2.97(t,J=7.7Hz,2H),2.69(t,J=7.7Hz,2H)。Except using 2-trifluoromethylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-(trifluoromethyl)phenyl)pyridine) was obtained in a similar manner to Example 4 -2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (300MHz, CD3 Cl) δ=7.78(d,J=7.5Hz,1H),7.69–7.57(m,2H),7.52(t,J=7.3Hz,2H),7.39(d,J =8.1Hz,2H),7.22(d,J=8.1Hz,2H),7.02(d,J=7.3Hz,1H),6.81(dd,J=8.3,0.6Hz,1H),5.36(s,2H ), 2.97(t, J=7.7Hz, 2H), 2.69(t, J=7.7Hz, 2H).
实施例14：3-(4-(((6-(2-甲氧基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-011)的制备Example 14: Preparation of 3-(4-(((6-(2-methoxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-011)
除了使用2-甲氧基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-甲氧基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.64(t,J=7.8Hz,1H),7.32(dd,J=14.6,7.7Hz,3H),7.30-7.25(m,3H),7.21(d,J=7.9Hz,2H),6.98(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t,J=7.7Hz,2H),2.780(t,J=7.8Hz,2H)。Except using 2-methoxyphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-methoxyphenyl)pyridin-2-yl) was obtained in a similar manner to Example 4 )oxy)methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.64(t, J=7.8Hz, 1H), 7.32(dd, J=14.6, 7.7Hz, 3H), 7.30-7.25(m, 3H), 7.21(d, J=7.9Hz,2H),6.98(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t, J=7.7Hz, 2H), 2.780(t, J=7.8Hz, 2H).
实施例15：3-(4-(((6-(2-甲基氨基苯基)吡啶-2-基)氧)甲基)苯基)丙酸(化合物HYH-012)的制备Example 15: Preparation of 3-(4-(((6-(2-methylaminophenyl)pyridin-2-yl)oxy)methyl)phenyl)propionic acid (compound HYH-012)
除了使用2-甲氨基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2-甲基氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.76(t,J=7.8Hz,1H),7.31(dd,J=14.6,7.7Hz,3H),7.29-7.24(m,3H),7.21(d,J=7.9Hz,2H),6.88(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t,J=7.7Hz,2H),2.780(t,J=7.8Hz,2H).Except using 2-methylaminophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2-methylaminophenyl)pyridin-2-yl) oxy)methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.76(t, J=7.8Hz, 1H), 7.31(dd, J=14.6, 7.7Hz, 3H), 7.29-7.24(m, 3H), 7.21(d, J=7.9Hz,2H),6.88(d,J=7.3Hz,1H),6.74(d,J=8.1Hz,1H),5.38(s,2H),3.74(s,3H),2.97(t, J=7.7Hz,2H),2.780(t,J=7.8Hz,2H).
实施例16：3-(4-(((6-(2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-013)的制备Example 16: Preparation of 3-(4-(((6-(2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-013)
除了使用2,6-二甲基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2，6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.64(dd,J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10(d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethylphenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(2,6-dimethylphenyl)pyridine -2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.64(dd, J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10 (d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t, J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例17：3-(4-(((6-(2,6-二乙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-014)的制备Example 17: Preparation of 3-(4-(((6-(2,6-diethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-014)
除了使用2,6-二乙基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二乙基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。Except using 2,6-diethylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-diethylphenyl)pyridine -2-yl)oxy)methylene)phenyl)propanoic acid.
1H NMR(400MHz,CDCl3)δ=7.64(dd,J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10(d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.50(q,J=7.1Hz,1H,2H)，1.25(dd,J=8.2,6.1Hz,3H).1 H NMR (400MHz, CDCl3 )δ=7.64(dd, J=8.3,7.3Hz,1H),7.37(d,J=8.0Hz,2H),7.20(d,J=8.1Hz,3H),7.10 (d,J=7.7Hz,2H),6.80(dd,J=7.2,0.8Hz,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t, J=7.8Hz, 2H), 2.67(t, J=7.8Hz, 2H), 2.50(q, J=7.1Hz, 1H, 2H), 1.25(dd, J=8.2, 6.1Hz, 3H).
实施例18：3-(4-(((6-(2,6-二甲氧基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-015)的制备Example 18: 3-(4-(((6-(2,6-dimethoxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH-015) preparation
除了使用2,6-二甲氧基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2，6-二甲氧基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CDCl3)δ7.63(t,J=7.7Hz,1H),7.40(d,J=7.7Hz,2H),7.31(t,J=8.4Hz,1H),7.20(d,J=7.6Hz,2H),6.92(d,J=7.2Hz,1H),6.74(d,J=8.3Hz,1H),6.66(d,J=8.4Hz,2H),5.35(s,2H),3.74(s,6H),2.95(t,J=7.5Hz,2H),2.65(dd,J=16.0,8.3Hz,2H).Except using 2,6-dimethoxyphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-dimethoxyphenyl )pyridin-2-yl)oxy)methylene)phenyl)propionic acid.1 H NMR (300MHz, CDCl3 )δ7.63(t, J=7.7Hz, 1H), 7.40(d, J=7.7Hz, 2H), 7.31(t, J=8.4Hz, 1H), 7.20(d ,J=7.6Hz,2H),6.92(d,J=7.2Hz,1H),6.74(d,J=8.3Hz,1H),6.66(d,J=8.4Hz,2H),5.35(s,2H ),3.74(s,6H),2.95(t,J=7.5Hz,2H),2.65(dd,J=16.0,8.3Hz,2H).
实施例19：3-(4-(((6-(2，6-二氯苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-016)的制备Example 19: Preparation of 3-(4-(((6-(2,6-dichlorophenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-016)
除了使用2,6-二氯苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2，6-二氯苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CD2Cl)δ=7.69(dd,J=8.3,7.3Hz,1H),7.41(dd,J=4.9,3.7Hz,4H),7.28(d,J=7.3Hz,1H),7.22(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J=7.7Hz,2H),2.67(t,J=7.7Hz,2H)。Except using 2,6-dichlorophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-dichlorophenyl)pyridine-2 -yl)oxy)methylene)phenyl)propionic acid.1 H NMR(300MHz,CD2 Cl)δ=7.69(dd,J=8.3,7.3Hz,1H),7.41(dd,J=4.9,3.7Hz,4H),7.28(d,J=7.3Hz,1H ),7.22(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J =7.7Hz, 2H), 2.67(t, J=7.7Hz, 2H).
实施例20：3-(4-(((6-(2，6-二氟苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-017)的制备Example 20: Preparation of 3-(4-(((6-(2,6-difluorophenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH-017)
除了使用2,6-二氟苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2，6-二氟苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(300MHz,CD2Cl)δ=7.74(dd,J=8.3,7.3Hz,1H),7.42(dd,J=4.9,3.7Hz,4H),7.26(d,J=7.3Hz,1H),7.21(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J=7.7Hz,2H),2.67(t,J=7.7Hz,2H).Except using 2,6-difluorophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-difluorophenyl)pyridine-2 -yl)oxy)methylene)phenyl)propionic acid.1 H NMR(300MHz,CD2 Cl)δ=7.74(dd,J=8.3,7.3Hz,1H),7.42(dd,J=4.9,3.7Hz,4H),7.26(d,J=7.3Hz,1H ),7.21(t,J=6.1Hz,2H),6.92(d,J=7.2Hz,1H),6.83(d,J=8.3Hz,1H),5.34(s,2H),2.96(t,J =7.7Hz,2H),2.67(t,J=7.7Hz,2H).
实施例21：3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-018)的制备Example 21: 3-(4-(((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 018) Preparation
除了使用2,6-二甲基-4-羟基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-甲基-4-羟基苯基)吡啶基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethyl-4-hydroxyphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-methyl- 4-hydroxyphenyl)pyridyl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例22：3-(4-(((6-(2,4,6-三甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-019)的制备Example 22: 3-(4-(((6-(2,4,6-trimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH-019) preparation of
除了使用2,4,6-三甲基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,4,6-三甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.35(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),7.02(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H),2.14(s,3H)。Except using 2,4,6-trimethylphenylboronic acid instead of phenylboronic acid, the compound 3-(4-(((6-(2,4,6-trimethyl phenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.60(dd, J=8.3,7.3Hz,1H),7.35(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),7.02 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t, J=7.8Hz, 2H), 2.05(s, 6H), 2.14(s, 3H).
实施例23：3-(4-(((6-(4-氨基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-020)的制备Example 23: 3-(4-(((6-(4-amino-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 020) preparation
除了使用2,6-二甲基-4-氨基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-氨基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1HNMR(400MHz,CDCl3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.69(s,2H),6.56(d,J=8.3Hz,1H),6.22(brs,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。Except using 2,6-dimethyl-4-aminophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-amino-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 HNMR (400MHz, CDCl3 )δ=7.60(dd, J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78( d,J=7.2,1H),6.69(s,2H),6.56(d,J=8.3Hz,1H),6.22(brs,2H),5.32(s,2H),2.96(t,J=7.8Hz ,2H), 2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例24：3-(4-(((6-(4-巯基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-021)的制备Example 24: 3-(4-(((6-(4-mercapto-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid (compound HYH- 021) Preparation
除了使用2,6-二甲基-4-巯基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-巯基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1HNMR(400MHz,CDCl3)δ=7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.18(s,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(d,J=8.3Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).Except using 2,6-dimethyl-4-mercaptophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-mercapto-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 HNMR (400MHz, CDCl3 )δ=7.60(dd, J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.18(s,2H),7.01(d,J=7.7 Hz,2H),6.78(d,J=7.2,1H),6.56(d,J=8.3Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t ,J=7.8Hz,2H),2.05(s,6H).
实施例25：3-(4-(((6-(4-羧基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-022)的制备Example 25: 3-(4-(((6-(4-carboxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 022) Preparation
除了使用2,6-二甲基-4-甲酸苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-羧基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1HNMR(400MHz,CDCl3)δ=7.82(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.08(s,6H).Except using 2,6-dimethyl-4-formic acid phenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-carboxy-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 HNMR(400MHz, CDCl3 )δ=7.82(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7 Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67 (t,J=7.8Hz,2H),2.08(s,6H).
实施例26：3-(4-(((6-(4-酰胺基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-023)的制备Example 26: 3-(4-(((6-(4-amido-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH -023) preparation
除了使用2,6-二甲基-4-氨基甲酰基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-酰胺基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.64(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethyl-4-carbamoylphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-amido- 2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.64(s,2H),7.60(dd,J=8.3,7.3Hz,1H),7.32(d,J=8.0Hz,2H),7.01(d,J= 7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例27：3-(4-(((6-(4-溴-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-024)的制备Example 27: 3-(4-(((6-(4-bromo-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 024) Preparation
除了使用2,6-二甲基-4-溴苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-溴-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.38(dd,J=8.3,7.3Hz,1H),7.28(d,J=8.0Hz,2H),7.17(s,2H),7.02(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。Except using 2,6-dimethyl-4-bromophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-bromo-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.38(dd,J=8.3,7.3Hz,1H),7.28(d,J=8.0Hz,2H),7.17(s,2H),7.02(d,J= 7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t, J=7.8Hz, 2H), 2.06(s, 6H).
实施例28：3-(4-(((6-(4-氯-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-025)的制备Example 28: 3-(4-(((6-(4-chloro-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 025) preparation
除了使用2,6-二甲基-4-氯苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-氯-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.18(s,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethyl-4-chlorophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-chloro-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.18(s,2H),7.03(d,J= 7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例29：3-(4-(((6-(4-氟-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-026)的制备Example 29: 3-(4-(((6-(4-fluoro-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound HYH- 026) Preparation
除了使用2,6-二甲基-4-氟苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-氟-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.72(s,2H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).Except using 2,6-dimethyl-4-fluorophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-fluoro-2,6 -dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd, J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78 (d,J=7.2,1H),6.72(s,2H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t,J=7.8Hz,2H),2.05(s,6H).
实施例30：3-(4-(((6-(4-甲氧基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-027)的制备Example 30: 3-(4-(((6-(4-methoxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-027) Preparation
除了使用2,6-二甲基-4-甲氧基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-甲氧基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.92(s,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).Except using 2,6-dimethyl-4-methoxyphenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-methoxy -2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd, J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.92 (s,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(s,3H),2.96(t,J =7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
实施例31：3-(4-(((6-(4-甲硫基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-028)的制备Example 31: 3-(4-(((6-(4-methylthio-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-028) preparation
除了使用2,6-二甲基-4-甲基巯基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-甲硫基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.22(s,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.53(s,3H),2.06(s,6H).Except using 2,6-dimethyl-4-methylmercaptophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(4-methylthio -2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.22(s,2H),7.03(d,J= 7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t,J=7.8Hz,2H),2.53(s,3H),2.06(s,6H).
实施例32：3-(4-(((6-(2,6-二甲基-4-甲磺酰基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-029)的制备Example 32: 3-(4-(((6-(2,6-Dimethyl-4-methanesulfonylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound Preparation of HYH-029)
除了使用2,6-二甲基-4-甲基磺酰基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-甲磺酰基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.76(s,2H),7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.38(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethyl-4-methylsulfonyl phenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6- Dimethyl-4-methanesulfonylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.76(s,2H),7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J= 7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.38(s,3H),2.96(t,J =7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H).
实施例33：3-(4-(((6-(2,6-二甲基-4-甲氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-030)的制备Example 33: 3-(4-(((6-(2,6-Dimethyl-4-methylaminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH -030) preparation
除了使用2,6-二甲基-4-甲氨基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-甲氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.72(s,3H),2.68(t,J=7.8Hz,2H),2.06(s,6H).Except using 2,6-dimethyl-4-methylaminophenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2,6-dimethyl yl-4-methylaminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd, J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78 (d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.72(s,3H),2.68(t,J=7.8Hz,2H),2.06(s,6H).
实施例34：3-(4-(((6-(2,6-二甲基-4-二甲氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-031)的制备Example 34: 3-(4-(((6-(2,6-Dimethyl-4-dimethylaminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound Preparation of HYH-031)
除了使用2,6-二甲基-4-(二甲基氨基)苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-二甲氨基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.72(s,6H),2.67(t,J=7.8Hz,2H),2.04(s,6H).Except using 2,6-dimethyl-4-(dimethylamino) phenylboronic acid instead of phenylboronic acid, compound 3-(4-(((6-(2, 6-Dimethyl-4-dimethylaminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd, J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78 (d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.72(s,6H),2.67(t,J=7.8Hz,2H),2.04(s,6H).
实施例35：3-(4-(((6-(2,6-二甲基-4-(N-甲基甲磺酰胺)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-032)的制备Example 35: 3-(4-(((6-(2,6-Dimethyl-4-(N-methylmethanesulfonamide)phenyl)pyridin-2-yl)oxy)methylene)benzene base) the preparation of propionic acid (compound HYH-032)
除了使用2,6-二甲基-4-(甲基磺酰基)(甲基)氨基苯硼酸代替苯硼酸之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(N-甲基甲磺酰胺)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.37(dd,J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78(d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),3.32(s,3H),3.18(s,3H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).Except using 2,6-dimethyl-4-(methylsulfonyl) (methyl) aminophenylboronic acid instead of phenylboronic acid, compound 3-(4-((( 6-(2,6-Dimethyl-4-(N-methylmethanesulfonamide)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.37(dd, J=8.3,7.3Hz,1H),7.29(d,J=8.0Hz,2H),7.03(d,J=7.7Hz,2H),6.78 (d,J=7.2,1H),6.56(dd,J=8.3,0.8Hz,1H),6.48(s,2H),5.32(s,2H),3.32(s,3H),3.18(s,3H ),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.05(s,6H).
实施例36：3-(4-(((6-(2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-033)的制备Example 36: 3-(4-(((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid (compound HYH- 033) Preparation
除了使用2,6-二甲基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(300MHz,CDCl3)δ7.67(t,J=7.8Hz,1H),7.28–7.09(m,6H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.07(s,6H).In addition to using 2,6-dimethylphenylboronic acid instead of phenylboronic acid, and using ethyl 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoate Ester replaces 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propanoate, obtains compound 3-(4 according to a method similar to Example 4 -(((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (300MHz, CDCl3 )δ7.67(t, J=7.8Hz, 1H), 7.28–7.09(m, 6H), 6.81(dd, J=12.2, 7.8Hz, 2H), 5.35(s, 2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.07(s,6H).
实施例37：3-(4-(((6-(2,6-二环丙基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-034)的制备Example 37: 3-(4-(((6-(2,6-dicyclopropylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid (Compound HYH -034) preparation
除了使用2,6-二环丙基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二环丙基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(300MHz,CDCl3)δ7.67(t,J=7.8Hz,1H),7.35–7.09(m,6H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),1.48-1.62(m,2H),0.99-1.28(m,8H).In addition to using 2,6-dicyclopropylphenylboronic acid instead of phenylboronic acid, and using 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid Ethyl substitutes 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propanoate, obtains compound 3-( 4-(((6-(2,6-dicyclopropylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (300MHz, CDCl3 )δ7.67(t, J=7.8Hz, 1H), 7.35–7.09(m, 6H), 6.81(dd, J=12.2, 7.8Hz, 2H), 5.35(s, 2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),1.48-1.62(m,2H),0.99-1.28(m,8H).
实施例38：3-(4-(((6-(2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸(化合物HYH-035)的制备Example 38: 3-(4-(((6-(2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid (compound HYH- 035) preparation
除了使用2,6-二甲基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸。1H NMR(300MHz,CDCl3)δ7.67(t,J=7.8Hz,1H),7.28(s,2H),7.15-7.09(m,3H),6.81(dd,J=12.2,7.8Hz,2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.06(s,6H).In addition to using 2,6-dimethylphenylboronic acid instead of phenylboronic acid, and using ethyl 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoate Ester replaces 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propanoate, obtains compound 3-(4 according to a method similar to Example 4 -(((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid.1 H NMR (300MHz, CDCl3 )δ7.67(t, J=7.8Hz, 1H), 7.28(s, 2H), 7.15-7.09(m, 3H), 6.81(dd, J=12.2, 7.8Hz, 2H),5.35(s,2H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.7Hz,2H),2.06(s,6H).
实施例39：3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-036)的制备Example 39: 3-(4-(((6-(2,6-Dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid (Compound HYH-036) Preparation
除了使用2,6-二甲基-4-羟基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.59(dd,J=8.3,7.3Hz,1H),7.27(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。In addition to using 2,6-dimethyl-4-hydroxyphenylboronic acid instead of phenylboronic acid, and using 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl ) ethyl propionate instead of 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound was obtained according to a method similar to Example 4 3-(4-(((6-(2,6-Methyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.59(dd, J=8.3,7.3Hz,1H),7.27(d,J=8.0Hz,2H),7.13(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t, J=7.8Hz, 2H), 2.06(s, 6H).
实施例40：3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸(化合物HYH-037)的制备Example 40: 3-(4-(((6-(2,6-Dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid (Compound HYH-037) Preparation
除了使用2,6-二甲基-4-羟基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(2,6-甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氯苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.78(dd,J=8.3,7.3Hz,1H),7.48(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.88(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.06(s,6H)。In addition to using 2,6-dimethyl-4-hydroxyphenylboronic acid instead of phenylboronic acid, and using 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-chlorophenyl ) ethyl propionate instead of 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound was obtained according to a method similar to Example 4 3-(4-(((6-(2,6-Methyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.78(dd, J=8.3,7.3Hz,1H),7.48(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.88(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),2.96(t,J=7.8Hz,2H), 2.67(t, J=7.8Hz, 2H), 2.06(s, 6H).
实施例41：3-(4-(((6-(2，6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-038)的制备Example 41: 3-(4-(((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene base) phenyl) propionic acid (compound HYH-038)
取3-(4-(((6-(2,6-二甲基-4-羟基苯基)亚甲基)苯基)乙酸乙酯0.1g，2-甲磺酰基乙基对甲苯磺酰酯0.103g溶于10mL乙腈中，加入碳酸钾0.097g，回流反应8小时，将反应液冷至室温，过滤除去碳酸钾，滤液浓缩硅胶柱层析分离（乙酸乙酯/石油醚=1/15-1/5）。得到3-(4-(((6-(2，6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯85mg，为白色固体，产率66%。Take 0.1g of ethyl 3-(4-(((6-(2,6-dimethyl-4-hydroxyphenyl)methylene)phenyl)acetate, 2-methylsulfonylethyl p-toluenesulfonyl Dissolve 0.103g of the ester in 10mL of acetonitrile, add 0.097g of potassium carbonate, reflux for 8 hours, cool the reaction solution to room temperature, filter to remove potassium carbonate, and concentrate the filtrate to separate by silica gel column chromatography (ethyl acetate/petroleum ether=1/15 -1/5). to obtain 3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy ) methylene) phenyl) ethyl propionate 85 mg, as a white solid, yield 66%.
将上述所得85mg样品溶解于8mL乙腈，2mL水的混合液中，加入10mg氢氧化锂，在40℃中反应4小时，冷却，用1M的盐酸调pH=2-3，加入饱和食盐水20mL，乙酸乙酯萃取2次，合并有机层加入无水硫酸钠干燥，过滤浓缩得3-(4-(((6-(2，6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧基)亚甲基)苯基)丙酸68mg，为白色固体，产率84%。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.87(s,3H),2.69(t,J=7.6Hz,2H),2.05(s,6H)。Dissolve 85 mg of the sample obtained above in a mixture of 8 mL of acetonitrile and 2 mL of water, add 10 mg of lithium hydroxide, react at 40°C for 4 hours, cool, adjust the pH to 2-3 with 1M hydrochloric acid, add 20 mL of saturated saline, Ethyl acetate was extracted twice, the combined organic layers were added to anhydrous sodium sulfate to dry, filtered and concentrated to obtain 3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl)ethyl) Oxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid 68mg, as a white solid, yield 84%.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.77(t, J=7.2Hz, 2H), 2.98(t, J=7.6Hz, 2H), 2.87(s, 3H), 2.69(t, J=7.6Hz, 2H), 2.05(s, 6H).
实施例42：3-(4-(((6-(2，6-二甲基-4-(2-(乙磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-039)的制备Example 42: 3-(4-(((6-(2,6-Dimethyl-4-(2-(ethylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene base) phenyl) propionic acid (compound HYH-039) preparation
除了使用2-乙磺酰基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2，6-二甲基-4-(2-(乙磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=7.1Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.22(t,J=7.1Hz,,3H)。Compound 3-(4-((((6 -(2,6-Dimethyl-4-(2-(ethylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=7.1Hz,2H),2.69(t,J=7.6Hz,2H),2.05( s,6H), 1.22(t,J=7.1Hz,,3H).
实施例43：3-(4-(((6-(2，6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-040)的制备Example 43: 3-(4-(((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base) phenyl) propionic acid (compound HYH-040) preparation
除了使用3-甲磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.87(s,3H),2.69(t,J=7.6Hz,2H),2.37(m,2H),2.05(s,6H)。Compound 3-(4-((((6 -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.87(s,3H),2.69(t,J=7.6Hz,2H),2.37(m,2H), 2.05(s,6H).
实施例44：3-(4-(((6-(2，6-二甲基-4-(3-(乙磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-041)的制备Example 44: 3-(4-(((6-(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base) phenyl) propionic acid (compound HYH-041) preparation
除了使用3-乙磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(3-(乙磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。Compound 3-(4-((((6 -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=8.0Hz,2H),2.69(t,J=7.6Hz,2H),2.37(m,2H),2.05(s,6H),1.42(t,,J=8.0Hz,3H)。1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.77(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.94(q,J=8.0Hz,2H),2.69(t,J=7.6Hz,2H),2.37( m,2H), 2.05(s,6H), 1.42(t,,J=8.0Hz,3H).
实施例45：3-(4-(((6-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-042)的制备Example 45: 3-(4-(((6-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-042)
除了使用2-甲氧基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(4-(2-甲氧基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.87(t,J=7.2Hz,2H),3.45(s,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H).Compound 3-(4-((((6 -(4-(2-Methoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 3.87(t,J=7.2Hz,2H),3.45(s,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H).
实施例46：3-(4-(((6-(4-(2-乙氧基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-043)的制备Example 46: 3-(4-(((6-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-043)
除了使用2-乙氧基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41所示类似的方法制得化合物3-(4-(((6-(4-(2-乙氧基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.87(t,J=7.2Hz,2H),3.45(q,J=7.1Hz,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.12(t,J=7.1Hz,3H)。Compound 3-(4-(( (6-(4-(2-Ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 3.87(t,J=7.2Hz,2H),3.45(q,J=7.1Hz,3H),2.98(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.05( s,6H), 1.12(t,J=7.1Hz,3H).
实施例47：3-(4-(((6-(4-(2-二甲氨基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-044)的制备Example 47: 3-(4-(((6-(4-(2-Dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-044)
除了使用2-((二甲基)氨基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例42类似的方法制得化合物3-(4-(((6-(4-(2-二甲氨基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H)。Compound 3-(4 -(((6-(4-(2-Dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t, J=7.6Hz, 2H), 2.85(s, 6H), 2.77(t, J=7.2Hz, 2H), 2.69(t, J=7.6Hz, 2H), 2.05(s, 6H).
实施例48：3-(4-(((6-(4-(3-二甲氨基丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-045)的制备Example 48: 3-(4-(((6-(4-(3-dimethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-045)
除了使用3-((二甲基)氨基)丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(4-(3-二甲氨基丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.35(t,J=7.2Hz,2H),2.06(s,6H),2.26(s,6H),1.79(q,J=7.2Hz,2H)。Compound 3-(4 -(((6-(4-(3-Dimethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t,J=7.6Hz,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.35(t,J=7.2Hz,2H),2.06(s,6H), 2.26(s,6H),1.79(q,J=7.2Hz,2H).
实施例49：3-(4-(((6-(4-(2-二乙氨基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-046)的制备Example 49: 3-(4-(((6-(4-(2-diethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-046)
除了使用2-(二乙基氨基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(4-(2-二乙氨基乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.05(s,6H),1.18(t,J=7.5Hz,6H)。Compound 3-(4-( ((6-(4-(2-Diethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.05( s,6H), 1.18(t,J=7.5Hz,6H).
实施例50：3-(4-(((6-(4-(3-二乙氨基丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-047)的制备Example 50: 3-(4-(((6-(4-(3-diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) propionic acid (compound HYH-047)
除了使用3-(二乙胺基)丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(4-(3-二乙氨基丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.06(s,6H),1.81(q,J=7.5Hz,2H)1.16(t,J=7.5Hz,6H)。Compound 3-(4-( ((6-(4-(3-Diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 3.08(q,J=7.5Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.06( s,6H), 1.81(q,J=7.5Hz,2H)1.16(t,J=7.5Hz,6H).
实施例51：3-(4-(((6-(2,6-二甲基-4-((四氢-2H-吡喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-048)的制备Example 51: 3-(4-(((6-(2,6-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyridin-2-yl ) Oxygen) methylene) phenyl) propionic acid (compound HYH-048) preparation
除了使用四氢-2H-吡喃-4-对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-((四氢-2H-吡喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.75(m,1H),3.61(m,2H),3.52(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.15(m,2H),2.06(s,6H),1.88(m,2H)。Compound 3-(4-( ((6-(2,6-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.55(dd, J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.75(m,1H),3.61(m,2H ),3.52(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.15(m,2H),2.06(s,6H),1.88(m ,2H).
实施例52：3-(4-(((6-(2,6-二甲基-4-((四氢-2H-噻喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-049)的制备Example 52: 3-(4-(((6-(2,6-Dimethyl-4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl ) Oxygen) methylene) phenyl) propionic acid (compound HYH-049) preparation
除了使用四氢-2H-噻喃-4-对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-((四氢-2H-噻喃-4-基)氧)苯基)吡啶-2-基)氧基)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(m,1H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.61(m,2H),2.52(m,2H),2.22(m,2H),2.06(s,6H),1.98(m,2H)。Compound 3-(4-( ((6-(2,6-Dimethyl-4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.55(dd, J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.92(m,1H),2.96(t,J =7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.61(m,2H),2.52(m,2H),2.22(m,2H),2.06(s,6H),1.98(m ,2H).
实施例53：3-(4-(((6-(4-((1,1-二氧代四氢-2H-噻喃-4-基)氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-050)的制备Example 53: 3-(4-(((6-(4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-2,6-dimethylbenzene Base) pyridin-2-yl) oxygen) methylene) phenyl) propionic acid (compound HYH-050)
除了使用1,1-二氧代四氢-2H-噻喃-4-对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(4-((四氢-2H-噻喃-4-基)氧)-2,6-二甲基-苯基)吡啶-2-基)氧基)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.55(dd,J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.69(m,1H),3.48(m,2H),3.42(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.39(m,2H),2.14(m,2H),2.06(s,6H)。Except for using 1,1-dioxotetrahydro-2H-thiopyran-4-p-toluenesulfonyl ester instead of 2-methylsulfonylethyl p-toluenesulfonyl ester, it was prepared according to a method similar to Example 41 Compound 3-(4-(((6-(4-((tetrahydro-2H-thiopyran-4-yl)oxy)-2,6-dimethyl-phenyl)pyridin-2-yl)oxy ) methylene) phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.55(dd, J=8.3,7.3Hz,1H),7.34(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.32(s,2H),3.69(m,1H),3.48(m,2H ),3.42(m,2H),2.96(t,J=7.8Hz,2H),2.67(t,J=7.8Hz,2H),2.39(m,2H),2.14(m,2H),2.06(s ,6H).
实施例54：3-(4-(((6-(2,6-二甲基-4-(2-(吡咯烷-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-051)的制备Example 54: 3-(4-(((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy ) methylene) phenyl) propionic acid (compound HYH-051) preparation
除了使用2-(吡咯烷-1-基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(2-(吡咯烷-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.46-2.55(m,4H),2.06(s,6H),1.66-1.73(m,4H)。Compound 3-(4 -(((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.46-2.55(m,4H),2.06(s,6H ), 1.66-1.73 (m, 4H).
实施例55：3-(4-(((6-(2,6-二甲基-4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-052)的制备Example 55: 3-(4-(((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy ) methylene) phenyl) propionic acid (compound HYH-052) preparation
除了使用2-(哌啶-1-基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.45(m,4H),2.06(s,6H),1.61-1.69(m,6H)。Compound 3-(4 -(((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.45(m,4H),2.06(s,6H), 1.61-1.69 (m, 6H).
实施例56：3-(4-(((6-(2,6-二甲基-4-(2-吗啡啉乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-053)的制备Example 56: 3-(4-(((6-(2,6-Dimethyl-4-(2-morpholineethoxy)phenyl)pyridin-2-yl)oxy)methylene)benzene base) the preparation of propionic acid (compound HYH-053)
除了使用2-吗啡啉乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(2-吗啡啉乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),3.65(t,J=8.1Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.41(t,J=8.1Hz,4H),2.06(s,6H)。Compound 3-(4-(((6- (2,6-Dimethyl-4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 3.65(t,J=8.1Hz,4H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.41( t,J=8.1Hz,4H),2.06(s,6H).
实施例57：3-(4-(((6-(2,6-二甲基-4-(2-(哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-054)的制备Example 57: 3-(4-(((6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy ) methylene) phenyl) propionic acid (compound HYH-054) preparation
除了使用2-(哌嗪-1-基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(2-(哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.67(t,J=7.6Hz,2H),2.39(t,J=8.1Hz,4H),2.06(s,6H)。Compound 3-(4 -(((6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.67(t,J=7.6Hz,2H),2.39( t,J=8.1Hz,4H),2.06(s,6H).
实施例58：3-(4-(((6-(2,6-二甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸(化合物HYH-055)的制备Example 58: 3-(4-(((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridine-2 Preparation of -yl)oxy)methylene)phenyl)propionic acid (compound HYH-055)
除了使用2-(4-甲基哌嗪-1-基)乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H),2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.44(t,J=8.1Hz,4H),2.39(t,J=8.1Hz,4H),2.18(s,3H),2.06(s,6H)。Compounds were prepared in a similar manner to Example 41, except that 2-(4-methylpiperazin-1-yl)ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester 3-(4-(((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy ) methylene) phenyl) propionic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.36(d,J=8.0Hz,2H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.79(t,J=7.2Hz,2H), 2.98(t,J=7.6Hz,2H),2.77(t,J=7.2Hz,2H),2.67(t,J=7.6Hz,2H),2.44(t,J=8.1Hz,4H),2.39( t,J=8.1Hz,4H),2.18(s,3H),2.06(s,6H).
实施例59：3-(4-(((6-(2,6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-056)的制备Example 59: 3-(4-(((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2-fluorophenyl) propionic acid (compound HYH-056)
除了使用3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2，6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.98(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.78(t,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.89(s,3H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。Except for ethyl 3-(4-(((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoate Instead of ethyl 3-(4-(((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoate according to the Compound 3-(4-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl) was obtained in a similar manner to Example 41 )oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.98 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.78(t, J=7.2Hz, 2H), 2.99(t, J=7.6Hz, 2H), 2.89(s, 3H), 2.69(t, J=7.6Hz, 2H), 2.07(s, 6H).
实施例60：3-(4-(((6-(2，6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-057)的制备Example 60: 3-(4-(((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2-fluorophenyl) propionic acid (compound HYH-057)
除了使用3-甲磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯，以及使用3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.81–7.72(m,1H),7.24(t,J=8.0Hz,1H),7.15–7.05(m,2H),6.89–6.78(m,2H),6.67(s,2H),5.23(s,2H),4.13–3.94(m,2H),3.29–3.21(m,2H),3.01(s,3H),2.79–2.66(m,2H),2.18–2.08(m,4H),1.92(s,6H).In addition to using 3-methylsulfonylpropyl-p-toluenesulfonyl ester instead of 2-methylsulfonylethyl-p-toluenesulfonyl ester, and using 3-(4-(((6-(2,6-dimethyl-4 -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-(((6-(2,6-dimethyl-4- Except for hydroxyphenyl) pyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound 3-(4-(((6-(2, 6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.81–7.72(m,1H),7.24(t,J=8.0Hz,1H),7.15–7.05(m,2H),6.89–6.78(m,2H), 6.67(s,2H),5.23(s,2H),4.13–3.94(m,2H),3.29–3.21(m,2H),3.01(s,3H),2.79–2.66(m,2H),2.18– 2.08(m,4H),1.92(s,6H).
实施例61：3-(4-(((6-(2,6-二甲基-4-(2-甲氧基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-058)的制备Example 61: 3-(4-(((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2-fluorophenyl) propionic acid (compound HYH-058)
除了使用2-甲氧基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯，以及使用3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2，6-二甲基-4-(2-甲氧基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.82(t,J=7.2Hz,2H),3.42(s,3H),2.99(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。In addition to using 2-methoxyethyl p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-(((6-(2,6-dimethyl-4 -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-(((6-(2,6-dimethyl-4- Except for hydroxyphenyl) pyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound 3-(4-(((6-(2, 6-dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.82(t, J=7.2Hz, 2H), 3.42(s, 3H), 2.99(t, J=7.6Hz, 2H), 2.69(t, J=7.6Hz, 2H), 2.07(s, 6H).
实施例62：3-(4-(((6-(2,6-二甲基-4-(3-甲氧基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-059)的制备Example 62: 3-(4-(((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2-fluorophenyl) propionic acid (compound HYH-059)
除了使用3-甲氧基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯，以及使用3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2，6-二甲基-4-(3-甲氧基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),3.49(t,J=7.2Hz,2H),3.42(s,3H),2.99(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.14(m,J=7.2Hz,2H),2.07(s,6H)。In addition to using 3-methoxypropyl p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-(((6-(2,6-dimethyl-4 -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-(((6-(2,6-dimethyl-4- Except for hydroxyphenyl) pyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound 3-(4-(((6-(2, 6-dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 3.49(t, J=7.2Hz, 2H), 3.42(s, 3H), 2.99(t, J=7.6Hz, 2H), 2.69(t, J=7.6Hz, 2H), 2.14(m, J=7.2 Hz, 2H), 2.07(s, 6H).
实施例63：3-(4-(((6-(2,6-二甲基-4-(2-二甲氨基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-060)的制备Example 63: 3-(4-(((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2-fluorophenyl) propionic acid (compound HYH-060)
除了使用2-二甲氨基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯，以及使用3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例41类似的方法制得化合物3-(4-(((6-(2，6-二甲基-4-(2-二甲氨基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=7.62(dd,J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96(s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H),2.99(t,J=7.6Hz,2H),2.82(s,6H),2.69(t,J=7.2Hz,2H),2.69(t,J=7.6Hz,2H),2.07(s,6H)。In addition to using 2-dimethylaminoethyl-p-toluenesulfonyl ester instead of 2-methanesulfonylethyl-p-toluenesulfonyl ester, and using 3-(4-(((6-(2,6-dimethyl-4 -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-(((6-(2,6-dimethyl-4- Except for hydroxyphenyl) pyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound 3-(4-(((6-(2, 6-dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=7.62(dd, J=8.3,7.3Hz,1H),7.38(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,2H),6.96 (s,2H),6.78(d,J=7.2,1H),6.76(dd,J=8.3,0.8Hz,1H),5.35(s,2H),4.82(t,J=7.2Hz,2H), 2.99(t, J=7.6Hz, 2H), 2.82(s, 6H), 2.69(t, J=7.2Hz, 2H), 2.69(t, J=7.6Hz, 2H), 2.07(s, 6H).
实施例64：2-(6-(溴甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯的制备Example 64: Preparation of ethyl 2-(6-(bromomethyl)-2,3-dihydrobenzofuran-3-yl)acetate
步骤1：将14.15g（102.4mmol）3-甲氧基苄醇和32.8mL三乙胺溶解于50mL干燥的二氯甲烷中，冰水浴下加入1.3g DMAP，搅拌下滴加入11.1mL乙酸酐，然后升至室温搅拌过夜，浓缩除去大部分溶剂，加入乙酸乙酯200mL，用1N盐酸溶液洗涤3次，有机层用无水硫酸钠干燥后浓缩，用硅胶柱层析分离（乙酸乙酯：石油醚=1:20），得到3-甲氧基苄醇乙酸酯17.7g，为无色油状物，产率96%。1H NMR(CDCl3,400MHz)δ：7.25(t,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H),6.89(s,1H),6.85(d,J=8.0Hz,1H),5.06(s,2H),3.78(s,3H),2.08(s,3H)。Step 1: Dissolve 14.15g (102.4mmol) of 3-methoxybenzyl alcohol and 32.8mL of triethylamine in 50mL of dry dichloromethane, add 1.3g of DMAP in an ice-water bath, add 11.1mL of acetic anhydride dropwise under stirring, and then Rise to room temperature and stir overnight, concentrate to remove most of the solvent, add 200 mL of ethyl acetate, wash with 1N hydrochloric acid solution for 3 times, dry the organic layer with anhydrous sodium sulfate, concentrate, and separate by silica gel column chromatography (ethyl acetate: petroleum ether =1:20) to obtain 17.7 g of 3-methoxybenzyl alcohol acetate as a colorless oil, with a yield of 96%.1 H NMR (CDCl3 , 400MHz) δ: 7.25(t, J=8.0Hz, 1H), 6.92(d, J=8.0Hz, 1H), 6.89(s, 1H), 6.85(d, J=8.0Hz ,1H), 5.06(s,2H), 3.78(s,3H), 2.08(s,3H).
步骤2:将3-甲氧基苄醇乙酸酯9.7g溶于40mL无水二氯甲烷中，室温下滴加入12.8mL氯乙酰氯，然后分多批次加入23.6g无水氯化铝，然后回流反应16小时。将反应液冷至室温后倾倒入500mL冰水中，用二氯甲烷萃取三次，合并二氯甲烷后用饱和碳酸氢钠溶液洗涤，然后用无水硫酸钠干燥，浓缩后硅胶柱层析分离（乙酸乙酯：石油醚=1:9～1:1），得到4-(2-氯-乙酰基)-3-羟基-苄醇乙酸酯2.63g，为浅褐色固体，产率20%。1H NMR(CDCl3,400MHz)δ：11.67(s,1H),7.67(d,J=8.0Hz,1H),6.97(s,1H),6.88(d,J=8.0Hz,1H),5.09(s,2H),4.69(s,2H),2.14(s,3H)。Step 2: Dissolve 9.7 g of 3-methoxybenzyl alcohol acetate in 40 mL of anhydrous dichloromethane, add 12.8 mL of chloroacetyl chloride dropwise at room temperature, then add 23.6 g of anhydrous aluminum chloride in batches, Then reflux for 16 hours. After the reaction solution was cooled to room temperature, it was poured into 500 mL of ice water, extracted three times with dichloromethane, washed with saturated sodium bicarbonate solution after combining dichloromethane, then dried with anhydrous sodium sulfate, concentrated and separated by silica gel column chromatography (acetic acid Ethyl ester:petroleum ether=1:9～1:1) to obtain 2.63 g of 4-(2-chloro-acetyl)-3-hydroxy-benzyl alcohol acetate as a light brown solid with a yield of 20%.1 H NMR (CDCl3 ,400MHz)δ: 11.67(s,1H),7.67(d,J=8.0Hz,1H),6.97(s,1H),6.88(d,J=8.0Hz,1H),5.09 (s,2H), 4.69(s,2H), 2.14(s,3H).
步骤3:将4-(2-氯-乙酰基)-3-羟基-苄醇乙酸酯2.20g溶于40mL无水甲醇中，加入乙酸钠1.49g，回流反应2小时，冷至室温，旋蒸除去大部分溶剂，残留物溶于二氯甲烷中，水洗涤，干燥后柱层析分离（乙酸乙酯：石油醚=1:6），得3-氧代-2,3-二氢苯并呋喃-6-羟甲基乙酸酯1.30g，产率59%。1HNMR(CDCl3,400MHz)δ：7.67(d,J=8.0Hz,1H),7.13(s,1H),7.06(d,J=8.0Hz,1H),5.17(s,2H),4.65(s,2H),2.17(s,3H)。Step 3: Dissolve 2.20 g of 4-(2-chloro-acetyl)-3-hydroxy-benzyl alcohol acetate in 40 mL of anhydrous methanol, add 1.49 g of sodium acetate, reflux for 2 hours, cool to room temperature, spin Most of the solvent was evaporated, the residue was dissolved in dichloromethane, washed with water, dried and separated by column chromatography (ethyl acetate:petroleum ether=1:6) to obtain 3-oxo-2,3-dihydrobenzene And furan-6-hydroxymethyl acetate 1.30g, productive rate 59%.1 HNMR (CDCl3 , 400MHz) δ: 7.67(d, J=8.0Hz, 1H), 7.13(s, 1H), 7.06(d, J=8.0Hz, 1H), 5.17(s, 2H), 4.65( s,2H), 2.17(s,3H).
步骤4:将3-氧代-2,3-二氢苯并呋喃-6-羟甲基乙酸酯1.50g溶于100mL无水甲苯中，加入乙氧甲酰基亚甲基三苯基膦12.67g，混合液回流反应24小时，反应液冷却至室温，旋蒸除去大部分溶剂，残留物硅胶柱层析分离（乙酸乙酯：石油醚=1:20），得到(6-羟甲基乙酸酯-苯并呋喃-3-基)乙酸乙酯1.15g，为类白色固体，产率57%。1H NMR(CDCl3,400MHz)δ：7.65(s,1H),7.56(d,J=8.0Hz,1H),7.50(s,1H),7.26(d,J=8.0Hz,1H),5.21(s,2H),4.19(q,J=7.1Hz,2H),3.69(s,2H),2.11(s,3H),1.27(t,J=7.1Hz,3H).Step 4: Dissolve 1.50 g of 3-oxo-2,3-dihydrobenzofuran-6-hydroxymethyl acetate in 100 mL of anhydrous toluene, add ethoxyformylmethylene triphenylphosphine 12.67 g, the mixed solution was refluxed for 24 hours, the reaction solution was cooled to room temperature, and most of the solvent was removed by rotary evaporation, and the residue was separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:20) to obtain (6-hydroxymethyl ethyl ether) Acetate-benzofuran-3-yl)ethyl acetate 1.15g, as off-white solid, yield 57%.1 H NMR (CDCl3 ,400MHz)δ: 7.65(s,1H),7.56(d,J=8.0Hz,1H),7.50(s,1H),7.26(d,J=8.0Hz,1H),5.21 (s,2H),4.19(q,J=7.1Hz,2H),3.69(s,2H),2.11(s,3H),1.27(t,J=7.1Hz,3H).
步骤5：将(6-羟甲基乙酸酯-苯并呋喃-3-基)乙酸乙酯1.15g溶解入20mL乙酸乙酯中，加入10%Pd/C100mg,一个大气压力的氢气氛围下室温过夜，垫硅藻土过来除去钯碳，滤液浓缩后硅胶柱分离，得到(6-羟甲基乙酸酯-2,3-二氢苯并呋喃-3-基)乙酸乙酯1.0g，为白色固体，产率86%，1H NMR(CDCl3,400MHz)δ：7.26(d,J=8.0Hz,1H),7.05(s,1H),6.73(d,J=8.0Hz,1H),5.21(s,2H),4.36(m,1H),4.19(q,J=7.1Hz,2H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H),2.11(s,3H),1.27(t,J=7.1Hz,3H)。Step 5: Dissolve 1.15 g of ethyl (6-hydroxymethylacetate-benzofuran-3-yl) acetate into 20 mL of ethyl acetate, add 10% Pd/C 100 mg, and store at room temperature under an atmosphere of hydrogen at an atmospheric pressure Overnight, pad diatomaceous earth to remove palladium carbon, and the filtrate was concentrated and then separated on a silica gel column to obtain 1.0 g of ethyl (6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl)acetate, which was White solid, yield 86%,1 H NMR (CDCl3 , 400MHz) δ: 7.26(d, J=8.0Hz, 1H), 7.05(s, 1H), 6.73(d, J=8.0Hz, 1H), 5.21(s,2H),4.36(m,1H),4.19(q,J=7.1Hz,2H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m ,1H), 2.11(s,3H), 1.27(t,J=7.1Hz,3H).
步骤6：将(6-羟甲基乙酸酯-2,3-二氢苯并呋喃-3-基)乙酸乙酯1.0g溶解于20mL乙腈中，加入水4mL，搅拌下加入100mg氢氧化锂，50℃下反应4小时，冷却至室温，加入水50mL，用二氯甲烷萃取3次，合并有机层用无水硫酸钠干燥，得到(6-羟甲基-2,3-二氢苯并呋喃-3-基)乙酸0.68g，为类白色固体，产率91%。1H NMR(CDCl3,400MHz)δ：7.26(d,J=8.0Hz,1H),7.05(s,1H),6.73(d,J=8.0Hz,1H),5.21(s,2H),4.36(m,1H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H)。Step 6: Dissolve 1.0 g of ethyl (6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl) acetate in 20 mL of acetonitrile, add 4 mL of water, and add 100 mg of lithium hydroxide under stirring , reacted at 50°C for 4 hours, cooled to room temperature, added 50 mL of water, extracted 3 times with dichloromethane, combined organic layers and dried over anhydrous sodium sulfate to obtain (6-hydroxymethyl-2,3-dihydrobenzo Furan-3-yl)acetic acid 0.68g, as off-white solid, yield 91%.1 H NMR (CDCl3 ,400MHz)δ: 7.26(d,J=8.0Hz,1H),7.05(s,1H),6.73(d,J=8.0Hz,1H),5.21(s,2H),4.36 (m,1H), 4.08(m,1H), 3.89(m,1H), 2.65(m,1H), 2.44(m,1H).
步骤7：将(6-羟甲基-2,3-二氢苯并呋喃-3-基)乙酸0.65g加入到10mL圆底烧瓶中，滴加入1mL三溴化磷，80℃下反应2小时，将反应液冷至0℃，缓慢滴加入1.0mL无水乙醇，然后将反应液倾倒至100mL冰水中，乙酸乙酯萃取三次，合并有机层用无水硫酸钠干燥，过滤浓缩得(6-羟甲基-2,3-二氢苯并呋喃-3-基)乙酸乙酯0.72g，为浅黄色固体，产率84%。1HNMR(CDCl3,400MHz)δ：7.24(d,J=8.0Hz,1H),6.95(s,1H),6.76(d,J=8.0Hz,1H),4.48(s,2H),4.36(m,1H),4.19(q,J=7.1Hz,2H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H),1.27(t,J=7.1Hz,3H)。Step 7: Add 0.65 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetic acid into a 10 mL round bottom flask, add 1 mL of phosphorus tribromide dropwise, and react at 80°C for 2 hours , the reaction solution was cooled to 0°C, and 1.0 mL of absolute ethanol was slowly added dropwise, then the reaction solution was poured into 100 mL of ice water, extracted three times with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain (6- 0.72 g of ethyl hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetate was a light yellow solid with a yield of 84%.1 HNMR (CDCl3 , 400MHz) δ: 7.24(d, J=8.0Hz, 1H), 6.95(s, 1H), 6.76(d, J=8.0Hz, 1H), 4.48(s, 2H), 4.36( m,1H),4.19(q,J=7.1Hz,2H),4.08(m,1H),3.89(m,1H),2.65(m,1H),2.44(m,1H),1.27(t,J =7.1Hz, 3H).
实施例65：2-(6-(((6-(2,6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-061)的制备Example 65: 2-(6-(((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-061)
步骤1：将0.5g(6-羟甲基-2,3-二氢苯并呋喃-3-基)乙酸乙酯和0.29g2-溴-6-羟基吡啶溶解于20mL乙腈中，加入0.35g碳酸钾，然后置于60℃反应3小时，冷至室温，浓缩柱分离，得到2-(6-(((6-溴吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯0.58g，产率88%。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.19(q,J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H),1.27(t,J=7.1Hz,3H)。Step 1: Dissolve 0.5g (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl) ethyl acetate and 0.29g 2-bromo-6-hydroxypyridine in 20mL acetonitrile, add 0.35g carbonic acid Potassium, then placed at 60 ° C for 3 hours, cooled to room temperature, concentrated column separation, to obtain 2-(6-(((6-bromopyridin-2-yl)oxy)methylene)-2,3-dihydro Benzofuran-3-yl) ethyl acetate 0.58g, yield 88%.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.19(q, J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H),1.27(t,J= 7.1Hz, 3H).
步骤2:称取100.0mg化合物2-(6-(((6-溴吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯，65.0mg4-羟基-2,6-二甲基苯硼酸，15.0mg四（三苯基膦）钯和75.0mg碳酸钾加入到10mL微波反应器专用管中，加入2.0mL甲苯，0.4mL乙醇和0.4mL水，用氮气置换3次，然后置于CEM微波反应器中120℃反应30分钟，反应液浓缩后硅胶柱层析分离，得到2-(6-(((6-(4-羟基-2,6-二甲基苯基)吡啶-2-基)氧基)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯97.0mg，为白色固体。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.19(q,J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.27(t,J=7.1Hz,3H)。Step 2: Weigh 100.0mg compound 2-(6-(((6-bromopyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)ethyl acetate, Add 65.0mg of 4-hydroxy-2,6-dimethylphenylboronic acid, 15.0mg of tetrakis(triphenylphosphine) palladium and 75.0mg of potassium carbonate into a 10mL microwave reactor special tube, add 2.0mL of toluene, 0.4mL of ethanol and 0.4 mL of water, replaced 3 times with nitrogen, then placed in a CEM microwave reactor at 120 ° C for 30 minutes, the reaction solution was concentrated and separated by silica gel column chromatography to obtain 2-(6-((((6-(4-hydroxyl-2 ,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)ethyl acetate 97.0 mg as a white solid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.19(q,J=7.1Hz,2H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.67(m,1H),2.42-2.47(m,1H) ,2.08(s,6H),1.27(t,J=7.1Hz,3H).
步骤3和步骤4:除了使用2-(6-(((6-(4-羟基-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯代替3-(4-(((6-(2,6-二甲基-4-羟基苯基)吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例42所示类似的方法制备得2-(6-(((6-(2,6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=6.1Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.79(q,J=6.1Hz,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。Step 3 and Step 4: except using 2-(6-(((6-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3- Dihydrobenzofuran-3-yl)ethyl acetate instead of 3-(4-(((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene ) phenyl) propionate ethyl ester, prepare 2-(6-(((6-(2,6-dimethyl-4-(2-(methylsulfonyl) acyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H), 4.13(q, J=6.1Hz, 2H), 4.02-4.07(m, 1H), 3.82-3.89(m, 1H), 3.79(q, J=6.1Hz, 2H), 2.97(s, 3H ), 2.61-2.67(m,1H), 2.42-2.47(m,1H), 2.08(s,6H).
实施例66：2-(6-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-062)的制备Example 66: 2-(6-(((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-062)
除了使用3-甲磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H)。Compound 2-(6-((((6 -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61 -2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H).
实施例67：2-(6-(((6-(2,6-二甲基-4-(4-(甲磺酰基)丁氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-063)的制备Example 67: 2-(6-(((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-063)
除了使用4-甲磺酰基丁基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(4-(甲磺酰基)丁氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.67-1.85(m,4H)。Compound 2-(6-((((6 -(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61 -2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.67-1.85(m,4H).
实施例68：2-(6-(((6-(2,6-二甲基-4-(3-(乙磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-064)的制备Example 68: 2-(6-(((6-(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-064)
除了使用3-乙磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(3-(乙磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.23-3.31(m,2H),2.94(q,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H),1.28(t,J=7.2Hz,3H)。Compound 2-(6-(((6 -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H), 4.13(q, J=5.8Hz, 2H), 4.02-4.07(m, 1H), 3.82-3.89(m, 1H), 3.23-3.31(m, 2H), 2.94(q, J=7.2Hz ,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H),1.28(t,J=7.2Hz,3H).
实施例69：2-(6-(((6-(2,6-二甲基-4-(2-甲氧基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-065)的制备Example 69: 2-(6-(((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-065)
除了使用2-甲氧基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-甲氧基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(q,J=6.1Hz,2H),4.33-4.37(m,1H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.87(q,J=6.1Hz,2H),3.45(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。Except using 2-methoxyethyl p-toluenesulfonyl ester instead of 2-methylsulfonyl ethyl p-toluenesulfonyl ester, compound 2-(6-(((6 -(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3- base) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(q,J= 6.1Hz, 2H), 4.33-4.37(m, 1H), 4.02-4.07(m, 1H), 3.82-3.89(m, 1H), 3.87(q, J=6.1Hz, 2H), 3.45(s, 3H ), 2.61-2.67(m,1H), 2.42-2.47(m,1H), 2.08(s,6H).
实施例70：2-(6-(((6-(2,6-二甲基-4-(3-甲氧基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-066)的制备Example 70: 2-(6-(((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-066)
除了使用3-甲氧基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(3-甲氧基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.45(s,3H),3.18-3.27(m,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.11-2.17(m,2H),2.08(s,6H)。Except using 3-methoxypropyl p-toluenesulfonyl ester instead of 2-methylsulfonylethyl p-toluenesulfonyl ester, compound 2-(6-(((6 -(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3- base) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.13(q,J=5.8Hz,2H),4.02-4.07(m,1H),3.82-3.89(m,1H),3.45(s,3H),3.18-3.27(m,2H),2.61 -2.67(m,1H),2.42-2.47(m,1H),2.11-2.17(m,2H),2.08(s,6H).
实施例71：2-(6-(((6-(2,6-二甲基-4-(2-二甲氨基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-067)的制备Example 71: 2-(6-(((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-067)
除了使用2-二甲氨基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-二甲氨基乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。Compound 2-(6-(((6 -(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3- base) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz, 2H), 4.33-4.37(m, 1H), 4.02-4.09(m, 1H), 3.82-3.89(m, 1H), 2.85(s, 6H), 2.77(t, J=7.2Hz, 2H ), 2.61-2.67(m,1H), 2.42-2.47(m,1H), 2.08(s,6H).
实施例72：2-(6-(((6-(2,6-二甲基-4-(3-二甲氨基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-068)的制备Example 72: 2-(6-(((6-(2,6-Dimethyl-4-(3-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-068)
除了使用3-二甲氨基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(3-二甲氨基丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.79(q,J=7.2Hz,2H)。Compound 2-(6-((((6 -(2,6-Dimethyl-4-(3-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3- base) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz, 2H), 4.33-4.37(m, 1H), 4.02-4.09(m, 1H), 3.82-3.89(m, 1H), 2.85(s, 6H), 2.69(t, J=7.6Hz, 2H ),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.79(q,J=7.2Hz,2H).
实施例73：2-(6-(((6-(2,6-二甲基-4-((四氢-2H-吡喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-069)的制备Example 73: 2-(6-(((6-(2,6-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyridin-2-yl )Oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-069) preparation
除了使用四氢-2H-吡喃-4-甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-((四氢-2H-吡喃-4-基)氧)苯基)吡啶-2-基)氧基)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),3.57-3.61(m,2H),3.50-3.55(m,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。Compound 2-(6-(( (6-(2,6-Dimethyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),3.57-3.61(m,2H),3.50-3.55(m,2H),2.61- 2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.13-2.16 (m, 2H), 2.08 (s, 6H), 1.85-1.89 (m, 2H).
实施例74：2-(6-(((6-(2,6-二甲基-4-((四氢-2H-噻喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-070)的制备Example 74: 2-(6-(((6-(2,6-Dimethyl-4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl )Oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-070) preparation
除了使用四氢-2H-噻喃-4-甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-((四氢-2H-噻喃-4-基)氧)苯基)吡啶-2-基)氧基)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.88-3.97(m,1H),3.80-3.86(m,1H),2.61-2.67(m,3H),2.52-2.59(m,2H),2.42-2.47(m,1H),2.18-2.27(m,2H),2.08(s,6H),1.86-1.97(m,2H)。Compound 2-(6-(( (6-(2,6-Dimethyl-4-((tetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.02-4.09(m,1H),3.88-3.97(m,1H),3.80-3.86(m,1H),2.61-2.67(m,3H),2.52-2.59(m,2H),2.42- 2.47 (m, 1H), 2.18-2.27 (m, 2H), 2.08 (s, 6H), 1.86-1.97 (m, 2H).
实施例75：2-(6-(((6-(2,6-二甲基-4-(哌啶-4-基氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-071)的制备Example 75: 2-(6-(((6-(2,6-Dimethyl-4-(piperidin-4-yloxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-071)
除了使用哌啶-4-甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(哌啶-4-基氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。Compound 2-(6-(((6-(2 ,6-Dimethyl-4-(piperidin-4-yloxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid .1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.13- 2.16 (m, 2H), 2.08 (s, 6H), 1.85-1.89 (m, 2H).
实施例76：2-(6-(((6-(2,6-二甲基-4-((1-甲基哌啶-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-072)的制备Example 76: 2-(6-(((6-(2,6-Dimethyl-4-((1-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl) Preparation of oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-072)
除了使用1-甲基哌啶-4-甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(1-甲基哌啶-4-基)氧)苯基)吡啶-2-基)氧基)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.26(s,2H),2.13-2.16(m,2H),2.08(s,6H),1.85-1.89(m,2H)。Compound 2-(6-((( 6-(2,6-Dimethyl-4-(1-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydro Benzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.71-3.79(m,1H),2.61-2.67(m,5H),2.42-2.47(m,1H),2.26( s, 2H), 2.13-2.16 (m, 2H), 2.08 (s, 6H), 1.85-1.89 (m, 2H).
实施例77：2-(6-(((6-(2,6-二甲基-4-((1,1-二氧代四氢-2H-噻喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-073)的制备Example 77: 2-(6-(((6-(2,6-Dimethyl-4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)benzene Preparation of (yl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-073)
除了使用1,1-二氧代四氢-2H-噻喃-4-甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-((1,1-二氧代四氢-2H-噻喃-4-基)氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.42-3.48(m,4H),2.61-2.67(m,1H),2.42-2.47(m,3H),2.11-2.19(m,2H),2.08(s,6H)。Compounds were prepared in a similar manner to Example 65, except that 1,1-dioxotetrahydro-2H-thiopyran-4-toluenesulfonyl ester was used instead of 2-methylsulfonylethyl p-toluenesulfonyl ester 2-(6-(((6-(2,6-Dimethyl-4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)pyridine- 2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.42-3.48(m,4H),2.61-2.67(m,1H),2.42-2.47(m,3H),2.11- 2.19(m,2H),2.08(s,6H).
实施例78：2-(6-(((6-(4-((4-羟基-1,1-二氧代四氢-2H-噻喃-4-基)甲氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-074)的制备Example 78: 2-(6-(((6-(4-((4-Hydroxy-1,1-dioxotetrahydro-2H-thiopyran-4-yl)methoxy)-2,6 Preparation of -dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-074)
除了使用(4-羟基-1,1-二氧代四氢-2H-噻喃-4-基)甲基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(4-((4-羟基-1,1-二氧代四氢-2H-噻喃-4-基)甲氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.06(s,2H),4.76(t,J=9.1Hz,1H),4.29(dd,J=9.1,6.0Hz,1H),3.88(s,2H),3.75-3.86(m,1H),3.43-3.56(m,2H),2.90-3.01(m,2H),2.76-2.85(m,1H),2.56-2.67(m,1H),2.17-2.33(m,4H),2.06(s,6H)。Except that (4-hydroxy-1,1-dioxotetrahydro-2H-thiopyran-4-yl)methyl toluenesulfonyl ester was used instead of 2-methylsulfonylethyl p-toluenesulfonyl ester, following the same procedure as Compound 2-(6-(((6-(4-((4-hydroxyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)methoxy )-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.06(s,2H),4.76(t,J= 9.1Hz,1H),4.29(dd,J=9.1,6.0Hz,1H),3.88(s,2H),3.75-3.86(m,1H),3.43-3.56(m,2H),2.90-3.01(m ,2H), 2.76-2.85(m,1H), 2.56-2.67(m,1H), 2.17-2.33(m,4H), 2.06(s,6H).
实施例79：2-(6-(((6-(2,6-二甲基-4-(2-(吡咯烷-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-075)的制备Example 79: 2-(6-(((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy )methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-075)
除了使用2-(吡咯烷-1-基)乙基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(吡咯烷-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.61-2.72(m,3H),2.46-2.55(m,5H),2.06(s,6H),1.66-1.73(m,4H)。Compound 2-(6- (((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz, 2H), 4.33-4.37(m, 1H), 4.02-4.09(m, 1H), 3.82-3.89(m, 1H), 2.61-2.72(m, 3H), 2.46-2.55(m, 5H) ,2.06(s,6H),1.66-1.73(m,4H).
实施例80：2-(6-(((6-(2,6-二甲基-4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-076)的制备Example 80: 2-(6-(((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy )methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-076)
除了使用2-(哌啶-1-基)乙基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,5H),2.06(s,6H),1.61-1.69(m,6H)。Compound 2-(6- (((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz, 2H), 4.33-4.37(m, 1H), 4.02-4.09(m, 1H), 3.82-3.89(m, 1H), 2.77(t, J=7.2Hz, 2H), 2.61-2.67(m ,1H), 2.42-2.47(m,5H), 2.06(s,6H), 1.61-1.69(m,6H).
实施例81：2-(6-(((6-(2,6-二甲基-4-(2-(吗啡啉-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-077)的制备Example 81: 2-(6-(((6-(2,6-Dimethyl-4-(2-(morpholin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy )methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-077)
除了使用2-(吗啡啉-1-基)乙基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(吗啡啉-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.65(t,J=8.1Hz,4H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.41-2.47(m,5H),2.08(s,6H)。Compound 2-(6- (((6-(2,6-Dimethyl-4-(2-(morpholin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),3.65(t,J=8.1Hz,4H),2.77(t,J =7.2Hz, 2H), 2.61-2.67(m, 1H), 2.41-2.47(m, 5H), 2.08(s, 6H).
实施例82：2-(6-(((6-(2,6-二甲基-4-(2-(哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-078)的制备Example 82: 2-(6-(((6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy )methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-078)
除了使用2-(哌嗪-1-基)乙基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.61-2.67(m,1H),2.39-2.47(m,5H),2.08(s,6H)。Compound 2-(6- (((6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J =8.1Hz, 4H), 2.61-2.67(m, 1H), 2.39-2.47(m, 5H), 2.08(s, 6H).
实施例83：2-(6-(((6-(2,6-二甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸(化合物HYH-079)的制备Example 83: 2-(6-(((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridine-2 Preparation of -yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-079)
除了使用2-(4-甲基哌嗪-1-基)乙基甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(4-甲基哌嗪-1-基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并呋喃-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J=8.1Hz,4H),2.61-2.67(m,1H),2.39-2.47(m,5H),2.26(s,3H),2.08(s,6H)。Compound 2 was prepared in a similar manner to Example 65, except that 2-(4-methylpiperazin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methylsulfonylethyl p-toluenesulfonyl ester -(6-(((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy) methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz,2H),4.33-4.37(m,1H),4.02-4.09(m,1H),3.82-3.89(m,1H),2.77(t,J=7.2Hz,2H),2.71(t,J =8.1Hz, 4H), 2.61-2.67(m, 1H), 2.39-2.47(m, 5H), 2.26(s, 3H), 2.08(s, 6H).
实施例84：2-(6-(((6-(2,6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸(化合物HYH-080)的制备Example 84: 2-(6-(((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-080)
步骤1：除了使用3-甲硫基苄醇代替3-甲氧基苄醇之外，按照与实施例64类似的方法制得化合物2-(6-(溴甲基)-2,3-二氢苯并噻吩-3-基)乙酸乙酯。Step 1: Except using 3-methylthiobenzyl alcohol instead of 3-methoxybenzyl alcohol, compound 2-(6-(bromomethyl)-2,3-di Hydrobenzothiophen-3-yl) ethyl acetate.
步骤2：除了使用2-(6-(溴甲基)-2,3-二氢苯并噻吩-3-基)乙酸乙酯代替2-(6-(溴甲基)-2,3-二氢苯并呋喃-3-基)乙酸乙酯之外，按照与实施例65类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(2-(甲磺酰基)乙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.36(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.79(q,J=6.1Hz,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。Step 2: Except using ethyl 2-(6-(bromomethyl)-2,3-dihydrobenzothiophen-3-yl)acetate instead of 2-(6-(bromomethyl)-2,3-di Except hydrobenzofuran-3-yl) ethyl acetate, compound 2-(6-(((6-(2,6-dimethyl-4-(2- (methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.36(m, 1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.79(q,J=6.1Hz,2H),2.97(s,3H),2.61-2.67(m,1H),2.42 -2.47(m,1H),2.08(s,6H).
实施例85：2-(6-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯噻吩-3-基)乙酸(化合物HYH-081)的制备Example 85: 2-(6-(((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrophenylthiophen-3-yl)acetic acid (compound HYH-081)
除了使用3-甲磺酰基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例84类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(3-(甲磺酰基)丙氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.29-2.35(m,2H),2.08(s,6H)。Compound 2-(6-((((6 -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophene- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47( m,1H), 2.29-2.35(m,2H), 2.08(s,6H).
实施例86：2-(6-(((6-(2,6-二甲基-4-(4-(甲磺酰基)丁氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸(化合物HYH-082)的制备Example 86: 2-(6-(((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-082)
除了使用4-甲磺酰基丁基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例84类似的方法制得化合物2-(6-(((6-(2,6-二甲基-4-(4-(甲磺酰基)丁氧基)苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯噻吩-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m,1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.67-1.85(m,4H)。Compound 2-(6-((((6 -(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophene-3 -yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.33-4.37(m, 1H),4.11-4.19(m,3H),3.92-3.99(m,1H),3.23-3.31(m,2H),2.97(s,3H),2.61-2.67(m,1H),2.42-2.47( m,1H), 2.08(s,6H), 1.67-1.85(m,4H).
实施例87：2-(6-(((6-(4-(2-(二甲氨基)乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并[b]噻吩-3-基)乙酸(化合物HYH-083)的制备Example 87: 2-(6-(((6-(4-(2-(Dimethylamino)ethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzo[b]thiophen-3-yl)acetic acid (compound HYH-083)
除了使用2-二甲氨基乙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例84类似的方法制得化合物2-(6-(((6-(4-(2-(二甲氨基)乙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H)。Compound 2-(6-((((6 -(4-(2-(Dimethylamino)ethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophene- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.77(t,J=7.2Hz,2H),2.61-2.67(m,1H ), 2.42-2.47(m,1H), 2.08(s,6H).
实施例88：2-(6-(((6-(4-(3-(二甲氨基)丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸(化合物HYH-084)的制备Example 88: 2-(6-(((6-(4-(3-(dimethylamino)propoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene base)-2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-084)
除了使用3-二甲氨基丙基对甲苯磺酰酯代替2-甲磺酰基乙基对甲苯磺酰酯之外，按照与实施例84类似的方法制得化合物2-(6-(((6-(4-(3-(二甲氨基)丙氧基)-2,6-二甲基苯基)吡啶-2-基)氧)亚甲基)-2,3-二氢苯并噻吩-3-基)乙酸。1H NMR(CDCl3,400MHz)δ：7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95(s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J=7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.61-2.67(m,1H),2.42-2.47(m,1H),2.08(s,6H),1.79(q,J=7.2Hz,2H)。Compound 2-(6-(((6 -(4-(3-(Dimethylamino)propoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophene- 3-yl) acetic acid.1 H NMR(CDCl3 ,400MHz)δ: 7.41(dd,J=15.1,7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.07(d,J=7.4Hz,1H),6.95 (s,1H),6.87(s,2H),6.76(d,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),5.11(s,2H),4.79(t,J= 7.2Hz,2H),4.39-4.47(m,1H),4.12-4.19(m,2H),2.85(s,6H),2.69(t,J=7.6Hz,2H),2.61-2.67(m,1H ), 2.42-2.47(m,1H), 2.08(s,6H), 1.79(q,J=7.2Hz,2H).
实施例89：3-(4-(((6-(4-三氟甲基-2-甲基苯基)吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸(化合物HYH-085)的制备Example 89: 3-(4-(((6-(4-Trifluoromethyl-2-methylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid (Compound HYH-085) Preparation
除了使用4-三氟甲基-2-甲基苯硼酸代替苯硼酸，以及使用3-(4-(((6-溴吡啶-2-基)氧)亚甲基)-2-氟苯基)丙酸乙酯代替3-(4-(((6-溴吡啶-2-基)氧)亚甲基)苯基)丙酸乙酯之外，按照与实施例4类似的方法制得化合物3-(4-(((6-(4-三氟甲基苯基)吡啶-2-基)氧基)亚甲基)-2-氟苯基)丙酸。1H NMR(400MHz,CDCl3)δ=8.18(d,J=8.2Hz,2H),7.94-7.90(m,2H),7.69-7.61(m,2H),7.40(d,J=8.2Hz,1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,1H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J=7.7Hz,2H),2.73-.66(m,2H)。In addition to using 4-trifluoromethyl-2-methylphenylboronic acid instead of phenylboronic acid, and using 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl ) ethyl propionate instead of 3-(4-(((6-bromopyridin-2-yl) oxygen) methylene) phenyl) ethyl propionate, compound was obtained according to a method similar to Example 4 3-(4-(((6-(4-trifluoromethylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid.1 H NMR (400MHz, CDCl3 )δ=8.18(d,J=8.2Hz,2H),7.94-7.90(m,2H),7.69-7.61(m,2H),7.40(d,J=8.2Hz, 1H),7.31(dd,J=7.4,0.6Hz,1H),7.01(s,1H),6.81(dd,J=8.2,0.6Hz,1H),5.48(s,2H),2.97(t,J =7.7Hz, 2H), 2.73-.66(m, 2H).
实施例90：化合物对稳定转染人源GPR40的HEK293细胞株激动活性的筛选Example 90: Screening of the agonistic activity of compounds on HEK293 cell lines stably transfected with human GPR40
HEK293细胞，转染真核表达载体人源GPR40-pCDNA3.1，经筛选获得稳定表达人源GPR40的单克隆细胞株。稳定转染人源GPR40的HEK293细胞株，培养于含10%FBS的高糖DMEM培养液。实验前一天将细胞接种于96孔细胞培养板，每孔25000个细胞。实验当天，配制Fluo-8工作液（Hank's平衡盐溶液含Fluo-82μM，丙磺舒2mM，酒石黄1.5mM,酸性红14mM）。弃细胞培养液后加入Fluo-8工作液，100μL每孔，37℃5%CO2孵育1小时。待测化合物的DMSO储备液以Hank's平衡盐溶液稀释200倍置于96孔样品板。阳性对照化合物为终浓度为10μM的TAK-875，空白对照为含0.1%DMSO的Hank's平衡盐溶液。将孵育完成的细胞板、样品板放于Flexstation多功能酶标仪工作站，设置加药25μL每孔，检测加药后细胞内钙离子信号。钙离子信号取MAX-MIN转化为原始数据，根据如下公式计算效率%。应用GraphPad Prism软件计算化合物的EC50。HEK293 cells were transfected with the eukaryotic expression vector human GPR40-pCDNA3.1, and a monoclonal cell line stably expressing human GPR40 was obtained after screening. HEK293 cell lines stably transfected with human GPR40 were cultured in high-glucose DMEM medium containing 10% FBS. The day before the experiment, the cells were seeded in 96-well cell culture plates with 25000 cells per well. On the day of the experiment, Fluo-8 working solution (Hank's balanced salt solution containing Fluo-8 2μM, probenecid 2mM, tartrazine 1.5mM, acid red 14mM) was prepared. After discarding the cell culture medium, add Fluo-8 working solution, 100 μL per well, and incubate for 1 hour at 37°C in 5% CO2 . The DMSO stock solution of the compound to be tested was diluted 200 times with Hank's balanced salt solution and placed in a 96-well sample plate. The positive control compound was TAK-875 with a final concentration of 10 μM, and the blank control was Hank's balanced salt solution containing 0.1% DMSO. Place the incubated cell plate and sample plate on the Flexstation multifunctional microplate reader workstation, set the drug addition to 25 μL per well, and detect the intracellular calcium ion signal after drug addition. The calcium ion signal is converted into raw data by taking MAX-MIN, and the efficiency % is calculated according to the following formula. The EC50 of the compound was calculated using GraphPad Prism software.
效率%=[值(compound)-值(BC)]/[值(PC)-值(BC)]×100%Efficiency %=[value(compound) -value(BC) ]/[value(PC) -value(BC) ]×100%
Compound，受试化合物；BC，空白对照；PC，阳性对照TAK-875。结果如表1所示。Compound, test compound; BC, blank control; PC, positive control TAK-875. The results are shown in Table 1.
表1、本申请化合物对人源GPR40的HEK293细胞株的激动活性Table 1. The agonistic activity of the compounds of the present application on the HEK293 cell line of human GPR40
实施例91:化合物对II型糖尿病ob/ob小鼠的降血糖作用Embodiment 91: the hypoglycemic effect of compound on type II diabetes ob/ob mice
雄性遗传型自发性II型糖尿病ob/ob小鼠饲养于SPF级动物房中(温度:22-24°C，湿度：45-80%，光照：150-300Lx，12小时昼夜交替)，小鼠6-7周龄时预测随机血糖、空腹血糖和体重，根据这些指标将ob/ob小鼠分为3组，每组8只，分别口服给与100mg/kg受试化合物HYH-013、100mg/kg阳性对照TAK875，对照组口服给与0.5%CMC，于给药前和给药后1h、2h、4h、6h和8h测定血糖值，观察HYH-013对II型糖尿病ob/ob小鼠的降血糖作用。Male hereditary type II diabetic ob/ob mice are kept in SPF grade animal room (temperature: 22-24°C, humidity: 45-80%, light: 150-300Lx, 12 hours day and night alternation), mice Random blood glucose, fasting blood glucose and body weight were predicted at the age of 6-7 weeks, and ob/ob mice were divided into 3 groups according to these indicators, with 8 mice in each group, and 100mg/kg test compound HYH-013, 100mg/ The positive control TAK875 in kg, and the control group were orally administered with 0.5% CMC, the blood glucose was measured before administration and 1h, 2h, 4h, 6h and 8h after administration, and the effect of HYH-013 on type II diabetic ob/ob mice was observed. Blood sugar effect.
结果如表2和图1所示，对照组ob/ob小鼠给药前和给药后血糖均维持在较高的水平，100mg/kg HYH-013单次口服给药可显著降低ob/ob小鼠血糖。给药后1h，HYH-013小鼠血糖显著低于对照组（P<0.01），血糖下降率为22.3%，而阳性对照TAK-875组血糖与对照组相比无显著下降；给药后2h和4h时，HYH-013组小鼠血糖仍显著低于对照组（P<0.05）,血糖下降率分别为26.3%和23.4%，而此时阳性对照TAK875组小鼠血糖也出现一定程度的下降（P=0.09），血糖下降率分别为27.9%和23.3%；给药后6h和8h时，HYH-013组小鼠血糖仍然显著低于对照组（P<0.05，P<0.01），血糖下降率分别为24.7%和26.8%，而阳性对照TAK875组小鼠血糖与对照组相比已无明显下降。由此提示，HYH-013对2型糖尿病ob/ob小鼠具有显著的降血糖作用，其作用维持时间长于TAK875。The results are shown in Table 2 and Figure 1. The blood glucose levels of ob/ob mice in the control group were maintained at a high level before and after administration, and a single oral administration of 100 mg/kg HYH-013 could significantly reduce the ob/ob mouse blood glucose. 1 hour after administration, the blood glucose of HYH-013 mice was significantly lower than that of the control group (P<0.01), and the blood glucose drop rate was 22.3%, while the blood glucose of the positive control TAK-875 group had no significant drop compared with the control group; 2 hours after administration At 4h and 4h, the blood glucose of the mice in the HYH-013 group was still significantly lower than that of the control group (P<0.05), and the blood glucose drop rates were 26.3% and 23.4% respectively. At this time, the blood glucose of the mice in the positive control TAK875 group also dropped to a certain extent (P=0.09), the blood sugar drop rates were 27.9% and 23.3% respectively; 6h and 8h after administration, the blood sugar of mice in the HYH-013 group was still significantly lower than that of the control group (P<0.05, P<0.01), and the blood sugar dropped The rates were 24.7% and 26.8%, respectively, while the blood glucose of the mice in the positive control group TAK875 had no significant decrease compared with the control group. This suggests that HYH-013 has a significant hypoglycemic effect on ob/ob mice with type 2 diabetes, and its effect lasts longer than TAK875.
表2：HYH-013单次给药对ob/ob小鼠血糖的影响(mM，n=8)Table 2: Effect of single administration of HYH-013 on blood glucose in ob/ob mice (mM, n=8)
*，P<0.05，与对照组相比；**，P<0.01，与对照组相比。*, P<0.05, compared with the control group; **, P<0.01, compared with the control group.
以上是针对本发明的可行实施例具体说明，但该实施例并非用以限制本发明的专利范围，凡未脱离本发明技艺精神所为的等效实施或变更，均应包含于本发明的专利范围中。The above is a specific description of a feasible embodiment of the present invention, but this embodiment is not used to limit the scope of the patent of the present invention, and all equivalent implementations or changes that do not depart from the technical spirit of the present invention should be included in the patent of the present invention. in range.
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| CN201310132684.6ACN104109115B (en) | 2013-04-16 | 2013-04-16 | Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes of a kind of nitrogen heterocyclic ring link |
| PCT/CN2014/075466WO2014169817A1 (en) | 2013-04-16 | 2014-04-16 | Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| Date | Code | Title | Description |
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| C06 | Publication | ||
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| CB03 | Change of inventor or designer information | Inventor after:Hu Youhong Inventor after:Leng Ying Inventor after:Li Dewen Inventor after:Ning Mengmeng Inventor after:Chen Wuhong Inventor after:Zeng Limin Inventor before:Hu Youhong Inventor before:Leng Ying Inventor before:Li Dewen Inventor before:Ning Mengmeng | |
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| C14 | Grant of patent or utility model | ||
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee | Granted publication date:20161123 Termination date:20190416 |