CN1805943A - Alpha substituted carboxylic acid as PPAR modulators - Google Patents

Alpha substituted carboxylic acid as PPAR modulators Download PDF

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CN1805943A
CN1805943A CNA2004800167362A CN200480016736A CN1805943A CN 1805943 A CN1805943 A CN 1805943A CN A2004800167362 A CNA2004800167362 A CN A2004800167362A CN 200480016736 A CN200480016736 A CN 200480016736A CN 1805943 A CN1805943 A CN 1805943A
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methyl
phenyl
oxazol
ethoxy
acid
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西蒙·贝利
保罗·S·汉弗莱斯
唐纳德·J·斯卡利茨基
苏慰国
卢克·R·曾德
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Pfizer Inc
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Abstract

Alpha substituted carboxylic acids of formula (I): wherein R' and R2 are as defined in the specification and R3 is A) formula (II); B) formula (III); C) formula (IV); and D) formula (V); wherein Y, Art, Are, AP, R4, R5, R6, R7, R6, R9, R9a, R10, R'', R12, R17, ring A, and p are as defined in the specification; pharmaceutical compositions containing effective amounts of said compounds or their salts are useful for treating PPAR, specifically PPAR alpha/y related disorders, such as diabetes, dyslipidemia, obesity and inflammatory disorders.

Description

作为PPAR调节剂的α取代羧酸Alpha-Substituted Carboxylic Acids as PPAR Modulators

发明背景Background of the invention

本发明涉及α取代羧酸，其调节过氧化物酶体增殖物激活性受体(PPAR)的活性，优选PPAR-α、PPAR-δ或PPAR-γ中的两种或多种，从而可用于调节哺乳动物血糖和增加胰岛素敏感性。本发明还涉及治疗PPAR相关疾病，如糖尿病、异常脂血症、肥胖症及炎症。The present invention relates to alpha-substituted carboxylic acids that modulate the activity of peroxisome proliferator-activated receptors (PPARs), preferably two or more of PPAR-alpha, PPAR-delta, or PPAR-gamma, thereby being useful in Regulates blood sugar and increases insulin sensitivity in mammals. The present invention also relates to the treatment of PPAR related diseases, such as diabetes, dyslipidemia, obesity and inflammation.

过氧化物酶体增殖物为一组结构多样的化合物，当施用于啮齿动物时，引起肝肾过氧化物酶体的大小和数量显著增加，同时，通过增加表达β-氧化循环所需的酶提高过氧化物酶体代谢脂肪酸的能力。此类化合物包括贝特类降血脂药物、除草剂及邻苯二甲酸盐(或酯)成形剂(Reddy和Lalwani，Crit.Rev.Toxicol.，12：1-58(1983))。过氧化物酶体的增殖还可由饮食或生理因素，如高脂饮食和冷环境适应性引起。Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, cause a marked increase in the size and number of hepatic and renal peroxisomes and, concomitantly, by increasing the expression of enzymes required for the beta-oxidation cycle Improves the ability of peroxisomes to metabolize fatty acids. Such compounds include fibrate hypolipidemic drugs, herbicides and phthalate (or ester) formers (Reddy and Lalwani, Crit. Rev. Toxicol., 12:1-58 (1983)). Peroxisome proliferation can also be induced by dietary or physiological factors, such as high-fat diets and adaptation to cold environments.

通过研究由这些化学物质激活的核激素受体超家族成员，探究了过氧化物酶体增殖物发挥多种效应的机制(Isseman和Green，Nature，347-645-650(1990))。随后证明术语为PPAR-α的受体被各种介质和长链脂肪酸激活，刺激编码大鼠乙酰-CoA氧化酶和水合酶-脱氢酶(过氧化物酶体β-氧化所需的酶)及兔细胞色素P450 4A6的基因表达，后者为一种脂肪酸Ω-羟化酶。The mechanism by which peroxisome proliferators exert various effects was explored by studying members of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, Nature, 347-645-650 (1990)). It was subsequently demonstrated that the receptor, termed PPAR-α, is activated by various mediators and long-chain fatty acids, stimulating enzymes encoding rat acetyl-CoA oxidase and hydratase-dehydrogenase (required for peroxisomal β-oxidation) and gene expression of rabbit cytochrome P450 4A6, a fatty acid omega-hydroxylase.

PPAR-α及维甲酸类受体的杂二聚体与术语为过氧化物酶体增殖因子应答元件(PPRE)的DNA序列元件结合，激活转录。维甲酸受体被9-顺式维甲酸激活(见Kliewer，等，Nature，358：771-774(1992)，Gearing，等，Proc.Natl.Acad.Sci.USA，90：1440-1444(1993)，Keller等，Proc.Natl.Acad.Sci.USA，90：2160-2164(1993)，Heyman等，Cell，68：397-406(1992)及Levin等，Nature，355：359-361(1992))。由于PPAR-α-RXR复合物可被过氧化物酶体增殖物和/或9-顺式维甲酸激活，可推知维甲酸和脂肪酸信号通道会聚于调节脂质代谢。Heterodimers of PPAR-alpha and retinoid receptors bind to DNA sequence elements termed peroxisome proliferator response elements (PPREs) to activate transcription. Retinoic acid receptors are activated by 9-cis retinoic acid (see Kliewer, et al., Nature, 358:771-774 (1992), Gearing, et al., Proc.Natl.Acad.Sci.USA, 90:1440-1444 (1993 ), Keller et al., Proc.Natl.Acad.Sci.USA, 90:2160-2164 (1993), Heyman et al., Cell, 68:397-406 (1992) and Levin et al., Nature, 355:359-361 (1992 )). Since the PPAR-α-RXR complex can be activated by peroxisome proliferators and/or 9-cis retinoic acid, it was inferred that retinoic acid and fatty acid signaling pathways converge to regulate lipid metabolism.

自发现PPAR-α以来，已鉴别了PPAR的其它同工型，如PPAR-δ或PPAR-γ，它们在不同的部位表达。各PPAR受体显示出不同的组织表达模式，在被不同结构的化合物激活方面具有差异。例如，PPAR-γ在脂肪组织中表达最多，而在骨骼肌、心脏、肝、肠、肾、血管内皮、平滑肌细胞和巨噬细胞中则以较低水平表达。PPAR-γ存在两个同工型，分别为γ1和γ2。PPAR-γ介导脂肪细胞的信号传导、脂质储存及脂肪代谢。已有证据支持PPAR-γ为最主要的，可能为唯一的介导噻唑烷2，4二酮类抗糖尿病药物敏化胰岛素的分子靶标。Since the discovery of PPAR-alpha, other isoforms of PPAR have been identified, such as PPAR-delta or PPAR-gamma, which are expressed at different sites. Individual PPAR receptors display distinct tissue expression patterns and are differentially activated by compounds of different structures. For example, PPAR-γ is most expressed in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelium, smooth muscle cells, and macrophages. There are two isoforms of PPAR-γ, namely γ 1 and γ 2 . PPAR-γ mediates signal transduction, lipid storage and fat metabolism in adipocytes. Existing evidence supports that PPAR-γ is the most important and possibly the only molecular target that mediates thiazolidine 2,4 diketone antidiabetic drugs sensitization to insulin.

在单独治疗或联合治疗中，新的和已知的口服抗糖尿病药物仍视为具有不一致甚至有限的效力。口服治疗糖尿病的效力有限，部分原因可能为血糖控制差或有限，或不能接受的副作用引起很差的患者依从性。这些副作用包括水肿、体重增加或甚至更严重的并发症。例如，在一些服用磺酰脲类的病人中观察到低血糖症。二甲双胍，一种取代的双胍，可引起腹泻和胃肠不适。最后，水肿、体重增加及有时出现的肝脏毒性与使用一些噻唑烷2，4二酮抗糖尿病药物有关。通常使用上述两种或多种药物联合治疗，但通常仅引起血糖控制的改善。New and known oral antidiabetic drugs are still considered to have inconsistent or even limited efficacy, either alone or in combination. Oral therapy for diabetes has limited efficacy, partly because of poor or limited glycemic control, or poor patient compliance due to unacceptable side effects. These side effects include edema, weight gain or even more serious complications. For example, hypoglycemia has been observed in some patients taking sulfonylureas. Metformin, a substituted biguanide, can cause diarrhea and gastrointestinal upset. Finally, edema, weight gain, and sometimes hepatotoxicity have been associated with the use of some thiazolidine-2,4-dione antidiabetic drugs. Combination therapy with two or more of the above drugs is often used, but usually only results in an improvement in glycemic control.

因此，有必要找到可同时激活PPAR-α和PPAR-γ的抗糖尿病药物，这将导致发现有效降低葡萄糖和甘油三酯的药物，这些药物在治疗2型糖尿病和代谢综合征(即葡萄糖耐量受损、胰岛素耐受、高甘油三酯血症和/或肥胖症)具有很大潜力。Therefore, it is necessary to find antidiabetic drugs that activate both PPAR-α and PPAR-γ, which will lead to the discovery of drugs that are effective in lowering glucose and triglycerides. impairment, insulin resistance, hypertriglyceridemia and/or obesity) have great potential.

发明概述Summary of the invention

本发明提供新颖的式(I)的化合物或其可药用盐或溶剂合物，The present invention provides a novel compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

其中：in:

环Q为(C6-C10)芳基或(4-10)-员杂环基；Ring Q is (C 6 -C 10 ) aryl or (4-10)-membered heterocyclic group;

R1为H、卤素、(C1-C8)烷基、(C1-C8)烷氧基、CN、CF3、-O-CF3、-O-SO2-(C1-C8)烷基、-O-SO2-(CR11R12)t(C6-C10)芳基、-(CR11R12)t(C3-C10)环烷基-(CR11R12)t、-(CR11R12)t(C3-C10)环烷基-(CR11R12)t-O-、-(CR11R12)t(C6-C10)芳基-(CR11R12)t、-(CR11R12)t(C6-C10)芳基-(CR11R12)t-O-、-(CR11R12)t-(4-10)-员杂环基-(CR11R12)t、或-(CR11R12)t-(4-10)-员杂环基-(CR11R12)t-O-；其中R1的环碳原子任选被1～3个R13基团取代；R1的环氮原子任选被1～3个(C1-C8)烷基取代；R 1 is H, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy, CN, CF 3 , -O-CF 3 , -O-SO 2 -(C 1 -C 8 ) alkyl, -O-SO 2 -(CR 11 R 12 ) t (C 6 -C 10 ) aryl, -(CR 11 R 12 ) t (C 3 -C 10 ) cycloalkyl-(CR 11 R 12 ) t , -(CR 11 R 12 ) t (C 3 -C 10 )cycloalkyl-(CR 11 R 12 ) t -O-, -(CR 11 R 12 ) t (C 6 -C 10 ) Aryl-(CR 11 R 12 ) t , -(CR 11 R 12 ) t (C 6 -C 10 )aryl-(CR 11 R 12 ) t -O-, -(CR 11 R 12 ) t -( 4-10)-membered heterocyclyl-(CR 11 R 12 ) t , or -(CR 11 R 12 ) t -(4-10)-membered heterocyclyl-(CR 11 R 12 ) t -O-; wherein the ring carbon atoms of R 1 are optionally substituted by 1 to 3 R 13 groups; the ring nitrogen atoms of R 1 are optionally substituted by 1 to 3 (C 1 -C 8 ) alkyl groups;

R2为H、(C1-C8)烷基、-(CR11R12)t-(C3-C10)环烷基、-(CR11R12)t-(C6-C10)芳基或-(CR11R12)t(4-10)-员杂环基；其中R2的碳原子任选被1～3个R13基团取代；并且R2的环氮原子任选被1～3个(C1-C8)烷基取代；R 2 is H, (C 1 -C 8 ) alkyl, -(CR 11 R 12 ) t -(C 3 -C 10 ) cycloalkyl, -(CR 11 R 12 ) t -(C 6 -C 10 ) aryl or -(CR 11 R 12 ) t (4-10)-membered heterocyclic group; wherein the carbon atoms of R 2 are optionally substituted by 1 to 3 R 13 groups; and the ring nitrogen atoms of R 2 are optionally Optionally substituted by 1 to 3 (C 1 -C 8 ) alkyl groups;

R3选自： R3 is selected from:

Figure A20048001673600132
Figure A20048001673600132

Figure A20048001673600133
Figure A20048001673600133

Y为-(C＝O)-或-SO2-；Y is -(C=O)- or -SO 2 -;

Y″为NR10或-O-；Y″ is NR 10 or -O-;

p为0、1或2；p is 0, 1 or 2;

每个q、r及t独立地为0、1、2、3、4或5；each q, r and t is independently 0, 1, 2, 3, 4 or 5;

每个n独立地为0、1、2、3或4；each n is independently 0, 1, 2, 3 or 4;

每个k独立地为1、2或3；each k is independently 1, 2 or 3;

每个m和s独立地为0、1、2或3；each m and s is independently 0, 1, 2 or 3;

每个j为0、1或2；each j is 0, 1 or 2;

每个R4为-(CR11R12)n-、-(CR11R12)n-S-(CR11R12)n-、-(CR11R12)n-NR10-、-(CR11R12)n-NR10-(CR11R12)n-O-、-(CR11R12)n-O-(CR11R12)k-NR10-、-(CR11R12)n-O-(CR11R12)n-、-(CR11R12)n-O-(CR11R12)k-O-(CR11R12)n-、-(CR11R12)n-CR11＝CR12-(CR11R12)n-或-CH＝CH-(CR11R12)-O-(CH2)n-；Each R 4 is -(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -S-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -NR 10 -, -( CR 11 R 12 ) n -NR 10 -(CR 11 R 12 ) n -O-, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) k -NR 10 -, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) k -O-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -CR 11 =CR 12 -(CR 11 R 12 ) n -or -CH=CH-(CR 11 R 12 )-O-(CH 2 ) n -;

每个R5为键或-(CR11R12)m-Z-(CR11R12)s；其中Z为-CR11R12-、-O-、-NR10a-或-S(O)j-；Each R 5 is a bond or -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CR 11 R 12 -, -O-, -NR 10a - or -S(O) j- ;

每个R6为-(C＝O)-OH、-(C＝O)-OM+、-(C＝O)-(C1-C8)烷基、-(C＝O)-O-(C1-C8)烷基、-(C＝O)-NR10R11、-(C＝O)-NR10-SO2-R11、-SO2-NH-R10、-NH-SO2-R10、-(C＝O)-NH-C≡N，或R6具有下式结构：Each R 6 is -(C=O)-OH, -(C=O)-OM + , -(C=O)-(C 1 -C 8 )alkyl, -(C=O)-O- (C 1 -C 8 )alkyl, -(C=O)-NR 10 R 11 , -(C=O)-NR 10 -SO 2 -R 11 , -SO 2 -NH-R 10 , -NH- SO 2 -R 10 , -(C=O)-NH-C≡N, or R 6 has the following structure:

Figure A20048001673600141
或
Figure A20048001673600142
Figure A20048001673600141
or
Figure A20048001673600142

M+为碱金属阳离子或碱土金属阳离子；M + is an alkali metal cation or an alkaline earth metal cation;

每个R7和R8独立地为H、(C1-C8)烷基、(C1-C8)烷氧基、-(CR11R12)t(C3-C10)环烷基、-(CR11R12)t(C6-C10)芳基、-(CR11R12)t(C6-C10)芳基-O-、-(CR11R12)t(4-10)-员杂环基或-(CR11R12)t(4-10)-员杂环基-O-；Each R 7 and R 8 is independently H, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, -(CR 11 R 12 ) t (C 3 -C 10 )cycloalkane Base, -(CR 11 R 12 ) t (C 6 -C 10 )aryl, -(CR 11 R 12 ) t (C 6 -C 10 )aryl-O-, -(CR 11 R 12 ) t ( 4-10)-membered heterocyclyl or -(CR 11 R 12 ) t (4-10)-membered heterocyclyl-O-;

或R7和R8任选与其连接的碳原子一起形成(C3-C10)环烷基或(3-10)-员杂环基；Or R 7 and R 8 optionally form (C 3 -C 10 ) cycloalkyl or (3-10)-membered heterocyclyl together with the carbon atom to which they are attached;

每个Ar1、Ar2、Ar3和Ar4代表(C6-C10)芳基或(5-10)-员杂环基；其中每个Ar1、Ar2、Ar3和Ar4的环碳原子任选被1～3个R13基团取代；Each of Ar 1 , Ar 2 , Ar 3 and Ar 4 represents (C 6 -C 10 ) aryl or (5-10)-membered heterocyclyl; wherein each of Ar 1 , Ar 2 , Ar 3 and Ar 4 Ring carbon atoms are optionally substituted by 1 to 3 R groups;

环A代表3、4、5、6或7-员环，任选包含1～4个可相同或不同选自-N(R10a)-、O和S(O)j的杂原子，其中j为0、1或2，条件是该环不含两个相邻的O或S(O)j原子；其中环A部分的碳原子任选被1～3个R13基团取代；Ring A represents a 3, 4, 5, 6 or 7-membered ring, optionally containing 1 to 4 heteroatoms which may be the same or different and selected from -N(R 10a )-, O and S(O) j , wherein j is 0, 1 or 2, provided that the ring does not contain two adjacent O or S(O) j atoms; wherein the carbon atoms of the ring A part are optionally substituted by 1 to 3 R groups;

R9为(C1-C8)烷基、-(CR11R12)t(C6-C10)芳基或-(CR11R12)t(4-10)-员杂环基，其中t独立地为0、1、2、3、4或5，其中该R9基团被1～3个基团取代，这些基团独立地选自-(CR11R12)qNR10R11、-(CR11R12)qNR10(C1-C6)烷酰基、-(CR11R12)qO(CR11R12)rR10及-(CR11R12)qR10；其中前述基团的杂环基、芳基和烷基部分任选被1～3个R13基团取代；R 9 is (C 1 -C 8 ) alkyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl or -(CR 11 R 12 ) t (4-10)-membered heterocyclyl, Wherein t is independently 0, 1, 2, 3, 4 or 5, wherein the R 9 group is substituted by 1 to 3 groups, these groups are independently selected from -(CR 11 R 12 ) q NR 10 R 11 , -(CR 11 R 12 ) q NR 10 (C 1 -C 6 )alkanoyl, -(CR 11 R 12 ) q O(CR 11 R 12 ) r R 10 and -(CR 11 R 12 ) q R 10 ; wherein the heterocyclyl, aryl and alkyl parts of the aforementioned groups are optionally substituted by 1 to 3 R 13 groups;

R9a和R10独立地为H或(C1-C8)烷基；R 9a and R 10 are independently H or (C 1 -C 8 ) alkyl;

R11和R12独立地为H、(C1-C8)烷基、羟基或(C1-C6)烷氧基；R 11 and R 12 are independently H, (C 1 -C 8 ) alkyl, hydroxyl or (C 1 -C 6 ) alkoxy;

R10a选自H、(C1-C8)烷基、-(C＝O)-R14、-SO2NR15R16或-S(O)j(C1-C6)烷基；R 10a is selected from H, (C 1 -C 8 ) alkyl, -(C=O)-R 14 , -SO 2 NR 15 R 16 or -S(O) j (C 1 -C 6 ) alkyl;

每个R13和R13a独立地选自卤素、氰基、硝基、三氟甲氧基、三氟甲基、叠氮基、羟基、(C1-C6)烷氧基、(C1-C10)烷基、(C2-C6)链烯基、(C2-C6)炔基、-O-(CR11R12)k-O-(CR11R12)n-、-(C＝O)-R14、-(C＝O)-O-R15、-O-(C＝O)-R15、-NR15(C＝O)-R16、-NR15(C＝O)-O-R16、-(C＝O)-NR15R16、-NR15R16、-NR15OR16、-SO2NR15R16、-S(O)j(C1-C6)烷基、-O-SO2-R14、-NR15-SO2-R16、R15-(CR11R12)t(C6-C10芳基)、-(CR11R12)t(4-10)-员杂环基、-(CR11R12)q(C＝O)(CR11R12)t(C6-C10)芳基、-(CR11R12)q(C＝O)(CR11R12)t(4-10)-员杂环基、-(CR11R12)tO(CR11R12)q(C6-C10)芳基、-(CR11R12)tO(CR11R12)q(4-10)-员杂环基、-(CR11R12)qSO2(CR11R12)t(C6-C10)芳基及-(CR11R12)qSO2(CR11R12)t(4-10)-员杂环；前述R13和R13a基团的杂环部分的1或2个环碳原子任选被氧代(＝O)基团取代，并且前述R13和R13a基团的烷基、链烯基、炔基、芳基和杂环部分任选被1～3个取代基取代，这些取代基独立地选自卤素、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-OR15、-(C＝O)-R15、-(C＝O)-O-R15、-O-(C＝O)-R15、-NR15(C＝O)-R16、-(C＝O)-NR15R16、-NR15R16、-NR15OR16、(C1-C6)烷基、(C2-C6)链烯基、(C2-C6)炔基、-(CR11R12)t(C6-C10)芳基及-(CR11R2)t(4-10)-员杂环基；Each R 13 and R 13a is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 10 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -O-(CR 11 R 12 ) k -O-(CR 11 R 12 ) n -, -(C=O)-R 14 , -(C=O)-OR 15 , -O-(C=O)-R 15 , -NR 15 (C=O)-R 16 , -NR 15 (C= O)-OR 16 , -(C=O)-NR 15 R 16 , -NR 15 R 16 , -NR 15 OR 16 , -SO 2 NR 15 R 16 , -S(O) j (C 1 -C 6 ) alkyl, -O-SO 2 -R 14 , -NR 15 -SO 2 -R 16 , R 15 -(CR 11 R 12 ) t (C 6 -C 10 aryl), -(CR 11 R 12 ) t (4-10)-membered heterocyclyl, -(CR 11 R 12 ) q (C=O)(CR 11 R 12 ) t (C 6 -C 10 )aryl, -(CR 11 R 12 ) q (C=O)(CR 11 R 12 ) t (4-10)-membered heterocyclyl, -(CR 11 R 12 ) t O(CR 11 R 12 ) q (C 6 -C 10 )aryl, - (CR 11 R 12 ) t O(CR 11 R 12 ) q (4-10)-membered heterocyclyl, -(CR 11 R 12 ) q SO 2 (CR 11 R 12 ) t (C 6 -C 10 ) Aryl and -(CR 11 R 12 ) q SO 2 (CR 11 R 12 ) t (4-10)-membered heterocyclic ring; 1 or 2 ring carbon atoms of the heterocyclic part of the aforementioned R 13 and R 13a groups is optionally substituted by an oxo (=O) group, and the alkyl, alkenyl , alkynyl , aryl and heterocyclic moieties of the aforementioned R and R groups are optionally substituted by 1 to 3 substituents, These substituents are independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR 15 , -(C=O)-R 15 , -(C=O) -OR 15 , -O-(C=O)-R 15 , -NR 15 (C=O)-R 16 , -(C=O)-NR 15 R 16 , -NR 15 R 16 , -NR 15 OR 16. (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl And -(CR 11 R 2 ) t (4-10)-membered heterocyclyl;

每个R14、R15和R16独立地选自H、(C1-C6)烷基、-(CR11R12)t(C6-C10)芳基及-(CR11R12)t(4-10)-员杂环基；该杂环基团的1或2个环碳原子任选被氧代(＝O)基团取代，前述R14、R15和R16基团的烷基、芳基和杂环部分任选被1～3个取代基取代，这些取代基独立地选自卤素、氰基、硝基、-NR11R12、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C2-C6)链烯基、(C2-C6)炔基、羟基及(C1-C6)烷氧基；Each R 14 , R 15 and R 16 is independently selected from H, (C 1 -C 6 ) alkyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl and -(CR 11 R 12 ) t (4-10)-membered heterocyclic group; 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted by an oxo (=O) group, and the aforementioned R 14 , R 15 and R 16 groups The alkyl, aryl and heterocyclic moieties of are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, -NR 11 R 12 , trifluoromethyl, trifluoromethyl Oxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy and (C 1 -C 6 )alkoxy;

R17为H、(C1-C8)烷基、-O-(C1-C8)烷基、卤素、CN、OH、CF3或-O-CF3；R 17 is H, (C 1 -C 8 ) alkyl, -O-(C 1 -C 8 ) alkyl, halogen, CN, OH, CF 3 or -O-CF 3 ;

其中，上面提及的包括不与卤素、SO或SO2基团或不与N、O或S原子连接的CH3(甲基)、CH2(亚甲基)或CH(次甲基)的任何取代基，任选在所述的基团上连接选自羟基、卤素、(C1-C4)烷基、(C1-C4)烷氧基、-NH2、-NH(C1-C8)烷基及-N((C1-C8)烷基)2的取代基。Among them, the above-mentioned CH 3 (methyl), CH 2 (methylene) or CH (methine) not linked to halogen, SO or SO 2 groups or to N, O or S atoms Any substituent, optionally attached to the group selected from hydroxyl, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, -NH 2 , -NH(C 1 Substituents of -C 8 )alkyl and -N((C 1 -C 8 )alkyl) 2 .

在一个实施方案中，本发明涉及通式I化合物，其中R3为In one embodiment, the present invention relates to compounds of general formula I, wherein R 3 is

在另一个实施方案中，本发明涉及通式I化合物，其中R3为In another embodiment, the present invention relates to compounds of general formula I, wherein R 3 is

在此实施方案中，优选的-R4-Y-Y″-为-(CR11R12)n-O-(CR11R12)n-(C＝O)-NR10-或-(CR11R12)n-NR10-(C＝O)-O-。In this embodiment, preferred -R 4 -YY″- is -(CR 11 R 12 ) n -O-(CR 11 R 12 ) n -(C=O)-NR 10 - or -(CR 11 R 12 ) n -NR 10 -(C=O)-O-.

在另一个实施方案中，本发明涉及通式I化合物，其中R3为In another embodiment, the present invention relates to compounds of general formula I, wherein R 3 is

Figure A20048001673600162
Figure A20048001673600162

在另一个实施方案中，本发明涉及通式I化合物，其中R3为In another embodiment, the present invention relates to compounds of general formula I, wherein R 3 is

Figure A20048001673600163
Figure A20048001673600163

在另一个实施方案中，本发明涉及通式I化合物，其中环Q选自In another embodiment, the present invention relates to compounds of general formula I, wherein ring Q is selected from

Figure A20048001673600164
Figure A20048001673600164

Figure A20048001673600165
和
Figure A20048001673600166
Figure A20048001673600165
and
Figure A20048001673600166

在另一个实施方案中，本发明涉及通式I的化合物，其中R1为H、卤素、(C1-C8)烷基、(C1-C8)烷氧基、CF3、-O-CF3、-O-SO2-(C1-C8)烷基、-O-SO2-(CR11R12)t(C6-C10)芳基或-(CR11R12)t(C6-C10)芳基-O-，其中R1的环碳原子任选被1～3个R13基团取代。In another embodiment, the invention relates to compounds of general formula I, wherein R 1 is H, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, CF 3 , -O -CF 3 , -O-SO 2 -(C 1 -C 8 )alkyl, -O-SO 2 -(CR 11 R 12 ) t (C 6 -C 10 )aryl or -(CR 11 R 12 ) t (C 6 -C 10 )aryl-O-, wherein the ring carbon atoms of R 1 are optionally substituted by 1 to 3 R 13 groups.

在另一个实施方案中，本发明涉及通式I化合物，其中R2为H、苯基In another embodiment, the present invention relates to compounds of general formula I, wherein R 2 is H, phenyl

Figure A20048001673600171
Figure A20048001673600171

Figure A20048001673600172
和
Figure A20048001673600172
and

Figure A20048001673600173
Figure A20048001673600173

在另一个实施方案中，本发明涉及通式I化合物，其中该In another embodiment, the present invention relates to compounds of general formula I, wherein the

选自 selected from

Figure A20048001673600181
Figure A20048001673600181

      和 and

在另一个实施方案中，本发明涉及通式I化合物，其中R4为-CH2-O-、-CH2-O-CH2-、-CH2-CH2-O-、-CH＝CH-CH2-O-或-CH2-CH2-CH2-O-。In another embodiment, the invention relates to compounds of general formula I, wherein R 4 is -CH 2 -O-, -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-, -CH=CH -CH2 -O- or -CH2 - CH2 - CH2 -O-.

在另一个实施方案中，本发明涉及通式I化合物，其中R4为-(CH2)n-；其中n独立地为0、1、2或3。In another embodiment, the invention relates to compounds of general formula I, wherein R 4 is -(CH 2 ) n -; wherein n is 0, 1, 2 or 3 independently.

在另一个实施方案中，本发明涉及通式I化合物，其中R5为键或-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NR10a-或-S(O)j-；其中每个m和s独立地为0、1、2或3；其中j为0、1或2。In another embodiment, the present invention relates to compounds of general formula I, wherein R 5 is a bond or -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NR 10a -or-S(O) j- ; wherein each m and s is independently 0, 1, 2 or 3; wherein j is 0, 1 or 2.

在另一个实施方案中，本发明涉及通式I化合物，其中R5为键、-O-、-CH2-、-C(CH3)H-、-C(OH)H-或-C(O-(C1-C8)烷基)H-。In another embodiment, the present invention relates to compounds of general formula I, wherein R 5 is a bond, -O-, -CH 2 -, -C(CH 3 )H-, -C(OH)H- or -C( O-(C 1 -C 8 )alkyl)H-.

在另一个实施方案中，本发明涉及通式I化合物，其中R6为-(C＝O)-OH。In another embodiment, the invention relates to compounds of general formula I, wherein R 6 is -(C=O)-OH.

在另一个实施方案中，本发明涉及通式I化合物，其中R6为-(C＝O)-OM+，其中M+选自Ca++、Li+、Na+及K+。In another embodiment, the present invention relates to compounds of general formula I, wherein R 6 is -(C=O)-OM + , wherein M + is selected from Ca ++ , Li + , Na + and K + .

在另一个实施方案中，本发明涉及通式I化合物，其中每个R7和R8独立地为H、(C1-C8)烷基或(C1-C8)烷氧基。In another embodiment, the invention relates to compounds of general formula I, wherein each R 7 and R 8 is independently H, (C 1 -C 8 )alkyl or (C 1 -C 8 )alkoxy.

在另一个实施方案中，本发明涉及通式I化合物，其中每个R7和R8与其连接的碳原子一起形成(3-7)-员杂环基。In another embodiment, the invention relates to compounds of general formula I, wherein each R 7 and R 8 together with the carbon atom to which they are attached form a (3-7)-membered heterocyclyl.

在另一个实施方案中，本发明涉及具有以下通式的化合物：In another embodiment, the present invention relates to compounds having the general formula:

在此实施方案中，本发明涉及这些化合物，其中所述的-Ar1-Ar2-选自：In this embodiment, the invention relates to those compounds, wherein said -Ar 1 -Ar 2 - is selected from:

Figure A20048001673600193
和
Figure A20048001673600193
and

其中每个Ar1和Ar2的环碳原子任选被1～3个R13基团取代，这些基团选自卤素、(C1-C8)烷基及(C1-C8)烷氧基。wherein each ring carbon atom of Ar 1 and Ar 2 is optionally substituted by 1 to 3 R 13 groups selected from halogen, (C 1 -C 8 ) alkyl and (C 1 -C 8 ) alkane Oxygen.

优选地，所述的-Ar1-Ar2-选自：Preferably, said -Ar 1 -Ar 2 - is selected from:

和 and

在此实施方案中，本发明的具体化合物选自In this embodiment, specific compounds of the invention are selected from

2-甲基-2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)丙酸；2-Methyl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl- 3-yl}oxy)propionic acid;

2-甲基-2-[(3′-{[4-(三氟甲基)苄基]氧基}-1，1′-联苯-3-基)氧基]丙酸；2-Methyl-2-[(3'-{[4-(trifluoromethyl)benzyl]oxy}-1,1'-biphenyl-3-yl)oxy]propanoic acid;

2-甲基-2-[(3′-{2-[1-(6-甲基哒嗪-3-基)哌啶-4-基]乙氧基}-1，1′-联苯-3-基)氧基]丙酸；2-Methyl-2-[(3'-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1'-biphenyl- 3-yl)oxy]propionic acid;

1-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)环丁烷羧酸；1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl}oxygen base) cyclobutane carboxylic acid;

2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基)氧基)丁酸；2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl)oxy base) butanoic acid;

2-(3-{6[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)丁酸；2-(3-{6[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)butanoic acid;

1-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)环丁烷羧酸；1-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)cyclobutane carboxylic acid;

2-甲基-2-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)丙酸；2-Methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy base) propionic acid;

2-甲基-2-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡嗪-2-基}苯氧基)丙酸；2-methyl-2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyrazin-2-yl}benzene Oxygen) propionic acid;

及其可药用盐。and pharmaceutically acceptable salts thereof.

在此实施方案中，本发明的具体化合物为1-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1 , 1′-biphenyl-3-yl}oxy)cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)丁酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1 , 1′-biphenyl-3-yl}oxy)butanoic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)丁酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine -2-yl}phenoxy)butanoic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine -2-yl}phenoxy)cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-[(3′-{[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]甲氧基}联苯-3-基)氧基]环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-[(3'-{[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy }biphenyl-3-yl)oxy]cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-({3′-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]联苯-3-基}氧基)环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-({3'-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]biphenyl -3-yl}oxy)cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-[(3′-{[5-(4-甲氧基苯基)-1，2，4-噁二唑-3-基]甲氧基}联苯-3-基)氧基]环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-[(3'-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy }biphenyl-3-yl)oxy]cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-[(3′-{2-[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}联苯-3-基)氧基-2-甲基丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-[(3'-{2-[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl oxy}biphenyl-3-yl)oxy-2-methylpropionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲基-2-({3′-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]联苯-3-基}氧基)丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methyl-2-({3'-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy ]biphenyl-3-yl}oxy)propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-乙氧基-3-{3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]联苯-3-基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3-{3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl Oxy]biphenyl-3-yl}propionic acid or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，本发明涉及具有以下通式的化合物：In another embodiment, the present invention relates to compounds having the general formula:

Figure A20048001673600211
Figure A20048001673600211

其中Y为-(C＝O)-或-SO2-，Y″为NR10，p为1。Wherein Y is -(C=O)- or -SO 2 -, Y" is NR 10 , and p is 1.

优选地，每个R11和R12独立地为H。Preferably, each R 11 and R 12 is independently H.

优选地，Ar3为苯基。Preferably, Ar3 is phenyl.

在此实施方案中，本发明的具体化合物选自In this embodiment, specific compounds of the invention are selected from

1-(3-{[({2-[3-(三氟甲基)苯基]乙氧基}羰基)氨基]甲基}苯氧基)环丁烷羧酸；1-(3-{[({2-[3-(trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)cyclobutanecarboxylic acid;

2-(3-{[({2-[3-(三氟甲基)苯基]乙氧基}羰基)氨基]甲基}苯氧基)丁酸；2-(3-{[({2-[3-(trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)butanoic acid;

2-甲基-2-(3-{[({2-[3-(三氟甲基)苯基]乙氧基}羰基)氨基]甲基}苯氧基)丙酸；2-Methyl-2-(3-{[({2-[3-(trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)propanoic acid;

2-甲基-2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丙酸；2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]benzene Oxy}propionic acid;

2-甲基-2-(3-{[({[4-(5-甲基-1，2，4-噁二唑-3-基)苄基]氧基}羰基)氨基]甲基}苯氧基)丙酸；2-methyl-2-(3-{[({[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]oxy}carbonyl)amino]methyl} Phenoxy)propionic acid;

2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丁酸；2-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}butanoic acid ;

1-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}环丁烷羧酸；1-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}cyclobutane Alkane carboxylic acid;

1-{3-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯氧基}环丁烷羧酸；1-{3-[({[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]phenoxy}cyclobutane Alkane carboxylic acid;

2-{3-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯氧基}丁酸；2-{3-[({[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]phenoxy}butanoic acid ;

2-甲基-2-{3-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯氧基}丙酸；及其可药用盐。2-Methyl-2-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]benzene oxy}propionic acid; and pharmaceutically acceptable salts thereof.

在此实施方案中，本发明的具体化合物为2-甲基-2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl) Ethoxy]carbonyl}amino)methyl]phenoxy}propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲基-2-{3-[({[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]羰基}氨基)甲基]苯氧基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy base]carbonyl}amino)methyl]phenoxy}propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲基-2-{4-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯氧基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methyl-2-{4-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl) Propoxy]carbonyl}amino)methyl]phenoxy}propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-{3-氟-4-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}-2-甲基丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl Oxy]carbonyl}amino)methyl]phenoxy}-2-methylpropionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丁酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl }amino)methyl]phenoxy}butyric acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-{3-[({[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]羰基}氨基)甲基]苯氧基}丁酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]carbonyl}amino ) methyl]phenoxy}butyric acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl }amino)methyl]phenoxy}cyclobutanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲基-2-(3-{[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙基]氨基}羰基)氧基]甲基}苯氧基)丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl )ethyl]amino}carbonyl)oxy]methyl}phenoxy)propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-乙氧基-3-{3-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl )propoxy]carbonyl}amino)methyl]phenyl}propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-乙氧基-3-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl )ethoxy]carbonyl}amino)methyl]phenyl}propionic acid or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，本发明涉及具有以下通式的化合物：In another embodiment, the present invention relates to compounds having the general formula:

Figure A20048001673600221
Figure A20048001673600221

在另一个实施方案中，环A选自环丙基、环丁基、环戊基及环己基。In another embodiment, Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

在另一个实施方案中，环A选自In another embodiment, Ring A is selected from

其中---为任选的双键。Where --- is an optional double bond.

在另一个实施方案中，环A选自In another embodiment, Ring A is selected from

Figure A20048001673600232
Figure A20048001673600232

其中---为任选的双键。Where --- is an optional double bond.

在另一个实施方案中，环A选自In another embodiment, Ring A is selected from

和

Figure A20048001673600234
and
Figure A20048001673600234

其中---为任选的双键。Where --- is an optional double bond.

在此实施方案中，Ar4为苯基、萘基、吡啶基、嘧啶基或吡嗪基。In this embodiment, Ar4 is phenyl, naphthyl, pyridyl, pyrimidinyl or pyrazinyl.

在此实施方案中，本发明的具体化合物选自In this embodiment, specific compounds of the invention are selected from

1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环己烷羧酸；1-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclohexanecarboxylic acid;

1-(4-[2-(5-甲基-2-苯基-1，3-噁唑4-基)乙氧基]苄基}环戊烷羧酸；1-(4-[2-(5-methyl-2-phenyl-1,3-oxazol4-yl)ethoxy]benzyl}cyclopentanecarboxylic acid;

1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苄基}环戊烷羧酸；1-{4-[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclopentanecarboxylic acid;

4-{4-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]苄基}四氢-2H-吡喃-4-羧酸；4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}tetrahydro-2H-pyran-4-carboxylic acid;

4-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}四氢-2H-吡喃-4-羧酸；4-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydro-2H-pyran-4-carboxylic acid;

1-{4-[2-(4′-甲氧基-1，1′-联苯-4-基)乙氧基]苄基}环丁烷羧酸；1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[2-(4′-氟-1，1′-联苯-4-基)乙氧基]苄基}环丁烷羧酸；1-{4-[2-(4'-fluoro-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[2-(2′-甲氧基-1，1′-联苯-4-基)乙氧基]苄基}环丁烷羧酸；1-{4-[2-(2'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid;

1-(4-{2-[3′-(三氟甲氧基)-1，1′-联苯-4-基]乙氧基}苄基)环丁烷羧酸；1-(4-{2-[3'-(trifluoromethoxy)-1,1'-biphenyl-4-yl]ethoxy}benzyl)cyclobutanecarboxylic acid;

1-(4-{2-[4-(6-甲氧基吡啶-3-基)苯基]乙氧基}苄基)环丁烷羧酸；1-(4-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethoxy}benzyl)cyclobutanecarboxylic acid;

1-(4-{2-[4′-(甲基磺酰基)-1，1′-联苯-4-基]乙氧基}苄基)环丁烷羧酸；1-(4-{2-[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethoxy}benzyl)cyclobutanecarboxylic acid;

1-(4-{2-[4-(2，3-二氢-1-苯并呋喃-6-基)苯基]乙氧基}苄基)环丁烷羧酸；1-(4-{2-[4-(2,3-dihydro-1-benzofuran-6-yl)phenyl]ethoxy}benzyl)cyclobutanecarboxylic acid;

1-[4-(2-{4′-[(甲基磺酰基)氨基]-1，1′-联苯-4-基}乙氧基)苄基]环丁烷羧酸；1-[4-(2-{4'-[(methylsulfonyl)amino]-1,1'-biphenyl-4-yl}ethoxy)benzyl]cyclobutanecarboxylic acid;

1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苄基}环丁烷羧酸；1-{4-[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]苄基}环丁烷羧酸；1-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}cyclobutanecarboxylic acid;

1-{3-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环丁烷羧酸；1-{3-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环丁烷羧酸；1-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[(2，5-二苯基-1，3-噁唑-4-基)甲氧基]苄基}环丁烷羧酸；1-{4-[(2,5-diphenyl-1,3-oxazol-4-yl)methoxy]benzyl}cyclobutanecarboxylic acid;

1-{4-[3-(2，5-二苯基-1，3-噁唑-4-基)丙氧基]苄基)环丁烷羧酸；1-{4-[3-(2,5-diphenyl-1,3-oxazol-4-yl)propoxy]benzyl)cyclobutanecarboxylic acid;

1-{4-[(2，5-二苯基-1，3-噁唑-4-基)甲氧基]苯氧基}环丁烷羧酸；1-{4-[(2,5-diphenyl-1,3-oxazol-4-yl)methoxy]phenoxy}cyclobutanecarboxylic acid;

1-{4-[3-(2，5-二苯基-1，3-噁唑-4-基)丙氧基]苯氧基}环丁烷羧酸；1-{4-[3-(2,5-diphenyl-1,3-oxazol-4-yl)propoxy]phenoxy}cyclobutanecarboxylic acid;

1-(4-(2-[2-(1，1′-联苯-4-基)-5-甲基-1，3-噁唑-4-基]乙氧基}苯氧基)环丁烷羧酸；1-(4-(2-[2-(1,1′-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}phenoxy)ring Butane carboxylic acid;

1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯氧基}环丁烷羧酸；1-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenoxy}cyclobutanecarboxylic acid;

1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苯氧基}环丁烷羧酸；1-{4-[3-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]phenoxy}cyclobutanecarboxylic acid;

1-{4-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]苯氧基}环丁烷羧酸；1-{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}cyclobutanecarboxylic acid;

1-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环丁烷羧酸；1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclobutanecarboxylic acid;

1-(羟基{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环丁烷羧酸；1-(Hydroxy{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclobutanecarboxylic acid ;

1-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环戊烷羧酸；1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclopentanecarboxylic acid;

1-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环己烷羧酸；1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclohexanecarboxylic acid;

2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸；2-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid ;

2-({5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}甲基)四氢呋喃-2-羧酸；2-({5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}methyl)tetrahydrofuran-2-carboxylic acid ;

及其可药用盐。and pharmaceutically acceptable salts thereof.

在此实施方案中，本发明的具体化合物为1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苄基}环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl} ring Butanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环丁烷羧酸或其可药用盐。In this embodiment, a specific compound of the invention is the 1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl} ring Butanecarboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine-3 -yl}methyl)tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-({5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}甲基)四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-({5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine-2 -yl}methyl)tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢-2H-吡喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine-3 -yl}methyl)tetrahydro-2H-pyran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-[(6-{2-[2-(3-氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}吡啶-3-基)甲基]四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-[(6-{2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy Base}pyridin-3-yl)methyl]tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-[(6-{2-[2-(3-甲氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}吡啶-3-基)甲基]四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-[(6-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl] Ethoxy}pyridin-3-yl)methyl]tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪-2-基甲基}-四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-yl Methyl}-tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is -{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydrofuran- 2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-萘-2-基甲基}-四氢呋喃-2-羧酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-2-ylmethyl Base}-tetrahydrofuran-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，本发明涉及具有以下通式的化合物：In another embodiment, the present invention relates to compounds having the general formula:

Figure A20048001673600261
Figure A20048001673600261

在此实施方案中，优选地，本发明涉及具有以下通式的化合物：In this embodiment, preferably, the invention relates to compounds having the general formula:

Figure A20048001673600262
Figure A20048001673600262

在此实施方案中，优选地，本发明涉及具有以下通式的化合物：In this embodiment, preferably, the invention relates to compounds having the general formula:

Figure A20048001673600263
Figure A20048001673600263

在此实施方案中，优选的R9为甲基、乙基或苄基。优选的R17为H。In this embodiment, preferred R9 is methyl, ethyl or benzyl. Preferred R17 is H.

在此实施方案中，本发明的具体化合物为2-乙氧基-3{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy ]pyridin-3-yl}propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-3-(6-{2-[5-甲基-2-(3-甲基苯基)-1，3-噁唑-4-基]乙氧基}吡啶-3-基)丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-3-(6-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazole- 4-yl]ethoxy}pyridin-3-yl)propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-3-{6-[2-(4-苯氧基苯基)乙氧基]吡啶-3-基}丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-3-{6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl}propanoic acid or an alternative thereof Medicinal salt.

在此实施方案中，本发明的具体化合物为2-乙氧基-3-[6-(2-(4-[(苯磺酰基)氧基]苯基)乙氧基)吡啶-3-基]丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3-[6-(2-(4-[(benzenesulfonyl)oxy]phenyl)ethoxy)pyridin-3-yl ] Propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-乙氧基-3-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-2-基}-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-ethoxy-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- Pyridin-2-yl}-propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-2-甲基-3-{6-[3-(5-甲基-2-苯基-噁唑-4-基)-丙氧基]-吡啶-3-基}-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazol-4-yl)- Propoxy]-pyridin-3-yl}-propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-2-甲基-3-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-2-基}-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)- Ethoxy]-pyridin-2-yl}-propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为3-(6-{2-[2-(4-氯-苯基)-5-甲基-噁唑-4-基]-乙氧基}吡啶-3-基)-2-甲氧基-2-甲基-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 3-(6-{2-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}pyridine -3-yl)-2-methoxy-2-methyl-propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-2-甲基-3-{6-[2-(5-甲基-2-苯基噁唑-4-基)-乙氧基]-吡啶-3-基}-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyloxazol-4-yl)-ethyl Oxy]-pyridin-3-yl}-propionic acid or a pharmaceutically acceptable salt thereof.

在此实施方案中，本发明的具体化合物为2-甲氧基-3-(6-{2-[2-(3-甲氧基-苯基)-5-甲基-噁唑-4-基]-乙氧基}-吡啶-3-基)-2-甲基-丙酸或其可药用盐。In this embodiment, a specific compound of the invention is 2-methoxy-3-(6-{2-[2-(3-methoxy-phenyl)-5-methyl-oxazole-4- [yl]-ethoxy}-pyridin-3-yl)-2-methyl-propionic acid or a pharmaceutically acceptable salt thereof.

本发明还提供一种治疗哺乳动物非胰岛素依赖型糖尿病的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。在一个实施方案中，所述的哺乳动物具有葡萄糖耐量受损。The present invention also provides a method for treating non-insulin-dependent diabetes mellitus in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need. In one embodiment, said mammal has impaired glucose tolerance.

本发明还提供一种治疗哺乳动物多囊性卵巢综合征的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating polycystic ovary syndrome in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物肥胖症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating obesity in mammals, comprising administering a therapeutically effective amount of a compound of general formula (I) to a mammal in need.

本发明还提供一种减轻肥胖哺乳动物体重的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for reducing the body weight of an obese mammal, comprising administering a therapeutically effective amount of a compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物高血糖症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating hyperglycemia in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物高脂血症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating hyperlipidemia in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物高胆固醇血症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating hypercholesterolemia in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物动脉粥样硬化的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating atherosclerosis in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物高甘油三酯血症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating hypertriglyceridemia in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗哺乳动物高胰岛素血症的方法，包括对需要的哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating hyperinsulinemia in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal in need.

本发明还提供一种治疗患胰岛素异常和/或与循环的糖皮质激素、生长激素、儿茶酚胺、胰高血糖素或甲状旁腺激素有关的葡萄糖疾病迹象的患者的方法，所述的方法包括对所述的患者给药治疗有效量的通式(I)化合物。The present invention also provides a method of treating a patient suffering from insulin abnormalities and/or signs of glucose disease associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon or parathyroid hormone, said method comprising treating The patient is administered a therapeutically effective amount of a compound of general formula (I).

本发明还提供一种治疗人胰岛素耐受综合征的方法，包括根据治疗需要对患者给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating human insulin resistance syndrome, comprising administering a therapeutically effective amount of the compound of general formula (I) to the patient according to the treatment requirement.

本发明还提供一种治疗人PPAR相关疾病的方法，包括根据治疗需要对患者给药治疗有效量的通式(I)化合物。The present invention also provides a method for treating human PPAR-related diseases, comprising administering a therapeutically effective amount of the compound of general formula (I) to the patient according to the treatment needs.

本发明还提供一种调节哺乳动物PPAR活性的方法，包括对哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for regulating PPAR activity in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammals.

本发明还提供一种降低哺乳动物血糖的方法，包括对哺乳动物施用有效量降低血糖水平的通式(I)化合物。The present invention also provides a method for lowering blood sugar in mammals, comprising administering an effective amount of the compound of general formula (I) for lowering blood sugar levels to mammals.

本发明还提供一种调节哺乳动物脂肪细胞分化的方法，包括对哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for regulating adipocyte differentiation in mammals, comprising administering a therapeutically effective amount of the compound of general formula (I) to mammals.

本发明还提供一种调节哺乳动物PPAR介导过程的方法，包括对哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for regulating a PPAR-mediated process in a mammal, comprising administering a therapeutically effective amount of a compound of general formula (I) to the mammal.

本发明还提供一种提高哺乳动物对胰岛素敏感的方法，包括对哺乳动物给药治疗有效量的通式(I)化合物。The present invention also provides a method for improving the sensitivity of mammals to insulin, comprising administering a therapeutically effective amount of the compound of general formula (I) to the mammal.

本发明还提供一种治疗哺乳动物代谢综合征的方法，这些代谢综合征选自半乳糖血症、槭糖浆尿毒症、苯丙酮尿症、高肌氨酸血症、胸腺嘧啶尿症、sulfinuria、异戊酸血症、酵母氨酸尿、4-羟基丁酸尿、葡萄糖-6-磷酸脱氢酶缺乏症及丙酮酸脱氢酶缺乏症。The present invention also provides a method for treating metabolic syndrome in mammals selected from the group consisting of galactosemia, maple syrup uremia, phenylketonuria, hypersarcosinemia, thymidineuria, sulfinuria, Isovaleric acidemia, yeast aminouria, 4-hydroxybutyrateuria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.

本发明还提供一种组合物，包括至少一种通式(I)的PPAR调节剂及其可药用的载体。典型的可药用载体包括适于口服、静脉内、皮下、肌肉内、皮内等使用的载体。可以乳膏、洗液、片剂、可分散的粉剂、粒剂、糖浆、酏剂、无菌水溶液或非水溶液、悬液或乳剂等形式施用。The present invention also provides a composition comprising at least one PPAR modulator of general formula (I) and a pharmaceutically acceptable carrier thereof. Typical pharmaceutically acceptable carriers include those suitable for oral, intravenous, subcutaneous, intramuscular, intradermal and the like. It can be administered in the form of cream, lotion, tablet, dispersible powder, granule, syrup, elixir, sterile aqueous or non-aqueous solution, suspension or emulsion.

本发明的PPAR激动剂可与其它药物如α-葡萄糖苷酶抑制剂、醛糖还原酶抑制剂、双胍制剂、他汀类化合物(statin base compounds)、鲨烯合成抑制剂、贝特类化合物(fibrate base compounds)、LDL代谢促进剂及血管紧张素转换酶抑制剂联合使用。The PPAR agonist of the present invention can be combined with other drugs such as α-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, statin compounds (statin base compounds), squalene synthesis inhibitors, fibrate compounds (fibrate base compounds), LDL metabolism promoters and angiotensin-converting enzyme inhibitors are used in combination.

上述α-葡萄糖苷酶抑制剂为一种具有抑制消化酶，如淀粉酶、麦芽糖酶、α-糊精酶或蔗糖酶的活性从而阻止淀粉或蔗糖的消化的药物。α-葡萄糖苷酶抑制剂的实例包括阿卡波糖、N-(1，3-二羟基-2-丙基)variolamine(通用名：伏格列波糖)及米格列醇。The aforementioned α-glucosidase inhibitor is a drug that inhibits the activity of digestive enzymes such as amylase, maltase, α-dextrinase or sucrase, thereby preventing the digestion of starch or sucrose. Examples of α-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2-propyl)variolamine (common name: voglibose), and miglitol.

上述醛糖还原酶抑制剂为一种抑制多羟基化合物途径第一步限速酶从而抑制糖尿病并发症的药物。实例包括托瑞司他、依帕司他、2，7-二氟-螺(9H-芴基芴-9，4′-咪唑烷)-2′，5′-二酮(通用名：咪瑞司他)、3-[(4-溴-2-氟苯基)甲基]-7-氯-3，4-二氢-2，4-二氧-1(2H)-喹唑啉乙酸(通用名：折那司他)、6-氟-2，3-二氢-2，5＇-二氧-螺[4H-1-苯并吡喃-4，4＇-咪唑烷]-2-酰胺(SNK-860)、唑泊司他、索比尼尔和1-[(3-溴-2-苯并呋喃基)磺酰基]-2，4-咪唑二酮(M-16209)。The above-mentioned aldose reductase inhibitor is a drug that inhibits the first rate-limiting enzyme of the polyol pathway, thereby inhibiting diabetic complications. Examples include torristat, epalrestat, 2,7-difluoro-spiro(9H-fluorenylfluorene-9,4'-imidazolidine)-2',5'-dione (common name: Sestat), 3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid ( Common name: Zenastat), 6-fluoro-2,3-dihydro-2,5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2- amide (SNK-860), zopolrestat, sobinil and 1-[(3-bromo-2-benzofuryl)sulfonyl]-2,4-imidazoledione (M-16209).

上述双胍制剂为一种促进厌氧性糖酵解、增强胰岛素外周作用、抑制肠内葡萄糖吸收、抑制肝脏的葡糖异生作用、抑制脂肪酸氧化的药物，实例包括苯乙双胍、二甲双胍及丁福明。The above-mentioned biguanide preparation is a drug that promotes anaerobic glycolysis, enhances the peripheral action of insulin, inhibits intestinal glucose absorption, inhibits gluconeogenesis in the liver, and inhibits fatty acid oxidation, and examples include phenformin, metformin, and buformin.

上述他汀类化合物为一种抑制羟甲基戊二酰CoA(HMG-CoA)还原酶从而降低血胆固醇水平的药物，实例普伐他汀及其钠盐、辛伐他汀、洛伐他汀、阿托伐他汀及氟伐他汀。Above-mentioned statin compound is a kind of medicine that inhibits hydroxymethylglutaryl CoA (HMG-CoA) reductase thereby lowering blood cholesterol level, example pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin Statins and fluvastatin.

上述鲨烯合成抑制剂为一种抑制鲨烯合成从而降低血胆固醇水平的药物，实例包括(S)-a-[双(2，2-二甲基-1-氧代丙氧基)甲氧基]氧膦基(phosphinyl)-3-苯氧基苯丁基磺酸单钾(BMS-188494)。The aforementioned squalene synthesis inhibitor is a drug that inhibits squalene synthesis to lower blood cholesterol levels, and examples include (S)-a-[bis(2,2-dimethyl-1-oxopropoxy)methoxy base] monopotassium phosphinyl-3-phenoxyphenylbutylsulfonate (BMS-188494).

上述贝特类化合物为一种抑制肝脏合成和分泌甘油三酯、激活脂蛋白脂酶从而降低血液中的甘油三酯水平的药物。实例包括苯扎贝特、苄氯贝特、比尼贝特、环丙贝特、克利贝特、氯贝丁酯、氯贝酸、ethofibrate、非诺贝特、吉非贝齐、尼可贝特、吡贝特、氯烟贝特、双贝特及益多酯。The above-mentioned fibrate compound is a drug that inhibits the synthesis and secretion of triglyceride by the liver, activates lipoprotein lipase, thereby reducing the level of triglyceride in the blood. Examples include bezafibrate, benzofibrate, benifibrate, ciprofibrate, clifibrate, clofibrate, clofibrate, ethofibrate, fenofibrate, gemfibrozil, nicofibrate Special, pifibrate, clofibrate, bifibrate and benefitoate.

上述LDL代谢促进剂为一种增加LDL(低密度脂蛋白)受体从而降低血胆固醇水平的药物，实例包括如日本专利申请Kokai Hei 7-316144中所述的那些化合物或其盐，更具体为N-[2-[4-双(4-氟苯基)甲基-1-哌嗪基]乙基]-7，7-二苯基-2，4，6-庚三烯酰胺。The aforementioned LDL metabolism promoter is a drug that increases LDL (low density lipoprotein) receptors to lower blood cholesterol levels, and examples include those compounds or salts thereof as described in Japanese Patent Application Kokai Hei 7-316144, more specifically N-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienamide.

上述他汀类化合物、鲨烯合成抑制剂、贝特类化合物和LDL代谢促进剂可以其它有效降低血胆固醇或甘油三酯水平的化学药物代替。此类药物的实例包括烟酸衍生物制剂，如尼可莫尔和戊四烟酯；抗氧化剂，如普罗布考；及离子交换树脂制剂，如考来烯胺。The aforementioned statin compounds, squalene synthesis inhibitors, fibrates and LDL metabolism accelerators can be replaced by other chemical drugs that can effectively reduce blood cholesterol or triglyceride levels. Examples of such drugs include niacin derivative preparations, such as nicomol and penetrol; antioxidants, such as probucol; and ion exchange resin preparations, such as cholestyramine.

上述血管紧张素转换酶抑制剂为一种抑制血管紧张素转换酶，从而降低血压，同时部分降低糖尿病患者的血糖水平的药物。实例包括卡托普利、依那普利、阿拉普利、地拉普利、雷米普利、赖诺普利、咪达普利、贝那普利、西罗普利、西拉普利、依那普利拉、福辛普利、莫维普利、培哚普利、喹那普利、螺普利、替莫普利及群多普利。The above-mentioned angiotensin-converting enzyme inhibitor is a drug that inhibits angiotensin-converting enzyme, thereby lowering blood pressure, and at the same time partially lowering the blood sugar level of diabetic patients. Examples include captopril, enalapril, alazapril, delapril, ramipril, lisinopril, imidapril, benazepril, cilazepril, cilazapril , enalaprilat, fosinopril, movipril, perindopril, quinapril, siropril, temopril and trandolapril.

对于口腔液体制剂，合适的载体包括乳剂、溶液、悬液、糖浆等，任选包含添加剂，如润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂及香料等。For oral liquid preparations, suitable carriers include emulsions, solutions, suspensions, syrups, etc., optionally containing additives such as wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, spices, and the like.

对于肠胃外使用的流体制剂，合适的载体包括无菌水溶液或非水溶液、悬液或乳剂。非水溶剂或介质的实例为丙二醇、聚乙二醇、植物油，如橄榄油、玉米油、明胶，及可注射的有机酯，如油酸乙酯。这些剂型也可包含佐剂，如防腐剂、润湿剂、乳化剂及分散剂。可将其灭菌，例如，以滤除细菌的滤器过滤、将灭菌药物加至组合物中、以放射线照射组合物或加热组合物。也可在使用前将其以无菌水或其它无菌溶媒直接制备。For fluid formulations for parenteral use, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, corn oil, gelatin, and injectable organic esters such as ethyl oleate. These dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. It can be sterilized, for example, by filtration through a filter that removes bacteria, by adding a sterilizing drug to the composition, by irradiating the composition, or by heating the composition. It can also be directly prepared with sterile water or other sterile media before use.

定义definition

为此处描述和要求保护的本发明，下列术语定义如下：For purposes of the invention described and claimed herein, the following terms are defined as follows:

此处所用的术语“卤素”，除非另有说明，指氟、氯、溴或碘。优选的卤素为氟、氯和溴。The term "halogen" as used herein, unless otherwise stated, refers to fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine, chlorine and bromine.

此处所用的术语“烷基”，除非另有说明，包括具有直链或支链部分的饱和单价烃基。The term "alkyl" as used herein, unless otherwise stated, includes saturated monovalent hydrocarbon groups having straight or branched chain portions.

此处所用的术语“链烯基”，除非另有说明，包括具有至少一个碳-碳双键的烷基部分，其中烷基如上定义，并包括该链烯基部分的E和Z异构体。As used herein, the term "alkenyl", unless otherwise stated, includes an alkyl moiety having at least one carbon-carbon double bond, wherein alkyl is as defined above, and includes the E and Z isomers of the alkenyl moiety .

此处所用的术语“炔基”，除非另有说明，包括具有至少一个碳-碳叁键的烷基部分，其中烷基如上定义。As used herein, unless otherwise stated, the term "alkynyl" includes alkyl moieties having at least one carbon-carbon triple bond, wherein alkyl is as defined above.

此处所用的术语“烷氧基”，除非另有说明，包括O-烷基基团，其中烷基如上定义。The term "alkoxy" as used herein, unless otherwise stated, includes O-alkyl groups, wherein alkyl is as defined above.

术语“Me”指甲基，“Et”指乙基，“Ac”指乙酰基。The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl.

此处所用的术语“环烷基”，除非另有说明，指非芳香族、饱和或部分饱和的单环或稠合的、螺合的或非稠合的二环或三环烃基，包含总数为3～10个碳原子，优选5-8个环碳原子。典型的环烷基包括具有3-7个，优选3-6个碳原子的单环，如环丙基、环丁基、环戊基、环己基、环庚基等。环烷基的例示性实例衍生于但不限于下列化合物：The term "cycloalkyl" as used herein, unless otherwise stated, means a non-aromatic, saturated or partially saturated monocyclic or fused, spiro or non-fused bicyclic or tricyclic hydrocarbon group, inclusive of the total 3 to 10 carbon atoms, preferably 5 to 8 ring carbon atoms. Typical cycloalkyl groups include monocyclic rings having 3-7, preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Illustrative examples of cycloalkyl groups are derived from, but are not limited to, the following compounds:

和

Figure A20048001673600313
and
Figure A20048001673600313

此处所用的术语“芳基”，除非另有说明，包括衍生于脱去一个氢的芳香烃的有机基团，如苯基或萘基。The term "aryl" as used herein, unless otherwise stated, includes organic radicals derived from an aromatic hydrocarbon from which one hydrogen has been removed, such as phenyl or naphthyl.

此处所用的术语“4-10员杂环”，除非另有说明，包括含有1～4个选自O、S和N杂原子的芳香或非芳香杂环基团，其中每个杂环基团在其环系中具有4-10个原子，条件是该基团的环不含两个相邻的O或S原子。非芳香杂环基团包括环系中仅有4个原子的基团，但芳香杂环基团环系中必须具有至少5个原子。杂环基团包括与苯稠合的环系。4员杂环基团的实例为氮杂环丁基(衍生自氮杂环丁烷)。4员杂环基团的实例为噻唑基，10员杂环基团的实例为喹啉基。非芳香杂环基团的实例为吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢硫代吡喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、氧杂环庚基、硫杂环庚基、二氧杂基、二氮杂基、硫杂基、1，2，3，6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基，4H-吡喃基、二噁烷基、1，3-二氧戊环基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、3H-吲哚基及喹嗪基。芳香杂环基团的实例为吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯咪唑基、苯并呋喃基、噌啉基、吲唑基、中氮茚基、2，3-二氮杂萘基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹噁啉基、1，5-二氮杂萘基及呋喃并吡啶基。前述基团，当衍生于上述基团时，可能的时候可连接于碳或氮。例如，衍生于吡咯的基团可为吡咯-1-基(与N相连)或吡咯-3-基(与C相连)。此外，衍生于咪唑的基团可为咪唑-1-基(与N相连)或咪唑-3-基(与C相连)。4-10员杂环的各个环的任一环碳、硫或氮原子任选被1～2个氧代取代。杂环基团的实例为1，1-二氧代-硫代吗啉基，其中2个环碳原子被氧取代。4-10员杂环的其它例示性实例衍生于但不限于下列：The term "4-10 membered heterocyclic ring" as used herein, unless otherwise specified, includes aromatic or non-aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from O, S and N, wherein each heterocyclic group A group has 4-10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups with only 4 atoms in the ring system, but aromatic heterocyclic groups must have at least 5 atoms in the ring system. Heterocyclic groups include ring systems fused to benzene. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 4-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepyl, thia Cycloheptyl, dioxetinyl, diazepinyl, thiepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline Base, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl , dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H - indolyl and quinozinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl , isothiazolyl, pyrrolyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, indolizyl, 2,3-diazepine Naphthyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzo Thiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridine and furopyridyl. The aforementioned groups, when derived from the aforementioned groups, may be attached to carbon or nitrogen where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Furthermore, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). Any ring carbon, sulfur or nitrogen atom of each ring of the 4-10 membered heterocycle is optionally substituted by 1-2 oxo. An example of a heterocyclic group is 1,1-dioxo-thiomorpholinyl in which 2 ring carbon atoms are replaced by oxygen. Other illustrative examples of 4-10 membered heterocycles are derived from, but not limited to, the following:

Figure A20048001673600321
Figure A20048001673600321

                  和 and

除非另有说明，术语“氧代”指＝O。The term "oxo" refers to =O unless otherwise stated.

此处使用的术语“-Ar1-Ar2-”，除非另有说明，包括与R4和R5连接的顺序无任何限制的两个环。例如，若-Ar1-Ar2-被定义为The term "-Ar 1 -Ar 2 -" used herein, unless otherwise specified, includes two rings in which the order of attachment to R 4 and R 5 is not subject to any limitation. For example, if -Ar 1 -Ar 2 - is defined as

Figure A20048001673600331
则-Ar1-Ar2-基团可为
Figure A20048001673600331
Then the -Ar 1 -Ar 2 -group can be

Figure A20048001673600332
或
Figure A20048001673600332
or

若-Ar1-Ar2-被定义为

Figure A20048001673600334
则-Ar1-Ar2-基团可为If -Ar 1 -Ar 2 - is defined as
Figure A20048001673600334
Then the -Ar 1 -Ar 2 -group can be

或

Figure A20048001673600336
or
Figure A20048001673600336

此处所用的短语“可药用盐”，除非另有说明，包括可存在于通式(I)化合物中的酸性或碱性基团的盐。通式(I)中的碱性化合物可与各种无机酸和有机酸形成各种盐。可用于制备通式(I)碱性化合物的可药用酸性加成盐的酸为可形成非毒性酸性加成盐的那些化合物，即包含可药用阴离子盐，如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸、柠檬酸盐、二盐酸盐、依地酸盐、edislyate、丙酸酯月桂硫酸盐(estolate)、乙磺酸、乙基琥珀酸盐、延胡索酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酰砷酸盐、hexylresorcinate、海巴盐(hydrabamine)、氢溴酸盐、盐酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖酸盐、十二烷酸盐、苹果酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘液酸盐、萘磺酸盐、硝酸盐、油酸盐、草酸盐、双羟萘酸(恩布酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸、水杨酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐、甲苯磺酸盐、triethiodode及戊酸盐。The phrase "pharmaceutically acceptable salt" as used herein, unless otherwise stated, includes salts of acidic or basic groups that may be present in compounds of general formula (I). The basic compounds in the general formula (I) can form various salts with various inorganic acids and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of basic compounds of general formula (I) are those compounds which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions, such as acetate, benzenesulfonic acid Salt, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camphorsulfonate, Carbonate, Chloride, Clavulanic Acid, Citrate , dihydrochloride, edetate, edislyate, propionate lauryl sulfate (estolate), ethanesulfonic acid, ethylsuccinate, fumarate, glucoheptonate, gluconate, glutamate , glycolyl arsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothiosulfate, lactate, lactobionate, dodecanoate, malic acid Salt, Mandelate, Methanesulfonate, Methylsulfate, Mucate, Naphthalenesulfonate, Nitrate, Oleate, Oxalate, Pamoate (Embrotate), Palmitate , pantothenate, phosphate/diphosphate, polygalacturonic acid, salicylate, stearate, hypoacetate, succinate, tannate, tartrate, 8-chlorophylline , tosylate, triethiodode and valerate.

通式(I)化合物中，使用术语如(CR11R12)q或(CR11R12)t的时候，R11和R12可随大于1的q或t的迭代而变化。例如，在q或t为2时，术语(CR11R12)q或(CR11R12)t可等于-CH2CH2-或-CH(CH3)C(CH2CH3)(CH2CH2CH3)-，或为R11和R12定义范围内任意数量的类似基团。此外，上面提及的不与卤素、SO或SO2基团或N、O或S原子连接的任何包括CH3(甲基)、CH2(亚甲基)或CH(次甲基)的取代基任选连接选自羟基、C1-C4烷氧基及胺的取代基。In compounds of general formula (I), when terms such as (CR 11 R 12 ) q or (CR 11 R 12 ) t are used, R 11 and R 12 may vary with iterations of q or t greater than 1. For example, when q or t is 2, the term (CR 11 R 12 ) q or (CR 11 R 12 ) t may be equal to -CH 2 CH 2 - or -CH(CH 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )-, or any number of similar groups within the range defined for R 11 and R 12 . In addition, any of the above mentioned substitutions including CH3 (methyl), CH2 (methylene) or CH (methine) not attached to a halogen, SO or SO2 group or N, O or S atom The group is optionally connected with a substituent selected from hydroxyl, C 1 -C 4 alkoxy and amine.

此处使用的术语“治疗”，除非另有说明，指逆转、减轻、抑制该术语应用的疾病或状态，或其中一或多种症状的进程，或预防其发生。此处使用的术语“治疗”，除非另有说明，指紧接上述“治疗”所指的治疗行为。The term "treating" as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting the progression of, or preventing the occurrence of, the disease or condition to which the term applies, or one or more symptoms thereof. As used herein, the term "treatment", unless otherwise stated, refers to the act of treatment immediately preceding the reference to "treatment" above.

此处使用的术语“调节”，除非另有说明，指能够调节甾体/甲状腺超家族成员，直接(通过作为配体与受体结合)或间接(作为配体的前体或促进配体从前体产生的诱导物)诱导或抑制受激素表达控制的基因表达。As used herein, the term "modulates", unless otherwise stated, refers to the ability to modulate a member of the steroid/thyroid superfamily, either directly (by binding to a receptor as a ligand) or indirectly (as a precursor of a ligand or by facilitating the ligand's previous Inducers produced by the body) induce or inhibit the expression of genes controlled by hormone expression.

此处使用的术语“肥胖”，除非另有说明，通常指超过其年龄、性别和身高对应的平均体重约20-30％的个体。在技术上，男性“肥胖”被定义为体重指数大于27.8kg/m2，女性则定义为体重指数大于27.3kg/m2。本领域技术人员很容易确定本发明方法不限于落于上述标准的那些个体。事实上，本发明方法还可便利地施用于超出常规标准的个体，例如，那些易于肥胖的个体。The term "obese" as used herein, unless otherwise indicated, generally refers to an individual who is about 20-30% over their average body weight for their age, sex, and height. Technically, "obesity" is defined as a BMI greater than 27.8 kg/m 2 for men and as a BMI greater than 27.3 kg/m 2 for women. Those skilled in the art can readily ascertain that the methods of the present invention are not limited to those individuals who fall within the above criteria. In fact, the methods of the invention may also be conveniently administered to individuals beyond conventional norms, for example, those prone to obesity.

此处使用的术语“炎症”，指这些疾病，如类风湿性关节炎、强直性脊椎炎、牛皮癣性关节炎、牛皮癣、软骨钙质沉着病、痛风、炎性肠病、溃疡性结肠炎、节段性回肠炎、纤维肌痛及恶病质。The term "inflammation" as used herein refers to diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.

此处使用的术语“治疗有效量”，指施用于组织、系统、动物或人引起研究者、兽医、医生或其他人期望的生物学或医学反应的用药量。The term "therapeutically effective amount" as used herein refers to the amount administered to a tissue, system, animal or human to elicit a desired biological or medical response by a researcher, veterinarian, physician or others.

此处使用的术语“有效降低血液中葡萄糖水平的量”，指化合物足以提供足够高的循环浓度以达到所需效果的水平。这一浓度通常在约10nM～2μM范围内，优选的浓度范围为约100nM～500nM。如前所述，由于上述通式(I)定义的不同化合物的活性可能差异很大，并且患者个体症状的严重性可能存在很大差异，因此，应该由执业医师确定患者对治疗的反应，并相应地改变剂量。The term "an amount effective to lower blood glucose levels" as used herein refers to a level of a compound sufficient to provide circulating concentrations high enough to achieve the desired effect. This concentration is generally in the range of about 10 nM to 2 [mu]M, with a preferred concentration range of about 100 nM to 500 nM. As previously stated, since the activity of the various compounds defined by general formula (I) above may vary widely, and the severity of symptoms may vary widely in individual patients, it is up to a practitioner to determine a patient's response to treatment and Change dosage accordingly.

此处使用的短语“胰岛素耐受”，指整个身体或个别组织，如骨骼肌组织、心肌组织、脂肪组织或肝组织，对胰岛素作用的敏感性降低。胰岛素耐受发生于许多患有或不患有糖尿病的个体。The phrase "insulin resistance" as used herein refers to a decreased sensitivity to the action of insulin in the body as a whole or in individual tissues, such as skeletal muscle tissue, cardiac muscle tissue, adipose tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes.

此处使用的短语“胰岛素耐受综合征”，指许多症状，包括胰岛素耐受、高胰岛素血症、非胰岛素依赖型糖尿病(NIDDM)、动脉高血压、向心性肥胖(内脏)及血脂异常。The phrase "insulin resistance syndrome", as used herein, refers to a number of conditions including insulin resistance, hyperinsulinemia, non-insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central obesity (visceral) and dyslipidemia.

此处使用的短语“与...联合(用)”，指在施用前面段落所述的其它药物稍前、稍后、同时，或组合使用上述方式施用通式(I)的α取代羧酸化合物。因此，通式(I)的α取代羧酸化合物及其它药物可以一种组合物或两种单独的组合物同时使用，或以两种单独的组合物先后使用。The phrase "in conjunction with (for)" used herein refers to administering the α-substituted carboxylic acid of general formula (I) a little before, later, at the same time, or in combination with the other drugs described in the previous paragraph compound. Therefore, the α-substituted carboxylic acid compound of the general formula (I) and other drugs can be used in one composition or two separate compositions simultaneously, or sequentially used in two separate compositions.

通式(I)的某些化合物可能具有不对称中心，因而存在不同的对映体。通式(I)化合物的所有光学异构体和立体异构体及其混合物视为在本发明范围内。对于通式(I)化合物，本发明包括使用消旋体、一或多种对映体、一或多种非对映异构体，或其混合物。通式(I)化合物还可以互变异构体存在。本发明涉及使用所有这些互变异构体及其混合物。Certain compounds of general formula (I) may possess asymmetric centers and thus exist as different enantiomers. All optical isomers and stereoisomers of the compounds of general formula (I) and mixtures thereof are considered within the scope of the present invention. For compounds of general formula (I), the present invention includes the use of racemates, one or more enantiomers, one or more diastereomers, or mixtures thereof. The compounds of general formula (I) may also exist as tautomers. The present invention contemplates the use of all these tautomers and mixtures thereof.

本发明化合物包含的某些官能团可被生物电子等排基团取代，即与母基团具有相似的空间或电性要求，但显示出不同的或改善的物理化学特性或其它特性的基团。合适的实例为本领域技术人员熟知，包括，但不限于在Patini等，Chem.Rev，1996，96，3147-3176及其引用的文献中描述的部分。Certain functional groups contained in the compounds of the present invention may be substituted by bioisosteric groups, ie groups that have similar steric or electrical requirements to the parent group, but exhibit different or improved physicochemical or other properties. Suitable examples are well known to those skilled in the art and include, but are not limited to, those described in Patini et al., Chem. Rev., 1996, 96, 3147-3176 and references cited therein.

本发明还包括同位素标记的化合物，除一或多个原子被一个原子量或质量数与自然界中通常发现的原子量或质量数不同的原子取代外，其与通式(I)表示的那些化合物相同。可引入本发明化合物同位素的实例包括氢、碳、氮、氧、磷、氟及氯的同位素，分别如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F及36Cl。包括上述同位素或其它原子的同位素的本发明化合物及其前药、这些化合物或其前药的可药用盐，包括在本发明的范围内。本发明某些同位素标记化合物，例如，引入放射性同位素如3H和14C的化合物，用于药物和/或底物组织分布实验。氚，即3H，和碳-14，即14C同位素因其易于制备和检测被特别优选。此外，以较重的同位素，如氘，即2H取代可提供某些治疗优势，这源于其更大的代谢稳定性，例如，可增加体内的半衰期或减少必需剂量，因此，可在某些情况下优选。本发明同位素标记的通式(I)化合物及其前药通常可以下述方案和/或实施例及制备中公开的方法制备，以易用的同位素标记的试剂取代非同位素标记的试剂。The present invention also includes isotopically labeled compounds identical to those represented by general formula (I) except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P , 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of these compounds or prodrugs thereof, including the above-mentioned isotopes or isotopes of other atoms, are included within the scope of the present invention. Certain isotope-labeled compounds of the present invention, eg, compounds incorporating radioactive isotopes such as 3 H and 14 C, are useful in drug and/or substrate tissue distribution assays. Tritium, ie3H , and carbon-14, ie14C isotopes are particularly preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, i.e. 2 H, may confer certain therapeutic advantages stemming from greater metabolic stability, e.g., may increase half-life in vivo or reduce necessary dosage, thus, may be used at certain preferred in some cases. The isotope-labeled compounds of general formula (I) and their prodrugs of the present invention can generally be prepared by the methods disclosed in the following schemes and/or examples and preparations, by substituting easy-to-use isotope-labeled reagents for non-isotope-labeled reagents.

本发明还包括治疗细菌感染的药学组合物及方法，通过使用通式(I)化合物的前药。具有游离氨基、酰氨基、羟基或羧基的通式(I)化合物可转变为前药。前药包括这些化合物，其中氨基酸残基，或两个或多个(如，两个、三个或四个)氨基酸残基的多肽链，通过酰胺键或酯键与通式(I)化合物的游离氨基、羟基或羧酸基团共价连接。这些氨基酸残基包括，但不限于通常以3个字母符号表示的20个天然存在的氨基酸，还包括4-羟基脯氨酸、羟基赖氨酸、demosine、isodemosine、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、鸟氨酸及甲硫氨酸砜。也包括其它类型前药。例如，游离的羧基可衍生为酰胺或烷基酯。游离的羟基可以这些基团衍生，包括但不限于Advanced Drug Delivery Reviews，1996，19，115中所述的半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯及磷酰氧基甲氧羰基。也包括羟基和氨基的氨基甲酸酯前药，还包括羟基的碳酸酯、磺酸酯与硫酸酯前药。还包括羟基衍生化为(酰氧基)甲基和(酰氧基)乙醚，其中酰基可为链烷酯，任选被下述基团取代，包括但不限于醚、胺及羧酸官能团，或酰基为上述氨基酸酯。该类型前药如J.Med.Chem.，1996，39，10中所述。游离胺还可衍生为酰胺、磺胺或磷酰胺。所有这些前药部分可引入下述基团，包括，但不限于醚、胺及羧酸官能团。The present invention also includes pharmaceutical compositions and methods for treating bacterial infections by using prodrugs of compounds of general formula (I). Compounds of general formula (I) with free amino, amido, hydroxyl or carboxyl groups can be converted into prodrugs. Prodrugs include those compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is bonded to a compound of general formula (I) via an amide bond or an ester bond. Free amino, hydroxyl or carboxylic acid groups are covalently attached. These amino acid residues include, but are not limited to, the 20 naturally-occurring amino acids usually represented by the 3-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Other types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized with groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate and phosphoryloxymethoxycarbonyl as described in Advanced Drug Delivery Reviews, 1996, 19, 115 . Also included are hydroxy and amino carbamate prodrugs, as well as hydroxy carbonate, sulfonate and sulfate prodrugs. Also included are derivatizations of hydroxyl groups to (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl groups may be alkanes, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, Or the acyl group is the above-mentioned amino acid ester. Prodrugs of this type are described in J. Med. Chem., 1996, 39, 10 . Free amines can also be derivatized as amides, sulfonamides or phosphoramides. All of these prodrug moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.

本发明的其它方面、优势及优选特征将在以下具体描述中显而易见。Other aspects, advantages and preferred features of the invention will be apparent from the following detailed description.

发明详述及优选实施方案Detailed Description of the Invention and Preferred Embodiments

下述反应方案阐释本发明化合物的制备。除非另有说明，下述的R-R17、O、Y、Ar1-Ar4及环A定义如上。The following reaction schemes illustrate the preparation of compounds of the invention. Unless otherwise specified, the following RR 17 , O, Y, Ar 1 -Ar 4 and ring A are as defined above.

                         方案1 plan 1

Figure A20048001673600371
Figure A20048001673600371

                         方案2 Scenario 2

Figure A20048001673600381
Figure A20048001673600381

                         方案3 Option 3

Figure A20048001673600391
Figure A20048001673600391

                         方案4 Option 4

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NR10a-或-S(O)j-；其中m和s独立地为0、1、2或3；其中j为0、1或2R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NR 10a - or -S(O) j -; wherein m and s are independently 0 , 1, 2 or 3; where j is 0, 1 or 2

                         方案5 Option 5

Figure A20048001673600411
Figure A20048001673600411

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NR10a-或-S(O)j-；其中每个m和s独立地为0、1、2或3；其中j为0、1或2R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NR 10a - or -S(O) j -; wherein each m and s are independently is 0, 1, 2 or 3; where j is 0, 1 or 2

                         方案6 Option 6

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-；其中每个m和s独立地为0、1、2或3。R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -;

                         方案7 Option 7

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-；其中每个m和s独立地为0、1、2或3。R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -;

                         方案8 Option 8

Figure A20048001673600441
Figure A20048001673600441

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-；其中每个m和s独立地为0、1、2或3。R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -;

                         方案9 Option 9

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-；其中每个m和s独立地为0、1、2或3。R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -;

                         方案10 Scheme 10

Figure A20048001673600461
Figure A20048001673600461

R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NR10a-或-S(O)j-；其中每个m和s独立地为0、1、2或3；其中j为0、1或2。R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NR 10a - or -S(O) j -; wherein each m and s are independently is 0, 1, 2 or 3; where j is 0, 1 or 2.

                         方案11 Scheme 11

Figure A20048001673600471
Figure A20048001673600471

                         方案12 Scheme 12

                         方案13 Scheme 13

Figure A20048001673600491
Figure A20048001673600491

关于上述方案1，通式1a化合物可通过水解化合物IIa(其中，CO2R基团为可水解的酯基团，如甲酯(CO2-CH3)或乙酯(CO2-CH2CH3))制备得到，反应以碱金属氢氧化物(例如，NaOH、LiOH、KOH)在合适溶剂中(例如，THF水溶液、甲醇水溶液或其组合)，在0～100℃下或以微波合成仪中加热进行。通式IIa化合物可通过化合物IVa，其中LV1为Cl、Br、I或三氟甲磺酸酯，与有机金属化合物IIIa偶联以钯(0)或其它过渡金属催化剂介导反应制备得到，其中Met＝硼酸或酯、甲锡烷等，并且基团CO2R如上所述。化合物IVa可通过用化合物VIa烷基化化合物Va获得，其中Lv1如上所述，Lv2为Cl、Br、I或三氟甲磺酸酯。With respect to Scheme 1 above, compounds of general formula 1a can be synthesized by hydrolyzing compound IIa (wherein the CO 2 R group is a hydrolyzable ester group such as methyl ester (CO 2 —CH 3 ) or ethyl ester (CO 2 —CH 2 CH 3 )) prepared by reacting alkali metal hydroxide (for example, NaOH, LiOH, KOH) in a suitable solvent (for example, THF aqueous solution, methanol aqueous solution or a combination thereof), at 0-100 ° C or with a microwave synthesizer Medium heating is carried out. The compound of general formula IIa can be prepared by compound IVa, wherein LV1 is Cl, Br, I or trifluoromethanesulfonate, coupled with organometallic compound IIIa and mediated by palladium (0) or other transition metal catalysts, wherein Met = boronic acid or ester, stannane, etc., and the group CO 2 R is as described above. Compound IVa can be obtained by alkylation of compound Va with compound VIa, wherein Lv 1 is as described above and Lv 2 is Cl, Br, I or triflate.

关于上述方案2，方案1中使用的式IIIa化合物可从化合物VIIa与诸如频哪醇合二硼烷(pinacolatodiborane)的试剂在钯(0)介导的偶联反应获得，其中，Lv3为Cl、Br、I或三氟甲磺酸酯。化合物VIIa，其中Lv3如上所述，可通过用化合物IXa烷基化化合物VIIIa获得，其中Lv3如上所述，Lv4为Cl、Br、I或三氟甲磺酸酯。With respect to Scheme 2 above, the compound of formula IIIa used in Scheme 1 can be obtained from the palladium(0)-mediated coupling reaction of compound VIIa with a reagent such as pinacolatodiborane, wherein Lv 3 is Cl , Br, I or triflate. Compound Vila, wherein Lv 3 is as described above, can be obtained by alkylation of Compound VIIIa, wherein Lv 3 is as described above and Lv 4 is Cl, Br, I or triflate, with compound IXa.

关于上述方案3，方案1中使用的酯IIa，其中CO2R如上所述，也可通过用化合物VIa烷基化化合物Xa获得，其中CO2R如上所述，Lv2如方案1所述。化合物Xa可自化合物XIa获得，其中CO2R如上所述，通过将化合物XIa与脱保护试剂，如氢气在金属催化剂(例如，钯炭)上，在合适的溶剂(例如，THF、甲醇、乙醇)中，在0～100℃下反应。Regarding Scheme 3 above, the ester IIa used in Scheme 1, wherein CO 2 R is as described above, can also be obtained by alkylation of compound Xa with compound VIa, wherein CO 2 R is as described above and Lv 2 is as described in Scheme 1 . Compound Xa can be obtained from Compound XIa, wherein CO2R is as described above, by reacting Compound XIa with a deprotecting reagent, such as hydrogen, over a metal catalyst (e.g., palladium on carbon) in a suitable solvent (e.g., THF, methanol, ethanol ), react at 0-100°C.

化合物XIa已商业化，或可由本领域技术人员制备得到。Compound XIa is commercially available or can be prepared by those skilled in the art.

关于上述方案4，通式1b化合物；其中R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NH10a-或-S(O)j-；其中每个m和s独立地为0、1、2或3；其中j为0、1或2；可通过水解化合物IIb制备，其中R5如通式Ib化合物中所述，并且CO2R如上所述，以碱金属氢氧化物(例如，NaOH、LiOH、KOH)在合适的溶剂(例如，THF水溶液、甲醇水溶液或其组合)中0～100℃下反应。通式IIb化合物，其中R5如通式Ib化合物中所述，可通过将化合物IIIb，其中R5如通式IIb化合物中所述，并且CO2R如上所述，与活化的酰化试剂如VIb在合适的溶剂(例如，THF、乙腈、二氧杂环乙烷、甲苯)中在0～100℃温度下反应。化合物IVb可自化合物Vb与化合物VIb反应获得，其中Lv6为离去基团。合适的化合物VIb包括N，N′-羰基二咪唑。Regarding Scheme 4 above, compounds of general formula 1b; wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NH 10a - or -S(O) j -; wherein each m and s is independently 0, 1, 2 or 3; wherein j is 0, 1 or 2; can be prepared by hydrolyzing compound IIb, wherein R 5 is as described in the compound of general formula Ib, and CO 2 R is reacted with alkali metal hydroxide (eg, NaOH, LiOH, KOH) in a suitable solvent (eg, THF aqueous solution, methanol aqueous solution or a combination thereof) at 0-100°C as described above. The compound of general formula IIb, wherein R 5 is as described in the compound of general formula Ib, can be prepared by combining compound IIIb, wherein R 5 is as described in the compound of general formula IIb, and CO 2 R is as described above, with an activated acylating agent such as VIb is reacted in a suitable solvent (eg, THF, acetonitrile, dioxane, toluene) at a temperature of 0-100°C. Compound IVb can be obtained by reacting compound Vb with compound VIb, wherein Lv 6 is a leaving group. Suitable compounds VIb include N,N'-carbonyldiimidazole.

化合物Vb和VIb已商业化，或由本领域技术人员制备得到。Compounds Vb and VIb are commercialized or prepared by those skilled in the art.

关于上述方案5，方案4中使用的通式IIIb化合物，其中R5如方案4所述，并且CO2R如上所述，可通过化合物VIIb，其中R5如前面段落所述，与合适的通式Lv6-C(R7R8)-COOR亲电试剂，其中Lv6为离去基团，如卤素，在碱(例如，碳酸铯、碳酸钾)存在情况下，在合适的溶剂(例如，THF、DMF、乙腈或DMSO)中0～100℃反应制备。合适的通式Lv6-C(R7R8)-COOR亲电试剂包括2-溴-2-甲基丙酸甲酯。化合物VIIb已商业化，或可由本领域技术人员制备得到。With respect to Scheme 5 above, the compound of general formula IIIb used in Scheme 4, wherein R5 is as described in Scheme 4, and CO2R is as described above, can be obtained by compound VIIb, wherein R5 is as described in the previous paragraph, with the appropriate formula Formula Lv 6 -C(R 7 R 8 )-COOR electrophile, wherein Lv 6 is a leaving group, such as halogen, in the presence of a base (for example, cesium carbonate, potassium carbonate), in a suitable solvent (for example , THF, DMF, acetonitrile or DMSO) at 0 ~ 100 ° C reaction preparation. Suitable electrophiles of general formula Lv6 -C( R7R8 )-COOR include methyl 2-bromo-2-methylpropionate. Compound VIIb is commercially available or can be prepared by those skilled in the art.

通式Ib、IIb、IIIb及VIIb化合物；其中R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-，其中每个m和s如上所述；可通过本领域技术人员公知的方法制备。Compounds of general formula Ib, IIb, IIIb and VIIb; wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 )s; wherein Z is -CH 2 -, wherein each m and s are as above described; can be prepared by methods known to those skilled in the art.

关于上述方案6，通式Ic化合物，其中R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-，可通过水解化合物IIc制备得到，其中CO2R如上所述，使用碱金属氢氧化物(例如，NaOH、LiOH、KOH)，在合适的溶剂(例如，THF水溶液、甲醇水溶液或其组合)中0～100℃下或以微波合成仪加热进行。化合物IIc可通过用化合物IVc(Lv7为碘、溴、氯或其它离去基团)烷基化化合物IIIc制备，其中Lv5为离去基团。可使用不同方法实现此反应，如以碱，如双(三甲基甲硅烷基)胺基钠对化合物IIIc(Lv5＝H)去质子化。化合物IVc可自化合物Vc与卤化试剂或卤化系统，如乙二酰氯及二甲基甲酰胺，或与其它卤化物(例如，将化合物IVc，Lv7＝Cl与碘化钠反应)反应制备。化合物Vc可自化合物VIc通过化合物VIIIc与还原剂，如硼氢化钠反应制备。化合物VIc可自化合物VIIc(Lv8＝Br或其它卤素)通过金属-卤素交换(例如，与丁基锂)，然后与二甲基甲酰胺反应制备。With respect to Scheme 6 above, compounds of general formula Ic, wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -, can be prepared by hydrolyzing compound IIc, wherein CO 2 R As described above, use alkali metal hydroxide (eg, NaOH, LiOH, KOH), in a suitable solvent (eg, THF aqueous solution, methanol aqueous solution, or a combination thereof) at 0-100 ° C or in a microwave synthesizer Heating is carried out. Compound IIc can be prepared by alkylating compound IIIc with compound IVc (Lv 7 is iodine, bromine, chlorine or other leaving group), wherein Lv 5 is a leaving group. This reaction can be achieved using different methods such as deprotonation of compound IIIc (Lv 5 =H) with a base such as sodium bis(trimethylsilyl)amide. Compound IVc can be prepared from compound Vc with a halogenating reagent or halogenation system, such as oxalyl chloride and dimethylformamide, or with other halides (eg, reacting compound IVc, Lv 7 =Cl with sodium iodide). Compound Vc can be prepared from compound VIc by reacting compound VIIIc with a reducing agent such as sodium borohydride. Compound VIc can be prepared from compound VIIc (Lv 8 =Br or other halogen) by metal-halogen exchange (eg, with butyllithium) followed by reaction with dimethylformamide.

或者，关于上述方案7，通式IIc化合物，其中R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-CH2-，可以甲硅烷或酸源，通常为三乙基甲硅烷和三氟乙酸，将化合物VIIIc还原脱氧制备得到。化合物VIIIc可通过将化合物IIIc加入VIc中获得。可以不同方法实现此反应，如以碱，如二异丙胺基锂对化合物IIIc(Lv5＝H)去质子化作用，或以金属或金属盐(例如，氯化铬(II))对化合物IIIc(Lv5＝Br)进行Reformatsky反应。化合物VIc可自化合物VIIc(Lv8＝Br或其它卤素)通过金属-卤素交换(例如，与丁基锂)，然后与二甲基甲酰胺反应制备。Alternatively, with regard to Scheme 7 above, compounds of general formula IIc, wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CH 2 -, can be silane or an acid source, Usually triethylsilane and trifluoroacetic acid, prepared by reductive deoxygenation of compound VIIIc. Compound VIIIc can be obtained by adding compound IIIc to VIc. This reaction can be achieved in different ways, such as deprotonation of compound IIIc (Lv 5 =H) with a base, such as lithium diisopropylamide, or deprotonation of compound IIIc with a metal or a metal salt (eg, chromium(II) chloride) (Lv 5 =Br) undergoes a Reformatsky reaction. Compound VIc can be prepared from compound VIIc (Lv 8 =Br or other halogen) by metal-halogen exchange (eg, with butyllithium) followed by reaction with dimethylformamide.

或者，关于上述方案8，化合物IIc，其中R5为-(CR11R12)m-Z-(CR11R12)；其中Z为-CH2-，可通过化合物IXc与合适的通式VIa偶联试剂反应获得。这些反应可使用亲电试剂VIa(例如，Lv2＝卤化物、磺酸酯)在碱(例如，碳酸铯)存在情况下，或与醇(Lv2＝OH)在Mitsunobu-型条件(例如，三苯基膦与偶氮二羧酸二乙酯)下反应实现。化合物IXc可通过保护的化合物Xc脱保护进行制备。合适的保护基团包括烯丙基、苄基等。Xc(P＝烯丙基)的脱保护可通过在碱，例如吗啉存在的情况下，接触可溶的过渡金属(例如，四(三苯基膦)钯(0))完成。Alternatively, with respect to Scheme 8 above, compound IIc, wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ); wherein Z is -CH 2 -, can be obtained by compound IXc with the appropriate general formula VIa The coupling reagent reaction is obtained. These reactions can use electrophiles VIa (eg, Lv2 = halides, sulfonates) in the presence of bases (eg, cesium carbonate), or with alcohols ( Lv2 = OH) under Mitsunobu-type conditions (eg, Triphenylphosphine reacts with diethyl azodicarboxylate). Compound IXc can be prepared by deprotection of protected compound Xc. Suitable protecting groups include allyl, benzyl, and the like. Deprotection of Xc (P=allyl) can be accomplished by contacting a soluble transition metal (eg tetrakis(triphenylphosphine)palladium(0)) in the presence of a base such as morpholine.

中间体Xc-XIIIc可以方案6中所述的方法制备。Intermediates Xc-XIIIc can be prepared as described in Scheme 6.

或者，关于上述方案9，化合物Xc可通过化合物XIVc(例如，Lv10＝卤化物、磺酸酯)与化合物IIIc反应制备，其中Lv5如上所述。化合物XIVc可通过化合物XVc与(C＝O)Cl2在极性非质子溶剂，如二甲基甲酰胺中反应制备。化合物XVc可通过化合物XIIc与还原剂，如硼氢化钠反应制备。化合物XIIIc可以方案6中所述的方法制备。Alternatively, with respect to Scheme 9 above, compound Xc can be prepared by reacting compound XIVc (eg, Lv 10 = halide, sulfonate) with compound IIIc, wherein Lv 5 is as described above. Compound XIVc can be prepared by reacting compound XVc with (C=O) Cl2 in a polar aprotic solvent such as dimethylformamide. Compound XVc can be prepared by reacting compound XIIc with a reducing agent such as sodium borohydride. Compound XIIIc can be prepared as described in Scheme 6.

或者，关于上述方案10，通式Ic化合物，其中R5为-(CR11R12)m-Z-(CR11R12)s；其中Z为-O-、-NR10a或-S(O)j-；其中每个m和s独立地为0、1、2或3；其中j为0、1或2；可通过水解通式IIc化合物制备得到，利用碱金属氢氧化物(例如，NaOH、LiOH、KOH)中，在合适的溶剂(例如，THF水溶液、甲醇水溶液或其组合物)中0～100℃下或使用微波合成仪加热极性。通式IIc化合物可通过化合物IXc与合适的偶联试剂反应获得。这些反应可使用亲电试剂(例如，VIa；Lv2＝卤化物、磺酸酯)，在碱(例如，碳酸铯、碳酸钾或叔丁醇钾)存在的情况下实现，或与醇(VIa；Lv2＝OH)在Mitsunobu-型条件下(例如，三苯基膦及偶氮二羧酸二乙酯)实现。化合物IXc可通过化合物XIc脱保护制备，其中P为保护性基团。合适的保护基P包括烯丙基、苄基等。XIc(P＝烯丙基)的脱保护可通过在碱例如吗啉存在的情况下，与可溶的过渡金属(例如，四(三苯基膦)钯(0))接触实现，或者以氢气在金属催化剂(例如，钯炭)上，在合适的溶剂(例如，THF、甲醇、乙醇)中，在0～100℃下还原完成。化合物XIc可通过以化合物IIIc(Lv5＝Cl、Br、I、三氟甲磺酸酯，如上述)烷基化化合物XVc获得。Alternatively, with respect to Scheme 10 above, compounds of general formula Ic wherein R 5 is -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -O-, -NR 10a or -S(O ) j -; wherein each m and s is independently 0, 1, 2 or 3; wherein j is 0, 1 or 2; can be prepared by hydrolysis of the compound of general formula IIc, utilizing an alkali metal hydroxide (for example, NaOH , LiOH, KOH) in a suitable solvent (eg, aqueous THF, aqueous methanol, or a combination thereof) at 0-100° C. or using a microwave synthesizer to heat the polarity. Compounds of general formula IIc can be obtained by reacting compounds IXc with suitable coupling reagents. These reactions can be achieved using electrophiles (eg VIa; Lv2 = halides, sulfonates) in the presence of bases (eg cesium carbonate, potassium carbonate or potassium tert-butoxide), or with alcohols (VIa ; Lv 2 =OH) is achieved under Mitsunobu-type conditions (eg, triphenylphosphine and diethyl azodicarboxylate). Compound IXc can be prepared by deprotecting compound XIc, wherein P is a protecting group. Suitable protecting groups P include allyl, benzyl and the like. Deprotection of XIc (P=allyl) can be achieved by contact with a soluble transition metal (e.g., tetrakis(triphenylphosphine)palladium(0)) in the presence of a base such as morpholine, or with hydrogen The reduction is accomplished over a metal catalyst (eg, palladium on carbon) in a suitable solvent (eg, THF, methanol, ethanol) at 0-100°C. Compound XIc can be obtained by alkylation of compound XVc with compound IIIc (Lv 5 =Cl, Br, I, triflate, as above).

关于上述方案11，在一些情况下，以具有通式XVIc的苄基卤化物烷基化化合物IIIc的烯醇阴离子得化合物XVc。通过例如在本领域技术人员(例如，March，Advanced organic Chemistry，Fourth Edition)已知的在溶剂中的钯介导的偶联反应，化合物XVc可转换为化合物Ic。Referring to Scheme 11 above, in some cases alkylation of the enolate anion of compound IIIc with a benzyl halide of general formula XVIc affords compound XVc. Compound XVc can be converted to compound Ic by, for example, palladium-mediated coupling reactions in solvents known to those skilled in the art (eg, March, Advanced Organic Chemistry, Fourth Edition).

关于上述方案12，通式Id化合物可通过碱金属氢氧化物(例如，NaOH、LiOH、KOH)，在合适的溶剂(例如，THF水溶液、甲醇水溶液或其组合)中0～100℃下水解化合物IId制备。通式IId化合物可通过化合物IIId与合适的氢化试剂，如氢气在金属催化剂上(例如，钯炭)，在合适的溶剂(例如，THF、甲醇、乙醇)中0～100℃下反应制备。通式IIId化合物可通过化合物IVd与具有通式(C6H5)3P+-CH(OR9)(COOR)Cl-的合适三苯基鏻试剂发生Wittig反应制备。合适的三苯基膦试剂包括1，2-二乙氧基-2-氧代乙基)(三苯基)氯化鏻。通式IVd化合物可通过如方案9中所述的方法用化合物Vd的反应制备。通式Vd化合物可通过如方案9中所述的所述的方法用化合物VId与VIId反应制备。With respect to Scheme 12 above, the compound of general formula Id can be hydrolyzed by alkali metal hydroxide (eg, NaOH, LiOH, KOH) in a suitable solvent (eg, aqueous THF, aqueous methanol, or a combination thereof) at 0-100°C IId preparation. The compound of general formula IId can be prepared by reacting compound IIId with a suitable hydrogenation reagent, such as hydrogen, on a metal catalyst (eg, palladium on carbon) in a suitable solvent (eg, THF, methanol, ethanol) at 0-100°C. Compounds of general formula IIId can be prepared by Wittig reaction of compounds IVd with a suitable triphenylphosphonium reagent of general formula ( C6H5 ) 3P + -CH( OR9 )(COOR) Cl- . Suitable triphenylphosphine reagents include 1,2-diethoxy-2-oxoethyl)(triphenyl)phosphonium chloride. Compounds of general formula IVd can be prepared by reaction of compounds Vd as described in Scheme 9. Compounds of general formula Vd can be prepared by reacting compounds VId with VIId as described in Scheme 9.

或者，通式IId化合物可通过方案13的方法制备。关于方案13，以苄基卤化物IXd烷基化2-甲氧基丙酸甲酯的烯醇阴离子提供化合物VIIId。化合物VIIId可被例如钯介导的偶联反应生成化合物IId。化合物IId也可自化合物Xd制备。化合物Xd可自化合物XIId通过一系列反应制备，如(i)钯介导的偶联反应形成化合物XId，及(ii)酯还原成醇及(iii)卤化形成化合物IId。Alternatively, compounds of general formula IId can be prepared by the method of scheme 13. Referring to Scheme 13, alkylation of the enolate anion of methyl 2-methoxypropionate with benzyl halide IXd affords compound VIIId. Compound VIIId can be for example palladium mediated coupling reaction to give compound IId. Compound IId can also be prepared from compound Xd. Compound Xd can be prepared from compound XIId by a series of reactions such as (i) palladium mediated coupling reaction to form compound XId, and (ii) reduction of ester to alcohol and (iii) halogenation to form compound IId.

上述通式I的任一化合物及上述方案1-13中的任一化合物可通过标准的化学操作转变成另一类似物。这些化学操作为本领域技术人员熟知，包括a)如T.W.Greene和P.G.M.Wuts，Protective Groups in OrganicSynthesis″，Second Edition，John Wiley和Sons，New York，1991中所述的方法脱保护基；b)以伯胺或仲胺、硫醇或醇置换离去基团(卤化物、甲磺酸酯、甲磺酸酯等)，分别形成仲胺或叔胺、硫醚或醚；c)如Thavonekham，B等Synthesis(1997)，10，p1189所述的方法，以伯胺或仲胺处理苯基(或被取代的苯基)氨基甲酸酯，形成相应的脲；d)如Denmark，S.E.；Jones，T.K.J.Org.Chem.(1982)47，4595-4597或van Benthem，R.A.T.M.；Michels，J.J.；Speckamp，W.N.Synlett(1994)，368-370所述的方法，以双(2-甲氧基乙氧基)铝氢化钠(Red-AI)处理，将炔丙基醇或异炔苯基醇或N-BOC保护的伯胺还原为相应的E-烯丙基或E-高烯丙基衍生物；e)如Tomassy，B.等Synth.Commun.(1998)，28，p1201所述的方法，以氢气及Pd催化剂处理，将炔还原为相应的Z-链烯烃衍生物；f)以异氰酸酯、酰氯(或其它有活性的羧酸衍生物)、烷基芳基氯甲酸酯或磺酰氯处理伯胺或仲胺，得相应的脲、酰胺、氨基甲酸盐或磺胺；g)使用R1CH(O)将伯胺或仲胺还原胺化；及h)以异氰酸酯、酰氯(或其它有活性的羧酸衍生物)、烷基芳基氯甲酸盐或磺酰氯处理醇得相应的氨基甲酸酯、酯、碳酸酯或磺酸酯。Any compound of formula I above and any compound of Schemes 1-13 above can be converted into another analog by standard chemical manipulations. These chemical manipulations are well known to those skilled in the art and include a) deprotection as described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991; b) deprotection with primary amines Or secondary amines, thiols or alcohols replace leaving groups (halides, mesylate, mesylate, etc.) to form secondary or tertiary amines, thioethers or ethers, respectively; c) Synthesis such as Thavonekham, B, etc. (1997), 10, the method described in p1189, process phenyl (or substituted phenyl) carbamate with primary amine or secondary amine, form corresponding urea; d) such as Denmark, SE; Jones, TKJOrg. Chem.(1982) 47,4595-4597 or van Benthem, RATM; Michels, JJ; Speckamp, WNSynlett (1994), the method described in 368-370, with two (2-methoxyethoxy) sodium aluminum hydride (Red-AI) treatment, the reduction of propargyl alcohol or isoacetylenyl phenyl alcohol or N-BOC protected primary amines to the corresponding E-allyl or E-homoallyl derivatives; e) such as Tomassy, B. etc. Synth.Commun.(1998), 28, the method described in p1201, with hydrogen and Pd catalyst treatment, alkyne is reduced to corresponding Z-alkene derivative; f) with isocyanate, acid chloride (or other active carboxylic acid derivatives), alkylaryl chloroformate or sulfonyl chloride to treat primary or secondary amines to obtain the corresponding urea, amide, carbamate or sulfonamide; g) use R 1 CH(O) to convert the primary Reductive amination of amines or secondary amines; and h) treatment of alcohols with isocyanates, acid chlorides (or other reactive carboxylic acid derivatives), alkylaryl chloroformates or sulfonyl chlorides to give the corresponding carbamates, esters, Carbonate or Sulfonate.

本发明化合物可具有不对称的碳原子。非对映混合物可基于其物理、化学的差异以本领域技术人员熟知的方法，例如，以层析或分离结晶分离为其单独的非对映体。对映异构体可以下述方法分离，即与合适的光学活性化合物(例如，醇)反应，将对映异构体混合物转变为非对映异构体混合物，分离出非对映体，再制备(例如，水解)各相应的纯非对映体；或通过使用手性固定相或流动相层析分离。所有异构体，包括非对映混合物及纯对映体视为本发明的一部分。The compounds of the invention may have asymmetric carbon atoms. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical and chemical differences by methods well known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting with a suitable optically active compound (e.g. alcohol), separating the diastereomers, and then Each corresponding pure diastereomer is prepared (eg, hydrolyzed); or separated by chromatography using a chiral stationary or mobile phase. All isomers, including diastereomeric mixtures and pure enantiomers are considered as part of this invention.

通式(I)的碱性化合物能够与多种无机酸或有机酸形成多种不同的盐。尽管这些盐必须可药用以施用于动物，实践中通常期望首先从反应混合物中分离通式(I)化合物为非药用盐，然后以碱性试剂处理简单地将后者转变为游离碱化合物，再将该游离碱转变为可药用酸性加成盐。本发明碱性化合物的酸性加成盐易于制备，即在水溶介质或合适的有机溶剂如甲醇或乙醇中，以基本等量精选的无机酸或有机酸处理该碱性化合物。仔细蒸发溶剂，容易获得期望固体盐。所需的酸性盐也可通过向溶液中加入合适的无机酸或有机酸，自有机溶剂中将游离碱溶液沉淀出来。The basic compounds of general formula (I) are capable of forming a wide variety of different salts with various inorganic or organic acids. Although these salts must be pharmaceutically acceptable for administration to animals, it is generally desirable in practice to first isolate the compound of general formula (I) from the reaction mixture as a non-pharmaceutically acceptable salt and then simply convert the latter to the free base compound by treatment with an alkaline reagent , and then convert the free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of basic compounds of the invention are readily prepared by treating the basic compound with a substantially equivalent amount of a selected inorganic or organic acid in aqueous medium or in a suitable organic solvent such as methanol or ethanol. The desired solid salt was readily obtained by careful evaporation of the solvent. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding a suitable mineral or organic acid to the solution.

通式(I)的酸性化合物能够与各种可药用的阳离子形成碱式盐。这些盐的实例包括碱金属盐或碱土金属盐，特别是钠盐和钾盐。所有这些盐均可以常规技术制备。用作试剂制备本发明可药用碱式盐的化学碱与通式(I)的酸性化合物形成非毒性碱式盐。非毒性碱式盐包括那些衍生于可药用阳离子，如钠、钾、钙及镁等的盐。这些盐易于制备，以含有所需可药用阳离子的水溶液处理相应的酸性化合物，然后蒸发所得溶液至干，优选减压蒸发。或者，也可以下述方法制备，将酸性化合物的低级烷醇溶液与所需的烷氧基碱金属混合，然后以上述方法蒸发所得溶液至干。在各种方法中，为确保反应完全及终产物产率最高，优选使用计量的试剂。The acidic compounds of general formula (I) are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially sodium and potassium salts. All such salts can be prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of this invention form non-toxic base salts with acidic compounds of general formula (I). Non-toxic base salts include those derived from pharmaceutically acceptable cations, such as sodium, potassium, calcium and magnesium, and the like. These salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, it can also be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as described above. In various methods, in order to ensure the completion of the reaction and the highest yield of the final product, it is preferable to use metered reagents.

本发明化合物为PPAR优选PPARγ及α调节剂。本发明化合物可调节PPAR-γ介导的过程，即生物学、生理学、内分泌及其它身体过程，这些过程为对此处所述的PPAR激动剂敏感的受体或受体组合物所介导(例如，糖尿病、高脂血症、肥胖症、葡萄糖耐量受损、高血压、脂肪肝、糖尿病并发症(例如，视网膜病、肾病、神经症、白内障冠状动脉病等)、动脉粥样硬化、妊娠糖尿病、多囊性卵巢综合征、心血管疾病(例如，局部缺血性心脏病等)、动脉粥样硬化或局部缺血性心脏病引起的细胞损伤(例如，中风等引起的脑损伤)、痛风、炎症(例如，骨关节炎、疼痛、发热、类风湿性关节炎、炎性肠病、痤疮、日光灼伤、牛皮癣、湿疹、变态反应病、哮喘、GI溃疡、恶病质、自身免疫性疾病、胰腺炎等)、癌症、骨质疏松症及白内障。这些过程的调节可在体外或体内完成。可在多种对象，如，例如人、啮齿动物、绵羊、猪、奶牛等施行体内调节。The compounds of the invention are PPAR, preferably PPAR gamma and alpha modulators. Compounds of the present invention can modulate PPAR-γ-mediated processes, i.e. biological, physiological, endocrine and other bodily processes mediated by receptors or combinations of receptors sensitive to the PPAR agonists described herein ( For example, diabetes, hyperlipidemia, obesity, impaired glucose tolerance, hypertension, fatty liver, complications of diabetes (eg, retinopathy, nephropathy, neurosis, cataract, coronary artery disease, etc.), atherosclerosis, pregnancy Diabetes, polycystic ovary syndrome, cardiovascular disease (eg, ischemic heart disease, etc.), atherosclerosis or cell damage from ischemic heart disease (eg, brain damage from stroke, etc.), Gout, inflammation (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergies, asthma, GI ulcers, cachexia, autoimmune diseases, Pancreatitis, etc.), cancer, osteoporosis, and cataracts. Modulation of these processes can be accomplished in vitro or in vivo. In vivo modulation can be performed in a variety of subjects, such as, for example, humans, rodents, sheep, pigs, cows, and the like.

本发明化合物还可用于治疗与葡萄糖利用受损和胰岛素耐受相关的其它代谢综合征，包括NIDDM的主要晚期并发症，如糖尿病性血管病、动脉粥样硬化、糖尿病肾病、糖尿病性神经病及糖尿病性视觉综合征，如视网膜病、白内障形成及青光眼，及其它许多与NIDDM相关的疾病，包括异常脂血症糖皮质激素诱导的胰岛素耐受、异常脂血症、多囊性卵巢综合征、肥胖症、高血糖症、高脂血症、高胆固醇血症、高甘油三酯血症、高胰岛素血症及高血压。这些疾病的简明定义可见于任何医学词典，例如，Stedman＇s Medical Dictionary(Xth Ed.)。The compounds of the present invention are also useful in the treatment of other metabolic syndromes associated with impaired glucose utilization and insulin resistance, including major late complications of NIDDM such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy and diabetes mellitus Sexual vision syndromes, such as retinopathy, cataract formation, and glaucoma, and many other diseases associated with NIDDM, including dyslipidemia, glucocorticoid-induced insulin resistance, dyslipidemia, polycystic ovary syndrome, obesity hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia and hypertension. Concise definitions of these disorders can be found in any medical dictionary, eg, Stedman's Medical Dictionary (Xth Ed.).

通式(I)化合物的体外活性可以下述方法测定。The in vitro activity of the compounds of general formula (I) can be determined by the following method.

闪烁亲近测定(SPA)实验Scintillation proximity assay (SPA) experiment

在SPA实验中，3H标记的达格列酮(用于PPAR-γ)或GW2331(用于PPAR-α)与SPA多聚赖氨酸珠捕获的PPAR蛋白质结合，产生可以TopCounts(Packard)检测的放射性计数信号。与PPAR结合的3H标记的配体可被未标记的化合物替代。该化合物的Ki可以不同化合物浓度下的替代程度决定。In SPA experiments, 3 H-labeled dapaglitazone (for PPAR-γ) or GW2331 (for PPAR-α) binds to PPAR protein captured by SPA polylysine beads, producing radioactivity count signal. 3 H-labeled ligands bound to PPARs can be replaced by unlabeled compounds. The Ki of the compound can be determined by the degree of substitution at different compound concentrations.

试剂：Reagent:

SPA多聚赖氨酸珠可购自Amersham Bioscience。SPA polylysine beads are commercially available from Amersham Bioscience.

3H标记的达格列酮用于PPAR-γ。3H-labeled dapaglitazone for PPAR-γ.

3H标记的GW2331用于PPAR-α。3H-labeled GW2331 was used for PPAR-α.

PPAR蛋白质。PPAR protein.

缓冲液-PBS、10％甘油、14mM β-巯基乙醇。Buffer - PBS, 10% glycerol, 14 mM β-mercaptoethanol.

在至少一次上述SPA测试中，本发明受试化合物Ki均在0.3nM～30μM之间。本发明的一些化合物对不同的PPAR具有不同的选择性。优选的一组化合物具有对PPAR-α超过对PPAR-γ的选择活性。另一组优选的化合物具有对PPAR-γ超过对PPAR-α的选择活性。另一组优选的化合物对PPAR-α和PPAR-γ的选择性均超过对PPAR-δ的选择性。另一组优选的化合物对PPAR-δ的选择性超过对PPAR-α和PPAR-γ的选择性。In at least one of the above SPA tests, the Ki of the tested compounds of the present invention are all between 0.3 nM and 30 μM. Some compounds of the invention have different selectivities for different PPARs. A preferred group of compounds have selective activity on PPAR-alpha over PPAR-gamma. Another group of preferred compounds has selective activity for PPAR-gamma over PPAR-alpha. Another preferred group of compounds is selective for both PPAR-alpha and PPAR-gamma over PPAR-delta. Another preferred group of compounds is selective for PPAR-delta over PPAR-alpha and PPAR-gamma.

通式(I)的α取代羧酸化合物可以合适的局部、口服及肠胃外给药的药学制剂用于治疗PPAR介导的疾病。本发明化合物可以片剂或胶囊、油悬液或水悬液、锭剂、含片、粉剂、颗粒剂、乳剂、糖浆或酏剂口腔使用。口腔使用的组合物可包含一或多种矫味剂、增甜剂、色素及防腐剂，以产生形味俱佳的药学制剂。片剂可包含可药用的辅料有助于片剂的制备。根据本领域常规，这些片剂可覆上可药用的肠溶性薄层，如甘油单硬脂酸酯或甘油二硬脂酸酯，以延缓其在胃肠管道内分解和吸收，从而提供长期的缓释作用。The α-substituted carboxylic acid compounds of general formula (I) can be used in the treatment of PPAR-mediated diseases in suitable pharmaceutical formulations for topical, oral and parenteral administration. The compounds of this invention may be administered orally as tablets or capsules, oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. Compositions for oral use may contain one or more flavoring agents, sweetening agents, coloring agents and preservatives in order to produce pharmaceutical preparations that are both pleasant in form and taste. Tablets may contain pharmaceutically acceptable excipients to facilitate the manufacture of tablets. According to the routine in this field, these tablets can be coated with a pharmaceutically acceptable enteric layer, such as glycerol monostearate or glyceryl distearate, to delay its decomposition and absorption in the gastrointestinal tract, thereby providing long-term slow-release effect.

口腔制剂可为硬明胶胶囊形式，其中，活性成分与一种惰性固体稀释剂，例如，碳酸钙、磷酸钙或高岭土混合。它们也可为软明胶胶囊形式，其中，活性成分与水或油介质，如花生油、液体石蜡或橄榄油混合。Oral formulations may be in the form of hard gelatin capsules wherein the active ingredient is admixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin. They may also be in the form of soft gelatine capsules in which the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil.

水悬液通常包含活性成分与适于水悬液制备的辅料。这些辅料可为悬浮剂，如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶及阿拉伯胶；可为天然磷脂分散剂或湿润剂，如卵磷脂，环氧乙烷与长链脂肪酸的缩合物，例如聚氧乙烯硬脂酸酯，环氧乙烷与长链脂肪醇的缩合物，如十七烷基乙烯氧基十六烷醇，环氧乙烷与源自脂肪酸与己糖醇的偏酯的缩合物，如聚氧乙烯山梨糖醇单油酸酯或脂肪酸己糖醇酐，如聚氧乙烯山梨醇酐单油酸酯。Aqueous suspensions generally contain the active ingredient with excipients suitable for the manufacture of aqueous suspensions. These excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; they can be natural phospholipid dispersants or wetting Agents, such as lecithin, condensates of ethylene oxide and long-chain fatty acids, such as polyoxyethylene stearate, condensates of ethylene oxide and long-chain fatty alcohols, such as heptadecylethyleneoxyhexadecyl Alkanols, condensates of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate or fatty acid hexitol anhydrides, such as polyoxyethylene sorbitan monooleate ester.

药学组合物可为可注射的无菌水悬液或油质悬液形式。该悬液可按照已知方法使用合适的上述分散剂或湿润剂及悬浮剂制备。这些可注射的无菌制剂也可于无毒的可肠胃外使用的稀释剂或溶剂中制成悬液，例如制成1，3-丁二醇溶液。在可接受的介质和溶剂中，可采用水、Ringers溶液及等渗的氯化钠溶液。为此可使用任何无刺激性的不挥发油，包括合成的甘油单酯或甘油二酯。此外，脂肪酸，如油酸可用于注射剂的制备。The pharmaceutical compositions can be in the form of injectable sterile aqueous or oleaginous suspensions. This suspension may be prepared according to known methods using suitable dispersing or wetting agents and suspending agents which have been mentioned above. These injectable sterile preparations can also be prepared as suspensions in nontoxic parenterally acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers' solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

通式(I)的α取代羧酸化合物也可以直肠给药的栓剂形式使用。这些组合物可通过将药物与合适的无刺激辅料混合制备，该辅料在室温下为固体但在直肠温度下为液体，因而在直肠内溶解释放出药物。这些材料包括可可油及其它甘油酯。[alpha]-substituted carboxylic acid compounds of general formula (I) may also be used in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore dissolve in the rectum to release the drug. These materials include cocoa butter and other glycerides.

含有本发明化合物的可用作局部制剂，例如，乳膏、软膏、凝胶溶液或悬液。Compounds of this invention may be used as topical formulations, eg, creams, ointments, gel solutions or suspensions.

通式(I)的α取代羧酸化合物也采用脂质体递送系统，如单层小囊泡、单层大囊泡及多层囊泡形式使用。脂质体可以多种磷脂，如胆固醇、硬脂酰胺或磷脂酰胆碱形成。Alpha-substituted carboxylic acid compounds of general formula (I) are also used in the form of liposome delivery systems, such as unilamellar vesicles, unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamide or phosphatidylcholines.

本发明化合物剂量水平范围约为0.5～100mg/kg体重。优选的剂量比约为30～100mg/kg体重。然而，应当了解，任何具体患者的具体剂量水平依赖于许多因素，包括使用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、使用时间、使用途径、排泄速度、药物联用及治疗的具体疾病的严重性。为提高这些化合物的治疗活性，可伴用其它口服的抗糖尿病活性化合物，如磺酰脲类，例如，甲苯磺丁脲等。Dosage levels of the compounds of the present invention range from about 0.5 to 100 mg/kg body weight. A preferred dosage ratio is about 30-100 mg/kg body weight. It should be understood, however, that the specific dosage level for any particular patient will depend on many factors, including the activity of the particular compound being used, age, body weight, general health, sex, diet, duration of administration, route of administration, rate of excretion, drug combinations, and The severity of the specific disease being treated. To enhance the therapeutic activity of these compounds, other orally active antidiabetic compounds, such as sulfonylureas, for example, tolbutamide and the like, may be concomitantly administered.

以具体量的活性化合物制备各种药学组合物的方法对本领域技术人员而言是已知的，或将是显而易见的。例如，见Remington＇s PharmaceuticalSciences，Mack Publishing Company，Easter，Pa.，15th Edition(1975)。Methods for preparing various pharmaceutical compositions with specific amounts of active compounds are known, or will be apparent, to those skilled in the art. See, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

以下提供的实施例及制备进一步阐释和例示本发明的化合物及其制备。应当了解，本发明的范围不以任何方式受下列实施例及制备范围的限制。在下列实施例中，具有单个手性中心的分子，除非另有说明，以消旋混合物存在。那些具有两或多个手性中心的分子，除非另有说明，以非对映的消旋混合物存在。单一的对映体/非对映体可通过本领域技术人员熟知的方法获得。The examples and preparations provided below further illustrate and exemplify the compounds of the invention and their preparation. It should be understood that the scope of the present invention is not limited in any way by the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise stated, exist as racemic mixtures. Those molecules with two or more chiral centers, unless otherwise stated, exist as diastereomeric racemic mixtures. Individual enantiomers/diastereomers may be obtained by methods well known to those skilled in the art.

在下列制备及实施例中涉及HPLC层析时，通常使用的条件如下，除非另有说明。使用的柱为ZORBAXTM RXC18柱(Hewlett Packard生产)，柱长150mm、内径为4.6mm。样品在Hewlett Packard-1100 system A以梯度溶剂100％乙酸铵/乙酸缓冲液(0.2M)至100％乙腈洗脱10分钟。然后该系统开始冲洗循环，以100乙腈冲洗1.5分钟，再以100％缓冲溶液冲洗3分钟。此时流动速度恒定为3ml/分钟。When HPLC chromatography is involved in the following preparations and examples, the conditions generally used are as follows, unless otherwise stated. The column used was a ZORBAX ™ RXC18 column (manufactured by Hewlett Packard), with a column length of 150 mm and an inner diameter of 4.6 mm. The sample was eluted in Hewlett Packard-1100 system A with gradient solvent 100% ammonium acetate/acetate buffer (0.2M) to 100% acetonitrile for 10 minutes. The system then starts a flush cycle with 100% acetonitrile for 1.5 minutes, followed by a 100% buffer solution for 3 minutes. At this time the flow rate was constant at 3 ml/min.

下列实施例及制备中，“Et”指乙基，“AC”指乙酰基，“Me”指甲基，“ETOAC”或“ETOAc”指乙酸乙酯，“THF”指四氢呋喃，“Bu”指丁基。In the following examples and preparations, "Et" refers to ethyl, "AC" refers to acetyl, "Me" refers to methyl, "ETOAC" or "ETOAc" refers to ethyl acetate, "THF" refers to tetrahydrofuran, and "Bu" refers to butyl.

手性超临界流体色谱(SFC)条件Chiral Supercritical Fluid Chromatography (SFC) Conditions

某些消旋化合物的单一对映体通过SFC获得，使用chiralpak AD-H柱，140巴、2.5mL/分钟，chiralpak AS-H柱，140巴、2.5mL/分钟及手性pak OJ-H柱，140巴、2.5mL/分钟。Single enantiomers of certain racemic compounds were obtained by SFC using chiralpak AD-H columns at 140 bar, 2.5 mL/min, chiralpak AS-H columns at 140 bar, 2.5 mL/min and chiralpak OJ-H columns , 140 bar, 2.5 mL/min.

在全部下述部分，下述通式化合物以类似于Heterocycles，2001，55(4)，689-703中所述的方法制备。Throughout the following sections, compounds of the general formula below were prepared analogously to the methods described in Heterocycles, 2001, 55(4), 689-703.

实施例A-1Example A-1

2-甲基-2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)丙酸2-Methyl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl- 3-yl}oxy)propanoic acid

Figure A20048001673600582
Figure A20048001673600582

向2-甲基-2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)丙酸甲酯(0.89g，1.76mmol)的甲醇(20mL)溶液中加入水(2.6mL)及碳酸钾(0.73g，2.0当量)。回流加热混合物5小时后，冷至室温。将溶液倒入水中，以1N盐酸酸化至pH 2，乙酸乙酯萃取(3×30mL)。合并有机层，以饱和氯化钠水溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩至干，得到标题化合物为(0.6g，70％)，白色结晶固体。To 2-methyl-2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl To a solution of methyl-3-yl}oxy)propionate (0.89g, 1.76mmol) in methanol (20mL) was added water (2.6mL) and potassium carbonate (0.73g, 2.0eq). After heating the mixture at reflux for 5 hours, it was cooled to room temperature. The solution was poured into water, acidified to pH 2 with 1N hydrochloric acid, extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to afford the title compound as (0.6 g, 70%) as a white crystalline solid.

元素分析：C28H27NO5的计算值C 73.51，H 5.95，N 3.06。测试值：C 73.26，H 6.08，N 3.06。Elemental analysis: Calcd. for C28H27NO5 C 73.51 , H 5.95, N 3.06. Test values: C 73.26, H 6.08, N 3.06.

LRMS：458(M+H)+。LRMS: 458 (M+H) + .

1H NMR(CDCl3，400MHz)：7.97(2H，dd，J＝3.0，6.6Hz)，7.43(2H，d，J＝2.8Hz)，7.41(1H，s)，7.31(2H，t，J＝8.0Hz)，7.23(2H，d，J＝8.6Hz)，7.17(1H，d，J＝7.6Hz)，7.12(1H，bs)，6.93(1H，dd，J＝1.4，8.2Hz)，6.87(1H，dd，J＝2.0，8.1Hz)，4.29(2H，t，J＝7.7Hz)，3.07(2H，t，J＝7.7Hz)，2.40(3H，s)，1.63(6H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.97 (2H, dd, J = 3.0, 6.6Hz), 7.43 (2H, d, J = 2.8Hz), 7.41 (1H, s), 7.31 (2H, t, J = 8.0Hz), 7.23 (2H, d, J = 8.6Hz), 7.17 (1H, d, J = 7.6Hz), 7.12 (1H, bs), 6.93 (1H, dd, J = 1.4, 8.2Hz), 6.87(1H, dd, J=2.0, 8.1Hz), 4.29(2H, t, J=7.7Hz), 3.07(2H, t, J=7.7Hz), 2.40(3H, s), 1.63(6H, s ).

实施例A-2Example A-2

2-甲基-2-[(3′-{[4-(三氟甲基)苄基]氧基}-1，1’-联苯-3-基)氧基]丙酸2-Methyl-2-[(3'-{[4-(trifluoromethyl)benzyl]oxy}-1,1'-biphenyl-3-yl)oxy]propanoic acid

如实施例A-1所述的步骤，以2-甲基-2-[(3′-{[4-(三氟甲基)苄基]氧基}-1，1’-联苯-3-基)氧基]丙酸甲酯为起始原料，得到标题化合物。According to the procedure described in Example A-1, 2-methyl-2-[(3'-{[4-(trifluoromethyl)benzyl]oxy}-1,1'-biphenyl-3 Starting from methyl -yl)oxy]propionate, the title compound was obtained.

LRMS：431(M+H)+。LRMS: 431 (M+H) + .

实施例A-3Example A-3

2-甲基-2-[(3′-{2-[1-(6-甲基哒嗪-3-基)哌啶-4-基]乙氧基}-1，1’-联苯-3-基)氧基]丙酸2-Methyl-2-[(3'-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-1,1'-biphenyl- 3-yl)oxy]propanoic acid

如实施例A-1所述的步骤，以2-甲基-2-[(3′-{2-[1-(6-甲基哒嗪-3-基)哌啶-4-基]乙氧基}-1，1’-联苯-3-基)氧基]丙酸甲酯为起始原料，得到为淡黄色结晶固体的标题化合物。According to the steps described in Example A-1, with 2-methyl-2-[(3'-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethyl Starting from methyl oxy}-1,1'-biphenyl-3-yl)oxy]propionate, the title compound was obtained as a pale yellow crystalline solid.

LRMS：477(M+H)+。LRMS: 477 (M+H) + .

1H NMR(CDCl3，400MHz)：7.27(2H，q，J＝8.1Hz)，7.20-7.18(2H，m)，7.12(1H，bd，J＝7.8Hz)，7.08-7.06(2H，m)，6.94-6.93(1H，m)，6.91-6.90(1H，m)，6.84(1H，dd，J＝2.0，7.8Hz)，4.25(2H，bd，J＝13.1Hz)，4.04(2H，t，J＝6.1Hz)，2.88(2H，t，J＝13.4Hz)，2.48(3H，s)，1.80-1.70(5H，m)，1.65(6H，s)，1.33-1.27(2H，m)。 1 H NMR (CDCl 3 , 400MHz): 7.27 (2H, q, J=8.1Hz), 7.20-7.18 (2H, m), 7.12 (1H, bd, J=7.8Hz), 7.08-7.06 (2H, m ), 6.94-6.93 (1H, m), 6.91-6.90 (1H, m), 6.84 (1H, dd, J=2.0, 7.8Hz), 4.25 (2H, bd, J=13.1Hz), 4.04 (2H, t, J=6.1Hz), 2.88(2H, t, J=13.4Hz), 2.48(3H, s), 1.80-1.70(5H, m), 1.65(6H, s), 1.33-1.27(2H, m ).

实施例A-4Example A-4

1-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1’-联苯-3-基}氧基)环丁烷羧酸1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl}oxy base) cyclobutane carboxylic acid

Figure A20048001673600592
Figure A20048001673600592

向1-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1’-联苯-3-基}氧基)环丁烷羧酸乙酯(0.138g，0.278mmol)的四氢呋喃(3mL)和甲醇(1mL)溶液中加入2M氢氧化锂溶液(0.28mL)。将所得混合物在室温下搅拌16小时。加入水(5mL)和乙醚(10mL)，将所得溶液搅拌10分钟。移去乙醚层，在0℃以1N盐酸酸化水层至pH 2，搅拌20分钟。过滤收集白色沉淀，以冰水洗涤。在40℃高真空下干燥后，得到到标题化合物(0.091g，70％)，为白色结晶固体。To 1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl} To a solution of ethyl oxy)cyclobutanecarboxylate (0.138 g, 0.278 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added 2M lithium hydroxide solution (0.28 mL). The resulting mixture was stirred at room temperature for 16 hours. Water (5 mL) and diethyl ether (10 mL) were added and the resulting solution was stirred for 10 minutes. Remove the ether layer, acidify the aqueous layer to pH 2 with 1N hydrochloric acid at 0°C, and stir for 20 minutes. The white precipitate was collected by filtration and washed with ice water. After drying under high vacuum at 40°C, the title compound (0.091 g, 70%) was obtained as a white crystalline solid.

元素分析：C29H27NO5·0.15LiCl的计算值C 73.18，H 5.72，N 2.94。Elemental analysis: C 73.18 , H 5.72 , N 2.94 calcd. for C29H27NO5-0.15LiCl .

实测值：C 73.08，H 5.67，N 2.93。Found values: C 73.08, H 5.67, N 2.93.

LRMS：471(M+H)+。LRMS: 471 (M+H) + .

1H NMR(CDCl3，400MHz)：8.03-8.00(2H，m)，7.43(3H，t，J＝3.3Hz)，7.30(2H，t，J＝7.8Hz)，7.16(2H，d，J＝6.8Hz)，7.09(1H，t，J＝2.3Hz)，6.91-6.85(3H，m)，4.27(2H，t，J＝7.8Hz)，3.06(3H，t，J＝8.1Hz)，2.83-2.76(2H，m)，2.53-2.46(2H，m)，2.40(3H，s)，2.06-1.97(2H，m)。 1 H NMR (CDCl 3 , 400MHz): 8.03-8.00 (2H, m), 7.43 (3H, t, J = 3.3Hz), 7.30 (2H, t, J = 7.8Hz), 7.16 (2H, d, J =6.8Hz), 7.09(1H, t, J=2.3Hz), 6.91-6.85(3H, m), 4.27(2H, t, J=7.8Hz), 3.06(3H, t, J=8.1Hz), 2.83-2.76 (2H, m), 2.53-2.46 (2H, m), 2.40 (3H, s), 2.06-1.97 (2H, m).

实施例A-5至A-28Examples A-5 to A-28

实施例A-5至A-28以类似于实施例A-4中所述的步骤制备。Examples A-5 to A-28 were prepared in a procedure similar to that described in Example A-4.

Figure A20048001673600611
Figure A20048001673600611

Figure A20048001673600621
Figure A20048001673600621

Figure A20048001673600631
Figure A20048001673600631

实施例A-1至A-28的起始原料的制备(制备a-1至a-11)Preparation of Starting Materials for Examples A-1 to A-28 (Preparation a-1 to a-11)

制备a-1preparation a-1

2-(3-碘苯氧基)-2-甲基丙酸甲酯Methyl 2-(3-iodophenoxy)-2-methylpropionate

Figure A20048001673600642
Figure A20048001673600642

向3-碘苯酚(1.08g，4.9mmol)的N，N-二甲基甲酰胺(10mL)溶液中加入2-溴-2-甲基-丙酸甲酯(0.76mL，1.2当量)及碳酸铯(3.45g，2当量)。所得混合物90℃加热24小时，然后冷至室温。加入水，以乙醚萃取混合物(3×20mL)。合并有机层，以水和饱和氯化钠水溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩。残留物以硅胶层析纯化，使用0-30％乙酸乙酯/己烷溶液，得到标题化合物(0.83g，53％)。To a solution of 3-iodophenol (1.08 g, 4.9 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromo-2-methyl-propionic acid methyl ester (0.76 mL, 1.2 equiv) and carbonic acid Cesium (3.45 g, 2 equiv). The resulting mixture was heated at 90°C for 24 hours and then cooled to room temperature. Water was added and the mixture was extracted with ether (3 x 20 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-30% ethyl acetate/hexane solution to afford the title compound (0.83 g, 53%).

LRMS：321(M+H)+。LRMS: 321 (M+H) + .

1H NMR(CDCl3，400MHz)：7.22(1H，dt，J＝1.3，7.8Hz)，7.12(1H，dd，J＝1.6，2.4Hz)，6.84(1H，t，J＝8.1Hz)，6.66(1H，ddd，J＝0.8，2.5，8.3Hz)，3.66(3H，s)，1.47(6H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.22 (1H, dt, J=1.3, 7.8Hz), 7.12 (1H, dd, J=1.6, 2.4Hz), 6.84 (1H, t, J=8.1Hz), 6.66 (1H, ddd, J=0.8, 2.5, 8.3Hz), 3.66 (3H, s), 1.47 (6H, s).

制备a-2Preparation a-2

2-(3-碘苯氧基)丁酸甲酯Methyl 2-(3-iodophenoxy)butyrate

Figure A20048001673600651
Figure A20048001673600651

如制备a-1中所述的步骤，室温下使用2-溴丙酸乙酯代替2-溴-2-甲基-丙酸甲酯，以93％产率得到标题化合物。The title compound was obtained in 93% yield as described in Preparation a-1, using ethyl 2-bromopropionate instead of methyl 2-bromo-2-methyl-propionate at room temperature.

LRMS：321(M+H)+。LRMS: 321 (M+H) + .

1H NMR(CDCl3，400MHz)：7.30(1H，ddd，J＝1.0，1.5，7.8Hz)，7.24(1H，dd，J＝1.6，2.4Hz)，6.97(1H，dd，J＝7.8，8.3Hz)，6.82(1H，ddd，J＝1.0，2.5，8.6Hz)，4.53(1H，dd，J＝5.8，6.6Hz)，3.75(3H，s)，2.00-1.93(2H，m)，1.05(3H，t，J＝7.5Hz)。 1 H NMR (CDCl 3 , 400MHz): 7.30 (1H, ddd, J=1.0, 1.5, 7.8Hz), 7.24 (1H, dd, J=1.6, 2.4Hz), 6.97 (1H, dd, J=7.8, 8.3Hz), 6.82(1H, ddd, J=1.0, 2.5, 8.6Hz), 4.53(1H, dd, J=5.8, 6.6Hz), 3.75(3H, s), 2.00-1.93(2H, m), 1.05 (3H,t,J=7.5Hz).

制备a-3Preparation a-3

1-(3-溴苯氧基)环丁烷羧酸乙酯Ethyl 1-(3-bromophenoxy)cyclobutanecarboxylate

如制备a-1中所述的步骤，以3-溴苯酚和1-溴环丁烷羧酸乙酯作为起始原料，在乙腈溶液中加热，以56％产率得到标题化合物。Following the procedure described in Preparation a-1, starting from 3-bromophenol and ethyl 1-bromocyclobutanecarboxylate, heated in acetonitrile solution, the title compound was obtained in 56% yield.

LRMS：300(M+H)+。LRMS: 300(M+H) + .

制备a-4Preparation a-4

4-[2-(3-碘苯氧基)乙基]-5-甲基-2-苯基-1，3-噁唑4-[2-(3-Iodophenoxy)ethyl]-5-methyl-2-phenyl-1,3-oxazole

如制备a-1中所述的步骤，在室温下以3-碘苯酚和2-(5-甲基-2-苯基-1，3-噁唑-4-基)-乙基-4-甲基苯磺酸酯为起始原料，以77％产率得到标题化合物，为无色油。Following the procedure described in Preparation a-1, 3-iodophenol and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethyl-4- Starting from tosylate, the title compound was obtained in 77% yield as a colorless oil.

LRMS：406(M+H)+。LRMS: 406 (M+H) + .

1H NMR(CDCl3，400MHz)：7.87(2H，dd，J＝1.9，7.7Hz)，7.34-7.29(3H，m)，7.15-7.13(2H，m)，6.86(1H，t，J＝8.1Hz)，6.76-6.73(1H，m)，4.10(2H，t，J＝6.6Hz)，2.85(2H，t，J＝6.6Hz)，2.26(3H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.87 (2H, dd, J = 1.9, 7.7Hz), 7.34-7.29 (3H, m), 7.15-7.13 (2H, m), 6.86 (1H, t, J = 8.1 Hz), 6.76-6.73 (1H, m), 4.10 (2H, t, J=6.6Hz), 2.85 (2H, t, J=6.6Hz), 2.26 (3H, s).

制备a-5Preparation a-5

2-溴-6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶2-Bromo-6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine

Figure A20048001673600661
Figure A20048001673600661

在0℃下，向2-(5-甲基-2-苯基-1，3-噁唑-4-基)-乙醇(1.04g，5.1mmol)和2，6-二溴吡啶(1.21g，5.1mmol)的无水二噁烷(20mL)溶液中加入氢化钠(在油中浓度为60％，0.368g，3当量)。将所得混合物室温下搅拌16小时。将混合物倒入冰水中，以乙酸乙酯萃取(3×50mL)。合并有机层，以饱和的碳酸氢钠溶液和饱和的氯化钠溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩。残留物以硅胶层析纯化，使用0-50％乙酸乙酯/己烷溶液，得到标题化合物(1.19g，65％)，为白色结晶固体。2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol (1.04g, 5.1mmol) and 2,6-dibromopyridine (1.21g , 5.1 mmol) in anhydrous dioxane (20 mL) was added sodium hydride (60% in oil, 0.368 g, 3 equiv). The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-50% ethyl acetate/hexanes solution to afford the title compound (1.19 g, 65%) as a white crystalline solid.

LRMS：359(M+H)+。LRMS: 359 (M+H) + .

1H NMR(CDCl3，400MHz)：7.97(2H，dd，J＝1.8，7.8Hz)，7.44-7.35(4H，m)，7.03(1H，d，J＝7.3Hz)，6.65(1H，d，J＝8.1Hz)，4.55(2H，t，J＝6.8Hz)，2.97(2H，t，J＝6.8Hz)，2.34(3H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.97 (2H, dd, J = 1.8, 7.8Hz), 7.44-7.35 (4H, m), 7.03 (1H, d, J = 7.3Hz), 6.65 (1H, d , J=8.1 Hz), 4.55 (2H, t, J=6.8 Hz), 2.97 (2H, t, J=6.8 Hz), 2.34 (3H, s).

制备a-6Preparation a-6

2-氯-6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡嗪2-Chloro-6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyrazine

如制备a-5中所述的步骤，以2-(5-甲基-2-苯基-1，3-噁唑-4-基)-乙醇和2，6-二氯吡嗪为起始原料，以64％产率得到标题化合物。As described in the preparation a-5, starting from 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol and 2,6-dichloropyrazine Starting material, the title compound was obtained in 64% yield.

LRMS：316(M+H)+。LRMS: 316 (M+H) + .

1H NMR(CDCl3，400MHz)：8.11(2H，d，J＝10.4Hz)，7.97(2H，dd，J＝1.9，7.7Hz)，7.44-7.39(3H，m)，4.60(2H，t，J＝6.7Hz)，2.99(2H，t，J＝6.7Hz)，2.35(3H，s)。 1 H NMR (CDCl 3 , 400MHz): 8.11 (2H, d, J = 10.4Hz), 7.97 (2H, dd, J = 1.9, 7.7Hz), 7.44-7.39 (3H, m), 4.60 (2H, t , J=6.7Hz), 2.99 (2H, t, J=6.7Hz), 2.35 (3H, s).

制备a-7Preparation a-7

2-[3-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊-2-基)苯氧基]丁酸甲酯Methyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]butanoate

Figure A20048001673600671
Figure A20048001673600671

向2-(3-碘苯氧基)-2-甲基丙酸甲酯(制备a-2)(1.49g，4.65mmol)的二甲基亚砜(40mL)溶液中加入乙酸钾(1.37g，3当量)、双(频哪醇)二硼烷(1.3g，1.1当量)及[1，1’-二(二苯基膦基)-二茂铁]二氯钯(II)复合物(0.152g，0.04当量)的二氯甲烷溶液。所得混合物在80℃下加热16小时，冷至室温。加入水，混合物以乙醚萃取(3×30mL)。合并有机层，以5％碳酸氢钠溶液(2×50mL)和饱和的氯化钠溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩。残留物以硅胶层析纯化，使用0-25％乙酸乙酯/己烷溶液，得到标题化合物(0.92g，62％)。LRMS：321(M+H)+。To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Preparation a-2) (1.49 g, 4.65 mmol) in dimethylsulfoxide (40 mL) was added potassium acetate (1.37 , 3 equivalents), bis(pinacol) diborane (1.3g, 1.1 equivalents) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex ( 0.152g, 0.04 equivalent) in dichloromethane solution. The resulting mixture was heated at 80°C for 16 hours and cooled to room temperature. Water was added and the mixture was extracted with ether (3 x 30 mL). The organic layers were combined, washed with 5% sodium bicarbonate solution (2 x 50 mL) and saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 0-25% ethyl acetate/hexane solution to afford the title compound (0.92 g, 62%). LRMS: 321 (M+H) + .

1H NMR(CDCl3，400MHz)：7.40(1H，d，J＝7.3Hz)，7.32(1H，d，J＝2.8Hz)，7.28(1H，d，J＝8.1Hz)，6.97(1H，ddd，J＝1.0，2.8，8.1Hz)，4.64(1H，t，J＝6.3Hz)，3.73(3H，s)，2.01-1.94(2H，m)，1.32(12H，s)，1.06(3H，t，J＝7.5Hz)。 1 H NMR (CDCl 3 , 400MHz): 7.40 (1H, d, J = 7.3Hz), 7.32 (1H, d, J = 2.8Hz), 7.28 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J=1.0, 2.8, 8.1Hz), 4.64(1H, t, J=6.3Hz), 3.73(3H, s), 2.01-1.94(2H, m), 1.32(12H, s), 1.06(3H , t, J=7.5Hz).

制备a-8Preparation a-8

2-甲基-2-[3-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊-2-基)苯氧基]丙酸甲酯Methyl 2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]propanoate

如制备a-7中所述的步骤，使用2-(3-碘苯氧基)-2-甲基丙酸甲酯(制备1)为起始原料，以75％产率得到标题化合物。The title compound was obtained in 75% yield following the procedure described in Preparation a-7, using methyl 2-(3-iodophenoxy)-2-methylpropanoate (Preparation 1) as starting material.

LRMS：321(M+H)+。LRMS: 321 (M+H) + .

1H NMR(CDCl3，400MHz)：7.42(1H，d，J＝7.1Hz)，7.29(1H，d，J＝2.8Hz)，7.22(1H，t，J＝7.8Hz)，6.90(1H，ddd，J＝0.8，2.8，8.1Hz)，3.75(3H，s)，1.56(6H，s)，1.30(12H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.42 (1H, d, J=7.1Hz), 7.29 (1H, d, J=2.8Hz), 7.22 (1H, t, J=7.8Hz), 6.90 (1H, ddd, J=0.8, 2.8, 8.1 Hz), 3.75 (3H, s), 1.56 (6H, s), 1.30 (12H, s).

制备a-9Preparation a-9

1-[3-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊-2-基)苯氧基]环丁烷羧酸乙酯Ethyl 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]cyclobutanecarboxylate

Figure A20048001673600681
Figure A20048001673600681

如制备a-7中所述的步骤，使用1-(3-溴苯氧基)环丁烷羧酸乙酯(制备3)作为起始原料，以80％产率得到标题化合物。The title compound was obtained in 80% yield as described in Preparation a-7, using ethyl 1-(3-bromophenoxy)cyclobutanecarboxylate (Preparation 3) as starting material.

LRMS：347(M+H)+。LRMS: 347 (M+H) + .

制备a-10Preparation a-10

2-{[3′-(苄氧基)-1，1’-联苯-3-基]氧基}-2-甲基丙酸甲酯2-{[3'-(Benzyloxy)-1,1'-biphenyl-3-yl]oxy}-2-methylpropanoic acid methyl ester

Figure A20048001673600682
Figure A20048001673600682

向2-(3-碘苯氧基)-2-甲基丙酸甲酯(制备a-1)(1.14g，3.56mmol)的苯溶液(20mL)中加入3-苄氧基苯基硼酸(0.89g，1.1当量)、2M碳酸钠溶液(3.56mL)及四(三苯基膦)钯(0)(0.2g，0.05当量)。将所得混合物回流加热2小时，冷至室温。加入水，混合物以乙醚萃取(3×20mL)。合并有机层，以5％碳酸氢钠溶液和饱和的氯化钠溶液洗涤、干燥(无水硫酸钠)并浓缩。残留物以硅胶层析纯化，使用0-15％乙酸乙酯/己烷溶液，得到无色油状的标题化合物(1.08g，81％)。To a solution of methyl 2-(3-iodophenoxy)-2-methylpropanoate (Preparation a-1) (1.14 g, 3.56 mmol) in benzene (20 mL) was added 3-benzyloxyphenylboronic acid ( 0.89 g, 1.1 equiv), 2M sodium carbonate solution (3.56 mL) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.05 equiv). The resulting mixture was heated at reflux for 2 hours and cooled to room temperature. Water was added and the mixture was extracted with ether (3 x 20 mL). The organic layers were combined, washed with 5% sodium bicarbonate solution and saturated sodium chloride solution, dried (anhydrous sodium sulfate) and concentrated. The residue was purified by silica gel chromatography using 0-15% ethyl acetate/hexane solution to afford the title compound (1.08 g, 81%) as a colorless oil.

LRMS：377(M+H)+。LRMS: 377 (M+H) + .

1H NMR(CDCl3，400MHz)：7.47-7.45(2H，m)，7.39(2H，t，J＝7.3Hz)，7.33(2H，t，J＝7.8Hz)，7.28(1H，t，J＝8.0Hz)，7.21(1H，ddd，J＝1.0，1.5，8.1Hz)，7.17(1H，dd，J＝1.8，2.3Hz)，7.14(1H，dm，J＝7.6Hz)，7.08(1H，dd，J＝1.8，2.3Hz)，6.96(1H，ddd，J＝0.8，2.5，8.3Hz)，6.79(1H，ddd，J＝1.0，2.5，8.1Hz)，5.11(2H，s)，3.78(3H，s)，1.62(6H，s)。 1 H NMR (CDCl 3 , 400 MHz): 7.47-7.45 (2H, m), 7.39 (2H, t, J = 7.3 Hz), 7.33 (2H, t, J = 7.8 Hz), 7.28 (1 H, t, J = 7.8 Hz) = 8.0Hz), 7.21 (1H, ddd, J = 1.0, 1.5, 8.1Hz), 7.17 (1H, dd, J = 1.8, 2.3Hz), 7.14 (1H, dm, J = 7.6Hz), 7.08 (1H , dd, J=1.8, 2.3Hz), 6.96 (1H, ddd, J=0.8, 2.5, 8.3Hz), 6.79 (1H, ddd, J=1.0, 2.5, 8.1Hz), 5.11 (2H, s), 3.78 (3H, s), 1.62 (6H, s).

制备a-11Preparation a-11

2-甲基-2-({3′-[2-(5-甲基-2-苯基-2H-1，2，3-三唑-4-基)乙氧基]联苯-3-基}氧基)丙酸甲酯2-methyl-2-({3'-[2-(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)ethoxy]biphenyl-3- methyl}oxy)propionate

Figure A20048001673600683
Figure A20048001673600683

将2-(5-甲基-2-苯基-2H-1，2，3-三唑-4-基)乙醇(51mg，0.25mmol)、2-[(3′-羟基联苯-3-基)氧基]-2-甲基丙酸甲酯(86mg，0.30mmol)及Ph3P(98mg，0.375mmol)溶于无水THF(1mL)中，然后在室温下以注射器滴加偶氮二羧酸二乙酯(65mg，0.375mmol)的无水THF(1mL)溶液。将所得反应溶液在室温下搅拌18小时，并且浓缩。以胶柱纯化，使用20-40％乙酸乙酯/己烷溶液得69mg(59％)淡黄色油。2-(5-Methyl-2-phenyl-2H-1,2,3-triazol-4-yl)ethanol (51 mg, 0.25 mmol), 2-[(3′-hydroxybiphenyl-3- Base)oxyl]-2-methylpropionate (86mg, 0.30mmol) and Ph 3 P (98mg, 0.375mmol) were dissolved in anhydrous THF (1mL), then azo was added dropwise with a syringe at room temperature Diethyl dicarboxylate (65 mg, 0.375 mmol) in anhydrous THF (1 mL). The resulting reaction solution was stirred at room temperature for 18 hours, and concentrated. Purified by gel column using 20-40% ethyl acetate/hexane solution to obtain 69 mg (59%) of a pale yellow oil.

1H NMR(400MHz，CDCl3)1.55(s，6H)，2.31(s，3H)，3.10(t，2H)，3.68(s，3H)，4.25(t，2H)，6.70(m，1H)，6.82(m，1H)，7.00(s，1H)，7.05(d，1H)，7.20(m，4H)，7.32(t，2H)，7.90(d，2H) 1 H NMR (400MHz, CDCl 3 ) 1.55(s, 6H), 2.31(s, 3H), 3.10(t, 2H), 3.68(s, 3H), 4.25(t, 2H), 6.70(m, 1H) , 6.82(m, 1H), 7.00(s, 1H), 7.05(d, 1H), 7.20(m, 4H), 7.32(t, 2H), 7.90(d, 2H)

LRMS(m/z)：472(M+H)+。LRMS (m/z): 472 (M+H) + .

实施例B-1Example B-1

1-(3-{[({2-[3-(三氟甲基)苯基]乙氧基}羰基)氨基]甲基}苯氧基)环丁烷羧酸1-(3-{[({2-[3-(Trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)cyclobutanecarboxylic acid

在0℃下，向1-(3-{[({2-[3-(三氟甲基)苯基]乙氧基}羰基)氨基]甲基}苯氧基)环丁烷羧酸乙酯(0.150g，0.32mmol)的四氢呋喃(3mL)和甲醇(0.6mL)溶液中加入2M氢氧化锂(0.32mL，2当量)。所得混合物在室温下搅拌24小时。加入水(10mL)，混合物以乙醚萃取(1×15mL，弃去)。水相以1N盐酸调节至pH 2，以乙酸乙酯萃取(3×20mL)。合并有机层，以饱和的氯化钠溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩至干得标题化合物(85％)。At 0°C, ethyl 1-(3-{[({2-[3-(trifluoromethyl)phenyl]ethoxy}carbonyl)amino]methyl}phenoxy)cyclobutanecarboxylate To a solution of the ester (0.150 g, 0.32 mmol) in tetrahydrofuran (3 mL) and methanol (0.6 mL) was added 2M lithium hydroxide (0.32 mL, 2 equiv). The resulting mixture was stirred at room temperature for 24 hours. Water (10 mL) was added and the mixture was extracted with ether (1 x 15 mL, discarded). The aqueous phase was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to afford the title compound (85%).

LRMS：438(M+H)+。LRMS: 438 (M+H) + .

1H NMR(CDCl3，400MHz)：7.62(1H，d，J＝7.8Hz)，7.46(1H，t，J＝7.3Hz)，7.36(1H，d，J＝7.3Hz)，7.31(1H，dd，J＝6.1，7.6Hz)，7.18(1H，t，J＝8.0Hz)，6.84(1H，d，J＝7.6Hz)，6.65(1H，s)，6.56(1H，d，J＝7.8Hz)，4.32-4.27(4H，m)，3.11(2H，t，J＝6.8Hz)，2.79-2.72(2H，m)，2.49-2.41(2H，m)，2.09-1.93(2H，m)。 1 H NMR (CDCl 3 , 400MHz): 7.62 (1H, d, J = 7.8Hz), 7.46 (1H, t, J = 7.3Hz), 7.36 (1H, d, J = 7.3Hz), 7.31 (1H, dd, J = 6.1, 7.6Hz), 7.18 (1H, t, J = 8.0Hz), 6.84 (1H, d, J = 7.6Hz), 6.65 (1H, s), 6.56 (1H, d, J = 7.8 Hz), 4.32-4.27(4H, m), 3.11(2H, t, J=6.8Hz), 2.79-2.72(2H, m), 2.49-2.41(2H, m), 2.09-1.93(2H, m) .

实施例B-2至B-29Examples B-2 to B-29

实施例B-2至B-29以类似于实施例B-1使用的方法制备。Examples B-2 to B-29 were prepared in a manner similar to that used in Example B-1.

Figure A20048001673600702
Figure A20048001673600702

Figure A20048001673600711
Figure A20048001673600711

Figure A20048001673600721
Figure A20048001673600721

实施例B-1至B-29的起始原料的制备(制备b-1至b-20)Preparation of Starting Materials for Examples B-1 to B-29 (Preparation b-1 to b-20)

制备b-1preparation b-1

2-(3-氰基苯氧基)-2-甲基丙酸甲酯Methyl 2-(3-cyanophenoxy)-2-methylpropionate

向3-氰基苯酚(5mmol)的乙腈(20mL)溶液或任一极性非质子溶剂如二甲基亚砜、N，N-二甲基甲酰胺等)溶液中加入2-溴-2-甲基-丙酸甲酯(1.2当量)和碳酸铯(2当量)。所得混合物在60℃下加热6小时，然后冷至室温。加入水(20mL)，混合物以乙酸乙酯萃取(3×20mL)。合并有机层，以饱和的碳酸氢钠及饱和的氯化钠溶液洗涤、干燥(无水硫酸钠)、过滤并浓缩至干以75％产率得到标题化合物。Add 2-bromo-2- Methyl-propionate (1.2 equiv) and cesium carbonate (2 equiv). The resulting mixture was heated at 60°C for 6 hours and then cooled to room temperature. Water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with saturated sodium bicarbonate and saturated sodium chloride solutions, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to afford the title compound in 75% yield.

LRMS：220(M+H)+。LRMS: 220 (M+H) + .

1H NMR(CDCl3，400MHz)：7.30(1H，t，J＝8.0Hz)，7.23(1H，dt，J＝1.3，7.6Hz)，7.05(1H，dd，J＝1.3，2.3Hz)，7.01(1H，ddd，J＝2.3，2.8，8.3Hz)，3.73(3H，s)，1.57(6H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.30 (1H, t, J=8.0Hz), 7.23 (1H, dt, J=1.3, 7.6Hz), 7.05 (1H, dd, J=1.3, 2.3Hz), 7.01 (1H, ddd, J=2.3, 2.8, 8.3Hz), 3.73 (3H, s), 1.57 (6H, s).

制备b-2至b-3Preparation b-2 to b-3

制备b-2至b-3使用类似于制备b-1中所述的方法制备。Preparations b-2 to b-3 were prepared using a method similar to that described in Preparation b-1.

Figure A20048001673600742
Figure A20048001673600742

制备b-4Preparation b-4

2-[3-(氨基甲基)苯氧基-2-甲基丙酸甲酯2-[3-(Aminomethyl)phenoxy-2-methylpropanoic acid methyl ester

Figure A20048001673600743
Figure A20048001673600743

向2-(3-氰基苯氧基)-2-甲基丙酸甲酯(制备b-1)(4mmol)的甲醇(20mL)溶液中加入10％钯炭(20％重量百分比)。所得混合物在氢气流下搅拌24小时，以Celite过滤。浓缩滤液，残留物溶解在乙酸乙酯中，以1N盐酸洗涤(2×20mL)。合并洗涤溶液，以4N氢氧化钠调节pH＞10，以二氯甲烷萃取(3×20mL)。合并有机萃取物，以饱和的氯化钠溶液洗涤、干燥(碳酸钾)、过滤并浓缩至干，以65％产率得到标题化合物。To a solution of methyl 2-(3-cyanophenoxy)-2-methylpropanoate (Preparation b-1) (4 mmol) in methanol (20 mL) was added 10% palladium on charcoal (20% by weight). The resulting mixture was stirred under a stream of hydrogen for 24 hours and filtered through Celite. The filtrate was concentrated, the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (2 x 20 mL). The washing solutions were combined, adjusted to pH>10 with 4N sodium hydroxide, and extracted with dichloromethane (3×20 mL). The organic extracts were combined, washed with saturated sodium chloride solution, dried (potassium carbonate), filtered and concentrated to dryness to afford the title compound in 65% yield.

LRMS：224(M+H)+。LRMS: 224 (M+H) + .

制备b-5至b-6Preparation b-5 to b-6

制备b-5至b-6使用类似于制备b-4中所述的方法制备。Preparations b-5 to b-6 were prepared using a method similar to that described in Preparation b-4.

Figure A20048001673600751
Figure A20048001673600751

制备b-7Preparation b-7

1H-咪唑-1-羧酸2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙基酯1H-Imidazole-1-carboxylic acid 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl ester

Figure A20048001673600752
Figure A20048001673600752

向2-(5-甲基-2-苯基-1，3-噁唑-4-基)-乙醇(1.015g，5mmol)的甲苯溶液(25mL)加入碳酸钾(1.38g，2当量)和N，N＇-羰基二咪唑(0.97g，1.2当量)。所得混合物在室温下搅拌24小时，然后加入水(20mL)。以乙酸乙酯萃取，饱和的氯化钠溶液洗涤合并的有机萃取物、干燥(无水硫酸钠)、过滤并浓缩至干得标题化合物(100％)。To a solution of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol (1.015 g, 5 mmol) in toluene (25 mL) was added potassium carbonate (1.38 g, 2 equiv) and N,N'-Carbonyldiimidazole (0.97 g, 1.2 equiv). The resulting mixture was stirred at room temperature for 24 hours, then water (20 mL) was added. Extracted with ethyl acetate, washed the combined organic extracts with saturated sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to afford the title compound (100%).

LRMS：298(M+H)+。LRMS: 298 (M+H) + .

1H NMR(CDCl3，400MHz)：8.10(1H，s)，7.97-7.93(2H，m)，7.44-7.39(5H，m)，4.68(2H，t，J＝6.7Hz)，2.98(2H，t，J＝6.7Hz)，2.34(3H，s)。 1 H NMR (CDCl 3 , 400MHz): 8.10 (1H, s), 7.97-7.93 (2H, m), 7.44-7.39 (5H, m), 4.68 (2H, t, J=6.7Hz), 2.98 (2H , t, J=6.7Hz), 2.34 (3H, s).

制备b-8至b-10Preparation b-8 to b-10

制备b-8至b-10使用类似于制备b-7中所述的方法制备。Preparations b-8 to b-10 were prepared using a method similar to that described in Preparation b-7.

Figure A20048001673600761
Figure A20048001673600761

制备b-11preparation b-11

2-甲基-2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丙酸甲酯2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]benzene Methyl oxy}propionate

Figure A20048001673600763
Figure A20048001673600763

向1H-咪唑-1-羧酸2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙基酯(制备7)(0.48g，1.6mmol)的四氢呋喃溶液(3mL)中加入2-[3-(氨基甲基)苯氧基]-2-甲基丙酸甲酯(制备b-4)(0.39g，1.1当量)。将所得混合物回流加热16小时，然后冷至室温。浓缩，并经硅胶层析纯化使用0-50％乙酸乙酯/己烷溶液，得到标题化合物(0.39g，53％)。To 1H-imidazole-1-carboxylic acid 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl ester (Preparation 7) (0.48g, 1.6mmol) in tetrahydrofuran (3 mL) was added methyl 2-[3-(aminomethyl)phenoxy]-2-methylpropanoate (Preparation b-4) (0.39 g, 1.1 equiv). The resulting mixture was heated at reflux for 16 hours, then cooled to room temperature. Concentration and purification by silica gel chromatography using 0-50% ethyl acetate/hexanes gave the title compound (0.39 g, 53%).

LRMS：453(M+H)+。LRMS: 453 (M+H) + .

1H NMR(CDCl3，400MHz)：7.96(2H，dd，J＝1.9，7.7Hz)，7.44-7.38(3H，m)，7.16(1H，t，J＝8.0Hz)，6.89(1H，d，J＝7.3Hz)，6.77(1H，s)，6.67(1H，dd，J＝2.3，8.3Hz)，4.36(2H，t，J＝6.7Hz)，4.30(2H，d，J＝5.8Hz)，3.75(3H，s)，2.83(2H，t，J＝6.7Hz)，2.32(3H，s)，1.57(6H，s)。 1 H NMR (CDCl 3 , 400MHz): 7.96 (2H, dd, J = 1.9, 7.7Hz), 7.44-7.38 (3H, m), 7.16 (1H, t, J = 8.0Hz), 6.89 (1H, d , J=7.3Hz), 6.77(1H, s), 6.67(1H, dd, J=2.3, 8.3Hz), 4.36(2H, t, J=6.7Hz), 4.30(2H, d, J=5.8Hz ), 3.75 (3H, s), 2.83 (2H, t, J=6.7Hz), 2.32 (3H, s), 1.57 (6H, s).

制备b-12至b-20Preparation b-12 to b-20

制备b-12至b-20使用类似于制备b-11中使用的方法进行制备。Preparations b-12 to b-20 were prepared using a method similar to that used in Preparation b-11.

Figure A20048001673600781
Figure A20048001673600781

Figure A20048001673600782
Figure A20048001673600782

制备b-21preparation b-21

咪唑b-21c的制备Preparation of imidazole b-21c

向醇b-21b(1mmol)的甲苯溶液(5ml)中加入N，N″-羰基二咪唑(1.05mmol)和碳酸钾(1mmol)。所得溶液回流加热3小时。冷至室温后，加入水(20ml)，混合物以乙酸乙酯萃取(3×20ml)。合并萃取物，以盐水洗涤、硫酸钠干燥、真空浓缩以定量的产率得到酰基咪唑b-21c。Add N,N"-carbonyldiimidazole (1.05mmol) and potassium carbonate (1mmol) in the toluene solution (5ml) of alcohol b-21b (1mmol). The resulting solution is heated under reflux for 3 hours. After cooling to room temperature, add water ( 20ml), the mixture was extracted with ethyl acetate (3×20ml). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give acyl imidazole b-21c in quantitative yield.

醇b-21b的制备Preparation of alcohol b-21b

向3-羟基苯甲醇b-21a(1mmol)和碳酸铯(1mmol)的乙腈溶液(10ml)加入2-溴-2-甲基丙酸甲酯(2mmol)。混合物回流加热6小时。冷至室温后，加入水(50ml)，混合物以乙酸乙酯萃取(3×20ml)。合并有机层以盐水溶液洗涤、硫酸钠干燥、真空浓缩。硅胶层析(SGC)纯化，使用10-30％乙酸乙酯/己烷溶液洗脱，得到醇b-21b。产率为40-85％。To a solution of 3-hydroxybenzyl alcohol b-21a (1 mmol) and cesium carbonate (1 mmol) in acetonitrile (10 ml) was added methyl 2-bromo-2-methylpropionate (2 mmol). The mixture was heated at reflux for 6 hours. After cooling to room temperature, water (50ml) was added and the mixture was extracted with ethyl acetate (3 x 20ml). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (SGC) eluting with 10-30% ethyl acetate/hexanes gave alcohol b-21b. The yield was 40-85%.

Figure A20048001673600792
Figure A20048001673600792

甲酯b-21q的制备Preparation of methyl ester b-21q

如b-11中所述的步骤，甲酯b-21g以化合物b-21f与化合物b-21c反应制备，产率为60～90％。According to the procedure described in b-11, methyl ester b-21g was prepared by reacting compound b-21f with compound b-21c, and the yield was 60-90%.

胺b-21f的制备Preparation of amine b-21f

将叠氮化物b-21e(2mmol)的乙酸乙酯溶液(20ml)和钯炭(重量百分比10％，50mg)在室温下以氢气处理4小时。以Celite过滤除去钯并浓缩以定量的产率得到胺b-21f。Azide b-21e (2 mmol) in ethyl acetate (20 ml) and palladium on carbon (10% by weight, 50 mg) were treated with hydrogen at room temperature for 4 hours. Palladium was removed by filtration through Celite and concentration afforded amine b-21f in quantitative yield.

叠氮化物b-21e的制备Preparation of azide b-21e

向甲苯磺酸酯b-21d(1mmol)的DMF溶液(5ml)中加入叠氮化钠(3mmol)。所得混合物在室温下搅拌14小时，然后加入水(50ml)。以乙酸乙酯萃取(3×20ml)，用水、饱和的碳酸氢钠溶液和盐水溶液洗涤，合并有机层，硫酸钠干燥并浓缩得叠氮化物b-21e，产率为85％。To a DMF solution (5 ml) of tosylate b-21d (1 mmol) was added sodium azide (3 mmol). The resulting mixture was stirred at room temperature for 14 hours, then water (50ml) was added. Extracted with ethyl acetate (3×20 ml), washed with water, saturated sodium bicarbonate solution and brine solution, combined organic layers, dried over sodium sulfate and concentrated to give azide b-21e in 85% yield.

实施例C-1Example C-1

1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环己烷羧酸1-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclohexanecarboxylic acid

在室温下，将三乙基甲硅烷(1.03g，8.86mmol)加至1-(羟基1{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯基}甲基)环己烷羧酸甲酯(0.797g，1.77mmol)的二氯甲烷(5mL)和三氟乙酸(1mL)溶液中。将所得混合物搅拌1小时，然后真空浓缩，以庚烷共沸。残留物溶于四氢呋喃(3mL)和水(3mL)中，加入氢氧化锂一水合物(0.223g，5.31mmol)。所得混合物在室温下搅拌18小时，以4N盐酸酸化至pH 2，并以乙酸乙酯萃取。干燥有机相(无水硫酸镁)、过滤、蒸发得标题化合物(0.332g，45％)。Triethylsilane (1.03 g, 8.86 mmol) was added to 1-(hydroxy1{4-[2-(5-methyl-2-phenyl-1,3-oxazole-4- 1) In a solution of methyl)ethoxy]phenyl}methyl)cyclohexanecarboxylate (0.797g, 1.77mmol) in dichloromethane (5mL) and trifluoroacetic acid (1mL). The resulting mixture was stirred for 1 hour, then concentrated in vacuo and azeotroped with heptane. The residue was dissolved in tetrahydrofuran (3 mL) and water (3 mL), and lithium hydroxide monohydrate (0.223 g, 5.31 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, acidified to pH 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate), filtered and evaporated to give the title compound (0.332 g, 45%).

元素分析：C26H29NO4的计算值C74.44，H6.97，N3.34。实测值：C74.22，H6.89，N3.34。Elemental analysis: Calcd. for C26H29NO4 C74.44, H6.97, N3.34 . Found values: C74.22, H6.89, N3.34.

LRMS：420(M+H)+。LRMS: 420 (M+H) + .

1H NMR(DMSO-d6，400MHz)：7.90(2H，dd，J＝1.8，7.8Hz)，7.51-7.46(3H，m)，6.98(2H，d，J＝8.6Hz)，6.80(2H，d，J＝8.6Hz)，4.16(2H，t，J＝6.6Hz)，2.90(2H，t，J＝6.6Hz)，2.64(2H，s)，2.34(3H，s)，1.85(2H，d，J＝12.6Hz)，1.53-1.46(3H，m)，1.29-1.11(5H，m)。 1 H NMR (DMSO-d 6 , 400 MHz): 7.90 (2H, dd, J = 1.8, 7.8 Hz), 7.51-7.46 (3H, m), 6.98 (2H, d, J = 8.6 Hz), 6.80 (2H , d, J=8.6Hz), 4.16(2H, t, J=6.6Hz), 2.90(2H, t, J=6.6Hz), 2.64(2H, s), 2.34(3H, s), 1.85(2H , d, J=12.6Hz), 1.53-1.46 (3H, m), 1.29-1.11 (5H, m).

实施例C-2至C-5Examples C-2 to C-5

实施例C-2至C-5以类似于实施例C-1中使用的方法制备，除最后的水解步骤为将粗产物溶于二甲基亚砜(75mq/mL)及6N氢氧化物(1mL)中，并在微波合成仪中在150℃加热10分钟以外。Examples C-2 to C-5 were prepared in a manner similar to that used in Example C-1, except that the final hydrolysis step was to dissolve the crude product in dimethyl sulfoxide (75 mq/mL) and 6N hydroxide ( 1 mL) and heated at 150 °C for 10 min in a microwave synthesizer.

Figure A20048001673600811
Figure A20048001673600811

实施例C-6Example C-6

1-{4-[2-(4′-甲氧基-1，1’-联苯-4-基)乙氧基]苄基}环丁烷羧酸1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid

Figure A20048001673600812
Figure A20048001673600812

向1-{4-[2-(4′-甲氧基-1，1’-联苯-4-基)乙氧基]苄基}环丁烷羧酸乙酯(制备14)(0.3921mmol，1当量)的乙腈溶液(2mL)中加入1N氢氧化钠溶液(7.2mL，8当量)。所得混合物在Personal Chemistry Smith合成仪中以微波加热(100℃)40分钟。反应混合物冷却之后，加入1M盐酸直至pH 1。将混合物以乙酸乙酯萃取(3×50mL)。然后以饱和氯化钠水溶液(100mL)洗涤合并的有机萃取物、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。将残留物以乙醚研磨纯化得标题化合物(0.1321g，81％)，为白色结晶固体。To ethyl 1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylate (Preparation 14) (0.3921mmol , 1 equivalent) in acetonitrile solution (2 mL) was added 1N sodium hydroxide solution (7.2 mL, 8 equivalents). The resulting mixture was heated in a microwave (100°C) for 40 minutes in a Personal Chemistry Smith synthesizer. After the reaction mixture was cooled, 1M hydrochloric acid was added until pH 1. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were then washed with saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by trituration with ether to give the title compound (0.1321 g, 81%) as a white crystalline solid.

元素分析：C27H28O4的计算值C77.86，H6.78。实测值：C77.65，H6.85。Elemental analysis: C77.86, H6.78 , calculated for C27H28O4 . Measured values: C77.65, H6.85.

LRMS(m/z)：416(M)-。LRMS (m/z): 416 (M) - .

1H NMR(丙酮-d6，300MHz)：7.53(2H，d，J＝6.1Hz)，7.66(2H，d，J＝5.1Hz)，7.46(2H，d，J＝8.5Hz)，7.13(2H，d，J＝8.7Hz)，7.07(2H，d，J＝8.7Hz)，6.85(2H，d，J＝8.5Hz)，4.20(1H，t，J＝6.1Hz)，3.86(3H，s)，3.10(2H，t，J＝7.0Hz)，3.00(2H，s)，2.40-2.30(2H，m)，2.07-1.98(2H，m)，1.92-1.80(2H，m)。 1 H NMR (acetone-d 6 , 300 MHz): 7.53 (2H, d, J = 6.1 Hz), 7.66 (2H, d, J = 5.1 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.13 ( 2H, d, J = 8.7Hz), 7.07 (2H, d, J = 8.7Hz), 6.85 (2H, d, J = 8.5Hz), 4.20 (1H, t, J = 6.1Hz), 3.86 (3H, s), 3.10 (2H, t, J = 7.0 Hz), 3.00 (2H, s), 2.40-2.30 (2H, m), 2.07-1.98 (2H, m), 1.92-1.80 (2H, m).

实施例C-7至C-93Examples C-7 to C-93

实施例C-7至C-93以类似于实施例C-6中使用的方法制备，或在20℃～75℃的温度下，搅拌酯和氢氧化钠或氢氧化锂的甲醇水溶液、乙醇水溶液、四氢呋喃水溶液或其混合物中。Examples C-7 to C-93 were prepared in a manner similar to that used in Example C-6, or at a temperature of 20°C to 75°C, stirring esters and sodium hydroxide or lithium hydroxide in aqueous methanol, aqueous ethanol , tetrahydrofuran aqueous solution or a mixture thereof.

Figure A20048001673600821
Figure A20048001673600821

Figure A20048001673600831
Figure A20048001673600831

Figure A20048001673600851
Figure A20048001673600851

Figure A20048001673600861
Figure A20048001673600861

Figure A20048001673600871
Figure A20048001673600871

Figure A20048001673600881
Figure A20048001673600881

Figure A20048001673600891
Figure A20048001673600891

Figure A20048001673600921
Figure A20048001673600921

Figure A20048001673600931
Figure A20048001673600931

Figure A20048001673600941
Figure A20048001673600941

2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸对映体(实施例C-48a和C-48b)的其它制备方法2-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid Other Preparations of Enantiomers (Examples C-48a and C-48b)

实施例C-48aExample C-48a

2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸的对映体12-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid Enantiomer 1

Figure A20048001673600971
Figure A20048001673600971

将氢氧化锂一水合物(993mg，21.1mmol)加入到(4S)-4-苄基-3-{[2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-基]羰基}-1，3-噁唑烷-2-酮(600mg，1.06mmol)的四氢呋喃∶甲醇∶水(1∶1∶1，12mL)混合溶液中。将混合物在50℃下搅拌4.5小时，然后冷至室温，搅拌2天。蒸发去除挥发性成分，残留物以水(5mL)稀释，以1∶1己烷∶乙醚萃取。将水相酸化至pH 5，以乙酸乙酯萃取。有机相以盐水溶液洗涤、硫酸镁干燥、过滤并浓缩。残留物以快速柱层析纯化2次(95∶4∶1二氯甲烷∶甲醇∶氢氧化铵)，得到无色油状的标题化合物(72mg)。Lithium hydroxide monohydrate (993 mg, 21.1 mmol) was added to (4S)-4-benzyl-3-{[2-({6-[2-(5-methyl-2-phenyl-1, 3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-yl]carbonyl}-1,3-oxazolidin-2-one (600mg, 1.06mmol) in tetrahydrofuran : methanol: water (1:1:1, 12mL) mixed solution. The mixture was stirred at 50°C for 4.5 hours, then cooled to room temperature and stirred for 2 days. The volatile components were removed by evaporation and the residue was diluted with water (5 mL) and extracted with 1:1 hexane:ether. The aqueous phase was acidified to pH 5 and extracted with ethyl acetate. The organic phase was washed with brine solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified twice by flash column chromatography (95:4:1 dichloromethane:methanol:ammonium hydroxide) to give the title compound (72mg) as a colorless oil.

LRMS(m/z)：409(M+H)+。LRMS (m/z): 409 (M+H) + .

1H NMR(CDCl3，300MHz)7.99-7.94(3H，m)，7.49(1H，dd，J＝2.4，8.6Hz)，7.44-7.36(3H，m)，6.63(1H，d，J＝8.5Hz)，4.50(2H，t，J＝6.7Hz)，4.00-3.93(1H，m)，3.89-3.81(1H，m)，3.14(1H，d，J＝14.1Hz)，2.95(2H，t，J＝6.7Hz)，2.85(1H，d，J＝14.1Hz)，2.31(3H，s)，1.99-1.73(4H，m)。 1 H NMR (CDCl 3 , 300MHz) 7.99-7.94 (3H, m), 7.49 (1H, dd, J=2.4, 8.6Hz), 7.44-7.36 (3H, m), 6.63 (1H, d, J=8.5 Hz), 4.50(2H, t, J=6.7Hz), 4.00-3.93(1H, m), 3.89-3.81(1H, m), 3.14(1H, d, J=14.1Hz), 2.95(2H, t , J=6.7Hz), 2.85 (1H, d, J=14.1Hz), 2.31 (3H, s), 1.99-1.73 (4H, m).

实施例C-48bExample C-48b

2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸的对映体22-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid Enantiomer 2

对映体2使用类似于对映体1中所述的反应方法制备，除了以(4R)-4-苄基-1，3-噁唑烷-2-酮为起始原料以外。Enantiomer 2 was prepared using a reaction procedure similar to that described for Enantiomer 1, except starting from (4R)-4-benzyl-1,3-oxazolidin-2-one.

实施例C-94Example C-94

1-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基甲基}-环丙烷羧酸1-{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}-cyclopropanecarboxylic acid

Figure A20048001673600981
Figure A20048001673600981

向1-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基甲基}-环丙烷羧酸叔丁酯(0.2017g，0.4642mmol)的苯甲醚溶液(1.2mL)中加入三氟乙酸(1.2mL)。所得溶液在室温下搅拌3小时，然后在减压浓缩。粗产物以乙酸乙酯(25mL)和水(10mL)稀释，然后加入饱和的碳酸氢钠溶液碱化至pH 5-6。分离两相，水层以乙酸乙酯萃取(3×25mL)。然后干燥合并的有机萃取物(无水硫酸镁)、过滤并真空浓缩得粗产物。以乙醚/己烷重结晶，得到纯酸(0.071g，40％)，为白色固体。To 1-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}-cyclopropanecarboxylic acid tert-butyl ester ( To a solution (1.2 mL) of 0.2017 g, 0.4642 mmol) in anisole was added trifluoroacetic acid (1.2 mL). The resulting solution was stirred at room temperature for 3 hours, then concentrated under reduced pressure. The crude product was diluted with ethyl acetate (25 mL) and water (10 mL), and then basified to pH 5-6 by adding saturated sodium bicarbonate solution. The two phases were separated and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were then dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. Recrystallization from ether/hexanes gave pure acid (0.071 g, 40%) as a white solid.

LRMS(m/z)：379(M+H)+。LRMS (m/z): 379 (M+H) + .

1H NMR(MeOD，300MHz)：7.89-7.83(3H，m)，7.53(1H，dd，J＝8.5，1.9Hz)，7.37-7.35(3H，m)，6.60(1H，d，J＝8.5Hz)，4.39(2H，t，J＝6.5Hz)，2.87(2H，t，J＝6.4Hz)，2.73(2H，s)，2.23(3H，s)，1.14-1.11(2H，m)，0.77-0.74(2H，m)。 1 H NMR (MeOD, 300 MHz): 7.89-7.83 (3H, m), 7.53 (1H, dd, J=8.5, 1.9 Hz), 7.37-7.35 (3H, m), 6.60 (1H, d, J=8.5 Hz), 4.39(2H, t, J=6.5Hz), 2.87(2H, t, J=6.4Hz), 2.73(2H, s), 2.23(3H, s), 1.14-1.11(2H, m), 0.77-0.74 (2H, m).

实施例C-95Example C-95

2-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-5-[2-(1H-四唑-5-基)-四氢-呋喃-2-基甲基]-吡啶2-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-5-[2-(1H-tetrazol-5-yl)-tetrahydro-furan- 2-ylmethyl]-pyridine

Figure A20048001673600982
Figure A20048001673600982

将2-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基甲基}-四氢呋喃-2-腈(0.11g，0.27mmol)、叠氮化钠(0.04g，0.54mmol)及溴化锌(0.03g，0.14mmol)的水∶异丙醇(1∶2，1.24mL)溶液回流23小时。冷至室温后，反应以3N盐酸(0.14mL)和乙酸乙酯(2.8mL)终止，将混合物搅拌至完全均匀。水相以乙酸乙酯萃取(3×50mL)，合并有机萃取物，以水(30mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。产物以乙醚/己烷重结晶，得到标题化合物(0.052g，44％)，为白色固体。2-{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}-tetrahydrofuran-2-carbonitrile (0.11g , 0.27mmol), sodium azide (0.04g, 0.54mmol) and zinc bromide (0.03g, 0.14mmol) in water:isopropanol (1:2, 1.24mL) was refluxed for 23 hours. After cooling to room temperature, the reaction was quenched with 3N hydrochloric acid (0.14 mL) and ethyl acetate (2.8 mL), and the mixture was stirred until completely homogeneous. The aqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts were washed with water (30 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The product was recrystallized from ether/hexane to give the title compound (0.052 g, 44%) as a white solid.

元素分析：C22H23N7O3的计算值C60.96，H5.35，N22.62。实测值：C63.50，H5.62，N18.80。Elemental analysis: Calcd. for C22H23N7O3 C60.96, H5.35 , N22.62 . Measured values: C63.50, H5.62, N18.80.

1H NMR(CDCl3，300MHz)：δ7.93(2H，m)，7.86(1H，s)，7.40(3H，m)，7.11(1H，d，J＝1.7Hz)，6.49(1H，d，J＝8.5Hz)，4.42(2H，t，J＝6.6Hz)，3.88(2H，m)，3.12(2H，m)，2.92(2H，t，J＝6.5Hz)，2.62(1H，m)，2.31(3H，s)，2.23(1H，m)，1.89(2H，m)。 1 H NMR (CDCl 3 , 300MHz): δ7.93 (2H, m), 7.86 (1H, s), 7.40 (3H, m), 7.11 (1H, d, J=1.7Hz), 6.49 (1H, d , J=8.5Hz), 4.42(2H, t, J=6.6Hz), 3.88(2H, m), 3.12(2H, m), 2.92(2H, t, J=6.5Hz), 2.62(1H, m ), 2.31 (3H, s), 2.23 (1H, m), 1.89 (2H, m).

LRMS(m/z)：433(M+H)+。LRMS (m/z): 433 (M+H) + .

实施例C-1至C-95的起始原料的制备(制备c-1至c-130)Preparation of Starting Materials for Examples C-1 to C-95 (Preparation c-1 to c-130)

制备c-1Preparation c-1

4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯甲醛4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzaldehyde

Figure A20048001673600991
Figure A20048001673600991

在氮气流下，向4-羟基苯甲醛(5.05g，41.4mmol)、2-(5-甲基-2-苯基-噁唑-4-基)-乙-1-醇(8.39g，41.4mmol)及三苯基膦(10.9g，41.4mmol)的无水四氢呋喃溶液(165mL)中滴加偶氮二羧酸二乙酯(7.21g，41.4mmol)。所得溶液在室温下搅拌8小时，然后以水稀释，乙酸乙酯萃取。干燥有机相(无水硫酸镁)、过滤并真空浓缩。然后以快速柱层析(己烷至乙酸乙酯)纯化残留物，得到白色结晶固体的标题化合物(10.2g，80％)。Under nitrogen flow, 4-hydroxybenzaldehyde (5.05g, 41.4mmol), 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethan-1-ol (8.39g, 41.4mmol ) and triphenylphosphine (10.9 g, 41.4 mmol) in anhydrous tetrahydrofuran (165 mL) were added dropwise diethyl azodicarboxylate (7.21 g, 41.4 mmol). The resulting solution was stirred at room temperature for 8 hours, then diluted with water and extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo. The residue was then purified by flash column chromatography (hexane to ethyl acetate) to afford the title compound (10.2 g, 80%) as a white crystalline solid.

LRMS(m/z)：308(M+H)+。LRMS (m/z): 308 (M+H)+.

制备c-2Preparation c-2

1-(羟基{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯基}甲基)环己烷羧酸甲酯Methyl 1-(hydroxy{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}methyl)cyclohexanecarboxylate

Figure A20048001673600992
Figure A20048001673600992

向氯化铬(II)(1.00g，8.10mmol)和碘化锂(0.087g，0.648mmol)的四氢呋喃(20mL)悬液中加入4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯甲醛(制备1)(1.00g，3.24mmol)和1-溴环己烷羧酸甲酯(1.07g，4.85mmol)。所得混合物在50℃下加热直至TLC分析显示反应完全。将混合物冷却至室温，加入饱和的氯化钠溶液(15mL)。将所得混合物搅拌15分钟，然后分配于乙酸乙酯与水相中。有机相以水洗涤并干燥(无水硫酸镁)、过滤并浓缩。残留物以快速柱层析(己烷至50％乙酸乙酯/己烷)纯化，得到无色油状的标题化合物(0.797g，55％)。Add 4-[2-(5-methyl-2-phenyl- 1,3-oxazol-4-yl)ethoxy]benzaldehyde (Preparation 1) (1.00 g, 3.24 mmol) and methyl 1-bromocyclohexanecarboxylate (1.07 g, 4.85 mmol). The resulting mixture was heated at 50°C until TLC analysis showed the reaction was complete. The mixture was cooled to room temperature, and saturated sodium chloride solution (15 mL) was added. The resulting mixture was stirred for 15 minutes, then partitioned between ethyl acetate and aqueous. The organic phase was washed with water and dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by flash column chromatography (hexane to 50% ethyl acetate/hexane) to afford the title compound (0.797 g, 55%) as a colorless oil.

LRMS(m/z)：450(M+H)+。LRMS (m/z): 450 (M+H) + .

制备c-3Preparation c-3

1-(羟基{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苯基}甲基)环丁烷羧酸乙酯Ethyl 1-(hydroxy{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl}methyl)cyclobutanecarboxylate

使用类似于制备c-2中所述的步骤，得到无色油状的标题化合物。Using a procedure similar to that described in preparation c-2, the title compound was obtained as a colorless oil.

LRMS(m/z)：436(M+H)+。LRMS (m/z): 436 (M+H) + .

制备c-4Preparation c-4

1-[[4-(烯丙基)苯基](羟基)甲基]环戊烷羧酸甲酯Methyl 1-[[4-(allyl)phenyl](hydroxy)methyl]cyclopentanecarboxylate

在-78℃下，向环戊烷羧酸甲酯(3.84g，30.0mmol)的四氢呋喃溶液(30mL)中滴加二异丙酰胺基锂溶液(15.0mL，2M四氢呋喃溶液，30.0mmol)。将混合物搅拌2小时，然后加入4-烯丙氧基苯甲醛(2.12g，13.1mmol)。混合物温热至室温，搅拌18小时。混合物以水稀释，乙酸乙酯萃取。有机相以饱和氯化钠水溶液洗涤、干燥(无水硫酸镁)、过滤并浓缩。残留物以快速柱层析(己烷至50％乙酸乙酯/己烷)纯化，得到无色油状的标题化合物(3.67g，97％)。To a tetrahydrofuran solution (30 mL) of methyl cyclopentanecarboxylate (3.84 g, 30.0 mmol) was added dropwise a lithium diisopropionamide solution (15.0 mL, 2M in tetrahydrofuran, 30.0 mmol) at -78°C. The mixture was stirred for 2 hours, then 4-allyloxybenzaldehyde (2.12 g, 13.1 mmol) was added. The mixture was warmed to room temperature and stirred for 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by flash column chromatography (hexane to 50% ethyl acetate/hexane) to afford the title compound (3.67 g, 97%) as a colorless oil.

LRMS(m/z)：273(M-OH)+。LRMS (m/z): 273 (M-OH) + .

制备c-5preparation c-5

4-[[4-(丁-3-烯基氧基)苯基](羟基)甲基]四氢-2H-吡喃-4-羧酸甲酯4-[[4-(But-3-enyloxy)phenyl](hydroxy)methyl]tetrahydro-2H-pyran-4-carboxylic acid methyl ester

以类似于制备c-4中所述的步骤，得到无色油状的标题化合物。Following a procedure similar to that described for preparation c-4, the title compound was obtained as a colorless oil.

LRMS(m/z)：273(M-OH)+。LRMS (m/z): 273 (M-OH) + .

制备c-6Preparation c-6

1-[[4-(烯丙氧基)苯基](羟基)甲基]环丁烷羧酸乙酯Ethyl 1-[[4-(allyloxy)phenyl](hydroxy)methyl]cyclobutanecarboxylate

Figure A20048001673601011
Figure A20048001673601011

以类似于制备c-4中所述的步骤，得到无色油状的标题化合物。Following a procedure similar to that described for preparation c-4, the title compound was obtained as a colorless oil.

LRMS(m/z)：289(M)+。LRMS (m/z): 289 (M)+.

1H NMR(CDCl3，300MHz)7.22(2H，d，J＝8.5Hz)，6.85(2H，d，J＝8.7Hz)，6.10-5.98(1H，m)，5.39(1H，ddd，J＝1.5，3.2，17.3Hz)，5.27(1H，ddd，J＝1.5，2.8，10.4Hz)，4.85(1H，d，J＝6.4Hz)，4.51(2H，dt，J＝1.5，5.3Hz)，4.13(2H，dq，J＝0.9，7.2Hz)，3.12(1H，d，J＝6.6Hz)，2.84-2.78(1H，m)，2.64-2.58(1H，m)，2.35-2.29(2H，m)，1.89-1.83(1H，m)，1.72-1.66(1H，m)，1.19(3H，t，J＝7.0Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.22 (2H, d, J = 8.5Hz), 6.85 (2H, d, J = 8.7Hz), 6.10-5.98 (1H, m), 5.39 (1H, ddd, J = 1.5, 3.2, 17.3Hz), 5.27 (1H, ddd, J = 1.5, 2.8, 10.4Hz), 4.85 (1H, d, J = 6.4Hz), 4.51 (2H, dt, J = 1.5, 5.3Hz), 4.13(2H, dq, J=0.9, 7.2Hz), 3.12(1H, d, J=6.6Hz), 2.84-2.78(1H, m), 2.64-2.58(1H, m), 2.35-2.29(2H, m), 1.89-1.83 (1H, m), 1.72-1.66 (1H, m), 1.19 (3H, t, J = 7.0 Hz).

制备c-7Preparation c-7

1-(4-羟基苄基)环戊烷羧酸甲酯Methyl 1-(4-hydroxybenzyl)cyclopentanecarboxylate

在室温下，将三乙基甲硅烷(10.0mL，63mmol)加入至1-[[4-(烯丙氧基)苯基](羟基)甲基]环戊烷羧酸甲酯(制备c-4)(3.66g，12.6mmol)的二氯甲烷(30mL)和三氟乙酸(30mL)溶液中。将所得混合物搅拌1小时，然后真空浓缩，并与甲苯共沸。将残留物溶于四氢呋喃(32mL)，加入吗啉(3.62mL，41.6mmol)和四(三苯基膦)钯(0)(1.46g，1.26mmol)。所得混合物在室温下搅拌18小时，以Celite过滤并浓缩至干。将残留物溶于乙酸乙酯，以1N盐酸洗涤，再以饱和碳酸氢钠溶液洗涤。干燥有机相(无水硫酸镁)、过滤并浓缩，残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到白色结晶固体的标题化合物(1.75g，59％)。Triethylsilane (10.0 mL, 63 mmol) was added to methyl 1-[[4-(allyloxy)phenyl](hydroxy)methyl]cyclopentanecarboxylate (preparation c- 4) (3.66g, 12.6mmol) in dichloromethane (30mL) and trifluoroacetic acid (30mL). The resulting mixture was stirred for 1 hour, then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in tetrahydrofuran (32 mL), and morpholine (3.62 mL, 41.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.46 g, 1.26 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, filtered through Celite and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, and then with saturated sodium bicarbonate solution. The organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated, and the residue was purified by flash column chromatography (hexane to ethyl acetate) to give the title compound (1.75 g, 59%) as a white crystalline solid.

LRMS(m/z)：233(M)-。LRMS (m/z): 233 (M) - .

制备c-8preparation c-8

4-(4-羟基苄基)四氢-2H-吡喃-4-羧酸甲酯4-(4-Hydroxybenzyl)tetrahydro-2H-pyran-4-carboxylic acid methyl ester

使用类似于制备c-7中所述的步骤，得到白色结晶固体的标题化合物。Using a procedure similar to that described in preparation c-7, the title compound was obtained as a white crystalline solid.

LRMS(m/z)：249(M)-。LRMS (m/z): 249 (M) - .

制备c-9preparation c-9

1-(4-羟基苄基)环丁烷羧酸乙酯1-(4-Hydroxybenzyl)cyclobutanecarboxylate ethyl ester

使用类似于制备c-7中所述的步骤，得到白色结晶固体的标题化合物。Using a procedure similar to that described in preparation c-7, the title compound was obtained as a white crystalline solid.

LRMS(m/z)：234(M)-。LRMS (m/z): 234 (M) - .

1H NMR(CDCl3，300MHz)6.97(2H，d，J＝8.5Hz)，6.68(2H，d，J＝8.5Hz)，5.10(1H，bs)，4.10(2H，q，J＝7.2Hz)，3.00(2H，s)，2.44-2.35(2H，m)，2.07-1.99(2H，m)，1.91-1.80(2H，m)，1.20(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 6.97 (2H, d, J = 8.5Hz), 6.68 (2H, d, J = 8.5Hz), 5.10 (1H, bs), 4.10 (2H, q, J = 7.2Hz ), 3.00 (2H, s), 2.44-2.35 (2H, m), 2.07-1.99 (2H, m), 1.91-1.80 (2H, m), 1.20 (3H, t, J=7.2Hz).

制备c-10preparation c-10

1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基环戊烷羧酸甲酯Methyl 1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzylcyclopentanecarboxylate

Figure A20048001673601023
Figure A20048001673601023

使用类似于制备c-1至c-7中所述的步骤，得到无色油状的标题化合物。Using procedures similar to those described in Preparations c-1 to c-7, the title compound was obtained as a colorless oil.

LRMS(m/z)：249(M)-。LRMS (m/z): 249 (M) - .

制备c-11preparation c-11

1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苄基}环戊烷羧酸甲酯Methyl 1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclopentanecarboxylate

Figure A20048001673601024
Figure A20048001673601024

使用类似于制备c-1至c-7中所述的步骤，得到无色油状的标题化合物。Using procedures similar to those described in Preparations c-1 to c-7, the title compound was obtained as a colorless oil.

LRMS(m/z)：434(M+H)+。LRMS (m/z): 434 (M+H) + .

制备c-12preparation c-12

4-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}四氢-2H-吡喃-4-羧酸甲酯4-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydro-2H-pyran-4-carboxylic acid methyl ester

Figure A20048001673601031
Figure A20048001673601031

使用类似于制备c-1至c-7中所述的步骤，得到无色油状的标题化合物。Using procedures similar to those described in Preparations c-1 to c-7, the title compound was obtained as a colorless oil.

LRMS(m/z)：436(M+H)+。LRMS (m/z): 436 (M+H) + .

制备c-13preparation c-13

1-{4-[2-(4-溴苯基)乙氧基]苄基}环丁烷羧酸乙酯Ethyl 1-{4-[2-(4-bromophenyl)ethoxy]benzyl}cyclobutanecarboxylate

使用类似于制备c-1至c-7中所述的步骤，得到无色油状的标题化合物。Using procedures similar to those described in Preparations c-1 to c-7, the title compound was obtained as a colorless oil.

LRMS(m/z)：417(M)+。LRMS (m/z): 417 (M) + .

1H NMR(CDCl3，300MHz)7.36(2H，d，J＝8.3Hz)，7.08(2H，d，J＝8.3Hz)，6.96(2H，d，J＝8.7Hz)，6.70(2H，d，J＝8.7Hz)，4.04(2H，t，J＝6.8Hz)，4.03(2H，q，J＝7.2Hz)，2.95(2H，t，J＝6.8Hz)，2.94(2H，s)，2.37-2.27(2H，m)，2.00-1.91(2H，m)，1.84-1.73(2H，m)，1.14(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.36 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.3 Hz), 6.96 (2H, d, J = 8.7 Hz), 6.70 (2H, d , J=8.7Hz), 4.04(2H, t, J=6.8Hz), 4.03(2H, q, J=7.2Hz), 2.95(2H, t, J=6.8Hz), 2.94(2H, s), 2.37-2.27 (2H, m), 2.00-1.91 (2H, m), 1.84-1.73 (2H, m), 1.14 (3H, t, J=7.2Hz).

制备c-14至c-35Preparation c-14 to c-35

制备c-14至c-35使用类似于制备c-1中使用的方法。Preparations c-14 to c-35 used a method similar to that used in the preparation of cl.

Figure A20048001673601061
Figure A20048001673601061

Figure A20048001673601071
Figure A20048001673601071

制备c-36preparation c-36

1-{4-[2-(4′-甲氧基-1，1’-联苯-4-基)乙氧基]苄基}环丁烷羧酸乙酯Ethyl 1-{4-[2-(4'-methoxy-1,1'-biphenyl-4-yl)ethoxy]benzyl}cyclobutanecarboxylate

Figure A20048001673601081
Figure A20048001673601081

在氮气流下，向1-{4-[2-(4-溴苯基)乙氧基]苄基}环丁烷羧酸乙酯(制备c-13)(0.25g，0.5990mmol)、四(三苯基膦)钯(0)(0.1252g，0.6589mmol)、苯(1.6mL)及2M碳酸钠水溶液(0.8mL)的溶液中加入硼酸(0.8640mmol，1.1当量)的乙醇溶液(0.4mL)。将所得混合物脱气，然后回流加热16小时，再冷至室温。然后滴加30％过氧化氢水溶液(0.04mL)，所得溶液在室温下搅拌1小时。然后以乙酸乙酯萃取溶液(3×100mL)，合并有机萃取物，以饱和氯化钠水溶液(100mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至40％乙酸乙酯/己烷)纯化，得到无色油状的纯产物。Under a stream of nitrogen, ethyl 1-{4-[2-(4-bromophenyl)ethoxy]benzyl}cyclobutanecarboxylate (preparation c-13) (0.25 g, 0.5990 mmol), tetrakis( Triphenylphosphine) palladium (0) (0.1252g, 0.6589mmol), benzene (1.6mL) and 2M aqueous sodium carbonate solution (0.8mL) was added in ethanol solution (0.4mL) of boric acid (0.8640mmol, 1.1 equivalents) . The resulting mixture was degassed, then heated at reflux for 16 hours and cooled to room temperature. Then 30% aqueous hydrogen peroxide solution (0.04 mL) was added dropwise, and the resulting solution was stirred at room temperature for 1 hour. The solution was then extracted with ethyl acetate (3 x 100 mL) and the organic extracts were combined, washed with saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (hexanes to 40% ethyl acetate/hexanes) to give pure product as a colorless oil.

LRMS(m/z)：462(M+H2O)+。LRMS (m/z): 462 (M+H 2 O) + .

1H NMR(CDCl3，300MHz)7.51(2H，d，J＝5.7Hz)，7.49(2H，d，J＝4.7Hz)，7.32(2H，d，J＝8.1Hz)，7.03(2H，d，J＝8.5Hz)，6.97(2H，d，J＝8.9Hz)，6.80(2H，d，J＝8.5Hz)，4.15(1H，t，J＝7.2Hz)，4.10(2H，q，J＝7.2Hz)，3.84(3H，s)，3.10(2H，t，J＝7.1Hz)，3.01(2H，s)，2.43-2.34(2H，m)，2.07-1.98(2H，m)，1.90-1.80(2H，m)，1.20(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.51 (2H, d, J = 5.7 Hz), 7.49 (2H, d, J = 4.7 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.03 (2H, d , J=8.5Hz), 6.97 (2H, d, J=8.9Hz), 6.80 (2H, d, J=8.5Hz), 4.15 (1H, t, J=7.2Hz), 4.10 (2H, q, J =7.2Hz), 3.84(3H, s), 3.10(2H, t, J=7.1Hz), 3.01(2H, s), 2.43-2.34(2H, m), 2.07-1.98(2H, m), 1.90 -1.80 (2H, m), 1.20 (3H, t, J=7.2Hz).

制备c-37至c-43Preparation c-37 to c-43

制备c-37至c-43使用类似于制备c-36中使用的方法。Preparations c-37 to c-43 used a method similar to that used in the preparation of c-36.

Figure A20048001673601101
Figure A20048001673601101

制备c-44Preparation c-44

4-{4-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]苄基}四氢-2H-吡喃-4-羧酸甲酯4-{4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}tetrahydro-2H-pyran-4-carboxylic acid methyl ester

Figure A20048001673601102
Figure A20048001673601102

将4-(4-羟基苄基)四氢-2H-吡喃-4-羧酸甲酯(制备c-8)(0.500g，2.0mmol)、碳酸铯(1.96g，6.0mmol)及氯化物(0.458g，2.2mmol)的乙腈溶液在微波合成仪中140℃下加热10分钟。冷却混合物、过滤并浓缩滤液。残留物以快速柱层析(己烷对乙酸乙酯)纯化，得到白色结晶固体的标题化合物(0.827g，98％)。Methyl 4-(4-hydroxybenzyl)tetrahydro-2H-pyran-4-carboxylate (Preparation c-8) (0.500 g, 2.0 mmol), cesium carbonate (1.96 g, 6.0 mmol) and chloride (0.458g, 2.2mmol) in acetonitrile was heated in a microwave synthesizer at 140°C for 10 minutes. The mixture was cooled, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (hexanes versus ethyl acetate) to afford the title compound (0.827 g, 98%) as a white crystalline solid.

LRMS(m/z)：422(M+H)+。LRMS (m/z): 422 (M+H) + .

制备c-45Preparation c-45

5-溴-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶5-bromo-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine

Figure A20048001673601103
Figure A20048001673601103

在氮气流下，向2，5-二溴-吡啶(5g，21.1060mmol)及2-(5-甲基-2-苯基-噁唑-4-基)-乙醇(5.1472g，25.3271mmol)的无水四氢呋喃溶液(85mL)中加入叔丁醇钾(2.8422g，25.3271mmol)。将所得混合物回流加热16小时，然后冷至室温。将混合物浓缩至20mL，分配于饱和氯化铵(50mL)与乙酸乙酯(50mL)中。分离两相，水层以乙酸乙酯萃取(2×50mL)。然后以水(2×50mL)、饱和氯化钠水溶液(50mL)洗涤合并的有机萃取物，干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至20％乙酸乙酯/己烷)纯化，得到白色结晶固体(6.3g，83％)。Under nitrogen flow, to 2,5-dibromo-pyridine (5g, 21.1060mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (5.1472g, 25.3271mmol) Potassium tert-butoxide (2.8422 g, 25.3271 mmol) was added to anhydrous THF solution (85 mL). The resulting mixture was heated at reflux for 16 hours, then cooled to room temperature. The mixture was concentrated to 20 mL, partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL). The two phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were then washed with water (2 x 50 mL), saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (hexane to 20% ethyl acetate/hexane) to give a white crystalline solid (6.3 g, 83%).

LRMS(m/z)：359(M)+.LRMS(m/z): 359(M) + .

1H NMR(CDCl3，400MHz)8.17(1H，d，J＝2.0Hz)，7.96(2H，dd，J＝2.0，8.1Hz)，7.61(1H，dd，J＝2.7，8.7Hz)，7.43-7.38(3H，m)，6.62(1H，d，J＝8.6Hz)，4.52(2H，t，J＝6.8Hz)，2.96(2H，t，J＝6.8Hz)，2.32(3H，s)。 1 H NMR (CDCl 3 , 400MHz) 8.17 (1H, d, J=2.0Hz), 7.96 (2H, dd, J=2.0, 8.1Hz), 7.61 (1H, dd, J=2.7, 8.7Hz), 7.43 -7.38(3H, m), 6.62(1H, d, J=8.6Hz), 4.52(2H, t, J=6.8Hz), 2.96(2H, t, J=6.8Hz), 2.32(3H, s) .

制备c-46至c-47Preparation c-46 to c-47

制备c-46至c-47使用制备c-45的常规方法。The preparation of c-46 to c-47 used the conventional method of preparation of c-45.

Figure A20048001673601111
Figure A20048001673601111

制备c-48Preparation c-48

6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]烟碱醛6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde

在氮气流下，用45分钟向丁基锂(27.4mL，1.6M己烷溶液，43.8199mmol)的无水四氢呋喃溶液(200mL)中加入5-溴-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶(制备c-45)(14.31g，39.8363mmol)的无水四氢呋喃(170mL)和无水乙醚(170mL)的溶液。然后向该溶液中滴加无水N，N-二甲基甲酰胺(5.7mL)，混合物在0℃下搅拌1小时。加入饱和氯化铵(250mL)终止反应，然后加入乙酸乙酯(250mL)。将所得两层分离，水层以乙酸乙酯萃取(2×250mL)。合并有机萃取物，以水(2×250mL)、饱和氯化钠(250mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至50％乙酸乙酯/己烷)纯化，得到浅黄色结晶固体(7.17g，58％)。To a solution of butyllithium (27.4 mL, 1.6M in hexane, 43.8199 mmol) in dry tetrahydrofuran (200 mL) was added 5-bromo-2-[2-(5-methyl-2 - A solution of phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (preparation c-45) (14.31 g, 39.8363 mmol) in anhydrous tetrahydrofuran (170 mL) and anhydrous diethyl ether (170 mL). Anhydrous N,N-dimethylformamide (5.7 mL) was then added dropwise to the solution, and the mixture was stirred at 0°C for 1 hr. The reaction was quenched by adding saturated ammonium chloride (250 mL), followed by ethyl acetate (250 mL). The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 250 mL). The organic extracts were combined, washed with water (2 x 250 mL), saturated sodium chloride (250 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexane to 50% ethyl acetate/hexane) to give a pale yellow crystalline solid (7.17 g, 58%).

LRMS(m/z)：309(M+H)+。LRMS (m/z): 309 (M+H) + .

1H NMR(CDCl3，300MHz)9.93(1H，s)，8.61(1H，d，J＝2.3Hz)，8.04(1H，dd，J＝2.5，8.7Hz)，7.98-7.95(2H，m)，7.43-7.39(3H，m)，6.81(1H，d，J＝8.7Hz)，4.68(2H，t，J＝6.8Hz)，3.00(2H，t，J＝6.8Hz)，2.34(3H，s)。 1 H NMR (CDCl 3 , 300MHz) 9.93 (1H, s), 8.61 (1H, d, J=2.3Hz), 8.04 (1H, dd, J=2.5, 8.7Hz), 7.98-7.95 (2H, m) , 7.43-7.39(3H, m), 6.81(1H, d, J=8.7Hz), 4.68(2H, t, J=6.8Hz), 3.00(2H, t, J=6.8Hz), 2.34(3H, s).

制备c-49Preparation c-49

1-(羟基{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环丁烷羧酸乙酯1-(Hydroxy{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclobutanecarboxylic acid ethyl ester

在氮气流下，向6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]烟碱醛(制备c-48)(0.65g，2.1081mmol)、氯化铬(II)(1g，8.1367mmol)及碘化锂(0.0784g，0.5859mmol)的无水四氢呋喃溶液(15mL)中滴加1-溴-环丁烷羧酸乙酯(0.79mL，4.8821mmol)的无水四氢呋喃溶液(5mL)。将所得混合物在50℃下搅拌3小时，冷至室温。然后加入水(50mL)终止反应，分离有机层，以水(2×50mL)、饱和氯化钠水溶液(50mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(50％乙酸乙酯/己烷至乙酸乙酯)纯化，得到黄色油(0.3422g，37％)。6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]nicotinaldehyde (preparation c-48) (0.65g, 2.1081 mmol), chromium (II) chloride (1g, 8.1367mmol) and lithium iodide (0.0784g, 0.5859mmol) in anhydrous tetrahydrofuran solution (15mL) was added dropwise 1-bromo-cyclobutanecarboxylic acid ethyl ester (0.79 mL, 4.8821 mmol) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at 50°C for 3 hours and cooled to room temperature. Water (50 mL) was then added to quench the reaction, and the organic layer was separated, washed with water (2 x 50 mL), saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes to ethyl acetate) to give a yellow oil (0.3422 g, 37%).

LRMS(m/z)：437(M+H)+。LRMS (m/z): 437 (M+H) + .

1H NMR(CDCl3，400MHz)8.05(1H，d，J＝2.3Hz)，7.98-7.95(2H，m)，7.56(1H，dd，J＝2.5，8.7Hz)，7.44-7.37(3H，m)，6.67(1H，d，J＝8.7Hz)，4.85(1H，d，J＝6.6Hz)，4.54(2H，t，J＝6.6Hz)，4.18-4.07(2H，m)，3.31(1H，bs)，2.96(2H，t，J＝6.7Hz)，2.46-2.30(2H，m)，2.32(3H，s)，2.21-2.12(1H，m)，1.97-1.85(1H，m)，1.79-1.65(2H，m)，1.21(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 400MHz) 8.05 (1H, d, J=2.3Hz), 7.98-7.95 (2H, m), 7.56 (1H, dd, J=2.5, 8.7Hz), 7.44-7.37 (3H, m), 6.67 (1H, d, J = 8.7Hz), 4.85 (1H, d, J = 6.6Hz), 4.54 (2H, t, J = 6.6Hz), 4.18-4.07 (2H, m), 3.31 ( 1H, bs), 2.96(2H, t, J=6.7Hz), 2.46-2.30(2H, m), 2.32(3H, s), 2.21-2.12(1H, m), 1.97-1.85(1H, m) , 1.79-1.65 (2H, m), 1.21 (3H, t, J=7.2Hz).

制备c-50preparation c-50

1-(乙氧基-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基}-甲基)环丁烷羧酸乙酯1-(Ethoxy-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-yl}-methyl)cyclobutane ethyl carboxylate

向1-(羟基-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基}-甲基)-环丁烷羧酸乙酯(0.1711g，0.3920mmol)的无水乙腈溶液(2mL)中加入氧化银(I)(1.8168g，7.8396mmol)和碘乙烷(0.64mL，7.8396mmol)。将所得混合物搅拌5天，减压浓缩得粗产物，回收起始原料。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到无色油状的纯酯(0.0474g，26％)。To 1-(hydroxyl-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-yl}-methyl)-cyclobutane To a solution of ethyl carboxylate (0.1711 g, 0.3920 mmol) in anhydrous acetonitrile (2 mL) was added silver(I) oxide (1.8168 g, 7.8396 mmol) and ethyl iodide (0.64 mL, 7.8396 mmol). The resulting mixture was stirred for 5 days, concentrated under reduced pressure to obtain a crude product, and the starting material was recovered. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure ester as a colorless oil (0.0474 g, 26%).

LRMS(m/z)：465(M+H)+。LRMS (m/z): 465 (M+H) + .

1H NMR(CDCl3，400MHz)：8.05(1H，d，J＝2.3Hz)，7.98-7.95(2H，m)，7.56(1H，dd，J＝2.5，8.7Hz)，7.44-7.37(3H，m)，6.67(1H，d，J＝8.7Hz)，4.65(1H，m)，4.54(2H，t，J＝6.6Hz)，4.18-4.07(2H，m)，4.06(2H，q，J＝7.1Hz)，2.96(2H，t，J＝6.7Hz)，2.46-2.30(2H，m)，2.32(3H，s)，2.21-2.12(1H，m)，1.97-1.85(1H，m)，1.79-1.65(2H，m)，1.42(3H，t，J＝7.1Hz)，1.21(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 400MHz): 8.05 (1H, d, J=2.3Hz), 7.98-7.95 (2H, m), 7.56 (1H, dd, J=2.5, 8.7Hz), 7.44-7.37 (3H , m), 6.67(1H, d, J=8.7Hz), 4.65(1H, m), 4.54(2H, t, J=6.6Hz), 4.18-4.07(2H, m), 4.06(2H, q, J=7.1Hz), 2.96(2H, t, J=6.7Hz), 2.46-2.30(2H, m), 2.32(3H, s), 2.21-2.12(1H, m), 1.97-1.85(1H, m ), 1.79-1.65 (2H, m), 1.42 (3H, t, J = 7.1 Hz), 1.21 (3H, t, J = 7.2 Hz).

制备c-51Preparation c-51

{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲醇{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methanol

Figure A20048001673601132
Figure A20048001673601132

在室温下，将硼氢化钠(0.480g，12.7mmol)分次加入至6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]烟碱醛(制备c-48)(1.30g，4.22mmol)的甲醇溶液(40mL)中。将混合物搅拌30分钟后浓缩。将残留物分配于饱和氯化铵与乙酸乙酯中。有机相以饱和氯化钠水溶液洗涤、干燥(无水硫酸镁)、过滤并浓缩得白色结晶固体的标题化合物(1.24g，100％)。Sodium borohydride (0.480 g, 12.7 mmol) was added in portions to 6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy] at room temperature Nicotinic aldehyde (preparation c-48) (1.30 g, 4.22 mmol) in methanol (40 mL). The mixture was stirred for 30 minutes and then concentrated. The residue was partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to afford the title compound (1.24 g, 100%) as a white crystalline solid.

LRMS(m/z)：311(M+H)+。LRMS (m/z): 311 (M+H) + .

1H NMR(CDCl3，300MHz)8.11(1H，d，J＝2.6Hz)，8.00-7.95(2H，m)，7.60(1H，dd，J＝2.5，8.5Hz)，7.45-7.38(3H，m)，6.72(1H，d，J＝8.5Hz)，4.61(2H，bs)，4.56(2H，t，J＝6.8Hz)，2.98(2H，t，J＝6.8Hz)，2.33(3H，s)。 1 H NMR (CDCl 3 , 300MHz) 8.11 (1H, d, J=2.6Hz), 8.00-7.95 (2H, m), 7.60 (1H, dd, J=2.5, 8.5Hz), 7.45-7.38 (3H, m), 6.72(1H, d, J=8.5Hz), 4.61(2H, bs), 4.56(2H, t, J=6.8Hz), 2.98(2H, t, J=6.8Hz), 2.33(3H, s).

制备c-52Preparation c-52

{2-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-嘧啶-5-基}甲醇{2-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrimidin-5-yl}methanol

将5-溴-2-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-嘧啶(1.0g，2.7765mmol)、叔丁基-二甲基-三丁基锡烷基甲氧基-甲硅烷(1.8g，4.1648mmol)及四(三苯基膦)钯(0)(0.3209g，0.2777mmol)的1，4-二噁烷溶液(2.8mL)在150℃下加热(以微波照射)2小时。所得溶液冷至室温后，加入饱和氟化钾溶液(10mL)，搅拌30分钟。然后以乙酸乙酯萃取该混合物(3×25mL)，合并有机萃取物，干燥(无水硫酸镁)、过滤并真空浓缩得黄色油状的粗产物。向粗产物的无水四氢呋喃溶液(24mL)中加入氟化四丁基铵(3.1mL，1.0M四氢呋喃溶液)。将所得混合物在室温下搅拌16小时，减压浓缩。残留物以快速柱层析(50％乙酸乙酯/己烷至10％甲醇/乙酸乙酯)纯化，得到白色固体的纯醇(0.6137g，2步71％)。5-Bromo-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrimidine (1.0g, 2.7765mmol), tert-butyl-dimethyl - Tributylstannylmethoxy-silane (1.8g, 4.1648mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3209g, 0.2777mmol) in 1,4-dioxane (2.8mL) Heating (irradiation with microwaves) at 150° C. for 2 hours. After the resulting solution was cooled to room temperature, saturated potassium fluoride solution (10 mL) was added and stirred for 30 minutes. The mixture was then extracted with ethyl acetate (3 x 25 mL) and the organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product as a yellow oil. To a solution of the crude product in anhydrous THF (24 mL) was added tetrabutylammonium fluoride (3.1 mL, 1.0 M in THF). The resulting mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford pure alcohol as a white solid (0.6137 g, 71% over 2 steps).

LRMS(m/z)：312(M+H)+。LRMS (m/z): 312 (M+H) + .

制备c-53Preparation c-53

5-苄氧基-2-甲基-吡啶5-Benzyloxy-2-methyl-pyridine

Figure A20048001673601142
Figure A20048001673601142

向5-羟基-2-甲基吡啶(20g，183.2677mmol)及氢氧化钠(8.0638g，201.5944mmol)的丙酮(400mL)和水(120mL)溶液中加入苄基溴(24mL，201.5944mmol)。将所得混合物回流加热16小时，冷至室温。真空去除丙酮，再以乙酸乙酯萃取混合物(3×150mL)。合并有机萃取物，以饱和氯化钠水溶液(200mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得橙色油状的纯产物(31.35g，86％)。To a solution of 5-hydroxy-2-picoline (20 g, 183.2677 mmol) and sodium hydroxide (8.0638 g, 201.5944 mmol) in acetone (400 mL) and water (120 mL) was added benzyl bromide (24 mL, 201.5944 mmol). The resulting mixture was heated at reflux for 16 hours and cooled to room temperature. Acetone was removed in vacuo and the mixture was extracted with ethyl acetate (3 x 150 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride (200 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give pure product (31.35 g, 86%) as an orange oil.

LRMS(m/z)：200(M+H)+。LRMS (m/z): 200 (M+H) + .

1H NMR(CDCl3，300MHz)：8.25(1H，d，J＝2.8Hz)，7.43-7.31(5H，m)，7.15(1H，dd，J＝8.5，2.8Hz)，7.04(1H，d，J＝8.5Hz)，5.06(2H，s)，2.47(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 8.25 (1H, d, J = 2.8Hz), 7.43-7.31 (5H, m), 7.15 (1H, dd, J = 8.5, 2.8Hz), 7.04 (1H, d , J=8.5Hz), 5.06 (2H, s), 2.47 (3H, s).

制备c-54Preparation c-54

5-苄氧基-2-甲基-吡啶1-氧化物5-Benzyloxy-2-methyl-pyridine 1-oxide

Figure A20048001673601151
Figure A20048001673601151

在室温下，向5-苄氧基-2-甲基-吡啶(31.35g，157.34mmol)的无水氯仿溶液(800mL)中加入3-氯过氧苯甲酸(最大浓度77％)(38.7888g，173.074mmol)。将所得混合物搅拌2小时，然后以硫代硫酸钠(36.0805g，286.5mmol)的水溶液(500mL)终止反应，搅拌15分钟。分离所得两相，将有机相以水(500mL)、饱和氯化钠水溶液(500mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以丙酮/己烷重结晶，得到纯产物(33.1597g，97％)，为白色固体。To a solution of 5-benzyloxy-2-methyl-pyridine (31.35 g, 157.34 mmol) in anhydrous chloroform (800 mL) was added 3-chloroperoxybenzoic acid (77% maximum concentration) (38.7888 g , 173.074 mmol). The resulting mixture was stirred for 2 hours, then quenched with a solution of sodium thiosulfate (36.0805 g, 286.5 mmol) in water (500 mL) and stirred for 15 minutes. The resulting two phases were separated and the organic phase was washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was recrystallized from acetone/hexanes to give pure product (33.1597 g, 97%) as a white solid.

LRMS(m/z)：216(M+H)+。LRMS (m/z): 216 (M+H) + .

1H NMR(CDCl3，300MHz)：8.10-8.09(1H，bm)，7.38-7.34(5H，m)，7.10(1H，d，J＝8.7Hz)，6.87(1H，dd，J＝8.7，2.3Hz)，5.04(2H，s)，2.43(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 8.10-8.09 (1H, bm), 7.38-7.34 (5H, m), 7.10 (1H, d, J=8.7Hz), 6.87 (1H, dd, J=8.7, 2.3Hz), 5.04(2H, s), 2.43(3H, s).

制备c-55Preparation c-55

(5-苄氧基-吡啶-2-基)-甲醇(5-Benzyloxy-pyridin-2-yl)-methanol

在100℃下，将5-苄氧基-2-甲基-吡啶1-氧化物(0.92g，4.2741mmol)的乙酸酐溶液(6.5mL)加热30分钟。冷至室温后，将反应混合物倒入乙酸乙酯(50mL)中，以饱和碳酸氢钠溶液(50mL)、饱和氯化钠水溶液(50mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗制乙酸酯。A solution of 5-benzyloxy-2-methyl-pyridine 1-oxide (0.92 g, 4.2741 mmol) in acetic anhydride (6.5 mL) was heated at 100°C for 30 minutes. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution (50 mL), saturated aqueous sodium chloride solution (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo A crude acetate was obtained.

向粗制残留物的甲醇溶液(45mL)中加入碳酸钾(2.1784g，15.7719mmol)，室温下搅拌溶液16小时。将反应混合物倒入水(50mL)中，减压去除有机物。所得残留物以乙酸乙酯萃取(3×50mL)，合并有机萃取物，干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至20％甲醇/乙酸乙酯)纯化，得到纯醇的白色固体(0.5719g，两步62％)。To a solution of the crude residue in methanol (45 mL) was added potassium carbonate (2.1784 g, 15.7719 mmol), and the solution was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL), and the organics were removed under reduced pressure. The resulting residue was extracted with ethyl acetate (3 x 50 mL), and the organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (hexanes to 20% methanol/ethyl acetate) to afford pure alcohol as a white solid (0.5719 g, 62% for two steps).

LRMS(m/z)：216(M+H)+。LRMS (m/z): 216 (M+H) + .

1H NMR(CDCl3，300MHz)：8.31(1H，d，J＝2.8Hz)，7.44-7.31(5H，m)，7.27(1H，dd，J＝8.7，2.8Hz)，7.17(1H，d，J＝8.5Hz)，5.11(2H，s)，4.69(2H，s)。 1 H NMR (CDCl 3 , 300MHz): 8.31 (1H, d, J = 2.8Hz), 7.44-7.31 (5H, m), 7.27 (1H, dd, J = 8.7, 2.8Hz), 7.17 (1H, d , J=8.5Hz), 5.11 (2H, s), 4.69 (2H, s).

制备c-56Preparation c-56

2-甲基-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶1-氧化物2-Methyl-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine 1-oxide

在室温下，向2-甲基-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶(6.7973g，23.0917mmol)的无水氯仿溶液(140mL)中加入3-氯过氧苯甲酸(最大浓度77％)(7.7629g，34.6376mmol)。将所得混合物搅拌2小时，然后以硫代硫酸钠(4.3621g，34.6376mmol)水溶液(25mL)终止反应，再搅拌15分钟。分离所得两相，有机层以水(50mL)、饱和氯化钠水溶液(50mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。该浅黄色油粗品(7.0689g，98％)无需进一步纯化直接使用。To the anhydrous To the chloroform solution (140 mL) was added 3-chloroperoxybenzoic acid (77% max concentration) (7.7629 g, 34.6376 mmol). The resulting mixture was stirred for 2 hours, then quenched with aqueous sodium thiosulfate (4.3621 g, 34.6376 mmol) (25 mL) and stirred for an additional 15 minutes. The resulting two phases were separated and the organic layer was washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The crude pale yellow oil (7.0689 g, 98%) was used without further purification.

LRMS(m/z)：311(M+H)+。LRMS (m/z): 311 (M+H) + .

1H NMR(CDCl3，300MHz)：8.06(1H，d，J＝2.3Hz)，7.96-7.93(2H，m)，7.41-7.39(3H，m)，7.10(1H，d，J＝8.9Hz)，6.85(1H，dd，J＝8.8，2.4Hz)，4.23(2H，t，J＝6.6Hz)，2.95(2H，t，J＝6.6Hz)，2.43(3H，s)，2.35(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 8.06 (1H, d, J = 2.3Hz), 7.96-7.93 (2H, m), 7.41-7.39 (3H, m), 7.10 (1H, d, J = 8.9Hz ), 6.85(1H, dd, J=8.8, 2.4Hz), 4.23(2H, t, J=6.6Hz), 2.95(2H, t, J=6.6Hz), 2.43(3H, s), 2.35(3H , s).

制备c-57Preparation of c-57

{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-2-基}-甲醇{5-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-methanol

在100℃下，将2-甲基-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶1-氧化物(3.5979g，11.5181mmol)的乙酸酐溶液(17.5mL)加热30分钟。冷至室温后，将反应混合物倒入乙酸乙酯(150mL)中，以饱和碳酸氢钠溶液(150mL)、饱和氯化钠水溶液(150mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗制乙酸酯。向粗制残留物的甲醇溶液(120mL)加入碳酸钾(5.8705g，42.617mmol)，在室温下搅拌该溶液16小时。将反应混合物倒入水(150mL)中，减压去除有机物。将所得残留物以乙酸乙酯萃取(3×150mL)、合并有机萃取物，干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(乙酸乙酯至10％甲醇/乙酸乙酯)纯化，得到浅黄色低熔点固体的纯醇(1.52g，43％，两步)。At 100°C, 2-methyl-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine 1-oxide (3.5979g, 11.5181 mmol) in acetic anhydride (17.5 mL) was heated for 30 min. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution (150 mL), saturated aqueous sodium chloride solution (150 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo A crude acetate was obtained. To a solution of the crude residue in methanol (120 mL) was added potassium carbonate (5.8705 g, 42.617 mmol), and the solution was stirred at room temperature for 16 hours. The reaction mixture was poured into water (150 mL), and the organics were removed under reduced pressure. The resulting residue was extracted with ethyl acetate (3 x 150 mL), the combined organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (ethyl acetate to 10% methanol/ethyl acetate) to afford pure alcohol (1.52 g, 43%, two steps) as a pale yellow low melting point solid.

LRMS(m/z)：311(M+H)+。LRMS (m/z): 311 (M+H) + .

1H NMR(CDCl3，300MHz)：8.22(1H，d，J＝2.5Hz)，7.97-7.94(2H，m)，7.42-7.38(3H，m)，7.20(1H，dd，J＝8.5，2.6Hz)，7.15(1H，d，J＝8.7Hz)，4.67(2H，s)，4.28(2H，t，J＝6.7Hz)，2.98(2H，t，J＝6.7Hz)，2.37(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 8.22 (1H, d, J = 2.5Hz), 7.97-7.94 (2H, m), 7.42-7.38 (3H, m), 7.20 (1H, dd, J = 8.5, 2.6Hz), 7.15(1H, d, J=8.7Hz), 4.67(2H, s), 4.28(2H, t, J=6.7Hz), 2.98(2H, t, J=6.7Hz), 2.37(3H , s).

制备c-58Preparation c-58

5-(氯甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶5-(Chloromethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine

在0℃下，将草酰氯(0.30mL，3.44mmol)加入至{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲醇(制备26)(0.97g，3.13mmol)的二氯甲烷(30mL)和N，N-二甲基甲酰胺(3mL)溶液中。将混合物冷至室温，搅拌1小时后浓缩。将残留物分配于饱和碳酸氢钠溶液与乙酸乙酯。有机相以饱和氯化钠水溶液洗涤、干燥(无水硫酸镁)、过滤并浓缩得白色结晶固体的标题化合物(1.01g，100％)。Oxalyl chloride (0.30 mL, 3.44 mmol) was added to {6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine at 0 °C -3-yl}methanol (Preparation 26) (0.97 g, 3.13 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (3 mL). The mixture was cooled to room temperature, stirred for 1 hour and then concentrated. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to afford the title compound (1.01 g, 100%) as a white crystalline solid.

LRMS(m/z)：329(M+H)+。LRMS (m/z): 329 (M+H) + .

1H NMR(CDCl3，300MHz)8.12(1H，d，J＝2.5Hz)，7.98-7.95(2H，m)，7.60(1H，dd，J＝2.5，8.5Hz)，7.45-7.37(3H，m)，6.72(1H，d，J＝8.5Hz)，4.57(2H，t，J＝6.8Hz)，4.53(2H，s)，2.97(2H，t，J＝6.8Hz)，2.33(3H，s)。 1 H NMR (CDCl 3 , 300MHz) 8.12 (1H, d, J = 2.5Hz), 7.98-7.95 (2H, m), 7.60 (1H, dd, J = 2.5, 8.5Hz), 7.45-7.37 (3H, m), 6.72(1H, d, J=8.5Hz), 4.57(2H, t, J=6.8Hz), 4.53(2H, s), 2.97(2H, t, J=6.8Hz), 2.33(3H, s).

制备c-59至c-63Preparation c-59 to c-63

制备c-59至c-63使用制备c-58的常规方法进行制备。Preparations c-59 to c-63 were prepared using the conventional methods for preparing c-58.

制备c-64Preparation of c-64

5-(碘甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine

Figure A20048001673601182
Figure A20048001673601182

将碘化钠(0.750g)加入至5-(氯甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶(制备27)(0.690g，2.10mmol)的丙酮溶液(5mL)中，将混合物回流加热30分钟、冷却并浓缩。将残留物悬浮于乙酸乙酯中，以硅胶垫过滤。将滤出液浓缩得黄色结晶固体的标题化合物，直接用于后续反应。Sodium iodide (0.750 g) was added to 5-(chloromethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine (Preparation 27) (0.690 g, 2.10 mmol) in acetone (5 mL), the mixture was heated at reflux for 30 minutes, cooled and concentrated. The residue was suspended in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to obtain the title compound as a yellow crystalline solid, which was directly used in subsequent reactions.

LRMS(m/z)：421(M+H)+。LRMS (m/z): 421 (M+H) + .

制备c-65至c-69Preparations c-65 to c-69

制备c-65至c-69使用制备c-64的常规方法进行制备。Preparations c-65 to c-69 were prepared using the conventional methods for preparing c-64.

Figure A20048001673601191
Figure A20048001673601191

制备c-70preparation c-70

1-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)环丁烷羧酸乙酯1-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)cyclobutanecarboxylic acid ester

在-60℃下，将(双)三甲基甲硅烷基胺基钠(3.0mL，1M四氢呋喃溶液，3.0mmol)滴加入环丁烷羧酸乙酯(0.41mL，3.0mmol)的无水四氢呋喃溶液(5mL)中。将混合物搅拌1小时后，滴加5-(碘甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶(制备28)(0.271g，0.64mmol)的无水四氢呋喃溶液(4mL)。将所得混合物在-60℃下搅拌1小时，然后以饱和氯化铵水溶液终止反应，温热至室温。将混合物以乙酸乙酯萃取，干燥有机相(无水硫酸镁)、过滤并浓缩得标题化合物与二聚体的1∶1混合物(0.160g)，其在后续步骤中直接使用。Sodium (bis)trimethylsilylamide (3.0 mL, 1M solution in THF, 3.0 mmol) was added dropwise to ethyl cyclobutanecarboxylate (0.41 mL, 3.0 mmol) in anhydrous THF at -60°C solution (5 mL). After stirring the mixture for 1 hour, 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine was added dropwise ( A solution of 28) (0.271 g, 0.64 mmol) in anhydrous tetrahydrofuran (4 mL) was prepared. The resulting mixture was stirred at -60°C for 1 hour, then quenched with saturated aqueous ammonium chloride and allowed to warm to room temperature. The mixture was extracted with ethyl acetate, the organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated to give a 1:1 mixture of the title compound and dimer (0.160 g), which was used directly in the next step.

LRMS(m/z)：421(M+H)+。LRMS (m/z): 421 (M+H) + .

制备c-71preparation c-71

2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸乙基酯2-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid ethyl ester

Figure A20048001673601201
Figure A20048001673601201

在-50℃下，将(双)三甲基甲硅烷基胺基钠(3.18mL，1M四氢呋喃溶液，3.18mmol)滴加入2-四氢呋喃甲酸乙酯(0.458g，3.18mmol)的无水四氢呋喃溶液(4mL)中。搅拌混合物45分钟，然后滴加5-(碘甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶(制备28)(0.267g，0.64mmol)的无水四氢呋喃溶液(2mL)。在-50℃下搅拌所得混合物1.5小时后，以饱和氯化铵水溶液终止反应，温热至室温。混合物以乙酸乙酯萃取、干燥有机相(无水硫酸镁)、过滤并浓缩。残留物以快速柱层析(25％～35％乙酸乙酯/己烷)纯化，得到无色油状的标题化合物(0.250g，90％)。Sodium (bis)trimethylsilylamide (3.18mL, 1M solution in tetrahydrofuran, 3.18mmol) was added dropwise to a solution of ethyl 2-tetrahydrofurancarboxylate (0.458g, 3.18mmol) in anhydrous tetrahydrofuran at -50°C (4mL). The mixture was stirred for 45 minutes, then 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine was added dropwise (Preparation 28) (0.267g, 0.64mmol) in dry tetrahydrofuran (2mL). After stirring the resulting mixture at -50°C for 1.5 hours, the reaction was quenched with saturated aqueous ammonium chloride solution and allowed to warm to room temperature. The mixture was extracted with ethyl acetate, the organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by flash column chromatography (25%-35% ethyl acetate/hexane) to give the title compound (0.250 g, 90%) as a colorless oil.

LRMS(m/z)：437(M+H)+。LRMS (m/z): 437 (M+H) + .

1H NMR(CDCl3，300MHz)7.95(3H，m)，7.51(1H，dd，J＝2.5，8.5Hz)，7.43-7.36(3H，m)，6.61(1H，d，J＝8.5Hz)，4.51(2H，t，J＝6.8Hz)，4.29-4.18(9H，m)，4.13(2H，q，J＝7.2Hz)，3.95-3.82(2H，m)，3.10(1H，d，J＝14.1Hz)，2.95(2H，t，J＝6.8Hz)，2.86(1H，d，J＝14.1Hz)，2.31(3H，s)，2.26-2.20(1H，m)，1.92-1.77(2H，m)，1.70-1.61(1H，m)，1.21(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.95 (3H, m), 7.51 (1H, dd, J=2.5, 8.5Hz), 7.43-7.36 (3H, m), 6.61 (1H, d, J=8.5Hz) , 4.51(2H, t, J=6.8Hz), 4.29-4.18(9H, m), 4.13(2H, q, J=7.2Hz), 3.95-3.82(2H, m), 3.10(1H, d, J =14.1Hz), 2.95(2H, t, J=6.8Hz), 2.86(1H, d, J=14.1Hz), 2.31(3H, s), 2.26-2.20(1H, m), 1.92-1.77(2H , m), 1.70-1.61 (1H, m), 1.21 (3H, t, J=7.2Hz).

制备c-72至c-79Preparations c-72 to c-79

制备c-72至c-79使用制备c-71的常规方法进行制备。Preparations c-72 to c-79 were prepared using the conventional methods for preparation c-71.

Figure A20048001673601211
Figure A20048001673601211

制备c-80preparation c-80

2-溴-5-(溴甲基)吡啶2-Bromo-5-(bromomethyl)pyridine

将三溴化磷(100mmol，27.1g，2.0当量)小心地加入至2-氯-5-羟基甲基吡啶(50.0mmol，7.18g，1.0当量)中。吡啶成块，将混合物加热至160℃。在＞150℃下搅拌5分钟，可见混合物颜色变得很黑，并伴有气体放出。将混合物在同一温度下搅拌约2.5小时后冷至室温。将混合物进一步冷至0℃，小心加入饱和碳酸氢钠溶液(剧烈放热！)。当泡沫较少时，将冰加入至混合物中直至泡沫消失。然后小心加入固体碳酸氢钠使pH～8-9。以乙酸乙酯萃取混合物，有机层以盐水溶液洗涤，无水硫酸镁干燥。真空浓缩得黑色固体。将该材料溶于最小量的DCM中，使用Biotage Sp4 65i以0-100％乙酸乙酯/己烷溶液梯度纯化，得到浅黄色固体的标题化合物(5.57g，44％)。Phosphorus tribromide (100 mmol, 27.1 g, 2.0 equiv) was carefully added to 2-chloro-5-hydroxymethylpyridine (50.0 mmol, 7.18 g, 1.0 equiv). Pyridine clumps and the mixture is heated to 160°C. Stirring at >150°C for 5 minutes, it can be seen that the color of the mixture becomes very dark, accompanied by gas evolution. The mixture was stirred at the same temperature for about 2.5 hours and then cooled to room temperature. The mixture was cooled further to 0°C and saturated sodium bicarbonate solution was added carefully (vigorous exotherm!). When the foam is less, ice is added to the mixture until the foam disappears. Solid sodium bicarbonate was then added carefully to bring the pH to ~8-9. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gave a black solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i with a gradient of 0-100% ethyl acetate/hexanes to afford the title compound (5.57 g, 44%) as a light yellow solid.

LRMS：252(M+H)+。LRMS: 252 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.39(1H，s)7.59(1H，d，J＝8.5Hz)7.48(1H，d，J＝8.5Hz)4.46(2H，s) 1 H NMR (DMSO-d 6 , 400MHz): 8.39 (1H, s) 7.59 (1H, d, J = 8.5Hz) 7.48 (1H, d, J = 8.5Hz) 4.46 (2H, s)

制备c-81preparation c-81

2-[(6-溴吡啶-3-基)甲基]四氢呋喃-2-羧酸乙酯2-[(6-Bromopyridin-3-yl)methyl]tetrahydrofuran-2-carboxylic acid ethyl ester

向冷至-78℃的四氢呋喃-2-羧酸乙酯(52.9mmol，9.10g，1.5当量)的THF溶液(90mL)中滴加2M二异丙基胺基锂(52.9mmol，1.5当量)的庚烷/THF/乙苯混和溶液。在同一低温下形成烯醇化物1小时，然后滴加2-溴-5-(溴甲基)吡啶(35.3mmol，8.85g，1.0当量)的THF溶液。将反应缓慢冷至室温过夜。以饱和氯化铵水溶液终止反应。混合物以乙酸乙酯萃取，有机萃取物以盐水溶液洗涤。有机层以无水硫酸镁干燥，真空浓缩得黄色油。该粗产物以Biotage Sp465i通过5％～95％乙酸乙酯/己烷溶液梯度纯化，得到金色油(8.70g，78％)。To a solution of ethyl tetrahydrofuran-2-carboxylate (52.9mmol, 9.10g, 1.5eq) in THF (90mL) cooled to -78°C was added dropwise a solution of 2M lithium diisopropylamide (52.9mmol, 1.5eq) Heptane/THF/ethylbenzene mixed solution. The enolate was formed at the same low temperature for 1 hour, then a THF solution of 2-bromo-5-(bromomethyl)pyridine (35.3 mmol, 8.85 g, 1.0 equiv) was added dropwise. The reaction was cooled slowly to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic extract was washed with brine solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. The crude product was purified with Biotage Sp465i through a gradient of 5% to 95% ethyl acetate/hexane to give a golden oil (8.70 g, 78%).

LRMS：315(M+H)+。LRMS: 315 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.21(1H，s)7.40-7.49(2H，m)3.94(2H，q，J＝7.0Hz)3.71-3.85(2H，m)3.05-3.11(1H，m)2.91-2.97(1H，m)2.38-2.47(1H，m)1.83-2.09(3H，m)1.09(3H，t，J＝7.0Hz) 1 H NMR (DMSO-d 6 , 400MHz): 8.21 (1H, s) 7.40-7.49 (2H, m) 3.94 (2H, q, J=7.0Hz) 3.71-3.85 (2H, m) 3.05-3.11 (1H , m) 2.91-2.97 (1H, m) 2.38-2.47 (1H, m) 1.83-2.09 (3H, m) 1.09 (3H, t, J = 7.0Hz)

制备c-82preparation c-82

环丙烷羧酸叔丁酯tert-butyl cyclopropanecarboxylate

将浓硫酸(3.45mL，62.7832mmol)加入至剧烈搅拌的无水硫酸镁(30.1987g，251.1326mmol)的二氯甲烷悬液(250mL)中。搅拌混合物15分钟，加入环丙烷羧酸(5mL，62.7832mmol)和2-甲基-丙-2-醇(30mL，313.9158mmol)。塞紧混合物瓶口，在室温下搅拌16小时。然后以饱和碳酸氢钠溶液(450mL)终止反应混合物，搅拌直至所有硫酸镁溶解。分离两相，有机相以水(100mL)、饱和氯化钠水溶液(100mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得无色液体的纯酯(8.3921g，59.0162mmol)。Concentrated sulfuric acid (3.45 mL, 62.7832 mmol) was added to a vigorously stirred suspension of anhydrous magnesium sulfate (30.1987 g, 251.1326 mmol) in dichloromethane (250 mL). The mixture was stirred for 15 minutes and cyclopropanecarboxylic acid (5 mL, 62.7832 mmol) and 2-methyl-propan-2-ol (30 mL, 313.9158 mmol) were added. The mixture was stoppered tightly and stirred at room temperature for 16 hours. The reaction mixture was then quenched with saturated sodium bicarbonate solution (450 mL) and stirred until all magnesium sulfate was dissolved. The two phases were separated and the organic phase was washed with water (100 mL), saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the pure ester (8.3921 g, 59.0162 mmol) as a colorless liquid.

1H NMR(CDCl3，300MHz)：1.45(9H，s)，0.93-0.86(3H，m)，0.79-0.73(2H，m)。 1 H NMR (CDCl 3 , 300 MHz): 1.45 (9H, s), 0.93-0.86 (3H, m), 0.79-0.73 (2H, m).

制备c-83Preparation c-83

1-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基甲基}环丙烷羧酸叔丁酯tert-butyl 1-{6-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}cyclopropanecarboxylate

在0℃及氮气流下，向二异丙胺(0.14mL，0.9518mmol)的无水四氢呋喃溶液(2.4mL)中加入丁基锂(0.38mL，2.5M己烷溶液，0.9518mmol)。将所得溶液搅拌30分钟，然后冷至-50℃。加入环丙烷羧酸叔丁酯(0.1269g，0.8924mmol)的无水四氢呋喃溶液(1mL)，继续搅拌2小时。然后滴加5-碘甲基-2-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶(0.25g，0.5949mmol)的无水四氢呋喃溶液(1mL)，再搅拌溶液3小时。加入饱和氯化铵水溶液(25mL)终止反应，以乙酸乙酯萃取(3×25mL)。然后将合并的有机萃取物干燥(无水硫酸镁)、过滤并真空浓缩得粗产物及未反应的原料碘化物。粗残留物以快速柱层析(己烷至60％乙酸乙酯/己烷)纯化，得到浅黄色固体酯(0.0827g，32％)，其中含部分原料碘化物。To a solution of diisopropylamine (0.14 mL, 0.9518 mmol) in anhydrous THF (2.4 mL) was added butyllithium (0.38 mL, 2.5M in hexane, 0.9518 mmol) at 0°C under nitrogen flow. The resulting solution was stirred for 30 minutes, then cooled to -50°C. A solution of tert-butyl cyclopropanecarboxylate (0.1269 g, 0.8924 mmol) in anhydrous THF (1 mL) was added and stirring was continued for 2 hours. Then 5-iodomethyl-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine (0.25 g, 0.5949 mmol) in anhydrous THF was added dropwise solution (1 mL), and the solution was stirred for an additional 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were then dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product and unreacted starting iodide. The crude residue was purified by flash column chromatography (hexanes to 60% ethyl acetate/hexanes) to give the ester as a pale yellow solid (0.0827 g, 32%) containing some starting iodide.

LRMS(m/z)：435(M+H)+。LRMS (m/z): 435 (M+H) + .

制备c-84Preparation of c-84

2-({6-[2-(5-甲基-2-苯基-1，3-噻唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸乙酯2-({6-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid ethyl ester

向氩气吹扫过的溴吡啶(0.636mmol)的甲苯溶液(12mL)中加入乙酸钯(II)(11.4mg，0.0508mmol)和消旋-2-(二-叔丁基膦基)-1，1’-联萘(25.4mg，0.0636mmol)。约10分钟形成活性复合物，然后加入碳酸铯(414mg，1.27mmol)和合适的醇(0.956mmol)。将混合物加热至115℃，在此温度下搅拌12-18小时。将混合物冷至室温，通过硅胶垫过滤。滤垫以2-3份的乙酸乙酯洗涤，合并有机滤液并真空浓缩。所得残留物以快速层析纯化，或无需纯化直接使用。To an argon-purged solution of pyridine bromide (0.636 mmol) in toluene (12 mL) was added palladium(II) acetate (11.4 mg, 0.0508 mmol) and rac-2-(di-tert-butylphosphino)-1 , 1'-binaphthyl (25.4mg, 0.0636mmol). The active complex formed in about 10 minutes, then cesium carbonate (414mg, 1.27mmol) and the appropriate alcohol (0.956mmol) were added. The mixture was heated to 115°C and stirred at this temperature for 12-18 hours. The mixture was cooled to room temperature and filtered through a pad of silica gel. The filter pad was washed with 2-3 portions of ethyl acetate, and the organic filtrates were combined and concentrated in vacuo. The resulting residue was purified by flash chromatography or used without purification.

制备c-85至c-88Preparation c-85 to c-88

制备c-85至c-88使用类似于制备c-84中使用的方法进行制备。Preparations c-85 to c-88 were prepared using a method similar to that used in preparation c-84.

制备c-89Preparation c-89

5-{[叔丁基(二苯基)甲硅烷基]氧基}-2-(碘甲基)吡啶5-{[tert-butyl(diphenyl)silyl]oxy}-2-(iodomethyl)pyridine

向2-溴甲基-5-(叔丁基-二苯基-甲硅氧基)-吡啶(Schow，S.R.；QuinnDeJoy，S.；Wick，M.M.；Kerwar，S.S.J.Org.Chem.1994，59，6850-6852)(1.2692g，2.9763mmol)的丙酮溶液(15mL)中加入碘化钠(0.8922g，5.9526mmol)，将所得非均匀混合物在室温下搅拌3小时。将反应混合物真空浓缩，所得残留物以乙酸乙酯(50mL)稀释、水(50mL)洗涤。有机层再以饱和碳酸氢钠溶液(50mL)和饱和硫代硫酸钠溶液(50mL)洗涤。合并水层以乙酸乙酯萃取(3×50mL)，合并有机萃取物、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至20％乙酸乙酯/己烷)纯化，得到浅黄色油(0.72g，51％)。该化合物浓缩时不稳定，因而直接使用。To 2-bromomethyl-5-(tert-butyl-diphenyl-silyloxy)-pyridine (Schow, S.R.; QuinnDeJoy, S.; Wick, M.M.; Kerwar, S.S.J.Org.Chem.1994, 59, 6850-6852) (1.2692 g, 2.9763 mmol) in acetone (15 mL) was added sodium iodide (0.8922 g, 5.9526 mmol), and the resulting heterogeneous mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate (50 mL), washed with water (50 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium thiosulfate solution (50 mL). The combined aqueous layers were extracted with ethyl acetate (3 x 50 mL), and the organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to 20% ethyl acetate/hexanes) to give a light yellow oil (0.72 g, 51%). The compound was unstable in concentration and was used directly.

LRMS(m/z)：474(M+H)+。LRMS (m/z): 474 (M+H) + .

制备c-90preparation c-90

四氢呋喃-2-羧酸乙酯Ethyl tetrahydrofuran-2-carboxylate

向四氢呋喃-2-羧酸(20g，172.2356mmol)的无水乙醇溶液(100mL)中加入浓硫酸(0.46mL)。将所得混合物回流搅拌加热16小时，然后冷至室温。加入水(100mL)，以乙醚萃取(3×000mL)。合并有机萃取物，以饱和碳酸氢钠溶液(2×50mL)、饱和氯化钠水溶液(100mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得无色液体纯净的产物(22.5964g，91％)。To a solution of tetrahydrofuran-2-carboxylic acid (20 g, 172.2356 mmol) in absolute ethanol (100 mL) was added concentrated sulfuric acid (0.46 mL). The resulting mixture was heated at reflux with stirring for 16 hours, then cooled to room temperature. Water (100 mL) was added and extracted with ether (3 x 000 mL). The organic extracts were combined, washed with saturated sodium bicarbonate solution (2×50 mL), saturated aqueous sodium chloride solution (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the pure product (22.5964 g, 91%).

LRMS(m/z)：145(M+H)+。LRMS (m/z): 145 (M+H) + .

1H NMR(CDCl3，300MHz)4.38(1H，dd，J＝4.9，8.1Hz)，4.14(2H，q，J＝7.2Hz)，3.99-3.92(1H，m)，3.88-3.81(1H，m)，2.24-2.12(1H，m)，2.00-1.79(3H，m)，1.22(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300 MHz) 4.38 (1H, dd, J=4.9, 8.1 Hz), 4.14 (2H, q, J=7.2 Hz), 3.99-3.92 (1H, m), 3.88-3.81 (1H, m), 2.24-2.12 (1H, m), 2.00-1.79 (3H, m), 1.22 (3H, t, J=7.2Hz).

制备c-91preparation c-91

四氢-吡喃-2-羧酸乙酯Ethyl tetrahydro-pyran-2-carboxylate

上述化合物按照Rychnovsky，S.D.；Hata，T.；Kim，A.I.；Buckmelter，A.J.Org.Lett.2001，3，807-810所述的方法制备。The above compounds were prepared according to the methods described by Rychnovsky, S.D.; Hata, T.; Kim, A.I.; Buckmelter, A.J.Org.Lett. 2001, 3, 807-810.

制备c-92preparation c-92

2-[(5-{[叔丁基(二苯基)甲硅烷基]氧基}吡啶-2-基)甲基]四氢呋喃-2-羧酸乙酯2-[(5-{[tert-Butyl(diphenyl)silyl]oxy}pyridin-2-yl)methyl]tetrahydrofuran-2-carboxylic acid ethyl ester

Figure A20048001673601263
Figure A20048001673601263

在-50℃及氮气流下，向四氢呋喃-2-羧酸乙酯(制备32)(1.0965g，7.604mmol)的无水四氢呋喃溶液(7mL)中滴加双(三甲基甲硅烷基)胺基钠(7.6mL，1.0M四氢呋喃溶液，7.604mmol)。搅拌反应混合物1小时，然后滴加5-(叔丁基-二苯基-甲硅烷氧基)-2-碘甲基-吡啶(制备31)(0.72g，1.5208mmol)的无水四氢呋喃溶液(7mL)。所得溶液在-50℃下搅拌2小时后，以饱和氯化铵水溶液(25mL)终止反应。然后以乙酸乙酯萃取该溶液(3×25mL)、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至40％乙酸乙酯/己烷)纯化，得到无色油(0.2438g，33％)。To a solution (7 mL) of ethyl tetrahydrofuran-2-carboxylate (Preparation 32) (1.0965 g, 7.604 mmol) in anhydrous THF (7 mL) was added bis(trimethylsilyl)amine dropwise at -50°C under a nitrogen stream Sodium (7.6 mL, 1.0 M in tetrahydrofuran, 7.604 mmol). The reaction mixture was stirred for 1 hour, then a solution of 5-(tert-butyl-diphenyl-silyloxy)-2-iodomethyl-pyridine (Preparation 31) (0.72 g, 1.5208 mmol) in anhydrous THF was added dropwise ( 7mL). After the resulting solution was stirred at -50°C for 2 hours, the reaction was quenched with saturated aqueous ammonium chloride solution (25 mL). The solution was then extracted with ethyl acetate (3 x 25 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexanes to 40% ethyl acetate/hexanes) to give a colorless oil (0.2438 g, 33%).

LRMS(m/z)：490(M+H)+。LRMS (m/z): 490 (M+H) + .

1H NMR(CDCl3，300MHz)8.07(1H，d，J＝2.5Hz)，7.67-7.63(4H，m)，7.41-7.31(6H，m)，6.97(1H，d，J＝8.5Hz)，6.86(1H，dd，J＝2.8，8.5Hz)，4.21(2H，q，J＝7.2Hz)，4.09(2H，q，J＝7.2Hz)，3.22(1H，d，J＝13.9Hz)，3.07(1H，d，J＝13.9Hz)，2.53-2.44(1H，m)，2.31-2.15(1H，m)，1.82-1.72(1H，m)，1.60-1.46(1H，m)，1.25(3H，t，J＝7.2Hz)，1.09(9H，s)。 1 H NMR (CDCl 3 , 300MHz) 8.07 (1H, d, J = 2.5Hz), 7.67-7.63 (4H, m), 7.41-7.31 (6H, m), 6.97 (1H, d, J = 8.5Hz) , 6.86 (1H, dd, J = 2.8, 8.5Hz), 4.21 (2H, q, J = 7.2Hz), 4.09 (2H, q, J = 7.2Hz), 3.22 (1H, d, J = 13.9Hz) , 3.07(1H, d, J=13.9Hz), 2.53-2.44(1H, m), 2.31-2.15(1H, m), 1.82-1.72(1H, m), 1.60-1.46(1H, m), 1.25 (3H, t, J = 7.2 Hz), 1.09 (9H, s).

制备c-93Preparation c-93

2-[(5-羟基吡啶-2-基)甲基]四氢呋喃-2-羧酸乙酯2-[(5-Hydroxypyridin-2-yl)methyl]tetrahydrofuran-2-carboxylic acid ethyl ester

向2-[(5-{[叔丁基(二苯基)甲硅烷基]氧基}吡啶-2-基)甲基]四氢呋喃-2-羧酸乙酯(制备c-92)(0.5118g，1.1677mmol)的无水四氢呋喃溶液(10mL)中滴加氟化四丁基铵(1.3mL，1.0M四氢呋喃溶液)。所得混合物在室温下搅拌1小时，真空去除挥发物。残留物以快速柱层析(50％乙酸乙酯/己烷至10％甲醇/乙酸乙酯)纯化，得到无色油(0.2321g，79％)。To ethyl 2-[(5-{[tert-butyl(diphenyl)silyl]oxy}pyridin-2-yl)methyl]tetrahydrofuran-2-carboxylate (Preparation c-92) (0.5118g , 1.1677 mmol) in anhydrous THF solution (10 mL) was added dropwise tetrabutylammonium fluoride (1.3 mL, 1.0 M THF solution). The resulting mixture was stirred at room temperature for 1 hour and the volatiles were removed in vacuo. The residue was purified by flash column chromatography (50% ethyl acetate/hexane to 10% methanol/ethyl acetate) to give a colorless oil (0.2321 g, 79%).

LRMS(m/z)：252(M+H)+。LRMS (m/z): 252 (M+H) + .

1H NMR(CDCl3，300MHz)8.10(1H，d，J＝2.3Hz)，7.20(1H，d，J＝8.5Hz)，7.14(1H，dd，J＝2.6，8.5Hz)，4.14(2H，q，J＝7.2Hz)，3.88(2H，q，J＝7.8Hz)，3.35(1H，d，J＝13.9Hz)，3.12(1H，d，J＝13.9Hz)，2.30-2.21(1H，m)，2.04-1.94(1H，m)，1.89-1.76(1H，m)，1.75-1.63(1H，m)，1.20(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 8.10 (1H, d, J = 2.3Hz), 7.20 (1H, d, J = 8.5Hz), 7.14 (1H, dd, J = 2.6, 8.5Hz), 4.14 (2H , q, J=7.2Hz), 3.88(2H, q, J=7.8Hz), 3.35(1H, d, J=13.9Hz), 3.12(1H, d, J=13.9Hz), 2.30-2.21(1H , m), 2.04-1.94 (1H, m), 1.89-1.76 (1H, m), 1.75-1.63 (1H, m), 1.20 (3H, t, J=7.2Hz).

制备c-93aPreparation c-93a

2-[(5-羟基吡啶-2-基)甲基]四氢呋喃-2-羧酸乙酯的另一种制备Another preparation of ethyl 2-[(5-hydroxypyridin-2-yl)methyl]tetrahydrofuran-2-carboxylate

向2-(5-苄氧基-吡啶-2-基甲基)-四氢呋喃-2-羧酸乙酯(0.6065g，1.7765mmol)的无水乙醇溶液(10mL)中加入钯(0.0607g，占活性碳重量的10％)。所得溶液在45℃及氮气流下加热16小时。冷至室温后，溶液通过3”的Celite层过滤，以乙醇(100mL)洗涤。然后将滤出液真空浓缩得粗产物，无需进一步纯化直接使用。Palladium (0.0607 g, % 10% of the weight of activated carbon). The resulting solution was heated at 45°C under nitrogen flow for 16 hours. After cooling to room temperature, the solution was filtered through a 3" layer of Celite, washing with ethanol (100 mL). The filtrate was then concentrated in vacuo to give the crude product, which was used without further purification.

LRMS(m/z)：252(M+H)+。LRMS (m/z): 252 (M+H) + .

1H NMR(CDCl3，400MHz)：8.10(1H，d，J＝2.3Hz)，7.20(1H，d，J＝8.5Hz)，7.14(1H，dd，J＝2.6，8.5Hz)，4.14(2H，q，J＝7.2Hz)，3.88(2H，q，J＝7.8Hz)，3.35(1H，d，J＝13.9Hz)，3.12(1H，d，J＝13.Hz)，2.30-2.21(1H，m)，2.04-1.94(1H，m)，1.89-1.76(1H，m)，1.75-1.63(1H，m)，1.20(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 400 MHz): 8.10 (1H, d, J = 2.3 Hz), 7.20 (1 H, d, J = 8.5 Hz), 7.14 (1 H, dd, J = 2.6, 8.5 Hz), 4.14 ( 2H, q, J = 7.2Hz), 3.88 (2H, q, J = 7.8Hz), 3.35 (1H, d, J = 13.9Hz), 3.12 (1H, d, J = 13.Hz), 2.30-2.21 (1H, m), 2.04-1.94 (1H, m), 1.89-1.76 (1H, m), 1.75-1.63 (1H, m), 1.20 (3H, t, J=7.2Hz).

制备c-94至c-95Preparation c-94 to c-95

制备c-94至c-95使用制备c-93的常规方法进行制备。Preparations c-94 to c-95 were prepared using conventional methods for preparation c-93.

Figure A20048001673601281
Figure A20048001673601281

制备c-96Preparation c-96

2-({5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}甲基)四氢呋喃-2-羧酸乙酯2-({5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}methyl)tetrahydrofuran-2-carboxylic acid ethyl ester

Figure A20048001673601282
Figure A20048001673601282

在氮气流下，向2-[(5-羟基吡啶-2-基)甲基]四氢呋喃-2-羧酸乙酯(制备c-93)(0.2321g，0.9237mmol)、2-(5-甲基-2-苯基-噁唑-4-基)-乙醇(0.2065g，1.0161mmol)及三苯基膦(0.3634g，1.3856mmol)的无水四氢呋喃溶液(10mL)中滴加偶氮二羧酸二乙酯(0.22mL，1.3856mmol)的无水四氢呋喃溶液(1mL)。所得溶液在室温下搅拌16小时，真空去除挥发物。然后以快速柱层析(己烷至50％乙酸乙酯/己烷)纯化该残留物，得到浅黄色油(0.2618g，65％)。2-[(5-Hydroxypyridin-2-yl)methyl]tetrahydrofuran-2-carboxylic acid ethyl ester (preparation c-93) (0.2321 g, 0.9237 mmol), 2-(5-methyl -2-Phenyl-oxazol-4-yl)-ethanol (0.2065g, 1.0161mmol) and triphenylphosphine (0.3634g, 1.3856mmol) in anhydrous THF solution (10mL) was added dropwise azodicarboxylic acid Diethyl ester (0.22 mL, 1.3856 mmol) in anhydrous THF (1 mL). The resulting solution was stirred at room temperature for 16 hours and the volatiles were removed in vacuo. The residue was then purified by flash column chromatography (hexanes to 50% ethyl acetate/hexanes) to give a pale yellow oil (0.2618 g, 65%).

LRMS(m/z)：437(M+H)+。LRMS (m/z): 437 (M+H) + .

1H NMR(CDCl3，300MHz)8.20(AH，d，J＝2.8Hz)，7.99(1H，d，J＝2.5Hz)，7.96(1H，d，J＝1.7Hz)，7.70-7.64(1H，m)，7.49-7.39(2H，m)，7.19(1H，d，J＝8.5Hz)，7.11(1H，dd，J＝3.0，8.5Hz)，4.26(2H，t，J＝6.6Hz)，4.17(2H，q，J＝7.2Hz)，3.95-3.81(2H，m)，3.33(1H，d，J＝13.8Hz)，3.16(1H，d，J＝13.8Hz)，2.98(2H，t，J＝6.6Hz)，2.37(3H，s)，2.34-2.22(1H，m)，2.09-2.00(1H，m)，1.87-1.76(1H，m)，1.72-1.62(1H，m)，1.23(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz) 8.20 (AH, d, J=2.8Hz), 7.99 (1H, d, J=2.5Hz), 7.96 (1H, d, J=1.7Hz), 7.70-7.64 (1H , m), 7.49-7.39 (2H, m), 7.19 (1H, d, J=8.5Hz), 7.11 (1H, dd, J=3.0, 8.5Hz), 4.26 (2H, t, J=6.6Hz) , 4.17(2H, q, J=7.2Hz), 3.95-3.81(2H, m), 3.33(1H, d, J=13.8Hz), 3.16(1H, d, J=13.8Hz), 2.98(2H, t, J=6.6Hz), 2.37(3H, s), 2.34-2.22(1H, m), 2.09-2.00(1H, m), 1.87-1.76(1H, m), 1.72-1.62(1H, m) , 1.23 (3H,t,J=7.2Hz).

制备c-97至c-112Preparation C-97 to C-112

制备c-97至c-112使用制备c-96的常规方法进行制备。Preparations c-97 to c-112 were prepared using the conventional methods for preparing c-96.

Figure A20048001673601311
Figure A20048001673601311

制备c-113Preparation c-113

3-(5-甲基-2-苯基-噁唑-4-基)-丙醛3-(5-Methyl-2-phenyl-oxazol-4-yl)-propionaldehyde

Figure A20048001673601321
Figure A20048001673601321

向3-(5-甲基-2-苯基-噁唑-4-基)-丙-1-醇(1.0g，4.6026mmol)的二氯甲烷(20mL)溶液中加入氯铬酸吡啶鎓(9.9213g，占SiO2重量的～20％，9.2051mmol)。在室温及氮气流下，将所得混合物搅拌16小时，减压去除挥发物。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到无色油状的纯醛(0.4752g，48％)。To a solution of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propan-1-ol (1.0 g, 4.6026 mmol) in dichloromethane (20 mL) was added pyridinium chlorochromate ( 9.9213 g, ~20% by weight of SiO2 , 9.2051 mmol). The resulting mixture was stirred at room temperature under nitrogen flow for 16 h, and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give pure aldehyde (0.4752 g, 48%) as a colorless oil.

LRMS(m/z)：216(M+H)+。LRMS (m/z): 216 (M+H) + .

1H NMR(CDCl3，300MHz)：9.84(1H，s)，7.96-7.93(2H，m)，7.42-7.37(3H，m)，2.85(2H，dd，J＝6.0，0.9Hz)，2.80(2H，d，J＝6.0Hz)，2.33(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 9.84 (1H, s), 7.96-7.93 (2H, m), 7.42-7.37 (3H, m), 2.85 (2H, dd, J=6.0, 0.9Hz), 2.80 (2H, d, J = 6.0 Hz), 2.33 (3H, s).

制备c-114Preparation c-114

4-丁-3-烯基-5-甲基-2-苯基-噁唑4-but-3-enyl-5-methyl-2-phenyl-oxazole

Figure A20048001673601322
Figure A20048001673601322

在0℃及氮气流下，向碘化甲基三苯基鏻(1.7848g，4.4154mmol)的无水四氢呋喃溶液(95mL)中滴加丁基锂(1.8mL，2，5M己烷溶液，4.4154mmol)。悬液溶解呈橙色。10分钟后，滴加3-(5-甲基-2-苯基-噁唑-4-基)-丙醛(0.4752g，2.2077mmol)的无水四氢呋喃溶液(15mL)，将溶液温热至室温。16小时后，加入己烷(200mL)、过滤出沉淀。然后以水(200mL)萃取过滤物，干燥有机相(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到无色油状的纯标题化合物(0.291g，62％)。To a solution of methyltriphenylphosphonium iodide (1.7848g, 4.4154mmol) in anhydrous tetrahydrofuran (95mL) was added dropwise butyllithium (1.8mL, 2,5M hexane solution, 4.4154mmol) at 0°C under nitrogen flow. ). The suspension turns orange when dissolved. After 10 minutes, a solution of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propionaldehyde (0.4752 g, 2.2077 mmol) in anhydrous THF (15 mL) was added dropwise and the solution was warmed to room temperature. After 16 hours, hexane (200 mL) was added and the precipitate was filtered off. The filtrate was then extracted with water (200 mL), the organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexane to ethyl acetate) to give the pure title compound (0.291 g, 62%) as a colorless oil.

LRMS(m/z)：214(M+H)+。LRMS (m/z): 214 (M+H) + .

1H NMR(CDCl3，300MHz)：7.99-7.96(2H.m)，7.43-7.38(3H，m)，5.93-5.79(1H，m)，5.09-5.02(1H，m)，5.00-4.95(1H，m)，2.57(2H，t，J＝7.4Hz)，2.42(2H，t，J＝7.4Hz)，2.31(3H，s)。 1 H NMR (CDCl 3 , 300MHz): 7.99-7.96 (2H.m), 7.43-7.38 (3H, m), 5.93-5.79 (1H, m), 5.09-5.02 (1H, m), 5.00-4.95 ( 1H, m), 2.57 (2H, t, J = 7.4Hz), 2.42 (2H, t, J = 7.4Hz), 2.31 (3H, s).

制备c-115Preparation c-115

2-{6-[4-(5-甲基-2-苯基-噁唑-4-基)-丁基]-吡啶-3-基甲基}-四氢呋喃-2-羧酸乙酯2-{6-[4-(5-Methyl-2-phenyl-oxazol-4-yl)-butyl]-pyridin-3-ylmethyl}-tetrahydrofuran-2-carboxylic acid ethyl ester

将9-硼杂二环壬烷(5.5mL，0.5M的四氢呋喃溶液，2.729mmol)加入至4-丁-3-烯基-5-甲基-2-苯基-噁唑(0.291g，1.3645mmol)的无水四氢呋喃黄色溶液(1.3mL)中。在室温下搅拌混合物4小时，然后转入另一盛有2-(6-溴-吡啶-3-基甲基)-四氢呋喃-2-羧酸乙酯(0.3297g，1.0496mmol)、二(二苯膦基)二茂铁二氯化钯(0.0857g，0.1050mmol)、碳酸铯(0.9551g，2.9389mmol)、三苯胂(0.0322g，0.1050mmol)的N，N-二甲基甲酰胺(2.8mL)及水(0.23mL)溶液的烧瓶中。在室温及氮气流下，搅拌暗红色混合物16小时。冷至0℃后，反应以2M乙酸钠溶液(5mL)及30％过氧化氢溶液(2mL)终止。将所得溶液搅拌2小时，以水(25mL)稀释，乙酸乙酯萃取(4×50mL)。合并有机萃取物，以水(25mL)洗涤、干燥(无水硫酸镁)、过滤，真空浓缩得粗产物。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到浅黄色油状的标题化合物(0.2805g，60％)。9-Borabicyclononane (5.5 mL, 0.5 M in THF, 2.729 mmol) was added to 4-but-3-enyl-5-methyl-2-phenyl-oxazole (0.291 g, 1.3645 mmol) in anhydrous tetrahydrofuran yellow solution (1.3 mL). The mixture was stirred at room temperature for 4 hours, then transferred to another container containing ethyl 2-(6-bromo-pyridin-3-ylmethyl)-tetrahydrofuran-2-carboxylate (0.3297 g, 1.0496 mmol), bis(di N,N-dimethylformamide ( 2.8mL) and water (0.23mL) solution in the flask. The dark red mixture was stirred at room temperature under nitrogen flow for 16 hours. After cooling to 0°C, the reaction was quenched with 2M sodium acetate solution (5 mL) and 30% hydrogen peroxide solution (2 mL). The resulting solution was stirred for 2 hours, diluted with water (25 mL), and extracted with ethyl acetate (4 x 50 mL). The organic extracts were combined, washed with water (25 mL), dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexane to ethyl acetate) to give the title compound (0.2805 g, 60%) as a pale yellow oil.

LRMS(m/z)：449(M+H)+。LRMS (m/z): 449 (M+H) + .

1H NMR(CDCl3，300MHz)：8.34(1H，d，J＝1.9Hz)，7.95(2H，dd，J＝7.7，1.9Hz)，7.52(1H，dd，J＝8.0，2.2Hz)，7.42-7.36(3H，m)，7.04(1H，d，J＝7.9Hz)，4.13(2H，q，J＝7.2Hz)，3.96-3.84(2H，m)，3.16(1H，d，J＝13.9Hz)，2.90(1H，d，J＝13.9Hz)，2.77(2H，t，J＝7.3Hz)，2.50(2H，t，J＝6.9Hz)，2.31-2.19(1H，m)，2.28(3H，s)，1.92-1.64(7H，m)，1.20(3H，t，J＝7.2Hz)。 1 H NMR (CDCl 3 , 300MHz): 8.34 (1H, d, J=1.9Hz), 7.95 (2H, dd, J=7.7, 1.9Hz), 7.52 (1H, dd, J=8.0, 2.2Hz), 7.42-7.36 (3H, m), 7.04 (1H, d, J = 7.9Hz), 4.13 (2H, q, J = 7.2Hz), 3.96-3.84 (2H, m), 3.16 (1H, d, J = 13.9Hz), 2.90(1H, d, J=13.9Hz), 2.77(2H, t, J=7.3Hz), 2.50(2H, t, J=6.9Hz), 2.31-2.19(1H, m), 2.28 (3H, s), 1.92-1.64 (7H, m), 1.20 (3H, t, J=7.2Hz).

制备c-116Preparation c-116

2-{6-[3-(5-甲基-2-苯基-噁唑-4-基)-丙基]-吡啶-3-基甲基}-四氢呋喃-2-羧酸乙酯2-{6-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-pyridin-3-ylmethyl}-tetrahydrofuran-2-carboxylic acid ethyl ester

Figure A20048001673601332
Figure A20048001673601332

将9-硼杂二环壬烷(4.2mL，0.5M四氢呋喃溶液，2.07mmol)加入至4-烯丙基-5-甲基-2-苯基-噁唑(0.21g，1.04mmol)的无水四氢呋喃黄色溶液(1mL)中。将混合物在室温下搅拌4小时，然后转入另一盛有2-(6-溴-吡啶-3-基甲基)-四氢呋喃-2-羧酸乙酯(0.25g，0.80mmol)、双(二苯膦基)二茂铁二氯化钯(0.07g，0.1mmol)、碳酸铯(0.72g，2.90mmol)、三苯胂(0.02g，0.1mmol)的N，N-二甲基甲酰胺∶水(4∶1，2.63mL)溶液的烧瓶中。将暗红色混合物在室温及氮气流下搅拌16小时。冷至0℃后，反应以2M乙酸钠溶液(4.7mL)及30％过氧化氢水溶液(1.7mL)终止。将所得溶液搅拌2小时，以水(20mL)稀释，乙酸乙酯萃取(4×50mL)。合并的有机萃取物以水(20mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(40％～90％乙酸乙酯/己烷)纯化，得到无色油状的标题化合物(0.20g，57％)。9-Borabicyclononane (4.2 mL, 0.5M solution in tetrahydrofuran, 2.07 mmol) was added to 4-allyl-5-methyl-2-phenyl-oxazole (0.21 g, 1.04 mmol) without into a yellow solution (1 mL) in tetrahydrofuran in water. The mixture was stirred at room temperature for 4 hours, then transferred to another container containing ethyl 2-(6-bromo-pyridin-3-ylmethyl)-tetrahydrofuran-2-carboxylate (0.25 g, 0.80 mmol), bis( Diphenylphosphino)ferrocenepalladium dichloride (0.07g, 0.1mmol), cesium carbonate (0.72g, 2.90mmol), triphenylarsine (0.02g, 0.1mmol) in N,N-dimethylformamide : water (4:1, 2.63mL) solution in a flask. The dark red mixture was stirred at room temperature under nitrogen flow for 16 hours. After cooling to 0°C, the reaction was quenched with 2M sodium acetate solution (4.7 mL) and 30% aqueous hydrogen peroxide (1.7 mL). The resulting solution was stirred for 2 hours, diluted with water (20 mL), and extracted with ethyl acetate (4 x 50 mL). The combined organic extracts were washed with water (20 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (40%-90% ethyl acetate/hexane) to give the title compound (0.20 g, 57%) as a colorless oil.

LRMS(m/z)：435(M+H)+。LRMS (m/z): 435 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.35(1H，s)，7.96(2H，d，J＝7.9Hz)，7.55(1H，d，J＝8.3Hz)，7.39(3H，t，J＝5.9Hz)，7.09(1H，d，J＝8.1Hz)，3.91(2H，m)，3.80(2H，t，J＝10.9Hz)，3.17(1H，d，J＝14.0Hz)，2.91(1H，d，J＝13.94Hz)，2.81(2H，t)，2.53(2H，t，J＝7.3Hz)，2.28(3H，s)，2.09(2H，d，J＝7.5Hz)，1.87(4H，d，J＝10.9Hz)，1.23(3H，m)。 1 H NMR (DMSO-d 6 , 400MHz): 8.35 (1H, s), 7.96 (2H, d, J = 7.9Hz), 7.55 (1H, d, J = 8.3Hz), 7.39 (3H, t, J =5.9Hz), 7.09(1H, d, J=8.1Hz), 3.91(2H, m), 3.80(2H, t, J=10.9Hz), 3.17(1H, d, J=14.0Hz), 2.91( 1H, d, J = 13.94Hz), 2.81 (2H, t), 2.53 (2H, t, J = 7.3Hz), 2.28 (3H, s), 2.09 (2H, d, J = 7.5Hz), 1.87 ( 4H, d, J = 10.9 Hz), 1.23 (3H, m).

制备c-117Preparation c-117

1-{4-[(1E)-3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙-1-烯-1-基]苯氧基}环丁烷羧酸乙酯1-{4-[(1E)-3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)prop-1-en-1-yl]phenoxy}cyclobutane Ethyl alkane carboxylate

Figure A20048001673601341
Figure A20048001673601341

将Pd(OAc)2(12mg，0.05mmol)及Ph3P(26mg，0.05mmol)的甲苯混和溶液(2mL)在氮气及室温下搅拌1小时，然后加入Et3N(2mL)及4-烯丙基-5-甲基-2-苯基-1，3-噁唑(100mg，0.50mmol)和1-(4-碘苯氧基)环丁烷羧酸乙酯(173mg，0.50mmol)的甲苯溶液(2mL)。将所得反应溶液在80℃及氮气下加热17小时，冷至室温。去除溶剂后，将残留物分配于EtOAc与盐水溶液中。分离的有机层以盐水溶液洗涤，Na2SO4干燥，浓缩得棕色油状粗产物。产物硅胶柱纯化，使用20％EtOAc己烷溶液洗脱，得到85mg(41％)黄色油。A mixed solution of Pd(OAc) 2 (12 mg, 0.05 mmol) and Ph 3 P (26 mg, 0.05 mmol) in toluene (2 mL) was stirred under nitrogen at room temperature for 1 hour, then Et 3 N (2 mL) and 4-ene were added Propyl-5-methyl-2-phenyl-1,3-oxazole (100mg, 0.50mmol) and ethyl 1-(4-iodophenoxy)cyclobutanecarboxylate (173mg, 0.50mmol) Toluene solution (2 mL). The resulting reaction solution was heated at 80°C under nitrogen for 17 hours and cooled to room temperature. After removal of solvent, the residue was partitioned between EtOAc and brine solution. The separated organic layer was washed with brine solution, dried over Na2SO4 , and concentrated to afford crude product as brown oil . The product was purified on a silica gel column eluting with 20% EtOAc in hexanes to afford 85 mg (41%) of a yellow oil.

1H NMR(400MHz，CDCl3)1.19(t，3H)，1.98(m，2H)，2.38(s，3H)，2.43(m，2H)，2.72(m，2H)，3.41(d，2H)，4.18(q，2H)，6.20(td，1H)，6.40(d，1H)，6.60(d，2H)，7.25(d，2H)，7.40(d，3H)，8.00(d，2H)。 1 H NMR (400MHz, CDCl 3 ) 1.19(t, 3H), 1.98(m, 2H), 2.38(s, 3H), 2.43(m, 2H), 2.72(m, 2H), 3.41(d, 2H) , 4.18(q, 2H), 6.20(td, 1H), 6.40(d, 1H), 6.60(d, 2H), 7.25(d, 2H), 7.40(d, 3H), 8.00(d, 2H).

LRMS(m/z)：418(M+H)+。LRMS (m/z): 418 (M+H) + .

制备c-118Preparation c-118

1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙基]苯氧基}环丁烷羧酸乙酯Ethyl 1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propyl]phenoxy}cyclobutanecarboxylate

将1-{4-[(1E)-3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙-1-烯-1-基]苯氧基}环丁烷羧酸乙酯(85mg，0.20mmol)溶于MeOH(5mL)，然后加入10％Pd/C(15mg)。将一个充满氮气的气球与烧瓶相连，混合物在室温下搅拌16小时。将混合物通过Celite过滤，块状物以MeOH冲洗。浓缩滤出液，得到85mg(100％)黄色油。The 1-{4-[(1E)-3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)prop-1-en-1-yl]phenoxy}ring Ethyl butanecarboxylate (85 mg, 0.20 mmol) was dissolved in MeOH (5 mL), then 10% Pd/C (15 mg) was added. A nitrogen-filled balloon was attached to the flask, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite and the cake was rinsed with MeOH. The filtrate was concentrated to afford 85 mg (100%) of a yellow oil.

1H NMR(400MHz，CDCl3)1.19(t，3H)，1.92-2.02(m，4H)，2.27(s，3H)，2.39-2.51(m，4H)，2.60(t，2H)，2.66-2.77(m，2H)，4.19(q，2H)，6.60(d，2H)，7.05(d，2H)，7.36-7.47(m，3H)，7.98(dd，2H)。 1 H NMR (400MHz, CDCl 3 ) 1.19(t, 3H), 1.92-2.02(m, 4H), 2.27(s, 3H), 2.39-2.51(m, 4H), 2.60(t, 2H), 2.66- 2.77 (m, 2H), 4.19 (q, 2H), 6.60 (d, 2H), 7.05 (d, 2H), 7.36-7.47 (m, 3H), 7.98 (dd, 2H).

LRMS(m/z)：420(M+H)+。LRMS (m/z): 420 (M+H) + .

制备c-119Preparation c-119

5-溴-吡嗪-2-基胺5-Bromo-pyrazin-2-ylamine

Figure A20048001673601352
Figure A20048001673601352

在0℃下，向吡嗪-2-基胺(2.0g，21.03mmol)的无水二氯甲烷溶液(120mL)中缓慢加入N-溴代琥珀酰亚胺(3.74g，21.03mmol)，保持内温在0℃以下。在同一温度下搅拌混合物24小时，然后以饱和碳酸氢钠溶液(30mL)及水(30mL)洗涤。合并的萃取物水溶液以二氯甲烷萃取(3×100mL)。合并有机萃取物、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(10％～50％乙酸乙酯/己烷)纯化得黄色固体的标题化合物(2.57g，70％)。To a solution of pyrazin-2-ylamine (2.0 g, 21.03 mmol) in anhydrous dichloromethane (120 mL) was slowly added N-bromosuccinimide (3.74 g, 21.03 mmol) at 0°C, keeping The internal temperature is below 0°C. The mixture was stirred at the same temperature for 24 hours, then washed with saturated sodium bicarbonate solution (30 mL) and water (30 mL). The combined aqueous extracts were extracted with dichloromethane (3 x 100 mL). The organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give crude product. The residue was purified by flash column chromatography (10%-50% ethyl acetate/hexane) to obtain the title compound (2.57 g, 70%) as a yellow solid.

LRMS(m/z)：174(M)- LRMS(m/z): 174(M) -

1H NMR(CDCl3，300MHz)：8.08(1H，d，J＝1.3Hz)，7.76(1H，d，J＝1.3Hz)。 1 H NMR (CDCl 3 , 300 MHz): 8.08 (1H, d, J = 1.3 Hz), 7.76 (1 H, d, J = 1.3 Hz).

制备c-120Preparation c-120

5-溴-吡嗪-2-醇5-Bromo-pyrazin-2-ol

Figure A20048001673601353
Figure A20048001673601353

在0℃下，将亚硝酸钠(1.35g，19.53mmol)分次加入浓硫酸(9.8mL)中。在50℃加热混合物，直至所有亚硝酸钠溶解，将混合物再次冷至0℃。在0℃下，将5-溴-吡嗪-2-基胺(2.57g，14.68mmol)的浓硫酸溶液(14.7mL)滴加入硝鎓离子溶液中。移去冰浴，将混合物加热至室温，搅拌15分钟后，加热至45℃，保温7分钟。冷至室温后，将混合物缓慢小心地倒入碎冰水(100mL)中。水相以20％氢氧化钠溶液中和至pH 4，然后以乙酸乙酯萃取(3×100mL)。合并的有机萃取物以水(50mL)洗涤、干燥(无水硫酸镁)、过滤并浓缩得黄色固体的标题化合物(1.88g，73％)。Sodium nitrite (1.35 g, 19.53 mmol) was added portionwise to concentrated sulfuric acid (9.8 mL) at 0°C. The mixture was heated at 50°C until all the sodium nitrite had dissolved and the mixture was cooled to 0°C again. A solution of 5-bromo-pyrazin-2-ylamine (2.57 g, 14.68 mmol) in concentrated sulfuric acid (14.7 mL) was added dropwise to the nitronium ion solution at 0°C. The ice bath was removed, the mixture was warmed to room temperature, stirred for 15 minutes, then heated to 45°C for 7 minutes. After cooling to room temperature, the mixture was slowly and carefully poured into crushed ice water (100 mL). The aqueous phase was neutralized to pH 4 with 20% sodium hydroxide solution, then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to give the title compound as a yellow solid (1.88 g, 73%).

1H NMR(CDCl3，300MHz)：8.07(1H，s)，7.62(1H，d，J＝3.0Hz)。 1 H NMR (CDCl 3 , 300 MHz): 8.07 (1H, s), 7.62 (1H, d, J = 3.0 Hz).

制备c-121Preparation c-121

2-(叔丁基-二甲基-甲硅烷氧甲基)-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪2-(tert-butyl-dimethyl-silyloxymethyl)-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine

Figure A20048001673601361
Figure A20048001673601361

向2-溴-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪(0.50g，1.39mmol)及叔丁基-二甲基-三丁基甲锡烷基甲氧基-甲硅烷(0.91g，2.09mmol)的无水1，4-二噁烷溶液(8mL)中加入四(三苯基)膦(0)钯(0.16g，0.14mmol)。将混合物脱气3次，然后在120℃加热22小时。冷至室温后，混合物以乙醚(10mL)稀释，然后以饱和氟化钾溶液(5mL)终止反应。将所得混合物搅拌30分钟，然后以乙酸乙酯萃取(3×50mL)。有机相以水(30mL)洗涤、干燥(无水硫酸镁)、过滤并浓缩得标题化合物，无需进一步纯化。To 2-bromo-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazine (0.50g, 1.39mmol) and tert-butyl-dimethyl Tetrakis(triphenyl)phosphine(0)palladium (0.16g , 0.14 mmol). The mixture was degassed 3 times and then heated at 120 °C for 22 hours. After cooling to room temperature, the mixture was diluted with ether (10 mL), then quenched with saturated potassium fluoride solution (5 mL). The resulting mixture was stirred for 30 minutes, then extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with water (30 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to give the title compound without further purification.

LRMS(m/z)：426(M+H)+。LRMS (m/z): 426 (M+H) + .

1H NMR(CDCl3，300MHz)：8.20(1H，s)，8.09(1H，s)，7.97(2H，d，J＝7.4Hz)，7.41(3H，d，J＝5.3Hz)，4.78(2H，s)，4.58(2H，d，J＝6.6Hz)，2.98(2H，s)，2.34(3H，s)，0.97(2H，m)，0.14(6H，m)。 1 H NMR (CDCl 3 , 300 MHz): 8.20 (1H, s), 8.09 (1H, s), 7.97 (2H, d, J = 7.4 Hz), 7.41 (3H, d, J = 5.3 Hz), 4.78 ( 2H, s), 4.58 (2H, d, J = 6.6 Hz), 2.98 (2H, s), 2.34 (3H, s), 0.97 (2H, m), 0.14 (6H, m).

制备c-122Preparation c-122

{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪-2-基}-甲醇{5-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-yl}-methanol

Figure A20048001673601362
Figure A20048001673601362

将氟化四丁基铵(2.8mL，1M四氢呋喃溶液，2.78mmol)滴加入2-(叔丁基-二甲基-甲硅烷氧甲基)-5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪(～1.39mmol)的无水四氢呋喃溶液(20mL)中。将混合物在室温下搅拌16小时，然后以水(1mL)终止反应，以1M乙酸溶液酸化pH至5。真空浓缩去除有机物，水相以二氯甲烷萃取(3×50mL)。合并有机萃取物、干燥(无水硫酸镁)、过滤并真空浓缩得标题化合物(0.0928g，21％)。Tetrabutylammonium fluoride (2.8 mL, 1M solution in tetrahydrofuran, 2.78 mmol) was added dropwise to 2-(tert-butyl-dimethyl-silyloxymethyl)-5-[2-(5-methyl-2 -Phenyl-oxazol-4-yl)-ethoxy]-pyrazine (~1.39 mmol) in dry THF (20 mL). The mixture was stirred at room temperature for 16 hours, then quenched with water (1 mL) and acidified to pH 5 with 1M acetic acid solution. Concentrate in vacuo to remove organics and extract the aqueous phase with dichloromethane (3 x 50 mL). The organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the title compound (0.0928 g, 21%).

LRMS(m/z)：312(M+H)+。LRMS (m/z): 312 (M+H) + .

1H NMR(CDCl3，300MHz)：8.12(2H，s)，8.05(2H，d，J＝6.0Hz)，7.40(3H，d，J＝6.0Hz)，4.72(2H，s)，4.59(2H，t，J＝6.0Hz)，2.99(2H，t，J＝6.0Hz)，2.33(3H，s)。 1 H NMR (CDCl 3 , 300 MHz): 8.12 (2H, s), 8.05 (2H, d, J = 6.0 Hz), 7.40 (3H, d, J = 6.0 Hz), 4.72 (2H, s), 4.59 ( 2H, t, J = 6.0 Hz), 2.99 (2H, t, J = 6.0 Hz), 2.33 (3H, s).

制备c-123Preparation c-123

6-苄氧基-萘-2-羧酸苄酯Benzyl 6-benzyloxy-naphthalene-2-carboxylate

Figure A20048001673601371
Figure A20048001673601371

上述化合物按照Inui，S.；Suzuki，T.；limura，N.；Iwane，H.；Nohira，H.Mol Cryst.Liq.Cryst.Sci.Technol.Sect.A.1994，239，1-10中所述的方法进行制备。The above-mentioned compound according to Inui, S.; Suzuki, T.; limura, N.; Iwane, H.; Nohira, H. Mol Cryst. Prepared according to the method described.

制备c-124Preparation c-124

(6-苄氧基-萘-2-基)-甲醇(6-Benzyloxy-naphthalen-2-yl)-methanol

Figure A20048001673601372
Figure A20048001673601372

在0℃下氮气流下，向6-苄氧基-萘-2-羧酸苄酯(7.09g，19.24mmol)的无水四氢呋喃溶液(60mL)中加入二异丁基氢化铝(58mL，1.0M四氢呋喃溶液，57.73mmol)。将所得混合物温热至室温，搅拌16小时。滴加入柠檬酸(19g)的水溶液(40mL)(小心！剧烈放热)。然后以乙酸乙酯萃取水层(3×50mL)，合并的有机萃取物以饱和氯化钠水溶液(50mL)洗涤、干燥(无水硫酸镁)，真空浓缩得粗产物。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到标题化合物(4.37g，86％)，为白色固体。To a solution of benzyl 6-benzyloxy-naphthalene-2-carboxylate (7.09 g, 19.24 mmol) in anhydrous tetrahydrofuran (60 mL) was added diisobutylaluminum hydride (58 mL, 1.0 M solution in tetrahydrofuran, 57.73 mmol). The resulting mixture was warmed to room temperature and stirred for 16 hours. A solution of citric acid (19 g) in water (40 mL) was added dropwise (caution! violent exotherm). The aqueous layer was then extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (hexane to ethyl acetate) to afford the title compound (4.37 g, 86%) as a white solid.

LRMS(m/z)：287(M+Na)+。LRMS (m/z): 287 (M+Na) + .

1H NMR(CDCl3，400MHz)：7.76-7.72(3H，m)，7.50-7.33(6H，m)，7.25-7.23(2H，m)，5.18(2H，s)，4.82(2H，d，J＝6.1Hz)。 1 H NMR (CDCl 3 , 400MHz): 7.76-7.72 (3H, m), 7.50-7.33 (6H, m), 7.25-7.23 (2H, m), 5.18 (2H, s), 4.82 (2H, d, J = 6.1 Hz).

制备c-125Preparation c-125

2-[6-(5-甲基-2-苯基-噁唑-4-基甲氧基)-萘-2-基甲基]-四氢-呋喃-2-羧酸乙酯2-[6-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-naphthalene-2-ylmethyl]-tetrahydro-furan-2-carboxylic acid ethyl ester

Figure A20048001673601381
Figure A20048001673601381

将2-苯基-4-(氯甲基)-5-甲基噁唑(0.133g，0.639mmol)、2-(6-羟基-萘-2-基甲基)-四氢呋喃-2-羧酸乙酯(0.192g，0.639mmol)及碳酸铯(0.521g，1.59mmol)的无水乙腈非均匀混合物(2mL)在140℃加热(在微波炉中)10分钟。加入第二份2-苯基-4-(氯甲基)-5-甲基噁唑(0.5当量)，将混合物在200℃进一步加热20分钟。将反应混合物通过Celite过滤，乙腈(200mL)洗涤。真空浓缩滤液，残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到无色油状的标题化合物(0.180g，60％)。2-Phenyl-4-(chloromethyl)-5-methyloxazole (0.133g, 0.639mmol), 2-(6-hydroxy-naphthalen-2-ylmethyl)-tetrahydrofuran-2-carboxylic acid A heterogeneous mixture of ethyl ester (0.192 g, 0.639 mmol) and cesium carbonate (0.521 g, 1.59 mmol) in anhydrous acetonitrile (2 mL) was heated (in microwave) at 140 °C for 10 min. A second portion of 2-phenyl-4-(chloromethyl)-5-methyloxazole (0.5 equiv) was added and the mixture was heated at 200°C for a further 20 minutes. The reaction mixture was filtered through Celite, washing with acetonitrile (200 mL). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the title compound (0.180 g, 60%) as a colorless oil.

制备c-126Preparation c-126

(4S)-4-苄基-3-(四氢呋喃-2-基羰基)-1，3-噁唑烷-2-酮(4S)-4-Benzyl-3-(tetrahydrofuran-2-ylcarbonyl)-1,3-oxazolidin-2-one

Figure A20048001673601382
Figure A20048001673601382

在-78℃下，将正丁基锂(22.6mL，2.5M己烷溶液，56.4mmol)滴加入(4S)-4-苄基-1，3-噁唑烷-2-酮(10.0g，56.4mmol)的四氢呋喃溶液(200mL)中。将混合物搅拌30分钟，然后加入四氢呋喃-2-甲酰氯(9.12g，67.7mmol)的四氢呋喃溶液(25mL)。将混合物在-78℃下搅拌30分钟，1小时升温至0℃，以饱和氯化铵水溶液终止反应。以乙酸乙酯萃取混合物，将有机相以盐水溶液洗涤、硫酸镁干燥、过滤并浓缩。残留物以快速柱层析(先1∶3，然后1∶2的乙酸乙酯∶己烷)纯化，得到无色油状的标题化合物(15.0g，97％)，为约1∶1的非对映异构体混合物。At -78°C, n-butyllithium (22.6mL, 2.5M hexane solution, 56.4mmol) was added dropwise to (4S)-4-benzyl-1,3-oxazolidin-2-one (10.0g, 56.4mmol) in THF solution (200mL). The mixture was stirred for 30 minutes, then a solution of tetrahydrofuran-2-carbonyl chloride (9.12 g, 67.7 mmol) in tetrahydrofuran (25 mL) was added. The mixture was stirred at -78°C for 30 minutes, warmed to 0°C for 1 hour, and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, the organic phase was washed with brine solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (1:3, then 1:2 ethyl acetate:hexanes) to give the title compound (15.0 g, 97%) as a colorless oil in about 1:1 Enantiomer mixture.

制备c-127Preparation c-127

(4S)-4-苄基-3-{[2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-基]羰基}-1，3-噁唑烷-2-酮(4S)-4-Benzyl-3-{[2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine- 3-yl}methyl)tetrahydrofuran-2-yl]carbonyl}-1,3-oxazolidin-2-one

Figure A20048001673601391
Figure A20048001673601391

在-50℃下将(双)三甲基甲硅烷基胺基钠(3.57mL，1M四氢呋喃溶液，3.57mmol)滴加至(4S)-4-苄基-3-(四氢呋喃-2-基羰基)-1，3-噁唑烷-2-酮(0.983g，3.57mmol)的无水四氢呋喃溶液(6mL)中。将混合物搅拌45分钟，然后滴加5-(碘甲基)-2-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶(制备28)(0.500g，1.19mmol)的无水四氢呋喃溶液(6mL)。将所得混合物在-50℃下搅拌1.5小时，然后以饱和氯化铵水溶液终止反应，温热至室温。以乙酸乙酯萃取混合物，干燥有机相(无水硫酸镁)、过滤并浓缩。残留物以快速柱层析(1∶1乙酸乙酯∶己烷)纯化，得到无色油状的单一非对映异构体的标题化合物(0.617g，90％)。Sodium (bis)trimethylsilylamide (3.57 mL, 1M solution in tetrahydrofuran, 3.57 mmol) was added dropwise to (4S)-4-benzyl-3-(tetrahydrofuran-2-ylcarbonyl) at -50 °C )-1,3-oxazolidin-2-one (0.983g, 3.57mmol) in anhydrous THF solution (6mL). The mixture was stirred for 45 minutes, then 5-(iodomethyl)-2-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridine was added dropwise ( A solution of 28) (0.500 g, 1.19 mmol) in anhydrous tetrahydrofuran (6 mL) was prepared. The resulting mixture was stirred at -50°C for 1.5 hours, then quenched with saturated aqueous ammonium chloride and allowed to warm to room temperature. The mixture was extracted with ethyl acetate, the organic phase was dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by flash column chromatography (1:1 ethyl acetate:hexanes) to afford the title compound (0.617 g, 90%) as a single diastereoisomer as a colorless oil.

LRMS(m/z)：568(M+H)+。LRMS (m/z): 568 (M+H) + .

1H NMR(CDCl3，300MHz)8.01(1H，s)，7.96(2H，m)，7.61(1H，dd，J＝2.5，8.5Hz)，7.40(3H，m)，7.28(3H，m)，7.17(1H，m)，6.64(1H，d，J＝8.6Hz)，4.55(3H，m)，4.18(2H，m)，3.90(1H，m)，3.79(1H，m)，3.27(1H，d，J＝14Hz)，3.20(1H，m)，3.13(1H，d，J＝14Hz)，2.96(2H，t，J＝6.8Hz)，2.79(1H，m)，2.32(3H，s)，2.34(3H，m)，2.11(1H，m)，1.73(1H，m)，1.54(1H，m) 1 H NMR (CDCl 3 , 300MHz) 8.01 (1H, s), 7.96 (2H, m), 7.61 (1H, dd, J=2.5, 8.5Hz), 7.40 (3H, m), 7.28 (3H, m) , 7.17(1H, m), 6.64(1H, d, J=8.6Hz), 4.55(3H, m), 4.18(2H, m), 3.90(1H, m), 3.79(1H, m), 3.27( 1H, d, J=14Hz), 3.20(1H, m), 3.13(1H, d, J=14Hz), 2.96(2H, t, J=6.8Hz), 2.79(1H, m), 2.32(3H, s), 2.34(3H,m), 2.11(1H,m), 1.73(1H,m), 1.54(1H,m)

制备c-128Preparation c-128

四氢呋喃-2-羧酸酰胺Tetrahydrofuran-2-carboxamide

Figure A20048001673601392
Figure A20048001673601392

在0℃氮气流下，向四氢呋喃-2-羧酸(2.42g，20.82mmol)的无水四氢呋喃溶液中(120mL)加入三乙胺(8.5mL，61.23mmol)及氯甲酸乙酯(2.4mL，25.10mmol)。加入氯甲酸乙酯后形成白色沉淀，在0℃下将所得混合物搅拌45分钟。将氨气通入溶液2小时，移除气源。然后将反应混合物温热至室温，搅拌16小时。加入1N盐酸溶液调pH至1，然后以乙酸乙酯萃取(3×50mL)。合并有机萃取物，干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至10％乙酸乙酯/己烷)纯化，得到标题化合物(0.97g，41％)，为白色固体。Under nitrogen flow at 0°C, triethylamine (8.5 mL, 61.23 mmol) and ethyl chloroformate (2.4 mL, 25.10 mmol). A white precipitate formed after the addition of ethyl chloroformate and the resulting mixture was stirred at 0°C for 45 minutes. Ammonia gas was bubbled through the solution for 2 hours, and the gas source was removed. The reaction mixture was then warmed to room temperature and stirred for 16 hours. 1N hydrochloric acid solution was added to adjust the pH to 1, then extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give crude product. The residue was purified by flash column chromatography (hexanes to 10% ethyl acetate/hexanes) to afford the title compound (0.97 g, 41%) as a white solid.

LRMS(m/z)：116(M+H)+。LRMS (m/z): 116 (M+H) + .

1H NMR(CDCl3，300MHz)：4.35(1H，dd，J＝8.5，5.8Hz)，3.92(2H，m)，2.18(2H，m)，1.90(2H，m)。 1 H NMR (CDCl 3 , 300 MHz): 4.35 (1H, dd, J = 8.5, 5.8 Hz), 3.92 (2H, m), 2.18 (2H, m), 1.90 (2H, m).

制备c-129Preparation c-129

四氢呋喃-2-腈Tetrahydrofuran-2-carbonitrile

Figure A20048001673601401
Figure A20048001673601401

将三氟乙酸酐(1.55g，7.38mmol)以每10秒一滴的速度缓慢加入冰冷(0℃)的四氢呋喃-2-羧酸酰胺(0.77g，6.71mmol)及吡啶(1.06g，13.42mmol)的无水1，4-二噁烷溶液(10mL)中。加入三氟乙酸酐，同时监测内部温度保持在5℃以下，20分钟加完。将所得混合物冷至室温，搅拌3小时。将氯仿(100mL)加入混合物，然后以水(30mL)及饱和氯化钠水溶液(20mL)萃取。干燥有机萃取物(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至25％乙酸乙酯/己烷)纯化，得到无色油状的标题化合物(0.51g，62％)。Add trifluoroacetic anhydride (1.55g, 7.38mmol) slowly to ice-cold (0°C) tetrahydrofuran-2-carboxamide (0.77g, 6.71mmol) and pyridine (1.06g, 13.42mmol) at a rate of one drop every 10 seconds Anhydrous 1,4-dioxane solution (10 mL). Trifluoroacetic anhydride was added while monitoring that the internal temperature remained below 5°C, and the addition was completed in 20 minutes. The resulting mixture was cooled to room temperature and stirred for 3 hours. Chloroform (100 mL) was added to the mixture, followed by extraction with water (30 mL) and saturated aqueous sodium chloride solution (20 mL). The organic extracts were dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give crude product. The residue was purified by flash column chromatography (hexane to 25% ethyl acetate/hexane) to afford the title compound (0.51 g, 62%) as a colorless oil.

1H NMR(CDCl3，300MHz)：4.70(1H，m)，3.96(2H，m)，2.24(2H，m)，2.08(2H，m)。 1 H NMR (CDCl 3 , 300 MHz): 4.70 (1H, m), 3.96 (2H, m), 2.24 (2H, m), 2.08 (2H, m).

制备c-130Preparation c-130

2-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-3-基甲基}四氢呋喃-2-腈2-{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-3-ylmethyl}tetrahydrofuran-2-carbonitrile

在-78℃氮气流下，将双(三甲基甲硅烷基)胺基钠(1.8mL，1.79mmol)加入四氢呋喃-2-腈(0.17g，1.79mmol)的无水四氢呋喃溶液(6mL)中。所得黄色溶液搅拌50分钟后，将5-碘甲基-2-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶(0.25g，0.596mmol)的无水四氢呋喃溶液(3mL)加入至该烯醇化物溶液中。在-78℃下搅拌混合物1.5小时，以饱和氯化铵水溶液(5mL)终止反应。水相以乙酸乙酯萃取(3×50mL)，合并有机萃取物，以水(30mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(7％～45％乙酸乙酯/己烷)纯化，得到标题化合物(0.11g，46％)，为白色固体。Sodium bis(trimethylsilyl)amide (1.8 mL, 1.79 mmol) was added to a solution of tetrahydrofuran-2-carbonitrile (0.17 g, 1.79 mmol) in anhydrous THF (6 mL) at -78°C under nitrogen flow. After the resulting yellow solution was stirred for 50 minutes, 5-iodomethyl-2-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridine (0.25 g, 0.596 mmol) in anhydrous tetrahydrofuran (3 mL) was added to the enolate solution. The mixture was stirred at -78°C for 1.5 hours, and quenched with saturated aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts were washed with water (30 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography (7%-45% ethyl acetate/hexanes) to afford the title compound (0.11 g, 46%) as a white solid.

LRMS(m/z)：390(M+H)+。LRMS (m/z): 390 (M+H) + .

1H NMR(CDCl3，300MHz)：8.03(1H，d，J＝2.5Hz)，7.96(2H，m)，7.56(1H，dd，J＝8.5，2.5Hz)，7.40(3H，m)，6.68(1H，d，J＝8.5Hz)，4.54(2H，m)，3.96(2H，m)，3.00(4H，m)，2.33(5H，d，J＝3.2Hz)，1.92(2H，m)。 1 H NMR (CDCl 3 , 300MHz): 8.03 (1H, d, J = 2.5Hz), 7.96 (2H, m), 7.56 (1H, dd, J = 8.5, 2.5Hz), 7.40 (3H, m), 6.68(1H, d, J=8.5Hz), 4.54(2H, m), 3.96(2H, m), 3.00(4H, m), 2.33(5H, d, J=3.2Hz), 1.92(2H, m ).

实施例D-1Example D-1

2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙酸2-Ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}propanoic acid

Figure A20048001673601411
Figure A20048001673601411

将氢氧化锂一水合物(180mg，4.31mmol)加入至2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙酸乙酯(183mg，0.431mmol)的四氢呋喃∶甲醇∶水(1∶1∶1，6mL)混和溶液中。搅拌混合物18小时，然后浓缩去除挥发成分。水相以3M盐酸酸化，乙酸乙酯萃取。有机相以盐水溶液洗涤，硫酸镁干燥、过滤并浓缩。残留物以快速柱层析(98∶2二氯甲烷∶甲醇)纯化两次，得到无色玻璃状标题化合物(31mg)。Lithium hydroxide monohydrate (180 mg, 4.31 mmol) was added to 2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl ) Ethoxy]pyridin-3-yl}propanoic acid ethyl ester (183mg, 0.431mmol) in tetrahydrofuran:methanol:water (1:1:1, 6mL) mixed solution. The mixture was stirred for 18 hours, then concentrated to remove volatile components. The aqueous phase was acidified with 3M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified twice by flash column chromatography (98:2 dichloromethane:methanol) to give the title compound (31 mg) as a colorless glass.

LRMS(m/z)：396(M)+。LRMS (m/z): 396 (M) + .

1H NMR(CDCl3，300MHz)7.99(3H，m)，7.50(1H，m)，7.40(3H，m)，6.65(1H，m)，4.50(2H，t，J＝7Hz)，4.01(1H，m)，3.64(1H，m)，3.42(1H，m)，2.98(4H，m)，2.34(3H，s)，1.16(3H，t，J＝7Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.99 (3H, m), 7.50 (1H, m), 7.40 (3H, m), 6.65 (1H, m), 4.50 (2H, t, J = 7Hz), 4.01 ( 1H, m), 3.64 (1H, m), 3.42 (1H, m), 2.98 (4H, m), 2.34 (3H, s), 1.16 (3H, t, J=7Hz).

实施例D-2至D-45Examples D-2 to D-45

实施例D-2至D-45以类似于实施例D-1使用的方法制备，即在20℃～75℃下，在氢氧化钠或氢氧化锂的甲醇水溶液、乙醇水溶液、四氢呋喃水溶液或其混和溶液中搅拌酯。Examples D-2 to D-45 were prepared in a manner similar to that used in Example D-1, that is, at 20°C to 75°C, sodium hydroxide or lithium hydroxide in aqueous methanol, aqueous ethanol, aqueous tetrahydrofuran, or Stir the ester in the mixed solution.

Figure A20048001673601421
Figure A20048001673601421

Figure A20048001673601501
Figure A20048001673601501

实施例D-1至D-43起始原料(制备d-1至d-42)的制备：The preparation of embodiment D-1 to D-43 starting material (preparation d-1 to d-42):

制备d-1preparation d-1

2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙烯酸乙酯2-Ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}ethyl acrylate

Figure A20048001673601502
Figure A20048001673601502

将N，N，N′，N′-四甲基胍(0.305mL，2.43mmol)滴加至6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]烟碱醛(250mg，0.811mmol)及(1，2-二乙氧基-2-氧代乙基)(三苯基)氯化鏻(696mg，1.62mmol)的氯仿溶液(4mL)中。将混合物搅拌16小时，然后分配于饱和氯化铵水溶液与乙酸乙酯中。有机相以盐水溶液洗涤、硫酸镁干燥、过滤并浓缩。残留物以快速柱层析(1∶2乙酸乙酯∶己烷)纯化，得到标题化合物(330g，96％)，为白色固体。N, N, N', N'-tetramethylguanidine (0.305 mL, 2.43 mmol) was added dropwise to 6-[2-(5-methyl-2-phenyl-1,3-oxazole-4- chloroform solution of (1,2-diethoxy-2-oxoethyl)(triphenyl)phosphonium chloride (696mg, 1.62mmol) (4mL). The mixture was stirred for 16 hours, then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with brine solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexanes) to afford the title compound (330 g, 96%) as a white solid.

LRMS(m/z)：423(M+H)+。LRMS (m/z): 423 (M+H) + .

1H NMR(CDCl3，300MHz)8.42(1H，m)，8.10(1H，m)，7.97(1H，m)，7.40(2H，m)，7.28(3H，m)，6.90(1H，s)，6.73(1H，m)，4.60(2H，t，J＝7Hz)，4.30(2H，q，J＝7Hz)，4.01(2H，q，J＝7Hz)，2.99(2H，t，J＝7Hz)，2.34(3H，s)，1.36(6H，m) 1 H NMR (CDCl 3 , 300MHz) 8.42(1H,m), 8.10(1H,m), 7.97(1H,m), 7.40(2H,m), 7.28(3H,m), 6.90(1H,s) , 6.73(1H, m), 4.60(2H, t, J=7Hz), 4.30(2H, q, J=7Hz), 4.01(2H, q, J=7Hz), 2.99(2H, t, J=7Hz ), 2.34(3H, s), 1.36(6H, m)

制备d-2preparation d-2

2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙酸乙酯2-Ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}propionic acid ethyl ester

将2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙烯酸乙酯(328mg，0.776mmol)的乙醇溶液(10mL)在50psi下以10％钯碳(33mg)氢化3小时。混合物以Celite过滤，固体以乙酸乙酯洗涤。浓缩滤液及洗涤液，残留物以快速柱层析纯化(1∶2乙酸乙酯∶己烷)，得到无色油状的标题化合物(183mg，56％)。2-Ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}ethyl acrylate (328 mg, 0.776 mmol) in ethanol (10 mL) was hydrogenated with 10% palladium on carbon (33 mg) at 50 psi for 3 hours. The mixture was filtered through Celite and the solid was washed with ethyl acetate. The filtrate and washings were concentrated, and the residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound (183 mg, 56%) as a colorless oil.

LRMS(m/z)：425(M+H)+。LRMS (m/z): 425 (M+H) + .

1H NMR(CDCl3，300MHz)7.99(3H，m)，7.42(4H，m)，6.65(1H，m)，4.54(2H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，3.93(1H，m)，3.63(1H，m)，3.36(1H，m)，2.90(4H，m)，2.33(3H，s)，1.25(3H，t，J＝7Hz)，1.16(3H，t，J＝7Hz)。 1 H NMR (CDCl 3 , 300MHz) 7.99 (3H, m), 7.42 (4H, m), 6.65 (1H, m), 4.54 (2H, t, J=7Hz), 4.18 (2H, q, J=7Hz ), 3.93(1H, m), 3.63(1H, m), 3.36(1H, m), 2.90(4H, m), 2.33(3H, s), 1.25(3H, t, J=7Hz), 1.16( 3H,t,J=7Hz).

制备d-3preparation d-3

2-(苄氧基)-5-溴吡啶的制备Preparation of 2-(Benzyloxy)-5-bromopyridine

向5-溴吡啶-2(1H)-酮(100mmol，17.4g，1.0当量)的苯溶液(170mL)中加入碳酸银(I)(67.0mmol，18.5g，0.67当量)。烧瓶以铝箔包裹，然后通过注射器以稳定的流速加入苄基溴(120mmol，20.5g，1.2当量)。将混合物加热至50℃，在黑暗中搅拌约24小时。反应混合物的LC/MS显示两个峰，两者均具有M+H＝265，与预期分子量一致。基于相对极性，极性较大的峰被认为是N-烷基化产物，约占总量的20％。将反应混合物冷至室温，通过Celite垫过滤混合物去除银盐。滤块以苯洗涤，有机层以2％碳酸氢钠溶液洗涤两次，再以水洗涤两次。有机层以硫酸镁干燥，真空浓缩。粗品在Biotage Sp465i上以5-95％己烷的乙酸乙酯溶液梯度纯化，得到金色油状标题化合物(25.1g，95％)。To a solution of 5-bromopyridin-2(1H)-one (100 mmol, 17.4 g, 1.0 equiv) in benzene (170 mL) was added silver(I) carbonate (67.0 mmol, 18.5 g, 0.67 equiv). The flask was wrapped in aluminum foil, and benzyl bromide (120 mmol, 20.5 g, 1.2 equiv) was added via syringe at a steady flow rate. The mixture was heated to 50°C and stirred in the dark for about 24 hours. LC/MS of the reaction mixture showed two peaks, both with M+H = 265, consistent with the expected molecular weight. Based on relative polarity, the more polar peak was considered to be N-alkylated product and accounted for about 20% of the total. The reaction mixture was cooled to room temperature and the mixture was filtered through a pad of Celite to remove silver salts. The filter block was washed with benzene, and the organic layer was washed twice with 2% sodium bicarbonate solution and then twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on a Biotage Sp465i with a gradient of 5-95% hexane in ethyl acetate to afford the title compound (25.1 g, 95%) as a golden oil.

LRMS：265(M+H)+。LRMS: 265 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.29(1H，s)7.72(1H，d，J＝8.5Hz)7.31-7.43(5H，m)6.54(1H，d，J＝8.5Hz)5.34(2H，s) 1 H NMR (DMSO-d 6 , 400MHz): 8.29 (1H, s) 7.72 (1H, d, J = 8.5Hz) 7.31-7.43 (5H, m) 6.54 (1H, d, J = 8.5Hz) 5.34 ( 2H, s)

制备d-4preparation d-4

6-(苄氧基)烟碱醛的制备Preparation of 6-(Benzyloxy)Nicotinaldehyde

Figure A20048001673601521
Figure A20048001673601521

搅拌下，将正丁基锂(2.5M，95.9mmol，38.4mL，1.05当量)通过注射器滴加入冷至-78℃的2-(苄氧基)-5-溴吡啶(91.3mmol，24.1g，1.0当量)的THF溶液(260mL，c＝0.35)中。加入完毕，在同一低温下继续搅拌溶液1小时。然后，滴加N，N-二甲基甲酰胺(183mmol，13.4g，2.0当量)与5mL THF的溶液。在同一低温下继续搅拌30分钟，然后加入5％碳酸氢钠溶液终止反应。将混合物转移至分液漏斗，以乙醚萃取(3×250mL)。合并有机层，以盐水溶液洗涤、无水硫酸镁干燥、真空浓缩。所得黄色油在Biotage Sp4 65i上以0-50％己烷乙酸乙酯溶液梯度纯化，得到标题化合物(14.1g，73％)Under stirring, n-butyllithium (2.5M, 95.9mmol, 38.4mL, 1.05eq) was added dropwise to 2-(benzyloxy)-5-bromopyridine (91.3mmol, 24.1g, 1.0 eq) in THF solution (260 mL, c=0.35). After the addition was complete, the solution was continued to stir for 1 hour at the same low temperature. Then, a solution of N,N-dimethylformamide (183 mmol, 13.4 g, 2.0 eq) in 5 mL THF was added dropwise. Stirring was continued for 30 minutes at the same low temperature, and then 5% sodium bicarbonate solution was added to terminate the reaction. The mixture was transferred to a separatory funnel and extracted with ether (3 x 250 mL). The organic layers were combined, washed with brine solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting yellow oil was purified on a Biotage Sp4 65i with a gradient of 0-50% hexane in ethyl acetate to afford the title compound (14.1 g, 73%)

LRMS：214(M+H)+。LRMS: 214 (M+H) + .

1H NMR(DMSO-d6，400MHz)：10.02(1H，s)8.86(1H，s)8.03(1H，d，J＝9.3Hz)7.31-7.43(5H，m)6.50(1H，d，J＝9.3Hz)5.33(2H，s) 1 H NMR (DMSO-d 6 , 400MHz): 10.02 (1H, s) 8.86 (1H, s) 8.03 (1H, d, J=9.3Hz) 7.31-7.43 (5H, m) 6.50 (1H, d, J =9.3Hz)5.33(2H,s)

制备d-5preparation d-5

(2Z)-3-[6-(苄氧基)吡啶-3-基]-2-乙氧基丙烯酸乙酯的制备Preparation of (2Z)-3-[6-(benzyloxy)pyridin-3-yl]-2-ethoxyethyl acrylate

向6-(苄氧基)烟碱醛(1.0当量，33.1mmol，7.05g)及(1，2-二乙氧基-2-氧代乙基)(三苯基)氯化鏻(2.0当量，66.2mmol，28.4g)的氯仿溶液(165mL，0.2M)中加入四甲基胍(3.0当量，99.3mmol，11.4g)。烧瓶以中空玻璃塞塞紧，在室温下搅拌过夜。约18小时后，TLC分析显示有少量未反应的起始原料。将反应混合物加热回流，2小时后再以TLC分析。以饱和氯化铵水溶液终止反应。分离两相，有机相以盐水溶液洗涤，硫酸镁干燥、真空浓缩。沉淀出大量氧化三苯基膦。残留物以乙醚研磨、过滤。滤块以乙醚洗涤，真空浓缩合并的滤出液，得到浅黄色固体，将其溶于最小量的DCM中，在Biotage Sp4 65i上以10-100％己烷-乙酸乙酯溶液梯度洗脱。得12.3g无色透明的油(37.6mmol，定量反应)。To 6-(benzyloxy) nicotine aldehyde (1.0 equivalent, 33.1 mmol, 7.05 g) and (1,2-diethoxy-2-oxoethyl) (triphenyl) phosphonium chloride (2.0 equivalent , 66.2mmol, 28.4g) in chloroform (165mL, 0.2M) was added tetramethylguanidine (3.0eq, 99.3mmol, 11.4g). The flask was stoppered tightly with a hollow glass stopper and stirred overnight at room temperature. After about 18 hours, TLC analysis showed a small amount of unreacted starting material. The reaction mixture was heated to reflux and analyzed by TLC after 2 hours. The reaction was quenched with saturated aqueous ammonium chloride. The two phases were separated and the organic phase was washed with brine solution, dried over magnesium sulfate and concentrated in vacuo. A large amount of triphenylphosphine oxide precipitated out. The residue was triturated with ether and filtered. The filter cake was washed with ether and the combined filtrates were concentrated in vacuo to give a light yellow solid which was dissolved in a minimal amount of DCM and eluted on a Biotage Sp4 65i with a gradient of 10-100% hexane-ethyl acetate. This gave 12.3 g of a colorless, transparent oil (37.6 mmol, quantitative reaction).

LRMS：328(M+H)+。LRMS: 328 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.33(1H，s)7.92(1H，d，J＝8.0Hz)7.31-7.43(5H，m)6.76(1H，d，J＝8.1Hz)6.60(1H，s)5.37(2H，s)4.23(2H，q，J＝7.1Hz)3.90-3.99(2H，m)1.34(6H，dt，J＝15.8，7.0Hz) 1 H NMR (DMSO-d 6 , 400MHz): 8.33 (1H, s) 7.92 (1H, d, J = 8.0Hz) 7.31-7.43 (5H, m) 6.76 (1H, d, J = 8.1Hz) 6.60 ( 1H, s) 5.37 (2H, s) 4.23 (2H, q, J = 7.1Hz) 3.90-3.99 (2H, m) 1.34 (6H, dt, J = 15.8, 7.0Hz)

制备d-6preparation d-6

2-乙氧基-3-(6-氧-1，6-二氢吡啶-3-基)丙酸乙酯的制备Preparation of ethyl 2-ethoxy-3-(6-oxo-1,6-dihydropyridin-3-yl)propanoate

将10％钯碳(～1.23g)加入至盛有(2Z)-3-[6-(苄氧基)吡啶-3-基]-2-乙氧基丙烯酸乙酯的乙醇溶液的Parr搅拌瓶中。向瓶中吹扫氢气，减压脱气3次。将混合物置于50psi氢气下，室温下振摇过夜。～20小时后，停止振摇，将瓶以真空脱气。TLC显示起始原料消耗。将混合物通过Celite垫过滤去除钯。滤块以乙醇洗涤。真空浓缩溶液得去苄基的还原吡啶酮，为金色油。该油在Biotage Sp4 65i上，以80mL/分钟以0-10％MeOH的DCM溶液梯度纯化，得到2.77g无色油(11.6mmol，31％)。Add 10% palladium on carbon (~1.23 g) to a Parr stir bottle containing ethyl (2Z)-3-[6-(benzyloxy)pyridin-3-yl]-2-ethoxyacrylate in ethanol middle. The bottle was purged with hydrogen and degassed three times under reduced pressure. The mixture was placed under 50 psi of hydrogen and shaken overnight at room temperature. After ~20 hours, the shaking was stopped and the bottle was degassed with vacuum. TLC showed consumption of starting material. The mixture was filtered through a pad of Celite to remove palladium. The filter block was washed with ethanol. The solution was concentrated in vacuo to afford the debenzylated reduced pyridone as a golden oil. The oil was purified on a Biotage Sp4 65i with a gradient of 0-10% MeOH in DCM at 80 mL/min to afford 2.77 g of a colorless oil (11.6 mmol, 31%).

LRMS：240(M+H)+。LRMS: 240 (M+H) + .

1H NMR(DMSO-d6，400MHz)：7.29(1H，d，J＝9.5Hz)7.19(1H，d，J＝5.2Hz)6.55(1H，d，J＝9.5Hz)4.20(2H，q，J＝7.0Hz)4.10(1H，dd，J＝9.6，0.3Hz)3.59-3.73(2H，m)2.65-2.70(1H，m)2.53-2.61(1H，m)1.23(6H，td，J＝7.0，3.6Hz)。 1 H NMR (DMSO-d 6 , 400MHz): 7.29 (1H, d, J = 9.5Hz) 7.19 (1H, d, J = 5.2Hz) 6.55 (1H, d, J = 9.5Hz) 4.20 (2H, q , J = 7.0Hz) 4.10 (1H, dd, J = 9.6, 0.3Hz) 3.59-3.73 (2H, m) 2.65-2.70 (1H, m) 2.53-2.61 (1H, m) 1.23 (6H, td, J = 7.0, 3.6 Hz).

制备d-7preparation d-7

5-苄氧基-吡啶-2-甲醛5-Benzyloxy-pyridine-2-carbaldehyde

向(5-苄氧基-吡啶-2-基)-甲醇(2.3619g，10.9728mmol)的二氯甲烷(120mL)及吡啶溶液(2.68mL，32.9184mmol)中加入1，1，1-三乙酰氧基-1，1-二氢-1，2-苯并二氧环戊烯(benziodoxol)-3(1H)-酮(6.9812g，16.4592mmol)。将所得溶液在室温氮气流下搅拌16小时，然后以乙醚(100mL)稀释，再减压浓缩部分溶液。将残留物加入乙醚(150mL)中，以1∶110％硫代硫酸钠水溶液∶饱和碳酸氢钠水溶液萃取(2×100mL)去除沉淀。有机层以水(100mL)及饱和氯化钠水溶液(100mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得浅黄色油状的纯标题化合物(1.1694g，50％)。To a solution of (5-benzyloxy-pyridin-2-yl)-methanol (2.3619 g, 10.9728 mmol) in dichloromethane (120 mL) and pyridine (2.68 mL, 32.9184 mmol) was added 1,1,1-triacetyl Oxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one (6.9812 g, 16.4592 mmol). The resulting solution was stirred at room temperature under nitrogen flow for 16 hours, then diluted with diethyl ether (100 mL), and a portion of the solution was concentrated under reduced pressure. The residue was added to diethyl ether (150 mL), and extracted with 1:1 10% aqueous sodium thiosulfate:saturated aqueous sodium bicarbonate (2×100 mL) to remove the precipitate. The organic layer was washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the pure title compound (1.1694 g, 50%) as a pale yellow oil.

LRMS(m/z)：214(M+H)+。LRMS (m/z): 214 (M+H) + .

1H NMR(CDCl3，300MHz)：9.98(1H，d，J＝0.8Hz)，8.49(1H，d，J＝2.5Hz)，7.94(1H，d，J＝8.7Hz)，7.44-7.40(4H，m)，7.38-7.33(2H，m)，5.19(2H，s)。 1 H NMR (CDCl 3 , 300MHz): 9.98 (1H, d, J = 0.8Hz), 8.49 (1H, d, J = 2.5Hz), 7.94 (1H, d, J = 8.7Hz), 7.44-7.40 ( 4H, m), 7.38-7.33 (2H, m), 5.19 (2H, s).

制备d-8preparation d-8

3-(5-苄氧基-吡啶-2-基)-2-乙氧基-丙烯酸乙酯3-(5-Benzyloxy-pyridin-2-yl)-2-ethoxy-ethyl acrylate

在室温氮气流下，向5-苄氧基-吡啶-2-甲醛(1.1694g，5.4842mmol)、(乙氧羰基-甲氧基-甲基)-三苯基氯化鏻(4.7043g，10.9684mmol)的氯仿溶液(30mL)中滴加四甲基胍(2.1mL，16.4526mmol)。将所得溶液搅拌16小时，然后以饱和氯化铵水溶液(50mL)终止反应。分离两相，有机相以饱和氯化钠水溶液(50mL)洗涤、干燥(无水硫酸镁)、过滤并真空浓缩得粗产物。残留物以快速柱层析(己烷至乙酸乙酯)纯化，得到黄色油状的纯标题化合物(1.8051g，100％)。Under nitrogen flow at room temperature, 5-benzyloxy-pyridine-2-carbaldehyde (1.1694g, 5.4842mmol), (ethoxycarbonyl-methoxy-methyl)-triphenylphosphonium chloride (4.7043g, 10.9684mmol ) in chloroform (30 mL) was added dropwise with tetramethylguanidine (2.1 mL, 16.4526 mmol). The resulting solution was stirred for 16 hours, then quenched with saturated aqueous ammonium chloride (50 mL). The two phases were separated and the organic phase was washed with saturated aqueous sodium chloride (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the crude product. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to give the pure title compound (1.8051 g, 100%) as a yellow oil.

LRMS(m/z)：328(M+H)+。LRMS (m/z): 328 (M+H) + .

1H NMR(CDCl3，300MHz)：8.37(1H，d，J＝2.6Hz)，8.18(1H，d，J＝8.9Hz)，7.44-7.33(5H，m)，7.25(1H，dd，J＝8.9，3.0Hz)，7.13(1H，s)，5.13(2H，s)，4.27(2H，q，J＝7.2Hz)，4.05(2H，q，J＝7.2Hz)，1.35(3H，t，J＝7.0Hz)，1.34(3H，t，J＝7.0Hz)。 1 H NMR (CDCl 3 , 300MHz): 8.37 (1H, d, J = 2.6Hz), 8.18 (1H, d, J = 8.9Hz), 7.44-7.33 (5H, m), 7.25 (1H, dd, J =8.9, 3.0Hz), 7.13(1H, s), 5.13(2H, s), 4.27(2H, q, J=7.2Hz), 4.05(2H, q, J=7.2Hz), 1.35(3H, t , J=7.0 Hz), 1.34 (3H, t, J=7.0 Hz).

制备d-9preparation d-9

2-乙氧基-3-(5-羟基-吡啶-2-基)-丙酸乙酯2-Ethoxy-3-(5-hydroxy-pyridin-2-yl)-propionic acid ethyl ester

向3-(5-苄氧基-吡啶-2-基)-2-乙氧基-丙烯酸乙酯(1.8051g，5.5144mmol)的无水乙醇溶液(40mL)中加入钯(0.1805g，占活性碳重量的10％)。将所得溶液在室温及氢气氛(50psi)下搅拌16小时。将所得溶液通过3”的Celite层过滤，以乙醇(200mL)洗涤。然后真空浓缩滤液，得到浅黄色油状的纯标题化合物(1.2231g，93％)。To a solution of ethyl 3-(5-benzyloxy-pyridin-2-yl)-2-ethoxy-acrylate (1.8051 g, 5.5144 mmol) in absolute ethanol (40 mL) was added palladium (0.1805 g, accounted for active 10% of carbon weight). The resulting solution was stirred at room temperature under an atmosphere of hydrogen (50 psi) for 16 hours. The resulting solution was filtered through a 3" layer of Celite, washing with ethanol (200 mL). The filtrate was then concentrated in vacuo to afford the pure title compound (1.2231 g, 93%) as a pale yellow oil.

LRMS(m/z)：240(M+H)+。LRMS (m/z): 240 (M+H) + .

1H NMR(CDCl3，300MHz)：8.14(1H，s)，7.20-7.11(2H，m)，4.19-4.10(3H，m)，3.71(1H，q，J＝7.0Hz)，3.63-3.53(1H，m)，3.36-3.26(1H，m)，3.18-3.03(1H，m)，1.18(3H，t，J＝7.2Hz)，1.07(3H，t，J＝7.1Hz)。 1 H NMR (CDCl 3 , 300MHz): 8.14 (1H, s), 7.20-7.11 (2H, m), 4.19-4.10 (3H, m), 3.71 (1H, q, J=7.0Hz), 3.63-3.53 (1H, m), 3.36-3.26 (1H, m), 3.18-3.03 (1H, m), 1.18 (3H, t, J=7.2Hz), 1.07 (3H, t, J=7.1Hz).

制备d-10preparation d-10

2-乙氧基-3-{6-[2-(4-苯氧基苯基)乙氧基]吡啶-3-基}丙酸乙酯2-Ethoxy-3-{6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl}propanoic acid ethyl ester

向以氩气吹扫过的合适溴吡啶(0.636mmol)的甲苯溶液(12mL)中加入乙酸钯(II)(11.4mg，0.0508mmol)及消旋-2-(二-叔丁基膦基)-1，1’-联萘(25.4mg，0.0636mmol)。约10分钟形成活性复合物，然后加入碳酸铯(414mg，1.27mmol)及合适的醇(0.956mmol)。将混合物加热至115℃，在此温度下搅拌约12-18小时。将混合物冷至室温，以二氧化硅垫过滤。滤块以2-3份的乙酸乙酯洗涤、合并有机滤液、真空浓缩。所得残留物以快速层析纯化，或以常规水解方法处理。To a solution of the appropriate bromopyridine (0.636 mmol) in toluene (12 mL) purged with argon was added palladium(II) acetate (11.4 mg, 0.0508 mmol) and rac-2-(di-tert-butylphosphino) - 1,1'-binaphthyl (25.4mg, 0.0636mmol). The active complex formed in about 10 minutes, then cesium carbonate (414mg, 1.27mmol) and the appropriate alcohol (0.956mmol) were added. The mixture was heated to 115°C and stirred at this temperature for about 12-18 hours. The mixture was cooled to room temperature and filtered through a pad of silica. The filter cake was washed with 2-3 portions of ethyl acetate, and the combined organic filtrates were concentrated in vacuo. The residue obtained is purified by flash chromatography or worked up by conventional hydrolysis methods.

制备d-11至d-18Preparation D-11 to D-18

制备d-11至d-18使用类似于制备d-10使用的方法进行制备。Preparations d-11 to d-18 were prepared using a method similar to that used for preparation d-10.

1010

制备d-19preparation d-19

2-溴-5-(溴甲基)吡啶2-Bromo-5-(bromomethyl)pyridine

Figure A20048001673601572
Figure A20048001673601572

将三溴化磷(100mmol，27.1g，2.0当量)小心加入至2-氯-5-羟基甲基吡啶(50.0mmol，7.18g，1.0当量)中。吡啶成块，将混合物加热至160℃。在＞150℃下搅拌5分钟内，混合物颜色变得很暗，并有气体放出。在同一温度下搅拌混合物约2.5小时后，冷至室温。将混合物进一步冷至0℃，非常小心地加入饱和碳酸氢钠溶液(剧烈放热！)。当泡沫减少时，将冰加入混合物中，直至泡沫消失。然后小心加入固体碳酸氢钠至pH～8-9。将混合物以乙酸乙酯萃取，有机层以盐水溶液洗涤、无水硫酸镁干燥。真空浓缩得黑色固体。将该物质溶于最小量的DCM中，使用Biotage Sp4 65i以0-100％乙酸乙酯/己烷溶液梯度纯化，得到浅黄色固体的标题化合物(5.57g，44％)。Phosphorus tribromide (100 mmol, 27.1 g, 2.0 equiv) was carefully added to 2-chloro-5-hydroxymethylpyridine (50.0 mmol, 7.18 g, 1.0 equiv). Pyridine clumps and the mixture is heated to 160°C. Within 5 minutes of stirring at >150°C, the mixture became very dark in color and gas evolved. After stirring the mixture at the same temperature for about 2.5 hours, it was cooled to room temperature. The mixture was cooled further to 0°C and saturated sodium bicarbonate solution was added very carefully (vigorous exotherm!). When the foam decreases, add ice to the mixture until the foam disappears. Then solid sodium bicarbonate was added carefully to pH~8-9. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine solution and dried over anhydrous magnesium sulfate. Concentration in vacuo gave a black solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i with a gradient of 0-100% ethyl acetate/hexanes to afford the title compound (5.57 g, 44%) as a pale yellow solid.

LRMS：252(M+H)+。LRMS: 252 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.39(1H，s)7.59(1H，d，J＝8.5Hz)7.48(1H，d，J＝8.5Hz)4.46(2H，s) 1 H NMR (DMSO-d 6 , 400MHz): 8.39 (1H, s) 7.59 (1H, d, J = 8.5Hz) 7.48 (1H, d, J = 8.5Hz) 4.46 (2H, s)

制备d-20preparation d-20

[(6-溴吡啶-3-基)甲基](甲氧基)丙二酸二甲基酯Dimethyl [(6-bromopyridin-3-yl)methyl](methoxy)malonate

Figure A20048001673601581
Figure A20048001673601581

通过注射器向冷至0℃的叔丁醇钾(46.6mmol，5.22g，1.3当量)的无水DMF浆状物(250mL)中分多次加入甲氧基丙二酸二甲酯(46.6mmol，7.55g，1.3当量)。约30分钟内形成烯醇化物，此时分次加入2-溴-5-(溴甲基)吡啶。在3小时内缓慢将反应混合物温热至室温。将反应混合物以乙醚稀释，转移至含有饱和氯化铵水溶液的分液漏斗。振荡、分离两相，有机相以水洗涤。然后以无水硫酸镁干燥有机层、真空浓缩。所得黄色油在Biotage Sp4 65i上以0-100％乙酸乙酯/己烷溶液梯度纯化，得到无色油(12.1g，quant.)，静置固化。LRMS：333(M+H)+。Dimethyl methoxymalonate (46.6 mmol, 7.55 g, 1.3 equivalents). The enolate formed over about 30 minutes, at which point 2-bromo-5-(bromomethyl)pyridine was added in portions. The reaction mixture was slowly warmed to room temperature over 3 hours. The reaction mixture was diluted with ether and transferred to a separatory funnel containing saturated aqueous ammonium chloride. Shake, separate the two phases, and wash the organic phase with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting yellow oil was purified on a Biotage Sp4 65i with a gradient of 0-100% ethyl acetate/hexanes to give a colorless oil (12.1 g, quant.) which solidified on standing. LRMS: 333 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.27(1H，s)7.45-7.55(2H，m)3.82(6H，s)3.57(3H，s)3.42(2H，s) 1 H NMR (DMSO-d 6 , 400MHz): 8.27 (1H, s) 7.45-7.55 (2H, m) 3.82 (6H, s) 3.57 (3H, s) 3.42 (2H, s)

制备d-21preparation d-21

3-(6-溴吡啶-3-基)-2-甲氧基丙酸甲酯的制备Preparation of methyl 3-(6-bromopyridin-3-yl)-2-methoxypropionate

向[(6-溴吡啶-3-基)甲基](甲氧基)丙二酸二甲基酯(3.55mmol，1.18g，1.0当量)的无水DMF溶液(2mL)中加入溴化锂(3.20mmol，0.278g，0.9当量)，然后加入水(3.55mmol，0.064g，1.0当量)。将溶液置于预热至165℃的油浴中。迅速开始释放气体。在30分钟内停止形成气泡，此时LC/MS显示反应混合物反应完全。冷至室温，以水稀释。以乙醚萃取水层(4×25mL)。合并有机层，以盐水溶液洗涤。无水硫酸镁干燥有机层，真空浓缩得536mg棕色油，该油以TLC检测为单一的点。无需进一步纯化直接用于下一步。To a solution of dimethyl [(6-bromopyridin-3-yl)methyl](methoxy)malonate (3.55 mmol, 1.18 g, 1.0 equiv) in anhydrous DMF (2 mL) was added lithium bromide (3.20 mmol, 0.278 g, 0.9 equiv), then water (3.55 mmol, 0.064 g, 1.0 equiv) was added. The solution was placed in an oil bath preheated to 165°C. Rapidly begins to release gas. Bubble formation ceased within 30 minutes, at which point LC/MS indicated the reaction mixture was complete. Cool to room temperature and dilute with water. The aqueous layer was extracted with ether (4 x 25 mL). The organic layers were combined and washed with brine solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 536 mg of a brown oil which was detected as a single spot by TLC. It was used directly in the next step without further purification.

LRMS：275(M+H)+。LRMS: 275 (M+H) + .

1H NMR(DMSO-d6，400MHz)：8.23(1H，s)7.42-7.51(2H，m)4.26(1H，d，J＝8.1Hz)3.79(3H，s)3.51(3H，s)2.97-3.03(1H，m)2.82-2.88(1H，m)。 1 H NMR (DMSO-d 6 , 400MHz): 8.23 (1H, s) 7.42-7.51 (2H, m) 4.26 (1H, d, J=8.1Hz) 3.79 (3H, s) 3.51 (3H, s) 2.97 -3.03 (1H, m) 2.82-2.88 (1H, m).

制备d-22preparation d-22

3-[6-(2-{4-[(乙基磺酰基)氧基]苯基}乙氧基)吡啶-3-基]-2-甲氧基丙酸乙酯3-[6-(2-{4-[(Ethylsulfonyl)oxy]phenyl}ethoxy)pyridin-3-yl]-2-methoxypropionic acid ethyl ester

制备d-23至d-38Preparation D-23 to D-38

制备d-23至d-38使用类似于制备d-22使用的方法进行制备。Preparations d-23 to d-38 were prepared using a method similar to that used for preparation d-22.

Figure A20048001673601592
Figure A20048001673601592

Figure A20048001673601601
Figure A20048001673601601

Figure A20048001673601621
Figure A20048001673601621

已测试本发明化合物抗PPAR-γ和PPAR-α的活性。这些活性以Ki(μm)列表如下。 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm) 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm) 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm)   A-02   0.55   B-02   2.2   C-03   2.9   A-03   10   19   B-03   31   9   C-05   15   A-05 E/M   0.33   2.6   B-04   1.5   48   C-06   9.5   41   A-05 S/E   3.4   7.5   B-05   1.33   2.04   C-07   11   22   A-05 S/E   0.19   1.1   B-05   2.9   3.2   C-09   1.4   4.6   A-07   0.12   B-05   2   3.6   C-10   2.1   19   A-10   1.5   4.4   B-06   0.37   0.13   C-11   2   25   A-11   0.58   0.12   B-07   0.65   12   C-12   1.6   9.4   A-12   0.051   0.35   B-08   0.48   3.1   C-14   8   3.2   A-13   3.5   10   B-09   1.9   2.2   C-15   14   3.2   A-14   1.3   0.15   B-10   0.17   0.19   C-17   26   3.2   A-15   1.2   0.16   B-11   7.9   0.96   C-18   3.5   0.065   A-16   2.8   1.5   B-12   33   0.3   C-20   1.5   3.1   A-17   1.9   1.6   B-13   9   C-21   0.053   0.066   A-18   1.7   14   B-14   2.3   0.021   C-22   0.8   2.1   A-19   0.059   0.7   B-16   1.8   0.084   C-23   0.19   2.5   A-20   0.18   0.14   B-17   1.2   0.047   C-24   0.083   0.022   A-21   0.088   0.31   B-18   0.082   C-25   0.066   0.018   A-22   0.17   0.85   B-19   0.74   0.34   C-26   0.068   0.016   A-23   0.39   0.18   B-20   1.6   C-27   0.026   0.015   A-24   0.78   0.018   E-21   0.99   4   C-28   0.03   0.088   A-25   3.2   4.2   B-22   0.15   0.46   C-29   0.006   0.12   A-26   0.15   0.33   B-23   3.4   2.7   C-30   0.033   0.11   A-27   2.4   1.3   B-24   1.6   1   C-31   0.026   0.093   A-28 E/M   0.044   0.93   E-27   0.22   C-32   0.035   0.15   A-28 S/E   0.081   1.1   B-28   7.8   C-33   0.05   0.01   A-28 S/E   0.94   2.9   C-02   0.39   C-36   1.7   21 The compounds of the invention have been tested for activity against PPAR-γ and PPAR-α. These activities are listed below in Ki (μm). Examples# PPAR-γKi(μm) PPAR-αKi(μm) Examples# PPAR-γKi(μm) PPAR-αKi(μm) Examples# PPAR-γKi(μm) PPAR-αKi(μm) A-02 0.55 B-02 2.2 C-03 2.9 A-03 10 19 B-03 31 9 C-05 15 A-05 E/M 0.33 2.6 B-04 1.5 48 C-06 9.5 41 A-05 S/E 3.4 7.5 B-05 1.33 2.04 C-07 11 twenty two A-05 S/E 0.19 1.1 B-05 2.9 3.2 C-09 1.4 4.6 A-07 0.12 B-05 2 3.6 C-10 2.1 19 A-10 1.5 4.4 B-06 0.37 0.13 C-11 2 25 A-11 0.58 0.12 B-07 0.65 12 C-12 1.6 9.4 A-12 0.051 0.35 B-08 0.48 3.1 C-14 8 3.2 A-13 3.5 10 B-09 1.9 2.2 C-15 14 3.2 A-14 1.3 0.15 B-10 0.17 0.19 C-17 26 3.2 A-15 1.2 0.16 B-11 7.9 0.96 C-18 3.5 0.065 A-16 2.8 1.5 B-12 33 0.3 C-20 1.5 3.1 A-17 1.9 1.6 B-13 9 C-21 0.053 0.066 A-18 1.7 14 B-14 2.3 0.021 C-22 0.8 2.1 A-19 0.059 0.7 B-16 1.8 0.084 C-23 0.19 2.5 A-20 0.18 0.14 B-17 1.2 0.047 C-24 0.083 0.022 A-21 0.088 0.31 B-18 0.082 C-25 0.066 0.018 A-22 0.17 0.85 B-19 0.74 0.34 C-26 0.068 0.016 A-23 0.39 0.18 B-20 1.6 C-27 0.026 0.015 A-24 0.78 0.018 E-21 0.99 4 C-28 0.03 0.088 A-25 3.2 4.2 B-22 0.15 0.46 C-29 0.006 0.12 A-26 0.15 0.33 B-23 3.4 2.7 C-30 0.033 0.11 A-27 2.4 1.3 B-24 1.6 1 C-31 0.026 0.093 A-28 E/M 0.044 0.93 E-27 0.22 C-32 0.035 0.15 A-28 S/E 0.081 1.1 B-28 7.8 C-33 0.05 0.01 A-28 S/E 0.94 2.9 C-02 0.39 C-36 1.7 twenty one

E/M指对映混合物，包括消旋混合物。E/M refers to enantiomeric mixtures, including racemic mixtures.

S/E指单一对映体。 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm) 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm) 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm)   C-38   7.2   C-64   0.052   0.014   C-90   0.017   0.11   C-40   3.7   0.7   C-66   0.023   0.031   C-91   0.39   1.8   C-42   33   13   C-67   0.044   0.25   C-92   1.1   2.8   C-44   36   C-68   4.2   C-93   0.011   0.3   C-45   0.22   7.7   C-69   1.1   2.5   C-94   7   C-46   2   3.5   C-70   6.4   C-95   0.97   8.6   C-47   3.5   8.3   C-71   9.7   D-02   0.46   0.29   C-48   0.018   0.24   C-72   7.1   D-03   0.011   0.3   C-48 E/M   0.15   0.31   C-73   0.042   D-04   0.44   0.29   C-48 S/E   0.014   0.047   C-74   0.64   0.9   D-05   2.8   C-48 S/E   2.4   C-74 S/E   D-06   0.027   0.13   C-49   0.21   1.6   C-74 S/E   0.47   4.2   D-07   0.017   0.32   C-49   21   41   C-75   0.82   D-08   0.002   0.015   C-49   0.043   0.34   C-76   2.3   7.3   D-09   0.061   0.05   C-50   0.043   1.1   C-77   0.15   2.9   D-10   0.019   0.033   C-51   0.18   2.9   C-78   0.006   0.015   D-11   6.2   5.1   C-52   0.3   0.15   C-78 S/E   3.9   D-12   8.1   C-53   0.093   0.64   C-78 S/E   0.003   0.014   D-13   0.36   0.19   C-53 S/E   3.6   C-79   0.007   0.015   D-14   1.5   2.6   C-53 S/E   0.027   0.4   C-80   0.062   0.053   D-15   0.35   0.22   C-54   0.02   1.2   C-81   0.015   0.75   D-16   6.4   C-55   6   C-82   0.016   D-17   0.031   0.91   C-56   0.081   0.078   C-83   0.008   0.004   D-18   0.45   0.62   C-57   1.1   1.8   C-84   0.021   0.064   D-19   1.7   6.4   C-59   0.009   0.054   C-85   0.004   0.013   D-20   0.48   0.84   C-60   0.015   0.065   C-86   0.005   0.013   D-21   2.1   10   C-61   0.31   0.24   C-87   0.012   0.025   D-23 E/M   0.073   6.5   C-63   0.094   0.021   C-89   0.04   0.03   D-23 S/E   5 S/E refers to single enantiomer. Examples# PPAR-γKi(μm) PPAR-αKi(μm) Examples# PPAR-γKi(μm) PPAR-αKi(μm) Examples# PPAR-γKi(μm) PPAR-αKi(μm) C-38 7.2 C-64 0.052 0.014 C-90 0.017 0.11 C-40 3.7 0.7 C-66 0.023 0.031 C-91 0.39 1.8 C-42 33 13 C-67 0.044 0.25 C-92 1.1 2.8 C-44 36 C-68 4.2 C-93 0.011 0.3 C-45 0.22 7.7 C-69 1.1 2.5 C-94 7 C-46 2 3.5 C-70 6.4 C-95 0.97 8.6 C-47 3.5 8.3 C-71 9.7 D-02 0.46 0.29 C-48 0.018 0.24 C-72 7.1 D-03 0.011 0.3 C-48 E/M 0.15 0.31 C-73 0.042 D-04 0.44 0.29 C-48 S/E 0.014 0.047 C-74 0.64 0.9 D-05 2.8 C-48 S/E 2.4 C-74 S/E D-06 0.027 0.13 C-49 0.21 1.6 C-74 S/E 0.47 4.2 D-07 0.017 0.32 C-49 twenty one 41 C-75 0.82 D-08 0.002 0.015 C-49 0.043 0.34 C-76 2.3 7.3 D-09 0.061 0.05 C-50 0.043 1.1 C-77 0.15 2.9 D-10 0.019 0.033 C-51 0.18 2.9 C-78 0.006 0.015 D-11 6.2 5.1 C-52 0.3 0.15 C-78 S/E 3.9 D-12 8.1 C-53 0.093 0.64 C-78 S/E 0.003 0.014 D-13 0.36 0.19 C-53 S/E 3.6 C-79 0.007 0.015 D-14 1.5 2.6 C-53 S/E 0.027 0.4 C-80 0.062 0.053 D-15 0.35 0.22 C-54 0.02 1.2 C-81 0.015 0.75 D-16 6.4 C-55 6 C-82 0.016 D-17 0.031 0.91 C-56 0.081 0.078 C-83 0.008 0.004 D-18 0.45 0.62 C-57 1.1 1.8 C-84 0.021 0.064 D-19 1.7 6.4 C-59 0.009 0.054 C-85 0.004 0.013 D-20 0.48 0.84 C-60 0.015 0.065 C-86 0.005 0.013 D-21 2.1 10 C-61 0.31 0.24 C-87 0.012 0.025 D-23 E/M 0.073 6.5 C-63 0.094 0.021 C-89 0.04 0.03 D-23 S/E 5

E/M指对映混合物，包括消旋混合物。E/M refers to enantiomeric mixtures, including racemic mixtures.

S/E指单一对映体。 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm) 实施例#   PPAR-γKi(μm)   PPAR-αKi(μm)   D-23 S/E   0.039   1.1   D-33   0.69   0.55   D-24   no SPA   no SPA   D-34   9.1   3.2   D-24   0.58   0.93   D-35   0.56   0.33   D-25   2.9   D-35 S/E   027   0.57   D-26   no SPA   no SP   D-35 S/E   4.8   9   D-26 S/E   1.9   D-36   0.23   0.73   D-26 S/E   0.042   0.67   D-37   0.53   4.7   D-27   7.8   D-38   9.6   D-28   1.6   4.8   D-39   5   D-29   0.4   0.8   D-40   9.6   1.8   D-29 S/E   1.2   D-41   5.9   D-29 S/E   0.69   3   D-42   0.7   1   D-31   1   0.088   D-44   0.15   2.6   D-32   1.5   0.059   D-45   0.058   0.09 S/E refers to single enantiomer. Examples# PPAR-γKi(μm) PPAR-αKi(μm) Examples# PPAR-γKi(μm) PPAR-αKi(μm) D-23 S/E 0.039 1.1 D-33 0.69 0.55 D-24 no SPA no SPA D-34 9.1 3.2 D-24 0.58 0.93 D-35 0.56 0.33 D-25 2.9 D-35 S/E 027 0.57 D-26 no SPA no SP D-35 S/E 4.8 9 D-26 S/E 1.9 D-36 0.23 0.73 D-26 S/E 0.042 0.67 D-37 0.53 4.7 D-27 7.8 D-38 9.6 D-28 1.6 4.8 D-39 5 D-29 0.4 0.8 D-40 9.6 1.8 D-29 S/E 1.2 D-41 5.9 D-29 S/E 0.69 3 D-42 0.7 1 D-31 1 0.088 D-44 0.15 2.6 D-32 1.5 0.059 D-45 0.058 0.09

E/M指对映混合物，包括消旋混合物。E/M refers to enantiomeric mixtures, including racemic mixtures.

S/E指单一对映体。S/E refers to single enantiomer.

本发明已通过具体的和优选的实施方案详述，本领域技术人员应当了解，通过本发明的常规实验和实践，可对本发明进行变动和修改。因而，本发明不为前述说明书所限，但不脱离后述权利要求及其等同物的范围。While the present invention has been described in detail with reference to specific and preferred embodiments, those skilled in the art will appreciate that variations and modifications of the invention can be made through routine experimentation and practice of the invention. Accordingly, the invention is not to be limited by the foregoing description, but does not depart from the scope of the following claims and their equivalents.

Claims (15)

1.通式(I)的化合物或其可药用盐或溶剂合物，1. A compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof,
Figure A2004800167360002C1
Figure A2004800167360002C1
 其中：in: 环Q为(C6-C10)芳基或(4-10)-员杂环基；Ring Q is (C 6 -C 10 ) aryl or (4-10)-membered heterocyclic group; R1为H、卤素、(C1-C8)烷基、(C1-C8)烷氧基、CN、CF3、-O-CF3、-O-SO2-(C1-C8)烷基、-O-SO2-(CR11R12)t(C6-C10)芳基、-(CR11R12)t(C3-C10)环烷基-(CR11R12)t、-(CR11R12)t(C3-C10)环烷基-(CR11R12)t-O-、-(CR11R12)t(C6-C10)芳基-(CR11R12)t、-(CR11R12)t(C6-C10)芳基-(CR11R12)t-O-、-(CR11R12)t-(4-10)-员杂环基-(CR11R12)t、或-(CR11R12)t-(4-10)-员杂环基-(CR11R12)t-O-；其中R1的环碳原子任选被1～3个R13基团取代；R1的环氮原子任选被1～3个(C1-C8)烷基取代；R 1 is H, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) alkoxy, CN, CF 3 , -O-CF 3 , -O-SO 2 -(C 1 -C 8 ) alkyl, -O-SO 2 -(CR 11 R 12 ) t (C 6 -C 10 ) aryl, -(CR 11 R 12 ) t (C 3 -C 10 ) cycloalkyl-(CR 11 R 12 ) t , -(CR 11 R 12 ) t (C 3 -C 10 )cycloalkyl-(CR 11 R 12 ) t -O-, -(CR 11 R 12 ) t (C 6 -C 10 ) Aryl-(CR 11 R 12 ) t , -(CR 11 R 12 ) t (C 6 -C 10 )aryl-(CR 11 R 12 ) t -O-, -(CR 11 R 12 ) t -( 4-10)-membered heterocyclyl-(CR 11 R 12 ) t , or -(CR 11 R 12 ) t -(4-10)-membered heterocyclyl-(CR 11 R 12 ) t -O-; wherein the ring carbon atoms of R 1 are optionally substituted by 1 to 3 R 13 groups; the ring nitrogen atoms of R 1 are optionally substituted by 1 to 3 (C 1 -C 8 ) alkyl groups; R2为H、(C1-C8)烷基、-(CR11R12)t-(C3-C10)环烷基、-(CR11R12)t-(C6-C10)芳基或-(CR11R12)t(4-10)-员杂环基；其中R2的碳原子任选被1～3个R13基团取代；并且R2的环氮原子任选被1～3个(C1-C8)烷基取代；R 2 is H, (C 1 -C 8 ) alkyl, -(CR 11 R 12 ) t -(C 3 -C 10 ) cycloalkyl, -(CR 11 R 12 ) t -(C 6 -C 10 ) aryl or -(CR 11 R 12 ) t (4-10)-membered heterocyclic group; wherein the carbon atoms of R 2 are optionally substituted by 1 to 3 R 13 groups; and the ring nitrogen atoms of R 2 are optionally Optionally substituted by 1 to 3 (C 1 -C 8 ) alkyl groups; R3选自： R3 is selected from:
Figure A2004800167360002C2
Figure A2004800167360002C2
 Y为-(C＝O)-或-SO2-；Y is -(C=O)- or -SO 2 -; Y″为NR10或-O-；Y″ is NR 10 or -O-; p为0、1或2；p is 0, 1 or 2; 每个q、r及t独立地为0、1、2、3、4或5；each q, r and t is independently 0, 1, 2, 3, 4 or 5; 每个n独立地为0、1、2、3或4；each n is independently 0, 1, 2, 3 or 4; 每个k独立地为1、2或3；each k is independently 1, 2 or 3; 每个m和s独立地为0、1、2或3；each m and s is independently 0, 1, 2 or 3; 每个j为0、1或2；each j is 0, 1 or 2; 每个R4为-(CR11R12)n-、-(CR11R12)n-S-(CR11R12)n-、-(CR11R12)n-NR10-、-(CR11R12)n-NR10-(CR11R12)n-O-、-(CR11R12)n-O-(CR11R12)k-NR10-、-(CR11R12)n-O-(CR11R12)n-、-(CR11R12)n-O-(CR11R12)k-O-(CR11R12)n-、-(CR11R12)n-CR11＝CR12-(CR11R12)n-或-CH＝CH-(CR11R12)-O-(CH2)n-；Each R 4 is -(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -S-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -NR 10 -, -( CR 11 R 12 ) n -NR 10 -(CR 11 R 12 ) n -O-, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) k -NR 10 -, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -O-(CR 11 R 12 ) k -O-(CR 11 R 12 ) n -, -(CR 11 R 12 ) n -CR 11 =CR 12 -(CR 11 R 12 ) n -or -CH=CH-(CR 11 R 12 )-O-(CH 2 ) n -; 每个R5为键或-(CR11R12)m-Z-(CR11R12)s；其中Z为-CR11R12-、-O-、-NR10a-或-S(O)j-；Each R 5 is a bond or -(CR 11 R 12 ) m -Z-(CR 11 R 12 ) s ; wherein Z is -CR 11 R 12 -, -O-, -NR 10a - or -S(O) j- ; 每个R6为-(C＝O)-OH、-(C＝O)-OM+、-(C＝O)-(C1-C8)烷基、-(C＝O)-O-(C1-C8)烷基、-(C＝O)-NR10R11、-(C＝O)-NR10-SO2-R11、-SO2-NH-R10、-NH-SO2-R10、-(C＝O)-NH-C≡N，或R6具有下式结构：Each R 6 is -(C=O)-OH, -(C=O)-OM + , -(C=O)-(C 1 -C 8 )alkyl, -(C=O)-O- (C 1 -C 8 )alkyl, -(C=O)-NR 10 R 11 , -(C=O)-NR 10 -SO 2 -R 11 , -SO 2 -NH-R 10 , -NH- SO 2 -R 10 , -(C=O)-NH-C≡N, or R 6 has the following structure:
Figure A2004800167360003C1
或
Figure A2004800167360003C2
Figure A2004800167360003C1
or
Figure A2004800167360003C2
 M+为碱金属阳离子或碱土金属阳离子；M + is an alkali metal cation or an alkaline earth metal cation; 每个R7和R8独立地为H、(C1-C8)烷基、(C1-C8)烷氧基、-(CR11R12)t(C3-C10)环烷基、-(CR11R12)t(C6-C10)芳基、-(CR11R12)t(C6-C10)芳基-O-、-(CR11R12)t(4-10)-员杂环基或-(CR11R12)t(4-10)-员杂环基-O-；Each R 7 and R 8 is independently H, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, -(CR 11 R 12 ) t (C 3 -C 10 )cycloalkane Base, -(CR 11 R 12 ) t (C 6 -C 10 )aryl, -(CR 11 R 12 ) t (C 6 -C 10 )aryl-O-, -(CR 11 R 12 ) t ( 4-10)-membered heterocyclyl or -(CR 11 R 12 ) t (4-10)-membered heterocyclyl-O-; 或R7和R8任选与其连接的碳原子一起形成(C3-C10)环烷基或(3-10)-员杂环基；Or R 7 and R 8 optionally form (C 3 -C 10 ) cycloalkyl or (3-10)-membered heterocyclyl together with the carbon atom to which they are attached; 每个Ar1、Ar2、Ar3和Ar4代表(C6-C10)芳基或(5-10)-员杂环基；其中每个Ar1、Ar2、Ar3和Ar4的环碳原子任选被1～3个R13基团取代；Each of Ar 1 , Ar 2 , Ar 3 and Ar 4 represents (C 6 -C 10 ) aryl or (5-10)-membered heterocyclyl; wherein each of Ar 1 , Ar 2 , Ar 3 and Ar 4 Ring carbon atoms are optionally substituted by 1 to 3 R groups; 环A代表3、4、5、6或7-员环，任选包含1～4个可相同或不同选自-N(R10a)-、O和S(O)j的杂原子，其中j为0、1或2，条件是该环不含两个相邻的O或S(O)j原子；其中环A部分的碳原子任选被1～3个R13基团取代；Ring A represents a 3, 4, 5, 6 or 7-membered ring, optionally containing 1 to 4 heteroatoms which may be the same or different and selected from -N(R 10a )-, O and S(O) j , wherein j is 0, 1 or 2, provided that the ring does not contain two adjacent O or S(O) j atoms; wherein the carbon atoms of the ring A part are optionally substituted by 1 to 3 R groups; R9为(C1-C8)烷基、-(CR11R12)t(C6-C10)芳基或-(CR11R12)t(4-10)-员杂环基，其中t独立地为0、1、2、3、4或5，其中该R9基团被1～3个基团取代，这些基团独立地选自-(CR11R12)qNR10R11、-(CR11R12)qNR10(C1-C6)烷酰基、-(CR11R12)qO(CR11R12)rR10及-(CR11R12)qR10；其中前述基团的杂环基、芳基和烷基部分任选被1～3个R13基团取代；R 9 is (C 1 -C 8 ) alkyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl or -(CR 11 R 12 ) t (4-10)-membered heterocyclyl, Wherein t is independently 0, 1, 2, 3, 4 or 5, wherein the R 9 group is substituted by 1 to 3 groups, these groups are independently selected from -(CR 11 R 12 ) q NR 10 R 11 , -(CR 11 R 12 ) q NR 10 (C 1 -C 6 )alkanoyl, -(CR 11 R 12 ) q O(CR 11 R 12 ) r R 10 and -(CR 11 R 12 ) q R 10 ; wherein the heterocyclyl, aryl and alkyl parts of the aforementioned groups are optionally substituted by 1 to 3 R 13 groups; R9a和R10独立地为H或(C1-C8)烷基；R 9a and R 10 are independently H or (C 1 -C 8 ) alkyl; R11和R12独立地为H、(C1-C8)烷基、羟基或(C1-C6)烷氧基；R 11 and R 12 are independently H, (C 1 -C 8 ) alkyl, hydroxyl or (C 1 -C 6 ) alkoxy; R10a选自H、(C1-C8)烷基、-(C＝O)-R14、-SO2NR15R16或-S(O)j(C1-C6)烷基；R 10a is selected from H, (C 1 -C 8 ) alkyl, -(C=O)-R 14 , -SO 2 NR 15 R 16 or -S(O) j (C 1 -C 6 ) alkyl; 每个R13和R13a独立地选自卤素、氰基、硝基、三氟甲氧基、三氟甲基、叠氮基、羟基、(C1-C6)烷氧基、(C1-C10)烷基、(C2-C6)链烯基、(C2-C6)炔基、-O-(CR11R12)k-O-(CR11R12)n-、-(C＝O)-R14、-(C＝O)-O-R15、-O-(C＝O)-R15、-NR15(C＝O)-R16、-NR15(C＝O)-O-R16、-(C＝O)-NR15R16、-NR15R16、-NR15OR16、-SO2NR15R16、-S(O)j(C1-C6)烷基、-O-SO2-R14、-NR15-SO2-R16、R15-(CR11R12)t(C6-C10芳基)、-(CR11R12)t(4-10)-员杂环基、-(CR11R12)q(C＝O)(CR11R12)t(C6-C10)芳基、-(CR11R12)q(C＝O)(CR11R12)t(4-10)-员杂环基、-(CR11R12)tO(CR11R12)q(C6-C10)芳基、-(CR11R12)tO(CR11R12)q(4-10)-员杂环基、-(CR11R12)qSO2(CR11R12)t(C6-C10)芳基及-(CR11R12)qSO2(CR11R12)t(4-10)-员杂环；前述R13和R13a基团的杂环部分的1或2个环碳原子任选被氧代(＝O)基团取代，并且前述R13和R13a基团的烷基、链烯基、炔基、芳基和杂环部分任选被1～3个取代基取代，这些取代基独立地选自卤素、氰基、硝基、三氟甲基、三氟甲氧基、叠氮基、-OR15、-(C＝O)-R15、-(C＝O)-O-R15、-O-(C＝O)-R15、-NR15(C＝O)-R16、-(C＝O)-NR15R16、-NR15R16、-NR15OR16、(C1-C6)烷基、(C2-C6)链烯基、(C2-C6)炔基、-(CR11R12)t(C6-C10)芳基及-(CR11R2)t(4-10)-员杂环基；Each R 13 and R 13a is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 10 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -O-(CR 11 R 12 ) k -O-(CR 11 R 12 ) n -, -(C=O)-R 14 , -(C=O)-OR 15 , -O-(C=O)-R 15 , -NR 15 (C=O)-R 16 , -NR 15 (C= O)-OR 16 , -(C=O)-NR 15 R 16 , -NR 15 R 16 , -NR 15 OR 16 , -SO 2 NR 15 R 16 , -S(O) j (C 1 -C 6 ) alkyl, -O-SO 2 -R 14 , -NR 15 -SO 2 -R 16 , R 15 -(CR 11 R 12 ) t (C 6 -C 10 aryl), -(CR 11 R 12 ) t (4-10)-membered heterocyclyl, -(CR 11 R 12 ) q (C=O)(CR 11 R 12 ) t (C 6 -C 10 )aryl, -(CR 11 R 12 ) q (C=O)(CR 11 R 12 ) t (4-10)-membered heterocyclyl, -(CR 11 R 12 ) t O(CR 11 R 12 ) q (C 6 -C 10 )aryl, - (CR 11 R 12 ) t O(CR 11 R 12 ) q (4-10)-membered heterocyclyl, -(CR 11 R 12 ) q SO 2 (CR 11 R 12 ) t (C 6 -C 10 ) Aryl and -(CR 11 R 12 ) q SO 2 (CR 11 R 12 ) t (4-10)-membered heterocyclic ring; 1 or 2 ring carbon atoms of the heterocyclic part of the aforementioned R 13 and R 13a groups is optionally substituted by an oxo (=O) group, and the alkyl, alkenyl , alkynyl , aryl and heterocyclic moieties of the aforementioned R and R groups are optionally substituted by 1 to 3 substituents, These substituents are independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR 15 , -(C=O)-R 15 , -(C=O) -OR 15 , -O-(C=O)-R 15 , -NR 15 (C=O)-R 16 , -(C=O)-NR 15 R 16 , -NR 15 R 16 , -NR 15 OR 16. (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl And -(CR 11 R 2 ) t (4-10)-membered heterocyclyl; 每个R14、R15和R16独立地选自H、(C1-C6)烷基、-(CR11R12)t(C6-C10)芳基及-(CR11R12)t(4-10)-员杂环基；该杂环基团的1或2个环碳原子任选被氧代(＝O)基团取代，前述R14、R15和R16基团的烷基、芳基和杂环部分任选被1～3个取代基取代，这些取代基独立地选自卤素、氰基、硝基、-NR11R12、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C2-C6)链烯基、(C2-C6)炔基、羟基及(C1-C6)烷氧基；Each R 14 , R 15 and R 16 is independently selected from H, (C 1 -C 6 ) alkyl, -(CR 11 R 12 ) t (C 6 -C 10 ) aryl and -(CR 11 R 12 ) t (4-10)-membered heterocyclic group; 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted by an oxo (=O) group, and the aforementioned R 14 , R 15 and R 16 groups The alkyl, aryl and heterocyclic moieties of are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, -NR 11 R 12 , trifluoromethyl, trifluoromethyl Oxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy and (C 1 -C 6 )alkoxy; R17为H、(C1-C8)烷基、-O-(C1-C8)烷基、卤素、CN、OH、CF3或-O-CF3；R 17 is H, (C 1 -C 8 ) alkyl, -O-(C 1 -C 8 ) alkyl, halogen, CN, OH, CF 3 or -O-CF 3 ; 其中，上面提及的包括不与卤素、SO或SO2基团或不与N、O或S原子连接的CH3(甲基)、CH2(亚甲基)或CH(次甲基)的任何取代基，任选在所述的基团上连接选自羟基、卤素、(C1-C4)烷基、(C1-C4)烷氧基、-NH2、-NH(C1-C8)烷基及-N((C1-C8)烷基)2的取代基。Among them, the above-mentioned CH 3 (methyl), CH 2 (methylene) or CH (methine) not linked to halogen, SO or SO 2 groups or to N, O or S atoms Any substituent, optionally attached to the group selected from hydroxyl, halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, -NH 2 , -NH(C 1 Substituents of -C 8 )alkyl and -N((C 1 -C 8 )alkyl)2. 2.根据权利要求1的化合物，其中R3为2. The compound according to claim 1, wherein R 3 is
Figure A2004800167360005C1
Figure A2004800167360005C1
 3.根据权利要求1的化合物，其中R3为3. The compound according to claim 1, wherein R 3 is 4.根据权利要求1的化合物，其中R3为4. according to the compound of claim 1, wherein R 3 is
Figure A2004800167360005C3
Figure A2004800167360005C3
 5.根据权利要求1的化合物，其中R3为5. The compound according to claim 1, wherein R 3 is
Figure A2004800167360005C4
Figure A2004800167360005C4
 6.根据权利要求2的化合物，具有通式6. A compound according to claim 2, having the general formula 其中所述的-Ar1-Ar2选自Wherein said -Ar 1 -Ar 2 is selected from 和 and 其中每个Ar1和Ar2的环碳原子任选被1～3个R13基团取代，所述的R13基团选自卤素、(C1-C8)烷基及(C1-C8)烷氧基。wherein the ring carbon atoms of each of Ar 1 and Ar 2 are optionally substituted by 1 to 3 R 13 groups, and the R 13 groups are selected from halogen, (C 1 -C 8 ) alkyl and (C 1 - C 8 ) alkoxy. 7.根据权利要求2的化合物，选自7. A compound according to claim 2, selected from the group consisting of 1-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)环丁烷羧酸(实施例A-4)；1-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl}oxygen base) cyclobutanecarboxylic acid (Example A-4); 2-({3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]-1，1′-联苯-3-基}氧基)丁酸(实施例A-5)；2-({3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1,1'-biphenyl-3-yl}oxy base) butyric acid (Example A-5); 2-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)丁酸(实施例A-6)；2-(3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)butanoic acid ( Embodiment A-6); 1-(3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}苯氧基)环丁烷羧酸(实施例A-7)；1-(3-{6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}phenoxy)cyclobutane Carboxylic acid (Example A-7); 1-[(3′-{[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]甲氧基}联苯-3-基)氧基]环丁烷羧酸(实施例A-11)；1-[(3'-{[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}biphenyl-3-yl)oxyl]ring Butane carboxylic acid (Example A-11); 1-({3′-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]联苯-3-基}氧基)环丁烷羧酸(实施例A-12)；1-({3'-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]biphenyl-3-yl}oxy)cyclobutanecarboxy Acid (Example A-12); 1-1(3′-{[5-(4-甲氧基苯基)-1，2，4-噁二唑-3-基]甲氧基}联苯-3-基)氧基]环丁烷羧酸(实施例A-17)；1-1(3'-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}biphenyl-3-yl)oxy]ring Butane carboxylic acid (Example A-17); 2-[(3′-{2-[2-(3-氟苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}联苯-3-基)氧基]-2-甲基丙酸(实施例A-21)；2-[(3'-{2-[2-(3-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}biphenyl-3-yl)oxy ]-2-methylpropionic acid (Example A-21); 2-甲基-2-({3′-[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]联苯-3-基}氧基)丙酸(实施例A-24)；2-methyl-2-({3'-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]biphenyl-3-yl}oxy)propane Acid (Example A-24); 2-乙氧基-3-{3′-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]联苯-3-基}丙酸(实施例A-28)；2-Ethoxy-3-{3'-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]biphenyl-3-yl}propanoic acid (Embodiment A-28); 及其可药用盐。and pharmaceutically acceptable salts thereof. 8.根据权利要求3的化合物，具有通式：8. A compound according to claim 3, having the general formula: 其中Y为-(C＝O)-或-SO2-，Y″为NR10，及p为1。wherein Y is -(C=O)- or -SO 2 -, Y" is NR 10 , and p is 1. 9.根据权利要求3的化合物，选自9. The compound according to claim 3, selected from the group consisting of 2-甲基-2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丙酸(实施例B-5)；2-methyl-2-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]benzene Oxy}propionic acid (Example B-5); 2-甲基-2-{3-[({[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]羰基}氨基)甲基]苯氧基}丙酸(实施例B-6)；2-methyl-2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]carbonyl}amino)methyl]phenoxy } propionic acid (embodiment B-6); 2-甲基-2-{4-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯氧基}丙酸(实施例B-7)；2-methyl-2-{4-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl]benzene Oxy}propionic acid (Example B-7); 2-{3-氟-4-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}-2-甲基丙酸(实施例B-9)；2-{3-fluoro-4-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy Base}-2-methylpropionic acid (Example B-9); 2-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}丁酸(实施例B-13)；2-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}butanoic acid (embodiment B-13); 2-{3-[({[(5-甲基-2-苯基-1，3-噁唑-4-基)甲氧基]羰基}氨基)甲基]苯氧基}丁酸(实施例B-14)；2-{3-[({[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]carbonyl}amino)methyl]phenoxy}butanoic acid (implementation Example B-14); 1-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯氧基}环丁烷羧酸(实施例B-15)；1-{3-[({[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl]phenoxy}cyclobutane Alkanecarboxylic acids (Example B-15); 2-甲基-2-(3-{[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙基]氨基}羰基)氧基]甲基}苯氧基)丙酸(实施例B-21)；2-methyl-2-(3-{[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl]amino}carbonyl)oxy]methanol Base}phenoxy)propionic acid (Example B-21); 2-乙氧基-3-{3-[({[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]羰基}氨基)甲基]苯基}丙酸(实施例B-23)；2-Ethoxy-3-{3-[({[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]carbonyl}amino)methyl] Phenyl}propionic acid (Example B-23); 2-乙氧基-3-{3-[({[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]羰基}氨基)甲基]苯基}丙酸(实施例B-24)；2-Ethoxy-3-{3-[({[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbonyl}amino)methyl] Phenyl}propionic acid (Example B-24); 及其可药用盐。and pharmaceutically acceptable salts thereof. 10.根据权利要求4的化合物，具有通式：10. The compound according to claim 4, having the general formula: 其中，环A选自环丙基、环丁基、环戊基、环己基、Wherein, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure A2004800167360008C3
和
Figure A2004800167360008C4
Figure A2004800167360008C3
and
Figure A2004800167360008C4
 其中---为任选的双键。Where --- is an optional double bond. 11.根据权利要求4的化合物，选自11. A compound according to claim 4, selected from the group consisting of 1-{4-[3-(5-甲基-2-苯基-1，3-噁唑-4-基)丙氧基]苄基}环丁烷羧酸(实施例C-16)；1-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propoxy]benzyl}cyclobutanecarboxylic acid (Example C-16); 1-{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}环丁烷羧酸(实施例C-19)；1-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}cyclobutanecarboxylic acid (Example C-19); 2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢呋喃-2-羧酸(实施例C-48)；2-({6-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydrofuran-2-carboxylic acid (Embodiment C-48); 2-({5-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-2-基}甲基)四氢呋喃-2-羧酸(实施例C-49)；2-({5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-2-yl}methyl)tetrahydrofuran-2-carboxylic acid (Embodiment C-49); 2-({6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}甲基)四氢-2H-吡喃-2-羧酸(实施例C-56)；2-({6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}methyl)tetrahydro-2H-pyridine Fran-2-carboxylic acid (Example C-56); 2-[(6-{2-[2-(3-氯苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}吡啶-3-基)甲基]四氢呋喃-2-羧酸(实施例C-59)；2-[(6-{2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)methyl]tetrahydrofuran -2-carboxylic acid (Example C-59); 2-[(6-{2-[2-(3-甲基氧基苯基)-5-甲基-1，3-噁唑-4-基]乙氧基}吡啶-3-基)甲基]四氢呋喃-2-羧酸(实施例C-62)；2-[(6-{2-[2-(3-methyloxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}pyridin-3-yl)methyl Base] tetrahydrofuran-2-carboxylic acid (Example C-62); 2-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡嗪-2-基甲基}-四氢呋喃-2-羧酸(实施例C-77)；2-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyrazin-2-ylmethyl}-tetrahydrofuran-2-carboxylic acid (implementation Example C-77); -{4-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]苄基}四氢呋喃-2-羧酸(实施例C-78)；-{4-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}tetrahydrofuran-2-carboxylic acid (Example C-78); 2-{6-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-萘-2-基甲基}-四氢呋喃-2-羧酸(实施例C-91)；2-{6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalene-2-ylmethyl}-tetrahydrofuran-2-carboxylic acid (Example C-91); 及其可药用盐。and pharmaceutically acceptable salts thereof. 12.根据权利要求5的化合物，具有通式：12. The compound according to claim 5, having the general formula:
Figure A2004800167360009C1
或
Figure A2004800167360009C1
or
Figure A2004800167360009C2
Figure A2004800167360009C2
 13.根据权利要求12的化合物，选自13. A compound according to claim 12, selected from the group consisting of 2-乙氧基-3-{6-[2-(5-甲基-2-苯基-1，3-噁唑-4-基)乙氧基]吡啶-3-基}丙酸(实施例D-1)；2-ethoxy-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}propanoic acid (implementation Example D-1); 2-甲氧基-3-(6-{2-[5-甲基-2-(3-甲基苯基)-1，3-噁唑-4-基]乙氧基}吡啶-3-基)丙酸(实施例D-3)；2-methoxy-3-(6-{2-[5-methyl-2-(3-methylphenyl)-1,3-oxazol-4-yl]ethoxy}pyridine-3- base) propionic acid (Example D-3); 2-甲氧基-3-{6-[2-(4-苯氧基苯基)乙氧基]吡啶-3-基}丙酸(实施例D-13)；2-methoxy-3-{6-[2-(4-phenoxyphenyl)ethoxy]pyridin-3-yl}propionic acid (Example D-13); 2-乙氧基-3-[6-(2-{4-[(苯基磺酰基)氧基]苯基}乙氧基)吡啶-3-基]丙酸(实施例D-17)；2-ethoxy-3-[6-(2-{4-[(phenylsulfonyl)oxy]phenyl}ethoxy)pyridin-3-yl]propanoic acid (Example D-17); 2-乙氧基-3-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-2-基}-丙酸(实施例D-23)；2-Ethoxy-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}-propionic acid (Example D-23); 2-甲氧基-2-甲基-3-{6-[3-(5-甲基-2-苯基-噁唑-4-基)-丙氧基]-吡啶-3-基}-丙酸(实施例D-27)；2-Methoxy-2-methyl-3-{6-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propoxy]-pyridin-3-yl}- Propionic acid (Example D-27); 2-甲氧基-2-甲基-3-{5-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-吡啶-2-基}-丙酸(实施例D-29)；2-Methoxy-2-methyl-3-{5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-pyridin-2-yl}- Propionic acid (Example D-29); 3-(6-{2-[2-(4-氯-苯基)-5-甲基-噁唑-4-基]-乙氧基}-吡啶-3-基)-2-甲氧基-2-甲基-丙酸(实施例D-30)；3-(6-{2-[2-(4-Chloro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridin-3-yl)-2-methoxy - 2-methyl-propionic acid (Example D-30); 2-甲氧基-2-甲基-3-{6-[2-(5-甲基-2-苯基噁唑-4-基)-乙氧基]-吡啶-3-基}-丙酸(实施例D-35)；2-Methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-pyridin-3-yl}-propane Acid (Example D-35); 2-甲氧基-3-(6-{2-[2-(3-甲氧基-苯基)-5-甲基-噁唑-4-基]-乙氧基}-吡啶-3-基)-2-甲基-丙酸(实施例D-43)；2-Methoxy-3-(6-{2-[2-(3-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-pyridine-3- base)-2-methyl-propionic acid (Example D-43); 及其可药用盐。and pharmaceutically acceptable salts thereof. 14.一种治疗哺乳动物非胰岛素依赖性糖尿病、多囊性卵巢综合征、肥胖症、高血糖症、高脂血症、高胆固醇血症、动脉粥样硬化、高甘油三酯血症、高胰岛素血症、异常胰岛素和/或葡萄糖失调的迹象、胰岛素耐受综合征及PPAR相关疾病的方法，包括向需要治疗的哺乳动物给药治疗有效量的权利要求1的α取代羧酸化合物。14. A treatment for non-insulin-dependent diabetes mellitus, polycystic ovary syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertriglyceridemia, high A method for insulinemia, signs of abnormal insulin and/or glucose dysregulation, insulin resistance syndrome and PPAR-related diseases, comprising administering a therapeutically effective amount of an alpha-substituted carboxylic acid compound of claim 1 to a mammal in need thereof. 15.一种包括至少一种权利要求1所述的化合物及其可药用载体的组合物；该化合物优选与其它药物如α-葡萄糖苷酶抑制剂、醛糖还原酶抑制剂、双胍制剂、他汀类化合物、鲨烯合成抑制剂、贝特类化合物、LDL代谢促进剂及血管紧张素转换酶抑制剂联合使用。15. A composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier thereof; the compound is preferably combined with other drugs such as α-glucosidase inhibitors, aldose reductase inhibitors, biguanide preparations, Statins, squalene synthesis inhibitors, fibrates, LDL metabolism promoters and angiotensin-converting enzyme inhibitors are used in combination.
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