WO2008110062A1

WO2008110062A1 - Compounds with partial agonist activity of pparϝ and application thereof

Info

Publication number: WO2008110062A1
Application number: PCT/CN2008/000441
Authority: WO
Inventors: Jianhui Guo; Yong Jiang
Original assignee: Shanghai Allist Pharmaceuticals, Inc.
Priority date: 2007-03-09
Filing date: 2008-03-05
Publication date: 2008-09-18
Also published as: CN101627030A; CN101260103A

Abstract

The present invention discloses compounds with partial agonist activity of PPARϜ represented by formula?,pharmaceutical salts thereof, their preparation, pharmaceutical compositions containing the compounds or their pharmaceutical salts, and their application in the preparation of medicine used for the treatment and/or prevention of the diseases associated with PPARϜ, such as diabetes, diseases associated with blood sugar singularly rising, metabolic syndrome or adiposity.

Description

具有 PPAR γ部分激动剂活性的化合物及其应用技术领域 Compound having PPAR γ partial agonist activity and application thereof

本发明涉及具有 PPAR γ部分激动剂活性的化合物或其药学上可接受的盐、其制备方法、包含该化合物或其药学上可接受的盐的药物组合物及其在制备用于治疗和 /或预防 PPAR γ受体相关的疾病的药物中的应用，如糖尿病、血糖异常升高相关疾病、代谢综合症或肥胖症。背景技术 The present invention relates to a compound having PPAR gamma partial agonist activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition comprising the same or a pharmaceutically acceptable salt thereof, and the preparation thereof for use in therapy and/or Use in drugs that prevent PPAR gamma receptor-related diseases, such as diabetes, elevated blood sugar abnormalities, metabolic syndrome, or obesity. Background technique

糖尿病是由多种基因紊乱导致的疾病，它在全球范围内影响着人类的健康。糖尿病可分为两种类型：（1) I型糖尿病或胰岛素依赖型糖尿病（ IDDM )，其患者分泌极少或根本不分泌胰岛素，病人必须每天注射胰岛素；（2) II型糖尿病或非胰岛素依赖型糖尿病（ MDDM )， II型糖尿病患者血浆胰岛素的浓度与正常人基本相同，主要是胰岛素的敏感性降低、作用不正常导致胰岛素相对不足，这会进一步影响糖和脂肪在对胰岛素敏感的组织即肌肉、肝脏和脂肪组织中的代谢。 Π型糖尿病发病率高，约占糖尿病患者的 90%。 Diabetes is a disease caused by a variety of genetic disorders that affect human health on a global scale. Diabetes can be divided into two types: (1) Type I diabetes or insulin-dependent diabetes mellitus (IDDM), in which patients have little or no insulin secretion, patients must be injected with insulin daily; (2) Type II diabetes or non-insulin dependence Type 2 diabetes mellitus (MDDM), the level of plasma insulin in patients with type II diabetes is basically the same as that of normal people, mainly due to the decreased sensitivity of insulin and the abnormal function of insulin, which leads to the relative deficiency of insulin, which further affects the sugar and fat in insulin-sensitive tissues. Metabolism in muscle, liver and adipose tissue. The incidence of sputum diabetes is high, accounting for about 90% of diabetic patients.

近来研究发现， II型糖尿病与过氧化物酶增殖体活化受体 (peroxisome proliferators-activated receptor, PPAR)存在密切的关系。 PPAR属于由配体激活的转录因子 -核激素受体超家族中的一员，它可以和维甲酸 X受体（RXR)形成异二聚体，并与目标基因上的激素响应元件结合而激活基因表达。 PPAR/ RXR异二聚体在控制细胞脂质动态平衡和脂肪细胞分化方面起着重要作用。哺乳动物的 PPAR可分为 3个亚型，即 PPARa、 PPAR γ和 PPAR δ。其中 PPAR γ主要在脂肪组织相关基因的表达和分化方面起着重要的调控作用，也是葡萄糖和脂类代谢靶基因的重要调节因子。 PPARa刺激过氧化物酶的增殖，加速脂肪酸的氧化，从而减少血液中的脂肪酸含量， PPARa激动剂如纤维酸衍生物（Fibrates ) 可用于治疗血脂异常。 Recent studies have found that type II diabetes is closely related to peroxisome proliferators-activated receptor (PPAR). PPAR belongs to a member of the ligand-activated transcription factor-nuclear hormone receptor superfamily, which forms a heterodimer with the retinoic acid X receptor (RXR) and is activated by binding to a hormone response element on the target gene. gene expression. PPAR/RXR heterodimers play an important role in controlling cellular lipid homeostasis and adipocyte differentiation. Mammalian PPAR can be divided into three subtypes, namely PPARa, PPAR γ and PPAR δ. Among them, PPAR γ plays an important role in the regulation and expression of adipose tissue-related genes, and is also an important regulator of glucose and lipid metabolism target genes. PPARa stimulates the proliferation of peroxidase, accelerates the oxidation of fatty acids, and thus reduces the fatty acid content in the blood. PPARa agonists such as fibrate derivatives (Fibrates) can be used to treat dyslipidemia.

目前市场上的口服降血糖药物主要包括 5大类，即磺脲类、双胍类、 α—葡萄糖香制剂、 |坐坑二酮类（Thiazolidinediones, TZD)和钾通道阻滞剂。最近发展的 TZD类化合物是以 PPAR γ为作用靶点的新型胰岛素增敏剂，能够提高机体对胰岛素的敏感性，从而纠正糖代谢异常，降低高糖毒性。然而这类具有完全的 PPARy激动剂活性的药物，如已上市的罗格列酮（Rosiglitazone, 文迪雅， Avandia)和吡格列酮 (Pioglitazone, 艾汀， Actos) , 在临床应用过程中，会产生诸如病人体重增加、水肿、脂肪组织激增、骨髓脂肪酸改变等副作用。研究表明 TZD类药物是通过激动 PPARy来调节脂肪细胞的分化进而提高胰岛素的敏感性，这同时也能加剧体内的脂肪储藏进而产生体重增加等副作用。 Oral hypoglycemic drugs currently on the market mainly include five major categories, namely sulfonylureas, biguanides, alpha-glucose formulations, Thiazolidinediones (TZD) and potassium channel blockers. Recently developed TZD compounds are novel insulin sensitizers that target PPAR γ, which can improve the body's sensitivity to insulin, thereby correcting abnormal glucose metabolism and reducing high glucose toxicity. However, such drugs with complete PPARy agonist activity, For example, rosiglitazone (Rosiglitazone, Avandia) and pioglitazone (Pioglitazone, Attenin, Actos), such as patient weight gain, edema, adipose tissue ablation, bone marrow fatty acid changes during clinical application And other side effects. Studies have shown that TZD drugs modulate the differentiation of fat cells by activating PPARy to increase the sensitivity of insulin, which can also aggravate the body's fat storage and cause side effects such as weight gain.

完全的 PP AR γ激动剂临床应用的安全问题给 PP AR γ激动剂在糖尿病治疗中的应用带来了巨大的挑战。为此本领域迫切需要寻找一类新型的 PPARy部分激动剂，其应保留能使胰岛素增敏的有益作用且具有较小的副作用。部分激动剂（ partial agonist ) —般具有一定的亲和力，但其内在活性低，与受体结合后只能产生较弱的效应，即使浓度增加，也不能达到完全激动剂（full agonist ) 那样的最大效应。但是高浓度的部分激动剂的存在则会占领受体，拮抗完全激动剂的作用。 The safety of clinical applications of complete PP AR gamma agonists poses significant challenges for the use of PP AR gamma agonists in the treatment of diabetes. To this end, there is an urgent need in the art to find a new class of PPARy partial agonists that retain the beneficial effects of insulin sensitization and have fewer side effects. A partial agonist generally has a certain affinity, but its intrinsic activity is low, and it can only produce a weak effect when combined with a receptor. Even if the concentration is increased, it cannot reach the maximum of a full agonist. effect. However, the presence of a high concentration of a partial agonist will occupy the receptor and antagonize the action of a full agonist.

Metabolex公司在研的口服降血糖药 Metaglidasen具有与罗格列酮不同的化学结构母核。研究表明 MeUglidasen是 PPARy部分激动剂，可选择性地调节改善胰岛素敏感性的基因，而不会激活体重增加和液体潴留的基因。 Metabolda's oral hypoglycemic agent Metaglidasen has a different chemical structure than the rosiglitazone. Studies have shown that MeUglidasen is a PPARy partial agonist that selectively modulates genes that improve insulin sensitivity without activating genes that increase weight and fluid retention.

W09402467公开了一系列咪唑醚化合物，所述化合物具有血管紧张素 II ( Angiotensin II， AT II ) 受体拮抗剂的活性。发明综述 W09402467 discloses a series of imidazole ether compounds having an activity of an angiotensin II (AT II ) receptor antagonist. Summary of invention

本发明所要解决的技术问题是提供一类具有 P P A R γ部分激动剂活性的新型化合物（如下式结构 I )或其药学上可接受的盐、其制备方法、包含该化合物或其药学上可接受的盐的组合物及其在制备用于治疗和 /或预防 PPAR γ受体相关的疾病，如糖尿病、血糖异常升高相关疾病、代谢综合症或肥胖症中的应用。 The technical problem to be solved by the present invention is to provide a novel compound having a PPAR gamma partial agonist activity (structure I as follows) or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, or a pharmaceutically acceptable compound thereof A composition of a salt and its use in the preparation of a disease associated with the treatment and/or prevention of a PPAR gamma receptor, such as diabetes, a disease associated with elevated blood glucose abnormalities, metabolic syndrome or obesity.

本发明提供了以下技术方案： The invention provides the following technical solutions:

1. 结构通式（ I ) 所示化合物.' 1. A compound of the formula (I).'

或其药学上可接受的盐，

Or a pharmaceutically acceptable salt thereof,

其中，选自卤素、 d-C₄烷基、卤素取代的 d- C₄烷基、 d-C₄烷氧基、 C₃-C₇环烷基、羟基、氰基、 C,-C₄烷氧羰基、芳香环以及含至少一个选自 N、 S和 0杂原子的杂芳环；和 Wherein, selected from halogen, dC ₄ alkyl, halogen-substituted d-C ₄ alkyl, dC ₄ alkoxy, C ₃ -C ₇ cycloalkyl, hydroxy, cyano, C,-C ₄ alkoxycarbonyl, An aromatic ring and a heteroaryl ring containing at least one hetero atom selected from N, S and 0;

n= 1 ~ 5，且为整数。 n= 1 ~ 5, and is an integer.

2. 如技术方案 1所述的化合物，其中选自卤素、 C,-C₄烷基、卤素取代的 d- C₄烷基和氰基。 2. The compound according to claim 1, which is selected from the group consisting of halogen, C, -C ₄ alkyl, halogen-substituted d-C ₄ alkyl and cyano.

3. 如技术方案 1或 2所述的化合物，其中 n= l或 2。 3. The compound according to claim 1 or 2, wherein n = 1 or 2.

4. 如技术方案 3所述的化合物，其中 n= l，且是 3位或 4位取代基 4. The compound according to claim 3, wherein n = l, and is a 3- or 4-position substituent

如技术方案 4所述的化合物，其中 1 ,是4位取代基。 The compound according to claim 4, wherein 1 is a 4-substituent.

6. 如技术方案 3所述的化合物，其中 n= 2, 且 ^是 2位和 5位取代基。 6. The compound according to claim 3, wherein n = 2, and ^ is a 2- and 5-position substituent.

7. 如技术方案 6所述的化合物，其中 R,选自卤素、基和卤素取代的 {,- C₄烷基。 7. The compound according to claim 6, wherein R is selected from the group consisting of halogen, a group and a halogen-substituted {,-C ₄ alkyl group.

8. 如技术方案 1 所述的化合物，其中所述化合物为选自下组的化合物： 8. The compound according to claim 1, wherein the compound is a compound selected from the group consisting of:

1 ) 2-丁基- 4-氯- 1- {[2'-(1〃-四唑 -5-基） - -联苯 -4-基]甲基 }-5- [(4-氟苄氧基）甲基] -1〃-咪唑； 1) 2-Butyl- 4-chloro- 1- {[2'-(1〃-tetrazol-5-yl)--biphenyl-4-yl]methyl}-5- [(4-fluorobenzyl) Oxy)methyl]-1 〃-imidazole;

2 ) 2-丁基- 4-氯- 1- {[2'- (1 -四唑- 5-基）-： -联苯 -4-基]甲基} -5- [ (4-溴苄氧基）甲基] 咪唑； 2) 2-Butyl- 4-chloro- 1- {[2'-(1-tetrazol-5-yl)-:-biphenyl-4-yl]methyl}-5-[(4-bromobenzyl) Oxy)methyl]imidazole;

3 ) 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基）-： -联苯 -4-基]曱基} -5- [ (4-甲基苄氧基）曱基] - 咪唑； 3) 2-butyl-4-chloro-1- <{2'-tetrazole-5-yl)-:-biphenyl-4-yl]fluorenyl}-5-[(4-methylbenzyloxy) ) thiol] - imidazole;

4 ) 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基） -联苯 -4-基]甲基}-5- [ (4-三氟曱基苄氧基）甲基] - 1 ^咪唑； 4) 2-Butyl- 4-chloro-1-({[2'-tetrazol-5-yl)-biphenyl-4-yl]methyl}-5-[(4-trifluorodecylbenzyloxy) )methyl] - 1 ^imidazole;

5 ) 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基） - -联笨 -4-基]甲基 }- 5- [ (4-氰基苄氧基）甲基] - 咪唑； 5) 2-Butyl- 4-chloro-1-({[2'-tetrazole-5-yl)--phenyl]-4-yl]methyl}- 5-[(4-cyanobenzyloxy) Methyl]-imidazole;

6 ) 2-丁基- 4 -氯- 1- {[2'- 四唑 -5-基） -： -联苯 -4-基]甲基 }-5- [(3-氟苄氧基）甲基咪唑； 6) 2-butyl-4-chloro-1-su {[2'-tetrazol-5-yl)-:-biphenyl-4-yl]methyl}-5-[(3-fluorobenzyloxy) Methylimidazole

7 ) 2-丁基- 4 -氯- 1- {[2'- 四唑- 5-基） - -联苯 -4-基]甲基 }-5_[(3-三氟甲基苄氧基）甲基 ]_1 ^咪唑； 7) 2-Butyl-4-chloro-1-su {[2'-tetrazol-5-yl)--biphenyl-4-yl]methyl}-5-[(3-trifluoromethylbenzyloxy) )methyl]_1 ^imidazole;

8 ) 2-丁基- 4-氯- 1- {[2'- (1# -四唑 - 5-基） - -联苯 -4-基]甲基 }- 5- [(2， 5-二氟苄氧基）曱基] - 咪唑；和 9 ) 2-丁基- 4-氯- 1-{[2'- 四唑- 5-基） -1， 1'-联苯 -4-基]甲基} -5- { [2， 5-二（三氟甲基）苄氧基]甲基 } - 1 咪唑。 8) 2-butyl- 4-chloro- 1- {[2'-(1#-tetrazol-5-yl)--biphenyl-4-yl]methyl}- 5- [(2, 5- Difluorobenzyloxy)indolyl]-imidazole; 9) 2-butyl-4-chloro-1-{[2'-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl} -5- { [2, 5- Bis(trifluoromethyl)benzyloxy]methyl}-1 imidazole.

9. 一种制备技术方案 1-8中任一项所述化合物的方法，包括步骤： 9. A method of preparing the compound of any one of claims 1-8, comprising the steps of:

A) ：将三苯甲基氯沙坦（ΠΙ)溶于溶剂中，在碱存在下，与相应的苄溴衍生物（Π)发生成醚反应得到相应的中间体（IV)； A): triphenylmethyl valsartan (hydrazine) is dissolved in a solvent, and reacted with the corresponding benzyl bromide derivative (hydrazine) in the presence of a base to obtain the corresponding intermediate (IV);

B) ：将所得中间体（IV)溶于溶剂中，在碱存在下，加热脱除保护基得到目标化合物（I) ; B): The obtained intermediate (IV) is dissolved in a solvent, and the protecting group is removed by heating in the presence of a base to obtain the target compound (I);

以及任选的步骤 C) : 将所得化合物与合适的无机酸或者有机酸形成酸加成盐或者与合适的无机碱或者有机碱形成碱加成盐。

And optional step C): forming the acid addition salt of the compound obtained with a suitable inorganic or organic acid or a base addition salt with a suitable inorganic or organic base.

10. 一种药物组合物，所述药物组合物包含技术方案 1至 8中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. 如技术方案 10所述的药物组合物，其还包含一种或多种其他降血糖药。 11. The pharmaceutical composition of claim 10, further comprising one or more other hypoglycemic agents.

12. 如技术方案 11 所述的药物组合物，其中所述其他降血糖药选自磺脲类药物、双胍类药物、 α_葡萄糖苷酶抑制剂和二酮类药物，优选所述其他降血糖药选自甲磺丁脲、格列本脲、格列吡嗪、苯乙双胍、二曱双胍、丁双胍、阿卡波糖、米格列醇、伏格列波糖、罗格列酮和吡格列酮。 12. The pharmaceutical composition according to claim 11, wherein the other hypoglycemic agent is selected from the group consisting of a sulfonylurea, a biguanide, an alpha-glucosidase inhibitor, and a diketone, preferably the other hypoglycemic The drug is selected from the group consisting of metobutyramide, glibenclamide, glipizide, phenformin, diterpene, diammonium, acarbose, miglitol, voglibose, rosiglitazone, and Pioglitazone.

13. 如技术方案 10所述的药物组合物，其中所述药物组合物为技术方案 1 至 8 中任一项所述的化合物或其药学上可接受的盐的含量为 0.6mg-12g, 优选为 0.6mg- 6g，更优选为 0.6mg- 3g的单位剂量的药物。 The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in an amount of from 0.6 mg to 12 g, preferably It is a unit dose of the drug of 0.6 mg to 6 g, more preferably 0.6 mg to 3 g.

14. 如技术方案 10至 13中任一项所述的药物组合物，其中所述药物组合物为口服制剂、直肠给药制剂、肠胃外给药制剂或局部给药制剂。 15. 如技术方案 1-8中任一项所述的化合物或其药学上可接受的盐或技术方案 10至 13中任一项所述的药物组合物在制备用于治疗和 /或预防 PPAR γ受体相关的疾病的药物中的应用。 The pharmaceutical composition according to any one of claims 10 to 13, wherein the pharmaceutical composition is an oral preparation, a rectal administration preparation, a parenteral administration preparation or a topical preparation. 15. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 10 to 13 for use in the preparation and/or prevention of PPAR The use of drugs for gamma receptor-related diseases.

16. 如技术方案 15所述的应用，其中所述疾病选自糖尿病、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症。 16. The use according to claim 15, wherein the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.

17. 如技术方案 16所迷的应用，其中所述疾病为糖尿病或血糖异常升高相关疾病。 17. The use according to claim 16, wherein the disease is diabetes or a disease associated with elevated blood sugar abnormalities.

18. —种治疗和 /或预防哺乳动物 PPAR γ受体相关的疾病的方法，包括将治疗和 /或预防有效量的技术方案 1-8中任一所述的化合物或其药学上可接受的盐或技术方案 10至 13 中任一项所述的药物组合物给予需要的哺乳动物。 18. A method of treating and/or preventing a PPAR gamma receptor-associated disease in a mammal, comprising administering a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable thereof The salt or the pharmaceutical composition according to any one of claims 10 to 13 is administered to a mammal in need thereof.

19. 如技术方案 18所述的方法，其中所述疾病选自糖尿病、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症。 19. The method of claim 18, wherein the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.

20. 如技术方案 19所述的方法，其中所述疾病为糖尿病或血糖异常升高相关疾病。 20. The method of claim 19, wherein the disease is diabetes or a disease associated with elevated blood glucose abnormalities.

21. 如技术方案 18至 20中任一项所述的方法，其中进一步包括将其他的降血糖药物与技术方案 1 至 8 中任一项所述的化合物或其盐或技术方案 10至 13 中任一项所述的药物组合物同时或顺序地给予需要的哺乳动物。发明详述 The method according to any one of claims 18 to 20, further comprising the other hypoglycemic agent and the compound according to any one of claims 1 to 8 or a salt thereof or the technical solutions 10 to 13 The pharmaceutical composition of any of the above is administered to a mammal in need thereof simultaneously or sequentially. Detailed description of the invention

本发明的第一方面，提供了一种通式（ I ) 所示的化合物或其药学上可接受的盐： According to a first aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

其中，选自卤素、 C,- C₄烷基、卤素取代的 d- C₄烷基、 C,-C₄烷氧 C₃- (₇环烷基、羟基、氰基、 _(₄烷氧羰基、芳香环以及含至少一个选自 N、 S和 0杂原子的杂芳环，优选为卤素、 C,-^烷基、卤素取代的 ( ₄烷基或者氰基; Wherein, selected from halogen, C, -C ₄ alkyl, halogen-substituted d-C ₄ alkyl, C,-C ₄ alkoxy C ₃ - ( ₇ -cycloalkyl, hydroxy, cyano, _( ₄ alkoxy) a carbonyl group, an aromatic ring, and at least one a heteroaryl ring selected from the group consisting of N, S and 0 heteroatoms, preferably halogen, C, -alkyl, halogen substituted ( ₄ alkyl or cyano;

n = 1 ~ 5 , 且为整数，优选为 1或 2。 n = 1 ~ 5 and is an integer, preferably 1 or 2.

在本发明提供的一个优选的方案中， n = 1， ^是 3位或 4位取代基，其中选自卤素、 C,-C₄烷基、卤素取代的 C,-C₄烷基和氰基。 In a preferred embodiment provided by the present invention, n = 1, ^ is a 3- or 4-position substituent selected from the group consisting of halogen, C, -C ₄ alkyl, halogen-substituted C, -C ₄ alkyl and cyanide base.

在本发明提供的一个更为优选的方案中， n = l， 1^是4位取代基，其中 R,选自卤素、 d- C₄烷基、卤素取代的 d-C₄烷基和氰基。 In a more preferred embodiment provided by the present invention, n = 1, 1 is a substituent at the 4-position, wherein R is selected from the group consisting of halogen, d-C ₄ alkyl, halogen-substituted dC ₄ alkyl, and cyano.

在本发明提供的另一个优选的方案中， n = 2 , 是2位和 5位取代基，其中选自卤素、 C,- C₄烷基、卤素取代的 d-C₄烷基和氰基。 In another preferred embodiment provided by the present invention, n = 2 is a substituent at the 2-position and the 5-position, wherein is selected from the group consisting of halogen, C, -C ₄ alkyl, halogen-substituted dC ₄ alkyl, and cyano.

在本发明提供的另一个更为优选的方案中， n = 2 , 是2位和 5位取代基，其中选自卤素、 d- C₄烷基和卤素取代的 C,- C₄烷基。 In another more preferred embodiment provided by the present invention, n = 2 is a substituent at the 2-position and the 5-position, wherein is selected from the group consisting of halogen, d-C ₄ alkyl and halogen-substituted C,-C ₄ alkyl.

在本发明中，卤素是指氟、氯、溴或碘，优选氟、氯或溴； C,-C₄ 烷基是指含有 1 ~ 4个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基，优选甲基、乙基、丙基、异丙基，最优选甲基、乙基； d- (：₄烷氧基是指含有 1 ~ 4个碳原子的烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基或叔丁氧基； C₃- C₇环烷基是指含有 3 ~ 7个碳原子的环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基； C₄烷氧羰基可以是甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、仲丁氧羰基或叔丁氧羰基；芳香环包括具有单环、双环或多环*** 的芳香性环，例如苯、萘等；含至少一个选自 ^ S和 0杂原子的杂芳环是指至少含有一个选自 N、 S和 0杂原子且具有单环、双环或多环系统的杂芳环，例如吡咯、噻吩、呋喃、噁唑、吡啶、嘧啶、哌啶、喹啉、噻唑、吲哚等。 In the present invention, halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; and C, -C ₄ alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms, such as a Base, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, propyl, isopropyl, most preferably methyl, ethyl; - (: ₄ alkoxy means an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butyl Oxyl or tert-butoxy; C ₃ -C ₇ cycloalkyl means cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; The C ₄ alkoxycarbonyl group may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; the aromatic ring includes a single ring, An aromatic ring of a bicyclic or polycyclic system, such as benzene, naphthalene, etc.; a heteroaromatic ring containing at least one hetero atom selected from the group consisting of ^S and 0 means at least one heteroatom selected from N, S and 0 And having a monocyclic, bicyclic or polycyclic heteroaromatic ring system such as pyrrole, thiophene, furan, oxazole, pyridine, pyrimidine, piperidine, quinoline, thiazole, indole and the like.

本发明中，药学上可接受的盐包括酸加成盐和碱加成盐。代表的酸加成盐包括氢溴酸盐、盐酸盐、硫酸盐、亚硫酸盐、磷酸盐、乙酸盐、草一酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯曱酸盐、乳酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、苯曱酸盐、甲磺酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐等。代表的碱加成盐包括碱金属阳离子盐、碱土金属的阳离子盐以及季铵阳离子在较为具体的方案中，本发明所述化合物可以选自 2 -丁基 - 4-氯- 1_{[2'- 四唑- 5-基） - -联苯 -4-基] 曱基 }- 5-[(4-氟苄氧基）曱基] - 1#-咪唑； In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, sulfite, phosphate, acetate, oxalate, valerate, oleate, palmitate, stearic acid Salt, laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, Gluconate, lactobionate, lauryl sulfonate, and the like. Representative base addition salts include alkali metal cation salts, alkaline earth metal cation salts, and quaternary ammonium cations. In a more specific embodiment, the compounds of the present invention may be selected from 2-butyl-4-chloro-1_{[2'-tetrazole-5-yl)--biphenyl-4-yl]nonyl}- 5-[(4-fluorobenzyloxy)indolyl] 1#-imidazole;

2 -丁基 -4-氯 - 1- {[2'- 四唑- 5-基）- -联苯 -4-基] 甲基} -5- [ (4-溴苄氧基）甲基] - 咪唑； 2-butyl-4-chloro-1-{{2'-tetrazole-5-yl)-biphenyl-4-yl]methyl}-5-[(4-bromobenzyloxy)methyl] - imidazole;

2_丁基- 4-氯- 1- {[2'- 四唑- 5-基）- -联苯 -4 -基] 甲基}- 5_[(4-甲基苄氧基）甲基] - 1〃-咪唑； 2-butyl- 4-chloro- 1-{[2'-tetrazol-5-yl)-biphenyl-4-yl]methyl}- 5_[(4-methylbenzyloxy)methyl] - 1〃-imidazole;

2 -丁基 - 4-氯- 1- {[2'- (1〃-四唑- 5-基） - -联苯 -4-基] 甲基 }- 5- [(4-三氟甲基苄氧基）甲基] - 1〃-咪唑； 2-butyl- 4-chloro- 1- {[2'-(1〃-tetrazol-5-yl)--biphenyl-4-yl]methyl}- 5-[(4-trifluoromethyl) Benzyloxy)methyl] - 1 〃-imidazole;

2-丁基- 4 -氯- 1- {[2'- 四唑- 5-基） - -联苯 -4-基] 甲基} - 5- [ (4-氰基苄氧基）甲基] - 1 ^"咪唑； 2-butyl-4-chloro-1-({[2'-tetrazol-5-yl)--biphenyl-4-yl]methyl}-5-[(4-cyanobenzyloxy)methyl ] - 1 ^"imidazole;

2 -丁基- 4-氯- 1_{[2'- 四唑- 5-基） - -联苯 -4-基] 曱基 }- 5-[(3-氟苄氧基）甲基] 咪唑； 2-butyl-4-chloro-1_{[2'-tetrazole-5-yl)--biphenyl-4-yl]nonyl}- 5-[(3-fluorobenzyloxy)methyl]imidazole ;

2 -丁基 - 4-氯- 1- {[2'- (I 四唑- 5-基） - -联苯 -4-基] 曱基 }- 5- [(3-三氟甲基苄氧基）甲基] - 1〃-咪唑； 2-butyl- 4-chloro- 1- {[2'- (I tetrazole-5-yl)--biphenyl-4-yl] fluorenyl}- 5- [(3-trifluoromethylbenzyloxy) Methyl] - 1 〃-imidazole;

2 -丁基 - 4-氯- 1- {[2'- (1#-四唑 -5-基） - -联苯 -4-基] 曱基}-5- [(2， 5-二氟苄氧基）甲基] - 咪唑；和 2-butyl- 4-chloro- 1- {[2'-(1#-tetrazol-5-yl)--biphenyl-4-yl] fluorenyl}-5- [(2, 5-difluoro) Benzyloxy)methyl]-imidazole;

2-丁基 -4-氯 - 1- {[2'- 四唑 - 5-基） - -联苯 -4-基] 甲基 }- 5- {[2， 5-二（三氟曱基）苄氧基]曱基 }- 咪唑本发明的第二方面，提供一种制备本发明所述化合物的制备方法，通过以下工艺路线，采用合适的苄溴（如下式结构 II )处理三苯甲基氯沙坦（化学名为： 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基- 四唑 -5- 基） -1， -联苯 -4-基]曱基 }-5_羟甲基咪唑，如下式结构 III ) 制得相应的中间体（如下式结构 IV ) ，然后脱除保护基得到所述的化合物，包括步骤： 2-butyl-4-chloro-1-{{2'-tetrazole-5-yl)-biphenyl-4-yl]methyl}- 5- {[2, 5-di(trifluoromethyl) Benzyloxy]fluorenyl}-imidazole In a second aspect of the invention, there is provided a process for the preparation of a compound of the invention, which is prepared by the following route using a suitable benzyl bromide (structure II as follows) Losartan (chemical name: 2-butyl- 4-chloro-1- 1-[[2'-(1-trityl-tetrazol-5-yl)-1,-biphenyl-4-yl)曱-}-5-hydroxymethylimidazole, the following intermediate structure III) to obtain the corresponding intermediate (structure IV below), and then remove the protecting group to obtain the compound, including the steps:

A) ：将三苯甲基氯沙坦溶于合适的溶剂中，在碱存在下，与相应的苄溴衍生物发生成醚反应得到相应的中间体； A): The trityl losartan is dissolved in a suitable solvent and reacted with the corresponding benzyl bromide derivative in the presence of a base to form the corresponding intermediate;

B) ：将所得中间体溶于合适的溶剂中，在碱存在下，加热脱除保护基得到目标化合物； B): dissolving the obtained intermediate in a suitable solvent, and removing the protecting group by heating in the presence of a base to obtain a target compound;

以及任选的步骤 C ) ：将所得化合物与合适的无机酸或者有机酸形成酸加成盐或者与合适的无机碱或者有机碱形成碱加成盐。 And optional step C): forming the resulting compound into an acid addition salt with a suitable inorganic or organic acid or a base addition salt with a suitable inorganic or organic base.

在上图所示路线中， R,、 n的定义如上文所述；步骤 A中合适的溶剂包括 DMF、 DMS 0、丙酮或其混合溶剂，合适的碱包括 Na H、 K0H、 NaOH、 Na NH₂或其混合碱；步骤 B 中合适的溶剂包括甲醇、乙醇、异丙醇、四氢呋喃、 DMF、丙酮或其混合溶剂，合适的碱包括 NaOH、 K0H、 NaOE t 法纯化，例如采用柱层析的方法。 In the route shown above, R, n are as defined above; suitable solvents in step A include DMF, DMS 0, acetone or a mixed solvent thereof, and suitable bases include Na H, KOH, NaOH, Na NH ₂ or a mixed base thereof; a suitable solvent in the step B includes methanol, ethanol, isopropanol, tetrahydrofuran, DMF, acetone or a mixed solvent thereof, and a suitable base includes NaOH, K0H, NaOE t purification, for example, by column chromatography. method.

在上述制备过程中，步骤 A所示的反应可以在在 - 1 0。C至回流温度下进行，较佳的反应温度为 5 ~ 1 00 °C，更佳的为 2 0 ~ 8 0 °C ; 步骤 B所示的反应通常在加热的条件下进行，较佳的反应温度为 4 (TC至回流温度，更佳的为 5 0 °C至回流温度；各反应的反应时间通常没有特别限制，本领域技术人员通过本领域常规的技术手段就能容易地确定反应时间，例如通过 TLC监控反应终点。 In the above preparation, the reaction shown in the step A may be at -10. C is carried out at a reflux temperature, preferably a reaction temperature of 5 to 100 ° C, more preferably 20 to 80 ° C; the reaction shown in step B is usually carried out under heating, preferably a reaction The temperature is 4 (TC to reflux temperature, more preferably 50 °C to reflux temperature; the reaction time of each reaction is usually not particularly limited, and those skilled in the art can easily determine the reaction time by means of techniques conventional in the art. The reaction endpoint is monitored, for example, by TLC.

此外，通过上述内容的描述，按照本领域普通技术知识或者惯用手段，对上述提供的制备方法还可以有多种形式的修改和替换，例如采用相应的苄氯或者苄碘代替苄溴作为步骤 A中成醚试剂，又如步骤 A所示的反应结束后，可以不经分离纯化其中间体直接进行后续的步骤 B所示的脱保护反应。本发明的第三方面，提供了一种药物组合物，它含有本发明所述的化合物或其药学上可接受的盐和药学上可接受的载体。 In addition, the preparation methods provided above may also be modified and replaced in various forms according to the description of the above, according to the prior art or conventional means in the art, for example, using corresponding benzyl chloride or benzyl iodide instead of benzyl bromide as step A. After the completion of the reaction shown in Step A, the intermediate ether reagent can be directly subjected to the subsequent deprotection reaction shown in Step B without isolation and purification of the intermediate. According to a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

所述药物组合物可给药于哺乳动物（如人），可以口服、直肠、肠胃外（静脉内、肌肉内或皮下）、局部等方式给药，其中尤以口服方式最佳。使用药物组合物时，将含有治疗和 /或预防有效量的本发明所述的化合物或其药学上可接受的盐的药物组合物施用于需要治疗和 /或预防的哺乳动物（如人）。术语 "治疗和 /或预防有效量" 指的是足以在哺乳动物（如人）体内引起兽医或临床医师所探求的生物或医学反应的活性化合物的量。普通的医师、兽医和临床医师可容易地确定治疗和 /或预防指定疾病所需的本发明所述的化合物或其药学上可接受的盐的有效量。一般，为每天 0. 01 ~ 200mg/kg 患者体重，优选每天 0. 01 ~ 1 00mg/kg 患者体重，最佳为每天 0. 01 ~ 5 0mg /kg 患者体重。更具体而言，对于 60kg体重的人，日给药剂量通常为 0. 6mg ~ 1 2 g ,优选 0. 6mg ~ 6g，最佳为 0. 6mg ~ 3g。当然，具体剂量还应考虑给药途径，患者的年龄、性别、体重和健康状况，以及被治疗的特定状况等因素，这些都是熟练医师技能范围之内的。在本文中使用的术语 "哺乳动物" 包括但不限于猫、狗、兔、山羊、绵羊、大鼠、小鼠和人等，特别优选人。 The pharmaceutical composition can be administered to a mammal (e.g., a human) and can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, etc., with oral administration being most preferred. When a pharmaceutical composition is used, a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal (e.g., a human) in need of treatment and/or prevention. The term "therapeutic and/or prophylactically effective amount" means sufficient to feed The amount of active compound in a mammal, such as a human, that causes a biological or medical response as sought by a veterinarian or clinician. An exemplary physician, veterinarian, and clinician can readily determine the effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, required to treat and/or prevent a given condition. Generally, it is 0. 01 ~ 200 mg / kg patient body weight per day, preferably 0. 01 ~ 1 00 mg / kg patient body weight, preferably 0. 01 ~ 50 mg / kg patient weight per day. 6mg至3克。 The specific dose of 0. 6mg ~ 1 2 g, preferably 0. 6mg ~ 6g, preferably 0. 6mg ~ 3g. Of course, the specific dose should also take into account the route of administration, the age, sex, weight and health of the patient, as well as the specific condition being treated, which are within the skill of the skilled physician. The term "mammal" as used herein includes, but is not limited to, cats, dogs, rabbits, goats, sheep, rats, mice, humans, and the like, with humans being particularly preferred.

所述药物组合物可以配制为用于口服给药的固体剂型，包括胶嚢剂、片剂、丸剂、散剂和颗粒剂等。固体剂型中通常含有 0. 5 ~ 5 0°/。的活性成分，优选含有 1 ~ 2 5%的活性成分。在这些固体剂型中，本发明提供的化合物或其药学上可接受的盐可以与至少一种常规惰性赋形剂 (或载体）混合，所述惰性赋形剂（或载体）包括但不限于：（a) 填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；（b) 粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；（c) 保湿剂，例如，甘油；（d) 崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉、木薯淀粉、藻酸、某些复合硅酸盐、聚乙烯基聚吡咯烷酮和碳酸钠；（e) 緩溶剂，例如石蜡；（f) 吸收加速剂，例如，季胺化合物；（g) 润湿剂，例如鯨蜡醇和单硬脂酸甘油酯；（h) 吸附剂，例如，高岭土；和（i ) 润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶嚢剂、片剂和丸剂中，剂型也可包含緩沖剂。 The pharmaceutical composition may be formulated as a solid dosage form for oral administration, including capsules, tablets, pills, powders, granules and the like. The solid dosage form usually contains 0. 5 ~ 50 ° /. The active ingredient preferably contains from 1 to 25% of the active ingredient. In these solid dosage forms, the compounds provided herein, or a pharmaceutically acceptable salt thereof, may be admixed with at least one conventional inert excipient (or carrier) including, but not limited to: (a) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose And gum arabic; (c) humectants, for example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch, tapioca, alginic acid, certain complex silicates, polyvinylpolypyrrolidone and Sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and glyceryl monostearate; (h) an adsorbent, for example , kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

固体剂型如片剂、胶嚢剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物的释放可以延迟的方式在消化道内的某一部分中释放。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶嚢形式。 Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound in such compositions may be released in a portion of the digestive tract in a delayed manner. If necessary, the active compound may also form a microcapsule form with one or more of the above excipients.

所述药物组合物也可以配制为用于口服给药的液体剂型，包括药学上可接受的乳液、溶液、悬浮液或酊剂等。除了本发明提供的化合物或其药学上可接受的盐作为活性成分外，液体剂型可包含本领域中常规釆用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、 1，3-丁二醇、二曱基曱酰胺或植物油，特别是棉籽油、花生油、玉米胚油、橄榄油、篦麻油或芝麻油，或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂、悬浮剂、甜味剂、矫味剂或香料，或其适宜的混合物等。 The pharmaceutical compositions may also be formulated in liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions or elixirs, and the like. In addition to the compound provided by the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, the liquid dosage form may comprise a conventional hydrazine in the art. An inert diluent such as water or other solvent, solubilizer and emulsifier, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimercaptoamide or vegetable oil , especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil or sesame oil, or a mixture of these substances. In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavorings or flavors, or suitable mixtures thereof.

当本发明所述药物组合物以悬浮液存在时，除了本发明提供的化合物或其药学上可接受的盐外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂，或这些物质的混合物等。 When the pharmaceutical composition of the present invention is present as a suspension, in addition to the compound provided by the present invention or a pharmaceutically acceptable salt thereof, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, poly Oxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or a mixture of these, and the like.

所述药物组合物可以配制为用于肠胃外注射的剂型，包括生理上可接受的无菌含水或非水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。含水或非水载体、稀释剂、溶剂或赋形剂可用于制备所述无菌含水或非水溶液、分散液、悬浮液或乳液。适宜的含水或非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇，或其适宜的混合物等。 The pharmaceutical composition may be formulated for parenteral injection, including physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and for reconstitution into sterile injectable solutions or A sterile powder of the dispersion. Aqueous or non-aqueous vehicles, diluents, solvents or excipients can be employed in the preparation of such sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions. Suitable aqueous or nonaqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols, or suitable mixtures thereof and the like.

所述药物组合物可以配制为用于局部给药的剂型，包括软膏剂、散剂、贴剂、喷射剂和吸入剂。本发明提供的化合物或其药学上可接受的盐可在无菌条件下与生理上可接受的载体及任何防腐剂、緩冲剂，或必要时可能需要的推进剂一起混合。 The pharmaceutical compositions may be formulated in a dosage form for topical administration, including ointments, powders, patches, propellants, and inhalants. The compounds provided herein, or pharmaceutically acceptable salts thereof, can be combined under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants which may be required if necessary.

所述药物组合物还可以包括其他药学上可接受的治疗剂，尤其是其他降血糖药。所述其他降血糖药包括但不限于：磺脲类药物例如甲磺丁脲、格列本脲、格列吡嗪等；双胍类药物例如苯乙双胍、二曱双胍、丁双胍等、 α -葡萄糖苷酶抑制剂例如阿卡波糖、米格列醇、伏格列波糖等；噻唑烷二酮类（Th i azo l i d ined i ones , TZD)药物例如罗格列酮、吡格列酮等。另一方面，本发明所述的化合物或其药学上可接受的盐或含有所述的化合物或其药学上可接受的盐的药物组合物可用于制备用于治疗和 / 或预防 PPAR γ相关的疾病的药物，特别是与 RXR和 PPAR核受体调节相关的疾病。优选所述疾病选自糖尿病、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症，尤其是糖尿病和血糖异常升高相关疾病。度的激动活性，一种优选的评价方法如下描述： The pharmaceutical composition may also include other pharmaceutically acceptable therapeutic agents, especially other hypoglycemic agents. The other hypoglycemic agents include, but are not limited to, sulfonylureas such as metobutyramide, glibenclamide, glipizide, etc.; biguanide drugs such as phenformin, diterpene, diterpene, etc., alpha- Glucosidase inhibitors such as acarbose, miglitol, voglibose, etc.; thiazolidine diones (TZD) drugs such as rosiglitazone, pioglitazone and the like. In another aspect, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, can be used for the preparation of a PPAR γ-related therapeutic and/or prophylactic Diseased drugs, especially those associated with RXR and PPAR nuclear receptor regulation. Preferably, the disease is selected from the group consisting of diabetes, diseases associated with abnormal blood glucose elevation, lipid disorders, metabolic syndrome, cardiovascular disease, coronary artery disease, hypercholesterolemia, and obesity, particularly diseases associated with elevated diabetes and abnormal blood glucose. Degree of agonistic activity, a preferred method of evaluation is described as follows:

采用报告基因（reporter gene ) 的方法，利用核受体活化后能激活其下游基因转录的原理，设计了一种活细胞内筛选核受体激活剂的筛选模型，用来验证化合物激活 PPARy的活性。实验方法如下：用 RT- PCR方法（反转录（RT )和 cDNA的聚合酶链式扩增（ PCR )相结合的技术）从脂肪组织中克隆到 PPARy全长 cDNA, 将扩增的 PCR产物***表达载体 pcDNA3.1后测序鉴定。报告基因用 Promega公司的荧光素酶检测载体 pGL3 - Promoter构建。转染实验用 U20S细胞在 96孔板中进行，在转染报告基因的同时共转染 RXR 和 PPARy基因，转染 24 小时后加入待检测的化合物，并维持溶剂 DMS0 的终浓度为 0.1 %。化合物作用 24 小时后裂解细胞并进行荧光素酶活性的检测。通过观察发光的强度可以得知化合物对核受体的激活强度。为了校正转染效率、细胞接种数量及化合物毒性等因素造成的试验误差，还同时共转染了 GFP质粒作为内参，在实验结果分析时所有试验孔的发光值都用 GFP值进行了校正。试验结果用相对激活倍数表示，溶剂对照的值为 1，值越大表明激活能力越高。在模型筛选中，观察了样品在 6种不同浓度条件下对受体的激活情况，较全面地反应了化合物的药理特性，并且根据下面公式进行迭代计算拟合出化合物作用的浓度效应曲线，并计算出相应的半有效浓度 ( EC₅₀ ) 。A reporter model was used to activate the transcription of downstream genes after activation of nuclear receptors. A screening model for screening nuclear receptor activators in living cells was designed to verify the activity of compounds to activate PPARy. . The experimental method is as follows: The RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR) combined technique) was cloned from adipose tissue into PPARy full-length cDNA, and the amplified PCR product was obtained. The expression vector pcDNA3.1 was inserted and sequenced. The reporter gene was constructed using Promega's luciferase assay vector pGL3 - Promoter. The transfection experiments were carried out in 96-well plates using U20S cells. The RXR and PPARy genes were co-transfected at the same time as the transfection of the reporter gene, and the compound to be detected was added 24 hours after the transfection, and the final concentration of the solvent DMS0 was maintained at 0.1%. After 24 hours of compound action, the cells were lysed and tested for luciferase activity. The intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results. The test results are expressed as relative activation multiples, and the solvent control has a value of 1, and a larger value indicates a higher activation ability. In the model screening, the activation of the receptor at six different concentrations was observed, and the pharmacological properties of the compound were more comprehensively analyzed, and the concentration effect curve of the compound action was fitted by the iterative calculation according to the following formula. calculate the respective half-effective concentration (EC _50).

在糖尿病动物模型上，本发明提供的化合物具有良好的降血糖作用，一种优选的实验评价方法如下：健康自发性 II型糖尿病动物模型，雄性 GK大鼠（ Goto- Kakizaki 大鼠），体重 200g, 动物禁食 12小时，血糖仪测定空腹血糖值，之后连续灌胃给药（ 20 mg/kg ) 或对照液 0.5%CMC-Na (羧甲基纤维素钠）（10mL/kg ) , 连续给药 10天后再次测定空腹血糖值，通过比较给药前后的空腹血糖值来评价待测化合物的降血糖作用。再一方面，本发明还涉及治疗和 /或预防哺乳动物 PPARY受体相关的疾病的方法，包括将治疗和 /或预防有效量的本发明所述的化合物或其药学上可接受的盐或者含有本发明所述的化合物或其药学上可接受的盐的药物组合物给予需要此治疗和 /或预防的哺乳动物，优选所述疾病选自糖尿病、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症，尤其是糖尿病或血糖异常升高相关疾病。

In the diabetic animal model, the compound provided by the present invention has a good hypoglycemic effect, and a preferred experimental evaluation method is as follows: Healthy spontaneous type 2 diabetes animal model, male GK rat (Goto-Kakizaki rat), weighing 200 g The animals were fasted for 12 hours. The blood glucose meter measured the fasting blood glucose level, and then continued intragastric administration (20 mg/kg) or control solution 0.5% CMC-Na (carboxymethylcellulose sodium) (10 mL/kg). The fasting blood glucose level was measured again 10 days after the drug, and the hypoglycemic effect of the test compound was evaluated by comparing the fasting blood glucose values before and after administration. In a further aspect, the invention relates to a method of treating and/or preventing a PPARY receptor-associated disease in a mammal comprising administering a therapeutically and/or prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a a compound of the invention or a pharmaceutically acceptable compound thereof The pharmaceutical composition of the salt is administered to a mammal in need of such treatment and/or prevention, preferably the disease is selected from the group consisting of diabetes, a disease associated with abnormal blood glucose elevation, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, and a high Blood cholesterol and obesity, especially those associated with elevated levels of diabetes or abnormal blood sugar.

本发明所述的化合物或其药学上可接受的盐或含有本发明所述的化合物或其药学上可接受的盐的药物组合物可以单独给药，或者与其他药学上可接受的治疗剂联合给药，特别是与其他糖尿病治疗和 /或预防药物组合。所述治疗剂包括但不限于：磺脲类药物例如甲磺丁脲、格列本脲、格列吡嗪等；双胍类药物例如苯乙双胍、二曱双胍、丁双胍等、 (X -葡萄糖苷酶抑制剂例如阿卡波糖、米格列醇、伏格列波糖等；噻唑烷二酮类 (Thiazolidinediones, TZD)药物例如罗格列酮、吡格列酮等。本发明的主要优点在于：经实验证明本发明提供的化合物具有 PPAR Y部分激动剂的活性，与现有的完全的 PPARy激动剂相比，保留了降血糖的有益作用，且减少了由完全的 PPARy激动剂引起的体重增加、水肿、脂肪组织激增、骨髓脂肪酸改变等副作用。下面结合实施例来进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的保护范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。所采用的原料为可商业上购得的或者可以很容易地由本领域技术人员根据已知文献方法制得的。对于所涉及的缩写， DMF是指 N，N-二甲基甲酰胺， DMS0是指二曱基亚砜， PVPP指聚乙烯基聚吡咯烷酮， PVP指聚乙烯基吡咯烷酮。除非另有说明，否则份数和百分比为重量份数和重量百分比。实施例 The compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. Administration, especially in combination with other diabetes treatment and/or prophylaxis drugs. The therapeutic agents include, but are not limited to, sulfonylureas such as chlorpheniramine, glibenclamide, glipizide, and the like; biguanides such as phenformin, diterpene, diterpene, etc., (X-glucose) Glycosidase inhibitors such as acarbose, miglitol, voglibose, etc.; thiazolidinediones (TZD) drugs such as rosiglitazone, pioglitazone, etc. The main advantages of the present invention are: The experiments demonstrate that the compounds provided by the present invention have PPAR Y partial agonist activity, retain the beneficial effects of hypoglycemia, and reduce the weight gain caused by the complete PPARy agonist, compared to the existing full PPARy agonist, Side effects of edema, adipose tissue ablation, changes in bone marrow fatty acids, etc. The invention is further illustrated by the following examples, which are to be construed as illustrative only and not to limit the scope of the invention. Explain the specific conditions of the experimental method, usually in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. It is commercially available or can be readily prepared by those skilled in the art according to known literature methods. For the abbreviations involved, DMF means N,N-dimethylformamide, and DMS0 means dimercaptosulfoxide. PVPP means polyvinylpolypyrrolidone and PVP means polyvinylpyrrolidone. Parts and percentages are parts by weight and percentage by weight unless otherwise stated.

实施例 1: 2-丁基- 4-氯- 1- {[2'- (I 四唑- 5-基）- 1, -联笨 -4-基]曱基}-5- [(4-氟苄氧基）甲基 ]- 咪唑 Example 1: 2-Butyl- 4-chloro- 1-{[2'-(I tetrazole-5-yl)- 1,1-biphenyl-4-yl]indenyl}-5- [(4- Fluorobenzyloxymethyl]-imidazole

步骤 A: 2-丁基 -4-氯- 1- {[2'- (1-三苯曱基 - 四唑- 5-基）- 1， 1' - 联苯- 4-基]甲基 }- 5- [(4-氟苄氧基）甲基 ]- 咪唑

Step A: 2-butyl-4-chloro-1-({[2'-(1-triphenyl)-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl} - 5- [(4-Fluorobenzyloxy)methyl]-imidazole

将三苯曱基氯沙坦（化学名为： 2-丁基- 4-氯- 1- {[2'-(1-三苯曱基四唑- 5-基）- 1， 1'-联苯- 4-基]甲基 }_5-羟甲基咪唑）（购自浙江天宇医药化工有限公司） 665mg ( lmmol ) 溶于 10mL DMF 中，加 NaH (银灰色固体颗粒，含量 >60%，活性氢量（纯度） >97%) 44mg, 室温反应半小时，然后加 122μί 4-氟苄溴（ lmmol ) 。继续反应 12h。反应结束后，柱层析纯化得白色粉末 627mg, 经鉴别为中间产物（ 2-丁基- 4 - 氯- 1-{[2'- (1-三苯甲基 - 四唑 -5-基）- 1， -联苯- 4-基] 曱基}- 5-[(4-氟苄氧基）曱基] - 咪唑），收率 81%。 Trityl hydrazine losartan (chemical name: 2-butyl 4-chloro-1- 1-[[2'-(1-triphenylmethyltetrazol-5-yl)-1, 1'- linkage Benz-4-yl]methyl}_5-hydroxymethylimidazole) (purchased from Zhejiang Tianyu Pharmaceutical Chemical Co., Ltd.) 665mg (lmmol) dissolved in 10mL DMF, added NaH (silver gray solid particles, content >60%, active Amount of hydrogen (purity) >97%) 44 mg, react at room temperature for half an hour, then add 122 μί 4-fluorobenzyl bromide (1 mmol). Continue to react for 12h. After completion of the reaction, column chromatography was carried out to obtain 627 mg of white powder, which was identified as an intermediate product (2-butyl-4-chloro- 1-{[2'-(1-triphenylmethyl-tetrazol-5-yl)) -1 -biphenyl-4-yl]nonyl}- 5-[(4-fluorobenzyloxy)indolyl]-imidazole), yield 81%.

Ή-NMR (400Mz, DMS0) δ： 7.61-7.49 (m, 6H ) ， 7.46 ( s, 1H ) ， 7.46-7.39 ( m, 6H ) , 7.39-7.35 ( t, 1H ) , 7.33-7.27 ( d, 1H ) , 7.25-7.21 ( d， 1H ) , 7.11 ( t， 3Η )， 6.98-6.93 ( d, 2H )， 6.77-6.75 ( d, 2H ) , 6.42 ( d, 2Η ) ， 6.23 ( d, 2H ) ， 4.99 ( s, 2H ) , 4.72 ( s, 2Η ) , 4.54 ( s， 2Η ) ， 2.52 ( t, 2H ) , 1.72 ( m, 2Η ) ， 1.36 ( m, 2H ) , 0.87 ( t， 3Η) 。步骤 B: 2-丁基- 4-氯- 1- {[2'- (1#-四唑- 5-基） -1， 1'-联苯- 4-基] 甲基 }- 5-[(4-氟苄氧基）甲基] - 咪唑 Ή-NMR (400Mz, DMS0) δ: 7.61-7.49 (m, 6H), 7.46 ( s, 1H ) , 7.46-7.39 ( m, 6H ) , 7.39-7.35 ( t, 1H ) , 7.33-7.27 (d, 1H) , 7.25-7.21 ( d, 1H ) , 7.11 ( t, 3Η ), 6.98-6.93 ( d, 2H ), 6.77-6.75 ( d, 2H ) , 6.42 ( d, 2Η ) , 6.23 ( d, 2H ) , 4.99 ( s, 2H ) , 4.72 ( s, 2Η ) , 4.54 ( s, 2Η ) , 2.52 ( t, 2H ) , 1.72 ( m, 2Η ) , 1.36 ( m, 2H ) , 0.87 ( t, 3Η). Step B: 2-Butyl- 4-chloro- 1- {[2'-(1#-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5-[ (4-fluorobenzyloxy)methyl] -imidazole

将步骤 Α所得的中间体 382mg ( 0.495mmol )溶于 10mL无水甲醇中，加入 45mg的 K0H，回流反应 2h，，减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 188mg, 经鉴别为题述化合物，收率 72%。 The 382 mg (0.495 mmol) of the obtained intermediate was dissolved in 10 mL of anhydrous methanol, and then the mixture was evaporated to dryness. Identification as the title compound, yield 72%.

. p.： 153.3-155.9°C; p.: 153.3-155.9 ° C;

'H-NMR(400Mz, DMS0) δ： 10.80 ( s, 1H) ， 8.73— 8.71 (d, 1H) , 7.65-7.58 ( t, 1H ) , 7.51— 7.46 ( t， 1H)， 7.45-7.39( d, 1H ), 7.37-7.33 ( dd, 2H) , 7.32-7.28 ( dd, 2H ) , 7.27-7.21 ( dd, 2H ) , 7.02-6.57 ( dd, 2H )， 4.97 ( s, 2H ) , 4.76 ( s, 2H ) , 4.59 ( s, 2H ) , 2.67-2.54 ( t, 2H) ， 1.80-1.71 (m， 2H ) ， 1.37-1.32 ( m, 2H ) ， 0.89-0.86 ( t, 3H ) ； 'H-NMR (400Mz, DMS0) δ: 10.80 ( s, 1H) , 8.73 - 8.71 (d, 1H) , 7.65-7.58 ( t, 1H ) , 7.51 - 7.46 ( t, 1H), 7.45-7.39 (d , 1H ), 7.37-7.33 ( dd, 2H) , 7.32-7.28 ( dd, 2H ) , 7.27-7.21 ( dd, 2H ) , 7.02-6.57 ( dd, 2H ), 4.97 ( s, 2H ) , 4.76 ( s , 2H ) , 4.59 ( s, 2H ) , 2.67-2.54 ( t, 2H) , 1.80-1.71 (m, 2H ) , 1.37-1.32 ( m, 2H ) , 0.89-0.86 ( t, 3H ) ;

ESI— MS: (M+H) =531, (M-H)"=529₀ 实施例 2： 2 -丁基 - 4-氯- 1- {[2'- 四唑- 5-基） -1, -联苯- 4-基]曱基}- 5- [(4-溴苄氧基）甲基] - 咪唑

ESI-MS: (M+H) = 531, (MH) "= 529 ₀ Example 2: 2 -butyl- 4-chloro- 1- {[2'-tetrazole-5-yl) -1, - Biphenyl-4-yl]fluorenyl}- 5-[(4-bromobenzyloxy)methyl]-imidazole

步骤 A: 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基- 四唑 -5-基）- 1, - 联苯- 4-基]甲基 }-5- [(4 -溴苄氧基）甲基] 咪唑 Step A: 2-butyl-4-chloro-1 - {[2'-(1-trityl-tetrazol-5-yl)-1,-biphenyl-4-yl]methyl}-5 - [(4-bromobenzyloxy)methyl]imidazole

按照实施例 1步骤 A所示的方法，采用 250mg 4-溴苄溴（ lmmol ) 代替 122 L 4 -氟苄溴制得中间体 2-丁基- 4-氯- 1- {[2'- U-三苯甲基 - 四唑- 5-基）- 1， 1'-联苯- 4-基]甲基 }- 5- [(4-溴苄氧基）曱基] 咪唑 550mg (浅黄色油状物），收率 66°/。。 According to the method shown in the step A of Example 1, 250 mg of 4-bromobenzyl bromide (1 mmol) was used instead of 122 L 4 -fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro-1--[[2'-U -Trityl-tetrazole-5-yl)- 1,1'-biphenyl-4-yl]methyl}- 5-[(4-bromobenzyloxy)indolyl]imidazole 550mg (light yellow oil ()), yield 66 ° /. .

'Η-丽 R(400Mz, DMS0) δ： 7.64-7.59 ( m, 6H ) ， 7.57-7.51 ( d, 1H)， 7.46-7.39 ( m, 6H ) , 7.45-7.37 "， 1H ) , 7.36-7.31 ( d, 1H )， 7.27-7.23( d, 1H ) , 7.21-7.12( m, 3H ) , 6.98-6.93( m, 2H ) , 6.77-6.75 (m， 2H ) ， 6.42 (d， 2H ) , 6.23 (d， 2H ) ， 4.87 ( s， 2H ) , 4.69 ( s， 2H ) ， 4.54 ( s, 2H ) , 2.52 ( t, 2H ) , 1.71 ( m, 2H ) ， 1.35 ( m， 2H) , 0.86 ( t, 3H ) 。步骤 B: 2-丁基- 4-氯- 1_{[2'- 四唑- 5-基）- 1， 1'-联苯 -4-基] 甲基 }- 5-[(4-溴苄氧基）甲基] - 咪唑 'Η-丽R(400Mz, DMS0) δ: 7.64-7.59 (m, 6H), 7.57-7.51 (d, 1H), 7.46-7.39 (m, 6H), 7.45-7.37 ", 1H), 7.36-7.31 ( d, 1H ), 7.27-7.23( d, 1H ) , 7.21-7.12( m, 3H ) , 6.98-6.93( m, 2H ) , 6.77-6.75 (m, 2H ) , 6.42 (d, 2H ) , 6.23 (d, 2H) , 4.87 ( s, 2H ) , 4.69 ( s, 2H ) , 4.54 ( s, 2H ) , 2.52 ( t, 2H ) , 1.71 ( m, 2H ) , 1.35 ( m, 2H) , 0.86 ( t, 3H) Step B: 2-butyl-4-chloro-1_{[2'-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5-[ (4-bromobenzyloxy)methyl] -imidazole

将步骤 A所得的中间体 417mg ( 0.507mmol )溶于 lOmL无水甲醇中，加入 45mg的 K0H, 回流反应 2h, 减压浓缩除去溶剂，所得残留物经柱层析纯化得浅黄色粉末 201mg, 经鉴别为题述化合物，收率 68%。 The intermediate 417 mg (0.507 mmol) obtained in the step A was dissolved in EtOAc (MeOH) (MeOH) Identification as the title compound, yield 68%.

M. p.： 168.5-170°C; M. p.: 168.5-170 ° C;

Ή-NMR (400Mz, DMS0) δ： 10.76 ( s, 1H) , 8.72-8.60 ( d, 1H) ， 7.71-7.62 ( m, 1H ) , 7.52-7.45 ( m, 1H )， 7.45-7.40 ( d, 1H ) , 7.16 (d, 2H ) , 7.11-7.05 (d， 2H ) , 7.02-6.96 (m， 2H ) , 6.95-6.78 ( d， 2H ) , 4.96 ( s, 2H ) , 4.72 ( s, 2H ) ， 4.54 ( s, 2H )， 2.61-2.54 ( t, 2H ) ， 1.78-1.71 ( m, 2H ) , 1.37-1.29 (m, 2H ) ， 0.88-0.85 ( t, 3H) ； Ή-NMR (400Mz, DMS0) δ: 10.76 ( s, 1H) , 8.72-8.60 ( d, 1H) , 7.71-7.62 ( m, 1H ) , 7.52-7.45 ( m, 1H ), 7.45-7.40 (d, 1H ) , 7.16 (d, 2H ) , 7.11-7.05 (d, 2H ) , 7.02-6.96 (m, 2H ) , 6.95-6.78 ( d, 2H ) , 4.96 ( s, 2H ) , 4.72 ( s, 2H ) , 4.54 ( s, 2H ), 2.61-2.54 ( t, 2H ) , 1.78-1.71 ( m, 2H ) , 1.37-1.29 (m, 2H ) , 0.88-0.85 ( t, 3H) ;

ESI- MS: (Μ+ΗΓ=591， (M-H)— =589。实施例 3: 2-丁基- 4 -氯- 1- {[2'- 四唑 -5-基）- 1， -联苯 -4-基]甲基 }- 5- [(4-甲基苄氧基）甲基] 咪唑 ESI-MS: (Μ + ΗΓ = 591, (MH) - = 589. Example 3: 2-butyl-4-chloro-1 - {[2'-tetrazol-5-yl)- 1, - Phen-4-yl]A }}- 5- [(4-methylbenzyloxy)methyl]imidazole

步骤 A: 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基四唑- 5-基）- 1， V - 联苯- 4-基]甲基 }-5-[(4-甲基苄氧基）甲基] - I 咪唑 Step A: 2-butyl-4-chloro-1 - {[2'-(1-trityltetrazole-5-yl)- 1, V-biphenyl-4-yl]methyl}-5 -[(4-methylbenzyloxy)methyl] - I imidazole

按照实施例 1步骤 A所示的方法，采用 169 L 4-甲基苄溴（ lmmol ) 代替 122μί 4-氟苄溴制得中间体 2-丁基- 4-氯- 1- {[2'-(1-三苯甲基 - 四唑- 5-基）- 1，1'-联苯 -4-基] 曱基 }- 5- [(4-甲基苄氧基）曱基] - 咪唑 415mg (白色粉末），收率 54%。 According to the method shown in the step A of Example 1, 169 L 4-methylbenzyl bromide (1 mmol) was used instead of 122 μί 4-fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro-1 - {[2'- (1-tritylmethyl-tetrazole-5-yl)-1,1'-biphenyl-4-yl]nonyl}- 5-[(4-methylbenzyloxy)indolyl]-imidazole 415 mg (white powder), yield 54%.

'H-NMR(400Mz, DMS0) δ： 7.79-7.66 (m, 6H ) , 7.61 ( s, 1H ) ， 7.59-7.44(m, 6H), 7.39-7.33( t, 1H ), 7.31-7.27( d, 1H )， 7.24-7.21 (d， 1H ) ， 7.19-7.11 ( m, 3H ) ， 6.98-6.93 (d， 2H ) ， 6.77-6.75 (d, 2H ) , 6.42 ( d, 2H ) , 6.23 ( d, 2H ) ， 4.99 ( s, 2H ) ， 4.72 (s， 2H) ， 4.54 ( s， 2H ) , 2.54-2.51 ( t， 2H ) ， 2.15 ( s, 3H ) , 1.75-1.68 ( m, 2H ) , 1.41-1.32 (m, 2H ) , 0.88-0.85 ( t， 3H ) 。步骤 B: 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基）- 1, -联苯- 4-基] 甲基 }-5- [(4-曱基苄氧基）甲基] -咪唑 'H-NMR (400Mz, DMS0) δ: 7.79-7.66 (m, 6H), 7.61 ( s, 1H ) , 7.59-7.44 (m, 6H), 7.39-7.33 ( t, 1H ), 7.31-7.27 (d , 1H ), 7.24-7.21 (d, 1H ) , 7.19-7.11 ( m, 3H ) , 6.98-6.93 (d, 2H ) , 6.77-6.75 (d, 2H ) , 6.42 ( d, 2H ) , 6.23 ( d , 2H ) , 4.99 ( s, 2H ) , 4.72 (s, 2H) , 4.54 ( s, 2H ) , 2.54-2.51 ( t, 2H ) , 2.15 ( s, 3H ) , 1.75-1.68 ( m, 2H ) , 1.41-1.32 (m, 2H), 0.88-0.85 (t, 3H). Step B: 2-Butyl- 4-chloro-1-{{2'-tetrazole-5-yl)-1,-biphenyl-4-yl]methyl}-5-[(4-mercaptobenzyl) Oxy)methyl]-imidazole

将步骤 A所得的中间体 385mg ( 0.501mmol )溶于 10mL无水曱醇中，加入 45mg的 K0H，回流反应 2h, 减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 195mg，经鉴别为题述化合物，收率 74%。 385 mg (0.501 mmol) of the intermediate obtained in the step A was dissolved in 10 mL of anhydrous decyl alcohol, and then added to a mixture of 45 mg of K0H, and the mixture was refluxed for 2 hr. Identification as the title compound, yield 74%.

. p.： 127.3°C; p.: 127.3 ° C;

Ή-NMR (400Mz, DMS0) δ： 10.45 ( s， 1H) ， 8.67-8.61 ( d， 1H ) ， 7.64-7.58 ( t, 1H ) ， 7.53-7.48 (m, 3H ) ， 7.42-7.37 (dd， 1H ) ， 7.34-7.29 ( dd， 2H ) , 7.26-7.21 ( dd, 2H ) ， 7.06-6.95 ( dd， 2H ) , 4.97 ( s, 2H ) ， 4.91 ( s， 2H ) , 4.54 ( s, 2H ) ， 2.54 ( t, 2H ) , 2.15 ( s， 3H ) , 1.78-1.71 ( m, 2H ) ， 1.36-1.32 ( m, 2H ) ， 0.87-0.85 ( t, 3H ) ； Ή-NMR (400Mz, DMS0) δ: 10.45 ( s, 1H) , 8.67-8.61 ( d, 1H ) , 7.64-7.58 ( t, 1H ) , 7.53-7.48 (m, 3H ) , 7.42-7.37 (dd, 1H) , 7.34-7.29 ( dd, 2H ) , 7.26-7.21 ( dd, 2H ) , 7.06-6.95 ( dd, 2H ) , 4.97 ( s, 2H ) , 4.91 ( s, 2H ) , 4.54 ( s, 2H ) , 2.54 ( t, 2H ) , 2.15 ( s, 3H ) , 1.78-1.71 ( m, 2H ) , 1.36-1.32 ( m, 2H ) , 0.87-0.85 ( t, 3H ) ;

ESI— MS: ( +H)⁺=527, (M—H)—=525。实施例 4: 2-丁基- 4-氯- 1- {[2'- 四唑 -5-基） -1， 1'-联苯- 4-基]曱基}- 5- [(4-三氟甲基苄氧基）曱基] - 咪唑 ^{ESI- MS: (+ H) +} = 527, (M-H) - = 525. Example 4: 2-Butyl- 4-chloro- 1-{[2'-tetrazol-5-yl)-1,1'-biphenyl-4-yl]indenyl}- 5- [(4- Trifluoromethylbenzyloxy)indolyl] -imidazole

步骤 Α: 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基-; ^-四唑- 5-基）- 1， Γ- 联苯 -4-基]曱基 }-5_[(4-三氟甲基苄氧基）甲基] 咪唑 Step Α: 2-butyl-4-chloro-1-{{2'-(1-tritylmethyl-;^-tetrazole-5-yl)-1, fluorene-biphenyl-4-yl]indole }}-5_[(4-Trifluoromethylbenzyloxy)methyl]imidazole

按照实施例 1 步骤 Α 所示的方法，采用 264mg 4-三氟甲基苄溴 ( 1. Immol )代替 122μί 4 -氟苄溴制得中间体 2-丁基- 4-氯- 1- { [2' - (1- 三苯曱基 - 1# -四唑 _5_基）- 1， Γ-联苯 -4-基]甲基 }- 5- [(4-三氟曱基苄氧基）甲基] - 1〃-咪唑 617mg (白色粉末），收率 75%。 According to the procedure shown in the first step of Example 1, 264 mg of 4-trifluoromethylbenzyl bromide (1.1 mmol) was used instead of 122 μί 4 -fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro-1-{ 2'-(1-Triphenylindenyl-1#-tetrazole_5_yl)-1, fluorenyl-biphenyl-4-yl]methyl}- 5-[(4-trifluorodecylbenzyloxy) ) methyl] - 1 〃-imidazole 617 mg (white powder), yield 75%.

'H-NMR(400 z, DMS0) δ： 7.91— 7.79 (m， 6H ) , 7.73- 7.67 (d， 1H) ， 7.64-7.47 ( m, 6H )， 7.45-7.41 ( d, 2H) ， 7.38-7.32 ( t, 1H )， 7.25-7.21( d, 1H ) , 7.14-7.05( d, 1H ) , 6.98-6.91( m, 3H ) , 6.79—6, 72 ( d, 2H ) ， 6.46 (d， 2H ) , 6.25 (d， 2H ) , 5.02 ( s， 2H ) , 4.78 (s， 2H ) , 4.51 ( s, 2H ) , .2.57-2.54 ( t, 2H ) , 1.71-1.64 ( m, 2H )， 1.41-1.32 ( m, 2H ) , 0.88-0.85 ( t， 3H ) 。步骤 B: 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基）- 1， 1'-联苯- 4-基] 曱基 }- 5- [(4-三氟甲基苄氧基）曱基] - 咪唑 'H-NMR (400 z, DMS0) δ: 7.91 - 7.79 (m, 6H), 7.73- 7.67 (d, 1H), 7.64-7.47 (m, 6H), 7.45-7.41 (d, 2H), 7.38- 7.32 ( t, 1H ), 7.25-7.21( d, 1H ) , 7.14-7.05( d, 1H ) , 6.98-6.91( m, 3H ) , 6.79-6, 72 ( d, 2H ) , 6.46 (d, 2H ) , 6.25 (d, 2H ) , 5.02 ( s, 2H ) , 4.78 (s, 2H ) , 4.51 ( s, 2H ) , .2.57-2.54 ( t, 2H ) , 1.71-1.64 ( m, 2H ), 1.41 -1.32 ( m, 2H ) , 0.88-0.85 ( t, 3H ). Step B: 2-butyl-4-chloro-1-({[2'-tetrazole-5-yl)- 1,1'-biphenyl-4-yl] fluorenyl}- 5- [(4-3 Fluoromethylbenzyloxy)indolyl] -imidazole

将步骤 A所得的中间体 412mg ( 0.501mmol )溶于 10mL无水甲醇中，加入 45mg的 K0H，回流反应 2h, 减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 195mg，经鉴别为题述化合物，收率 67%。 412 mg (0.501 mmol) of the intermediate obtained in the step A was dissolved in 10 mL of anhydrous methanol, and then added to a solution of EtOAc (methanol). For the title compound, the yield was 67%.

M. p.： 140.6-141.4°C; M. p.: 140.6-141.4 ° C;

Ή-NMR (400Mz, DMS0) δ： 10.65 ( s, 1H) , 8.79-8.71 ( d, 1Η ) , 7.68-7.54( t, 1H ) , 7.55-7.45 (m, 3H ) , 7.43-7.39 ( d, 1H ), 7.36-7.29 (dd， 2H ) , 7.28-7.21 ( dd, 2H ) ， 7.12-6.95 ( dd, 2H ) ， 4.96 (s， 2H ) , 4.76 ( s, 2H ) , 4.59 ( s, 2H ) , 2.67-2.54 ( t, 2H ) , 1.80—1.71 ( m, 2H ) ， 1.37-1.32 ( m, 2H ) ， 0.87-0.85 ( t, 3H ) ； Ή-NMR (400Mz, DMS0) δ: 10.65 ( s, 1H) , 8.79-8.71 ( d, 1Η ) , 7.68-7.54 ( t, 1H ) , 7.55-7.45 (m, 3H ) , 7.43-7.39 (d, 1H ), 7.36-7.29 (dd, 2H ) , 7.28-7.21 ( dd, 2H ) , 7.12-6.95 ( dd, 2H ) , 4.96 (s, 2H ) , 4.76 ( s, 2H ) , 4.59 ( s, 2H ) , 2.67-2.54 ( t, 2H ) , 1.80-1.71 ( m, 2H ) , 1.37-1.32 ( m, 2H ) , 0.87-0.85 ( t, 3H ) ;

ESI-MS: (M+H)⁺=581, (M—H)—=579。实施例 5: 2-丁基- 4-氯- 1-{[2'- 四唑- 5-基）- 1， -联苯- 4-基]曱基} -5- [ (4-氰基苄氧基）甲基] - 咪唑 ESI-MS: (M+H) ⁺ = 581, (M - H) - = 579. Example 5: 2-butyl-4-chloro-1-{[2'-tetrazole-5-yl)-1,-biphenyl-4-yl]fluorenyl}-5-[(4-cyano) Benzyloxy)methyl] -imidazole

步骤 Α: 2-丁基- 4-氯- 1-{[2'- (1-三苯甲基 - 四唑- 5-基）- 1， Γ- 联苯 -4-基]曱基 }- 5_[(4-氰基苄氧基）甲基] -咪唑 Step Α: 2-butyl-4-chloro-1-o{[2'-(1-trityl-tetrazol-5-yl)-1, fluorene-biphenyl-4-yl]fluorenyl}- 5_[(4-cyanobenzyloxy)methyl]-imidazole

按照实施例 1步骤 Α所示的方法，采用 196mg 4-氰基苄溴（ lmmol ) 代替 122μί 4-氟苄溴制得中间体 2-丁基- 4-氯- 1- {[2'-(1-三苯甲基 -1〃-四唑- 5-基）- 1，1'-联苯- 4-基] 甲基 }- 5- [(4_氰基苄氧基）甲基]- 1 ^咪唑 491mg (乳白色粉末），收率 63%。 According to the procedure shown in the first step of Example 1, 196 mg of 4-cyanobenzyl bromide (1 mmol) was used instead of 122 μί 4-fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro-1--{[2'-( 1-tritylmethyl-1〃-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5-[(4-cyanobenzyloxy)methyl]- 1 ^imidazole 491 mg (milky powder), yield 63%.

'Η-匪 R(400Mz， DMS0) δ： 7.81-7.65 ( m, 6H ) ， 7.67- 7.56 (d， 1H)， 7.54-7.41 ( m, 6H ) , 7.36-7.28 ( t, 1H)， 7.25-7.21 ( d, 2H )， 7.19-7.16( t, 1H ) , 7.14-7.05( d, 1H ), 6.98-6.91(m， 3H)， 6.79-6.72 ( d, 2H ) , 6.46-6.37 ( d, 2H )， 6.25-6.17 ( d, 2H ) , 5.02 ( s, 2H ) , 4.78 ( s， 2H) , 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H ) , 1.71-1.64 (m， 2H ) , 1.41-1.32 ( m, 2H ) ， 0.91-0.87 ( t, 3H ) 。步骤 B: 2-丁基- 4-氯- 1- {[2'- 四唑 _5-基）- 1， 1'-联苯 -4-基] 甲基 }_5_[(4-氰基苄氧基）甲基] - 咪唑 'Η-匪R(400Mz, DMS0) δ: 7.81-7.65 ( m, 6H ) , 7.67- 7.56 (d, 1H), 7.54-7.41 ( m, 6H ) , 7.36-7.28 ( t, 1H), 7.25- 7.21 ( d, 2H ), 7.19-7.16( t, 1H ) , 7.14-7.05( d, 1H ), 6.98-6.91(m, 3H), 6.79-6.72 ( d, 2H ) , 6.46-6.37 ( d, 2H ), 6.25-6.17 ( d, 2H ) , 5.02 ( s, 2H ) , 4.78 ( s, 2H) , 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H ) , 1.71-1.64 (m, 2H ) , 1.41-1.32 ( m, 2H ) , 0.91-0.87 ( t, 3H ). Step B: 2-Butyl- 4-chloro- 1- {[2'-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}_5_[(4-cyanobenzyl) Oxy)methyl] -imidazole

将步骤 A所得的中间体 390mg ( 0.500mmol )溶于 10mL无水曱醇中，加入 45mg的 K0H，回流反应 2h，减压浓缩除去溶剂，所得残留物经柱层析纯化得乳白色固体 207mg, 经鉴别为题述化合物，收率 77%。 The 390 mg (0.500 mmol) of the intermediate obtained in the step A was dissolved in 10 mL of anhydrous methanol, and then added to a mixture of EtOAc (EtOAc) Identification as the title compound, yield 77%.

M. ρ·： 142.3-143.8°C; M. ρ·: 142.3-143.8 ° C;

Ή-NMR (400 z, D S0) δ： 10.58 ( s, 1H) ， 8.72-8.69 ( d, 1H ) , 7.65-7.54 ( t, 1H ) , 7.52-7.45 (m, 3H ), 7.44-7.39( d, 1H ), 7.35-7.29 ( d, 2H )， 7.27-7.21 ( d, 2H ) , 7.02-6.95 ( d, 2H )， 4.99 ( s, 2H )， 4.76 ( s, 2H ) ， 4.59 ( s, 2H ) , 2.67-2.54 ( s, 2H ) , 1.80-1.71 ( m, 2H ) ， 1.37-1.32 ( m, 2H ) , 0.91-0.87 ( t， 3H ) ； Ή-NMR (400 z, D S0) δ: 10.58 ( s, 1H) , 8.72-8.69 ( d, 1H ) , 7.65-7.54 ( t, 1H ) , 7.52-7.45 (m, 3H ), 7.44-7.39 ( d, 1H ), 7.35-7.29 ( d, 2H ), 7.27-7.21 ( d, 2H ) , 7.02-6.95 ( d, 2H ), 4.99 ( s, 2H ), 4.76 ( s, 2H ) , 4.59 ( s, 2H ) , 2.67-2.54 ( s, 2H ) , 1.80-1.71 ( m, 2H ) , 1.37-1.32 ( m, 2H ) , 0.91-0.87 ( t, 3H ) ;

ESI- MS: (M+H)⁺=538, (M- H) 536。实施例 6: 2-丁基- 4-氯- 1- {[2'- 四唑 - 5_基）- 1， _联苯- 4-基]曱基}-5- [(3-氟苄氧基）甲基] - 咪唑 ESI-MS: (M+H) ⁺ = 538, (M-H) 536. Example 6: 2-butyl-4-chloro-1 - {[2'-tetrazol-5-yl)-1, _biphenyl-4-yl]fluorenyl}-5- [(3-fluorobenzyl) Oxy)methyl] -imidazole

步骤 Α: 2-丁基- 4-氯 -1- {[2'- (1-三苯甲基 - 四唑- 5-基） -1， V - 联苯- 4-基]甲基 } -5- [(3 -氟苄氧基）甲基] 咪唑 Step Α: 2-butyl-4-chloro-1-{[2'-(1-trityl-tetrazol-5-yl)-1, V-biphenyl-4-yl]methyl} 5-[(3-fluorobenzyloxy)methyl]imidazole

按照实施例 1步骤 Α所示的方法，采用 122μί 3-氟苄溴（ lmmol ) 代替 122 L 4-氟苄溴制得中间体 2-丁基 -4-氯- 1- {[2'-(1-三苯曱基四唑- 5-基） -1， 1'-联苯- 4-基]甲基 }- 5_[(3-氟苄氧基）曱基] - 1#- 咪唑 620mg (白色粉末），收率 80°/。。 According to the method shown in the step 实施 of Example 1, 122 μί 3-fluorobenzyl bromide (1 mmol ) was used instead of 122 L 4-fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro- 1- {[2'-( 1-triphenylsulfonyltetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5_[(3-fluorobenzyloxy)indolyl] - 1#-imidazole 620mg ( White powder), yield 80°/. .

Ή-N R (400Mz, CDC1₃) δ： 7.94 ( m, 1H) , 7.52-7.46 ( m, 2H ) , 7.36-7.30 ( m, 4H ) , 7.28-7.21 ( m, 8H ) , 7.09 ( d, 2H )， 7.00-6.89 ( m, 8H) , 6.70 ( d， 2H ) , 5.04 ( s, 2H ) , 4.35 ( s, 2H ) , 4.21 ( s, 2H ) , 2.48 ( t, 2H ) , 1.70-1.61 ( m, 2H ) , 1.36-1.20 ( m, 2H )， 0.85 ( t, 3H ) 。步骤 B: 2-丁基 -4-氯- 1-{[2'- (1#-四唑 -5-基）- 1， 1'-联苯 -4-基] 甲基 }- 5- [(3-氟苄氧基）甲基] 咪唑 Ή-NR (400Mz, CDC1 ₃ ) δ: 7.94 ( m, 1H) , 7.52-7.46 ( m, 2H ) , 7.36-7.30 ( m, 4H ) , 7.28-7.21 ( m, 8H ) , 7.09 ( d, 2H ), 7.00-6.89 ( m, 8H) , 6.70 ( d, 2H ) , 5.04 ( s, 2H ) , 4.35 ( s, 2H ) , 4.21 ( s, 2H ) , 2.48 ( t, 2H ) , 1.70-1.61 ( m, 2H ) , 1.36-1.20 ( m, 2H ), 0.85 ( t, 3H ). Step B: 2-Butyl-4-chloro- 1-{[2'-(1#-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5- [ (3-fluorobenzyloxy)methyl]imidazole

将步骤 Α所得的中间体 386mg ( 0.500mmol )溶于 10mL无水甲醇中，加入 45mg的 K0H, 回流反应 2h，减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 180mg, 经鉴别为题述化合物，收率 68%。 386 mg (0.500 mmol) of the obtained intermediate was dissolved in 10 mL of anhydrous methanol, and then added to a mixture of EtOAc (EtOAc) For the title compound, the yield was 68%.

Ή-NMR (400 z, CDC1₃) δ： 7.87 ( d, 1H) ， 7.63-7.50 ( m, 2H ) , 7.37 ( d, 1H ) ， 7.26-7.19 ( m， 1H ) , 7.02 ( d, 2H ) ， 6.98-6.85 ( m, 3H ) , 6.71 ( d, 2H ) ， 5.08 ( s, 2H ) , 4.39 ( s, 2H ) , 4.21 ( s, 2H ) , 2.29 ( t, 2H ) , 1.59-1.40 ( m, 2H ) , 1.30-1.18 ( m, 2H ) , 0.82 ( t, 3H) 。实施例 7: 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基）- 1， 1'-联苯- 4-基]曱基}- 5- [(3-三氟甲基苄氧基）甲基] 咪唑

Ή-NMR (400 z, CDC1 ₃ ) δ: 7.87 ( d, 1H) , 7.63-7.50 ( m, 2H ) , 7.37 ( d, 1H ) , 7.26-7.19 ( m, 1H ) , 7.02 ( d, 2H ) , 6.98-6.85 ( m, 3H ) , 6.71 ( d, 2H ) , 5.08 ( s, 2H ) , 4.39 ( s, 2H ) , 4.21 ( s, 2H ) , 2.29 ( t, 2H ) , 1.59-1.40 ( m , 2H ) , 1.30-1.18 ( m, 2H ) , 0.82 ( t, 3H). Example 7: 2-Butyl- 4-chloro- 1-{[2'-tetrazole-5-yl)-1,1'-biphenyl-4-yl]fluorenyl}- 5- [(3- Trifluoromethylbenzyloxymethyl]imidazole

步骤 A: 2-丁基 -4-氯- 1_{[2'- (1-三苯甲基 - 四唑- 5-基）- 1， V - 联苯 -4-基]曱基 }- 5- [(3-三氟曱基苄氧基）甲基] - 咪唑 Step A: 2-butyl-4-chloro-1_{[2'-(1-trityl-tetrazol-5-yl)- 1, V-biphenyl-4-yl]fluorenyl}- 5 - [(3-Trifluoromethylbenzyloxy)methyl] -imidazole

按照实施例 1 步骤 A 所示的方法，采用 264mg 3-三氟甲基苄溴 ( 1. Immol )代替 122μΙ 4 -氟苄溴制得中间体 2 -丁基 - 4-氯- 1- { [2' - (1- 三苯甲基 - 四唑- 5-基）- 1， 1'-联苯- 4-基]曱基 }- 5- [(3-三氟曱基苄氧基）甲基 ]- 咪唑 594mg (白色粉末），收率 71%。 Prepare the intermediate 2 -butyl-4-chloro-1-{ by using 264 mg of 3-trifluoromethylbenzyl bromide (1.1 mmol) instead of 122μΙ 4-fluorobenzyl bromide according to the procedure shown in Step 1 of Example 1. 2'-(1-Trityl-tetrazole-5-yl)-1,1'-biphenyl-4-yl]fluorenyl}- 5-[(3-trifluorodecylbenzyloxy)- Base]-imidazole 594 mg (white powder), yield 71%.

'Η-丽 R(400Mz， DMS0) δ： 7.95-7.85 ( m, 6H ) ， 7.84-7.78 ( t, 1H ) , 7.77-7.68 (m, 6Η )， 7.64-7.59 ( t, 1H) , 7.57-7.54 ( d, 1H )， 7.53-7.48 ( t, 1H ) , 7.47-7.43( t, 1H ), 7.42-7.40( d， 1H )， 7.38-7.33 (d， 1H) ， 7.31-7.27 ( t, 3H ) , 7.25-7.17 (d， 2H ) , 6.96-6.91 ( d， 2H )， 5.02 ( s, 2H )， 4.72 ( s, 2H ) , 4.51 ( s, 2H )， 2.57-2.54 (d， 2H ) , 1.71-1.64 ( m, 2H ) , 1.41-1.32 ( m, 2H ) ， 0.90-0.87 ( t, 3H ) 。步骤 B: 2-丁基 -4-氯- 1-{[2'- 四唑- 5-基）- 1， 1'-联苯- 4-基] 甲基 }- 5_[(3-三氟甲基苄氧基）甲基] 咪唑 'Η-丽R(400Mz, DMS0) δ: 7.95-7.85 ( m, 6H ) , 7.84-7.78 ( t, 1H ) , 7.77-7.68 (m, 6Η ), 7.64-7.59 ( t, 1H) , 7.57- 7.54 ( d, 1H ), 7.53-7.48 ( t, 1H ) , 7.47-7.43 ( t, 1H ), 7.42-7.40 ( d, 1H ), 7.38-7.33 (d, 1H) , 7.31-7.27 ( t, 3H ), 7.25-7.17 (d, 2H), 6.96-6.91 (d, 2H), 5.02 ( s, 2H ), 4.72 ( s, 2H ) , 4.51 ( s, 2H ), 2.57-2.54 (d, 2H ) , 1.71-1.64 ( m, 2H ) , 1.41-1.32 ( m, 2H ) , 0.90-0.87 ( t, 3H ). Step B: 2-Butyl-4-chloro-1-{[2'-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5_[(3-trifluoro Methylbenzyloxy)methyl]imidazole

将步骤 A所得的中间体 412mg ( 0. SOlmmol )溶于 10mL无水甲醇中，加入 45mg的 K0H，回流反应 2h, 减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 227mg, 经鉴别为题述化合物，收率 78%。 412 mg (0. SOlmmol) of the intermediate obtained in the step A was dissolved in 10 mL of anhydrous methanol, and then added to a solution of EtOAc (EtOAc). Identification as the title compound, yield 78%.

M. p.： 128.3-129.3°C; M. p.: 128.3-129.3 ° C;

H-N R (400Mz, DMS0) δ：： 10. 56 ( s , 1Η) ， 8.56 ( s, 1H) ， 7.95 H-N R (400Mz, DMS0) δ: : 10. 56 ( s , 1Η) , 8.56 ( s, 1H) , 7.95

( s, 1H ) ， 7.72-7.63 ( d， 1H) 7. , 62 -7.56 ( t, 1H ) , 7.54- -7.48( s, 1H ) , 7.72-7.63 ( d, 1H) 7. , 62 -7.56 ( t, 1H ) , 7.54- -7.48

( d， 1H ) ， 7.51-7.46 ( t， 1H) 7, .44 -7.41 ( d, 1H) , 7.39- -7.35( d, 1H ) , 7.51-7.46 ( t, 1H) 7, .44 -7.41 ( d, 1H) , 7.39- -7.35

( t, 1H) , 7.34-7.30 ( d, 1H) 7. .28 -7.22 ( d, 2H ) , 7.07- -6.95(t, 1H), 7.34-7.30 (d, 1H) 7. .28 -7.22 ( d, 2H ) , 7.07- -6.95

(d, 2H ) ， 4.96 ( s, 2H ) ， 4. 72 ( s , 2H) ， 4.54 ( s, 2H) ， 2.57(d, 2H), 4.96 ( s, 2H ) , 4. 72 ( s , 2H) , 4.54 ( s, 2H) , 2.57

( t, 2H ) , 1.74-1.68 ( m, 2H ) ， 1. . 5 -1.36 ( m, 2H ) , 0.90- -0.87( t, 2H ) , 1.74-1.68 ( m, 2H ) , 1. . 5 -1.36 ( m, 2H ) , 0.90- -0.87

, 3H ) ; , 3H ) ;

ESI-MS: (M+H)⁺=581, (M- H)— =579。实施例 8: 2-丁基- 4-氯- 1- {[2'- 四唑 -5-基）- 1，联苯 -4-基]甲基}_5- [(2, 5-二氟苄氧基）曱基] - 咪唑 ESI-MS: (M + H ) + = 581, (M- H) - = 579. Example 8: 2-butyl-4-chloro-1 - {[2'-tetrazol-5-yl)-1,biphenyl-4-yl]methyl}_5- [(2, 5-difluoro) Benzyloxy)indenyl]-imidazole

步骤 Α: 2-丁基 -4-氯 -1- {[2'- (1-三苯甲基 - 四唑- 5-基） -1, 1'- 联笨- 4-基]甲基 }- 5-[(2，5-二氟苄氧基）甲基 ]- 咪唑 Step Α: 2-butyl-4-chloro-1-{[2'-(1-tritylmethyl-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl} - 5-[(2,5-Difluorobenzyloxy)methyl]-imidazole

按照实施例 1步骤 Α所示的方法，采用 206mg 2, 5-二氟苄溴（ lmmol ) 代替 122 L 4-氟苄溴制得中间体 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基四唑- 5-基）- 1， 1'-联苯- 4-基]甲基 }- 5- [(2, 5-二氟苄氧基）甲基]- 1〃-咪唑 441mg (白色粉末），收率 56°/。。 According to the procedure shown in the first step of Example 1, 206 mg of 2,5-difluorobenzyl bromide (1 mmol) was used instead of 122 L of 4-fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro-1 - {[2 '-(1-Triphenylmethyltetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5-[(2,5-difluorobenzyloxy)methyl] - 1 〃-imidazole 441 mg (white powder), yield 56 ° /. .

'H-NMR(400 z, DMS0) δ： 7.90-7.79 ( m, 6H ) ， 7.73- 7.68 ( t， 1H) , 7.65-7.59 ( m, 6Η )， 7.57-7.52 ( t, 1H)， 7.51-7.46 ( d, 1H)， 7.43-7.40( d, 1H ) , 7.37-7.34( t, 3H ) , 7.27-7.21( d, 1H )， 7.11-7.04 ( d， 2H ) , 7.02-6.96 ( d, 2H )， 6.84-6.82 ( d, 1H ) , 6.81 ( s, 1H )， 4.99 ( s, 2H ) , 4.72 ( s, 2H ) , 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H ) ， 1.71—1.64 ( m, 2H ) ， 1.41-1.32 (m, 2H ) , 0.90—0.87 ( t， 3H ) 。步骤 B: 2-丁基- 4-氯- 1- {[2'- 四唑 -5-基）- 1， -联苯 -4-基] 甲基 }- 5- [(2， 5-二氟苄氧基）曱基] - 1 -咪唑 'H-NMR(400 z, DMS0) δ: 7.90-7.79 ( m, 6H ) , 7.73- 7.68 ( t, 1H) , 7.65-7.59 ( m, 6Η ), 7.57-7.52 ( t, 1H), 7.51- 7.46 ( d, 1H), 7.43-7.40( d, 1H ) , 7.37-7.34( t, 3H ) , 7.27-7.21( d, 1H ), 7.11-7.04 ( d, 2H ) , 7.02-6.96 ( d, 2H ), 6.84-6.82 ( d, 1H ) , 6.81 ( s, 1H ), 4.99 ( s, 2H ) , 4.72 ( s, 2H ) , 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H ) , 1.71— 1.64 ( m, 2H ) , 1.41-1.32 (m, 2H ) , 0.90-0.87 ( t, 3H ). Step B: 2-butyl-4-chloro-1-{{2'-tetrazol-5-yl)-1,-biphenyl-4-yl]methyl}- 5- [(2, 5-di) Fluorobenzyloxy)indolyl] - 1 -imidazole

将步骤 A所得的中间体 396mg ( 0.501mmol )溶于 10mL无水甲醇中，加入 45mg的 K0H，回流反应 2h，减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 168mg，经鉴别为题述化合物，收率 61%。 The intermediate 396 mg (0.501 mmol) obtained in the step A was dissolved in 10 mL of anhydrous methanol, and then added to a solution of EtOAc (methanol). For the title compound, the yield was 61%.

M. p.： 168.5-170°C; M. p.: 168.5-170 ° C;

'Η-腿 (400Mz, DMS0) δ： 8.56 ( s, 1H) , 7.72-7.64 ( d, 1Η ) , 7.62-7.56 ( t, 1H ), 7.45-7.39( d, 1H ), 7.36-7.27 ( d, 1H )， 7· 22-7.15 (d， 2H ) , 7.12-7.05 ( d, 2H )， 6.95-6.87 ( d, 1H ) , 6.81 ( s, 1H) , 4.99 ( s， 2H ) , 4.72 ( s, 2H ) , 4.60 ( s, 2H ) , 2.57-2.54 ( t, 2H ) , 1.71-1.64 (m， 2H ) , 1.41-1.32 ( m, 2H ) , 0.90-0.87 ( t, 3H ) ； ESI-MS: (Μ+ΗΓ-549, (M—H)— =547。实施例 9: 2-丁基- 4-氯- 1- {[2'-(1#-四唑- 5-基） -1， -联苯- 4-基]甲基}- 5- {[2， 5-二（三氟甲基）苄氧基]曱基 }- 咪唑 'Η-legs (400Mz, DMS0) δ: 8.56 ( s, 1H) , 7.72-7.64 ( d, 1Η ) , 7.62-7.56 ( t, 1H ), 7.45-7.39( d, 1H ), 7.36-7.27 (d , 1H ), 7· 22-7.15 (d, 2H ) , 7.12-7.05 ( d, 2H ), 6.95-6.87 ( d, 1H ) , 6.81 ( s, 1H) , 4.99 ( s, 2H ) , 4.72 ( s , 2H ) , 4.60 ( s, 2H ) , 2.57-2.54 ( t, 2H ) , 1.71-1.64 (m, 2H ) , 1.41-1.32 ( m, 2H ) , 0.90-0.87 ( t, 3H ) ; ESI-MS : (Μ+ΗΓ-549, (M—H)—=547. Example 9: 2-butyl-4-chloro-1 - {[2'-(1#-tetrazol-5-yl)-1,-biphenyl-4-yl]methyl}- 5- {[ 2,5-bis(trifluoromethyl)benzyloxy]indolyl}-imidazole

步骤 Α: 2-丁基- 4-氯- 1- {[2'- (1-三苯甲基- 四唑 -5-基）- 1, Γ- 联苯- 4-基]曱基 } -5- { [2, 5-二（三氟甲基）苄氧基]曱基 } - 咪唑 Step Α: 2-butyl 4-chloro-1- 1-[[2'-(1-trityl-tetrazol-5-yl)-1, fluorene-biphenyl-4-yl]fluorenyl} 5- { [2, 5-bis(trifluoromethyl)benzyloxy]indolyl} -imidazole

按照实施例 1 步骤 Α 所示的方法，釆用 307mg 2,5-二（三氟甲基）苄溴（ 1隱 ol ) 代替 122 L 4 -氟苄溴制得中间体 2-丁基- 4 -氯 _1_{[2'- (1-三苯甲基- 四唑- 5-基）- 1， 1'-联苯基 _4 -基] 甲基 }-5-{[2， 5-二（三氟甲基）苄氧基]曱基 }- 咪唑 454mg(白色粉末），收率 51%。 The intermediate 2-butyl-4 was obtained by the procedure shown in the procedure of Example 1, Step Α, using 307 mg of 2,5-bis(trifluoromethyl)benzyl bromide (1 sec ol) instead of 122 L 4 -fluorobenzyl bromide. -chloro_1_{[2'-(1-trityl-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-5-{[2, 5- Bis(trifluoromethyl)benzyloxy]indolyl}-imidazole 454 mg (white powder), yield 51%.

Ή-N R (400Mz, D S0) δ： 8.10 ", 1H) , 7.87- 7.81 (d, 1H ) ， 7.79-7.75 ( d, 1H ), 7.73—7.69(m, 6H ), 7.67-7.63( d, 1H ) , 7.62-7.53 ( m, 6Η ) , 7.50-7.44 ( t， 1Η ) , 7.42-7.39 ( d， 1H ) ， 7.37-7.31 (d， 1H) , 7.29-7.17 ( m, 3H ) , 6.96-6.91 (d， 2H ) , 6.72-6.66 ( d， 2H )， 4.98 ( s, 2H )， 4.72 ( s， 2H ) ， 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H) ， 1.71-1.64 ( m, 2H ) ， 1.41-1.32 ( m, 2H ) ， 0.90-0.87 ( t, 3H) 。步骤 B: 2-丁基- 4-氯- 1_{[2'-(1#-四唑- 5-基）- 1， 1'-联苯- 4-基] 甲基 }- 5- {[2， 5-二（三氟甲基）苄氧基]甲基 }- 1〃-咪唑 Ή-NR (400Mz, D S0) δ: 8.10 ", 1H), 7.87- 7.81 (d, 1H), 7.79-7.75 (d, 1H), 7.73-7.69 (m, 6H), 7.67-7.63 (d, 1H), 7.62-7.53 (m, 6Η), 7.50-7.44 (t, 1Η), 7.42-7.39 (d, 1H), 7.37-7.31 (d, 1H), 7.29-7.17 (m, 3H), 6.96- 6.91 (d, 2H), 6.72-6.66 ( d, 2H ), 4.98 ( s, 2H ), 4.72 ( s, 2H ) , 4.51 ( s, 2H ) , 2.57-2.54 ( t, 2H) , 1.71-1.64 ( m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H). Step B: 2-butyl-4-chloro-1_{[2'-(1#-tetrazole-5- Base)-1,1'-biphenyl-4-yl]methyl}- 5-{[2,5-bis(trifluoromethyl)benzyloxy]methyl}- 1〃-imidazole

将步骤 A所得的中间体 325mg ( 0.501mmol )溶于 10mL无水曱醇中，加入 45mg的 K0H, 回流反应 2h，减压浓缩除去溶剂，所得残留物经柱层析纯化得白色固体 224mg，经鉴别为题述化合物，收率 69%。 325 mg (0.501 mmol) of the intermediate obtained in the step A was dissolved in 10 mL of anhydrous methanol, and then added to EtOAc (EtOAc) Identification as the title compound, yield 69%.

M. p.： 118.6—120.4°C; M. p.: 118.6-124.0 ° C;

Ή-NMR (400 z, DMS0) δ： 8.63 ( s , 1H ) , 8.31 ( s , 1H ) , 7.79-7.77 (d， 1H) , 7.74-7.69 (d， 1H ) ， 7.67-7.59 (d， 1H ) , 7.55-7.52 ( t, 1H ) ， 7.51-7.46 (d, 1H ) ， 7.44-7.39 (d， 1H ) , 7.34-7.26 ( t, 2H ) ， 7.22-7.05 ( m, 2H) , 5.01 ( s, 2H ) ， 4.72 ( s, 2H ) , 4.69 "， 2H ) , 2.54-2.37 ( t, 2H ) , 1.71-1.64 ( m, 2H ) , 1.41-1.32 ( m， 2H) , 0.90-0.87 ( t, 3H ) ； Ή-NMR (400 z, DMS0) δ: 8.63 ( s , 1H ) , 8.31 ( s , 1H ) , 7.79-7.77 (d, 1H) , 7.74-7.69 (d, 1H ) , 7.67-7.59 (d, 1H ) , 7.55-7.52 ( t, 1H ) , 7.51-7.46 (d, 1H ) , 7.44-7.39 (d, 1H ) , 7.34-7.26 ( t, 2H ) , 7.22-7.05 ( m, 2H) , 5.01 ( s , 2H ) , 4.72 ( s, 2H ) , 4.69 ", 2H ) , 2.54-2.37 ( t, 2H ) , 1.71-1.64 ( m, 2H ) , 1.41-1.32 ( m, 2H) , 0.90-0.87 ( t, 3H ) ;

ESI— MS: ( +H) ⁺=649, (Μ—ΗΓ=647。实施例 10 : PPAR Y激动活性测定 ESI-MS: (+H) ⁺ = 649, (Μ-ΗΓ = 647. Example 10: PPAR Y agonistic activity assay

用 RT- PCR 方法（反转录（RT) 和 cDNA的聚合酶链式扩增（ PCR ) 相结合的技术）从脂肪组织中克隆到 PPAR Y全长 cDNA, 将扩增的 PCR产物***表达载体 pcDNA3.1后测序鉴定。报告基因用 Promega公司的荧光素酶检测载体 pGL3 - Promoter 构建。转染实验用 U20S 细胞在 96 孔板中进行，在转染报告基因的同时共转染 RXR和 PPARy基因，转染 24小时后加入待检测的化合物，并维持溶剂 DMS0的终浓度为 0.1 %。化合物作用 24小时后裂解细胞并进行荧光素酶活性的检测。通过观察发光的强度可以得知化合物对核受体的激活强度。为了校正转染效率、细胞接种数量及化合物毒性等因素造成的试验误差，还同时共转染了 GFP质粒作为内参，在实验结果分析时所有试验孔的发光值都用 GFP 值进行了校正。试验结果用相对激活倍数表示，溶剂对照的值为 1，值越大表明激活能力越高。在模型筛选中，观察了样品在 6种不同浓度条件下对受体的激活情况，较全面地反应了化合物的药理特性，并且根据下面公式进行迭代计算拟合出化合物作用的浓度效应曲线，并计算出相应的半有效浓度（EC₅。）。 b The PPAR Y full-length cDNA was cloned from adipose tissue by RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR)), and the amplified PCR product was inserted into the expression vector. Sequencing after pcDNA3.1 was identified. The reporter gene was constructed using Promega's luciferase assay vector pGL3 - Promoter. The transfection experiments were carried out in 96-well plates using U20S cells. The RXR and PPARy genes were co-transfected at the same time as the transfection of the reporter gene. The compound to be detected was added 24 hours after transfection, and the final concentration of the solvent DMS0 was maintained at 0.1%. After 24 hours of compound action, the cells were lysed and tested for luciferase activity. The intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results. The test results are expressed as relative activation multiples, and the solvent control has a value of 1, and a larger value indicates a higher activation ability. In the model screening, the activation of the receptor at six different concentrations was observed, and the pharmacological properties of the compound were more comprehensively analyzed, and the concentration effect curve of the compound action was fitted by the iterative calculation according to the following formula. Calculate the corresponding semi-effective concentration (EC ₅ .). b

= « + - c + e = « + - c + e

具体结果详见下表: The specific results are detailed in the following table:

上述实验结果表明，在相同的浓度下，本发明实施例 1-9的化合物所测得的激活倍数均小于罗格列酮。因此，从上述实验结果得知，与完全的 PPAR Y激动剂罗格列酮相比，本发明实施例化合物 1 - 9对 PPAR y的激动活性较弱，是 PPAR y的部分激动剂。实施例 11: 对完全激动剂罗格列酮的 PPAR y激动活性的拮抗作用

The above experimental results show that the activation ratios of the compounds of Examples 1-9 of the present invention are all smaller than rosiglitazone at the same concentration. Therefore, it is known from the above experimental results that the compound of the present invention, 1-1, has a weak agonistic activity against PPAR y as compared with the complete PPAR Y agonist rosiglitazone, and is a partial agonist of PPAR y. Example 11: Antagonism of PPAR y agonistic activity of the full agonist rosiglitazone

用 RT - PCR 方法（反转录（RT) 和 cDNA的聚合酶链式扩增（ PCR ) 相结合的技术）从脂肪组织中克隆到 PPAR y全长 cDNA,将扩增的 PCR产物***表达载体 pcDNA3. 1后测序鉴定。报告基因用 Promega公司的荧光素酶检测载体 GL3 - Promoter构建。转染实验用 U20S细胞在 96孔板中进行，在转染报告基因的同时共转染 RXR和 PPAR γ基因，转染 24小时后，随机分组：一组不加化合物作为溶剂空白对照组，一组加 Ι. Ο μ Μ的罗格列酮作为阳性对照组，其他分别为加 0.001 μ Μ、 0. 01 μ Μ, 0. 1 μ Μ、 1 μ Μ、 5 μ Μ或 10 μ Μ浓度的待检测的化合物和 1. 0 μ Μ的罗格列酮作为检测组，并维持各组溶剂 DMS0 的终浓度为 0. 1 %。将以上各组作用 24小时后裂解细胞并进行荧光素酶活性的检测。通过观察发光的强度可以得知以上各组对核受体的激活强度。进而推出待测化合物对完全激动剂罗格列酮的 PPAR y激动活性的拮抗作用的强弱。为了校正转染效率、细胞接种数量及化合物毒性等因素造成的试验误差，还同时共转染了 GFP质粒作为内参，在实验结果分析时所有试验孔的发光值都用 GFP值进行了校正。试验结果用相对激活倍数表示，溶剂对照的值为 1, 值越大表明激活能力越高，待测化合物对完全激动剂罗格列酮的 PPAR γ激动活性的拮抗作用越弱。实验结果表明，加入了 1. Ο μΜ罗格列酮和 0· 001 μΜ、 0.01 μ Μ 0.1 μ Μ、 1 μΜ、 5 μ Μ或 10 μ Μ六个浓度的实施例 1 ~ 9的化合物所测得的相对激活倍数与仅加入了 1.0 μΜ罗格列酮所测得的相对激活倍数的比值均小于 1, 这表明实施例 1 ~ 9 的化合物在 0.001 μΜ、 0.01 μ 0.1 μΜ、 1 μΜ、 5 μ Μ及 10 μ Μ六个浓度下对完全激动剂罗格列酮的 PPAR γ激动活性均有拮抗作用。 The PPAR y full-length cDNA was cloned from adipose tissue by RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR)), and the amplified PCR product was inserted into the expression vector. After pcDNA3.1, sequencing was identified. The reporter gene was constructed using Promega's luciferase assay vector GL3 - Promoter. The transfection experiment was carried out in 96-well plates with U20S cells. The RXR and PPAR γ genes were co-transfected at the same time as the transfection of the reporter gene. After transfection for 24 hours, they were randomly grouped: one group without compound as a solvent blank control group, one The group was added with Ι μ Μ of rosiglitazone as a positive control group, and the others were added with a concentration of 0.001 μ Μ, 0.01 μ Μ, 0.1 μ Μ, 1 μ Μ, 5 μ Μ or 10 μ Μ. 1%。 The compound to be tested and 1.0 0 μ Μ of rosiglitazone as a test group, and the final concentration of the solvent DMS0 of each group was maintained at 0.1%. After the above groups were allowed to act for 24 hours, the cells were lysed and assayed for luciferase activity. The intensity of activation of nuclear receptors by the above groups can be known by observing the intensity of luminescence. Furthermore, the antagonism of the test compound against the PPAR y agonistic activity of the full agonist rosiglitazone was revealed. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference, and the luminescence values of all the test wells were used in the analysis of the experimental results. The GFP value was corrected. The results of the test are expressed as relative activation multiples. The value of the solvent control is 1, and the larger the value indicates the higher the activation ability, the weaker the antagonism of the test compound on the PPAR gamma agonistic activity of the full agonist rosiglitazone. The experimental results showed that the compounds of Examples 1 to 9 were added at a concentration of 1. Ο μΜ rosiglitazone and 0·001 μΜ, 0.01 μ Μ 0.1 μ Μ, 1 μΜ, 5 μ Μ or 10 μ Μ. The ratio of the relative activation multiples obtained to the relative activation multiples measured with 1.0 μM rosiglitazone was less than 1, indicating that the compounds of Examples 1 to 9 were 0.001 μΜ, 0.01 μ 0.1 μΜ, 1 μΜ, 5 There were antagonistic effects on the PPAR gamma agonistic activity of the full agonist rosiglitazone at six concentrations of μ Μ and 10 μ Μ.

上述实验结果表明本发明的化合物对完全 PPAR γ激动剂罗格列酮的 PPAR γ激动活性具有拮抗作用。实施例 12: 降糖药效实验 The above experimental results indicate that the compound of the present invention has an antagonistic effect on the PPAR γ agonistic activity of the complete PPAR γ agonist rosiglitazone. Example 12: Hypoglycemic effect test

健康自发性 II型糖尿病动物模型，雄性 GK大鼠（ Goto- Kakizaki 大鼠），体重 200g，动物禁食 12小时，血糖仪测定空腹血糖值，随机分组，分别连续灌胃给予实施例化合物（ 20 mg/kg )、罗格列酮（ 20 mg/kg ) 或对照液 0.5%CMC-Na (羧甲基纤维素钠）（ 10mL/kg ) ，连续给药 10天后再次测定空腹血糖值。 Healthy spontaneous type 2 diabetes animal model, male GK rats (Goto-Kakizaki rats), weighing 200 g, animals fasted for 12 hours, blood glucose meter was used to measure fasting blood glucose values, randomized, and the compounds of the examples were administered by continuous gavage. Mg/kg), rosiglitazone (20 mg/kg) or control solution 0.5% CMC-Na (carboxymethylcellulose sodium) (10 mL/kg), and the fasting blood glucose level was measured again after 10 days of continuous administration.

比较给药前后的血糖值可知实施例 1 ~ 9的化合物具有与阳性对照药罗格列酮相当的降血糖作用。实施例 13: 长期给药体重增加实验健康自发性 II型糖尿病动物模型，雄性 GK大鼠（Goto-Kakizaki大鼠），体重 200g，随机分组，分别连续给予含有实施例化合物 3、 4、 7 或罗格列酮的饲料（20 mg/kg/天），以给予正常飼料组为对照，连续给药 40天后观察体重增加情况。实验结果：空白对照组动物体重增长 23.2%;给予实施例化合物 3、 4、 7饲料组体重增长分别为 26. Vk、 26.2%、 25.5%, 并且体征、外观、行为、活动、粪便形状未见异常，均与空白对照组相似；给予罗格列酮的饲料组体重增长为 38.7%。表明实施例化合物 3、 4、 7长期给药对体重增加影响较小，长期毒性低，给药安全性高。实施例 14: 药物组合物

Comparing the blood glucose levels before and after administration, it was found that the compounds of Examples 1 to 9 have a hypoglycemic effect comparable to the positive control drug rosiglitazone. Example 13: Long-term administration of weight gain experiment Animal model of healthy spontaneous type 2 diabetes, male GK rats (Goto-Kakizaki rats) weighing 200 g, randomized, and continuously administered the feed containing the compound of Example 3, 4, 7 or rosiglitazone (20 mg/ Kg/day), the normal feed group was used as a control, and the weight gain was observed after 40 days of continuous administration. Experimental results: The body weight of the blank control group increased by 23.2%; the weight gain of the compound group 3, 4, and 7 of the example compound was 26. Vk, 26.2%, 25.5%, and the signs, appearance, behavior, activity, and stool shape were not observed. Abnormalities were similar to the blank control group; the weight gain of the diet group given rosiglitazone was 38.7%. It was shown that the long-term administration of the compounds of Examples 3, 4 and 7 had little effect on body weight gain, low long-term toxicity, and high drug safety. Example 14: Pharmaceutical composition

由以下组分制备含实施例化合物 3的胶嚢： A capsule containing the compound of Example 3 was prepared from the following components:

化合物 3 Compound 3

淀粉 Starch

乳糖 Lactose

PVP PVP

PVPP PVPP

滑石粉 Talc

十二烷基硫酸钠 Sodium dodecyl sulfate

按常规方法，将化合物 3与淀粉混合过筛，再与上述其他组分混合均匀后，装入普通明胶胶嚢，得到 1000颗胶嚢。 In a conventional manner, the compound 3 was mixed with starch and sieved, and then uniformly mixed with the above other components, and then filled into ordinary gelatin capsules to obtain 1000 capsules.

按类似方法，可分别制得含其他实施例化合物的胶嚢。实施例 15: 药物组合物 In a similar manner, capsules containing other example compounds were separately prepared. Example 15: Pharmaceutical composition

由以下组分制备含实施例化合物 3的片剂： A tablet containing the compound of Example 3 was prepared from the following components:

化合物 3 15g Compound 3 15g

淀粉 15g Starch 15g

乳糖 30g Lactose 30g

PVP 2.5g PVP 2.5g

PVPP 2.5g PVPP 2.5g

滑石粉 1.5g Talc powder 1.5g

十二烷基硫酸钠 4g Sodium lauryl sulfate 4g

按常规方法，将化合物 3与淀粉混合过，再与上述其他组分混合均匀后，直接压片，得到 1 000颗片剂。 Compound 3 is mixed with starch in a conventional manner and mixed with the other components described above. After homogenization, the tablets were directly compressed to obtain 1,000 tablets.

按类似方法，可分别制得含其他实施例化合物的片剂。本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 In a similar manner, tablets containing the other example compounds were separately prepared. All documents referred to in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the invention as described in the appended claims.

Claims

结构通式（ I ) 所示化合物: a compound of the formula (I):

或其药学上可接受的盐，

Or a pharmaceutically acceptable salt thereof,

其中， ^选自卤素、 c,- c₄烷基、卤素取代的（:,-( 4烷基、 c,- c₄烷氧基、 C广 C,环烷基、羟基、氰基、 d- c₄烷氧羰基、芳香环以及含至少一个选自 N、 S和 0杂原子的杂芳环；和 Wherein ^ is selected from the group consisting of halogen, c, - c ₄ alkyl, halogen substituted (:, -( 4 alkyl, c, - c ₄ alkoxy, C wide C, cycloalkyl, hydroxy, cyano, d a c ₄ alkoxycarbonyl group, an aromatic ring, and a heteroaryl ring containing at least one hetero atom selected from N, S and 0;

n= 1 ~ 5, 且为整数。 n= 1 ~ 5, and is an integer.

2. 如权利要求 1所述的化合物，其中 R,选自卤素、 C,- C烷基、卤素取代的 d- C₄烷基和氰基。 C 1-6 alkyl, halo-substituted d- C ₄ alkyl and cyano - 2. The compound of claim 1 wherein R, is selected from halo, C, required.

3. 如权利要求 1或 2所述的化合物，其中 n = 1或 2。 3. A compound according to claim 1 or 2, wherein n = 1 or 2.

4. 如权利要求 3所述的化合物，其中 n= l，且 1 ,是 3位或 4位取代基。 4. The compound of claim 3, wherein n = l, and 1 is a 3- or 4-position substituent.

5. 如权利要求 4所述的化合物，其中 ^是 4位取代基。 5. The compound of claim 4, wherein ^ is a 4-substituent.

6. 如权利要求 3所述的化合物，其中 n= 2，且！,是2位和 5位取代基。 6. The compound of claim 3, wherein n = 2, and! Is a 2-bit and 5-bit substitution base.

7. 如权利要求 6所述的化合物，其中 R,选自卤素、 C,-C₄烷基和卤素取代的 d- C₄烷基。 7. The compound according to claim 6, wherein R, is selected from halo, C, -C ₄ alkyl and halogen-substituted d- C ₄ alkyl group.

8. 如权利要求 1 所述的化合物，其中所述化合物为选自下组的化合物： 8. The compound of claim 1, wherein the compound is a compound selected from the group consisting of:

1) 2-丁基- 4-氯 -1- {[2'- 四唑- 5 -基） -1， 1'-联苯 -4-基] 甲基 }- 5- [(4-氟苄氧基）曱基] - 咪唑； 1) 2-butyl-4-chloro-1-{[2'-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}- 5-[(4-fluorobenzyl) Oxy)indenyl]-imidazole;

2) 2-丁基- 4-氯 -1- {[2'- 四唑- 5-基）- 1， Γ-联笨- 4-基] 曱基 }-5-[(4-溴苄氧基）曱基] 咪唑； 2) 2-butyl-4-chloro-1-{[2'-tetrazole-5-yl)- 1, Γ-linked stupid 4-yl] fluorenyl}-5-[(4-bromobenzyloxy) Imidazole

3) 2-丁基- 4-氯- 1- {[2'- 四唑 - 5_基）- 1， Γ-联苯- 4-基] 甲基 }- 5-[(4-甲基苄氧基）甲基] - 咪唑； 3) 2-Butyl- 4-chloro- 1-{[2'-tetrazole-5-yl)-1, fluorene-biphenyl-4-yl]methyl}- 5-[(4-methylbenzyl) Oxy)methyl]-imidazole;

4) 2-丁基 -4-氯- 1- {[2'- (1〃-四唑- 5-基）- 1, 1'_联苯- 4-基] 曱基 }- 5- [(4-三氟曱基苄氧基）曱基] - 1〃-咪唑； 4) 2-butyl-4-chloro- 1- {[2'-(1〃-tetrazole-5-yl)-1,1'-biphenyl-4-yl] 曱 }- 5- [(4-Trifluoromethylbenzyloxy)indolyl] - 1 〃-imidazole;

5) 2-丁基- 4-氯- 1- {[2'- 四唑- 5-基）联苯- 4-基] 甲基}-5-[(4-氰基苄氧基）曱基] - 咪唑; 5) 2-butyl-4-chloro-1-{{2'-tetrazole-5-yl)biphenyl-4-yl]methyl}-5-[(4-cyanobenzyloxy)fluorenyl ] - imidazole;

6) 2-丁基- 4-氯- 1- {[2'- (1〃-四唑- 5-基）- 1, 1 联苯- 4-基] 甲基 }- 5- [ (3-氟苄氧基）甲基] - 咪唑； 6) 2-Butyl- 4-chloro- 1- {[2'-(1〃-tetrazol-5-yl)- 1,1-biphenyl-4-yl]methyl}- 5- [ (3- Fluorobenzyloxymethyl]-imidazole;

7) 2-丁基- 4 -氯- 1- {[2'- 四唑- 5-基）联苯- 4-基] 曱基}- 5- [(3-三氟甲基苄氧基）甲基] - lyy-咪唑； 7) 2-butyl-4-chloro-1-su {[2'-tetrazole-5-yl)biphenyl-4-yl]nonyl}- 5-[(3-trifluoromethylbenzyloxy) Methyl]-lyy-imidazole;

8) 2-丁基- 4-氯- 1- {[2'- (1〃-四唑- 5-基） -联苯 -4-基] 甲基 }- 5- [(2， 5-二氟苄氧基）甲基] - 1#-咪唑；和 8) 2-Butyl- 4-chloro- 1- {[2'-(1〃-tetrazol-5-yl)-biphenyl-4-yl]methyl}- 5- [(2, 5- Fluorobenzyloxy)methyl] - 1#-imidazole;

9) 2-丁基- 4-氯- 1_{[2'- (1 -四唑- 5-基） -联苯 -4-基] 甲基} -5- { [2, ⁵_二（三氟甲基）苄氧基]甲基 } - 咪唑。 9) 2-butyl-4-chloro-1_{[2'-(1-tetrazol-5-yl)-biphenyl-4-yl]methyl}-5- { [2, ⁵ _ two (three Fluoromethyl)benzyloxy]methyl} -imidazole.

9. 一种制备权利要求 1-8中任一项所述化合物的方法，包括步骤： A ) ：将三苯甲基氯沙坦（III)溶于溶剂中，在碱存在下，与相应的 9. A process for the preparation of a compound according to any one of claims 1-8, comprising the steps of: A): dissolving trityl valsartan (III) in a solvent, in the presence of a base, and corresponding

、 B) ：将所得中间体 (ΐν)'^于溶剂中'，在碱存在下，加热脱除保护基得到目标化合物（I); And B): the obtained intermediate (ΐν) is dissolved in a solvent, and the protecting group is removed by heating in the presence of a base to obtain the target compound (I);

以及任选的步骤 C) ：将所得化合物与合适的无机酸或者有机酸形成酸加成盐或者与合适的无机碱或者有机碱形成碱加成盐。

10. 一种药物组合物，所述药物组合物包含权利要求 1至 8 中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. 如权利要求 10 所述的药物组合物，其还包含一种或多种其他降血糖药。 11. The pharmaceutical composition of claim 10, further comprising one or more other hypoglycemic agents.

12. 如权利要求 11 所述的药物组合物，其中所述其他降血糖药选自磺脲类药物、双胍类药物、 α-葡萄糖苷酶抑制剂和二酮类药物，优选所述其他降血糖药选自甲磺丁脲、格列本脲、格列吡嗪、苯乙双胍、二曱双胍、丁双胍、阿卡波糖、米格列醇、伏格列波糖、罗格列酮和吡格列酮。 12. The pharmaceutical composition according to claim 11, wherein the other hypoglycemic agent is selected from the group consisting of a sulfonylurea, a biguanide, an alpha-glucosidase inhibitor, and a diketone, preferably the other hypoglycemic The drug is selected from the group consisting of metobutyramide, glibenclamide, glipizide, phenformin, Diterpenoids, shuangshuang, acarbose, miglitol, voglibose, rosiglitazone and pioglitazone.

13. 如权利要求 10 所述的药物组合物，其中所述药物组合物为权利要求 1 至 8 中任一项所述的化合物或其药学上可接受的盐的含量为 0.6mg-12g, 优选为 0.6mg- 6g，更优选为 0.6mg- 3g的单位剂量的药物。 The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in an amount of from 0.6 mg to 12 g, preferably It is a unit dose of the drug of 0.6 mg to 6 g, more preferably 0.6 mg to 3 g.

14. 如权利要求 10至 13中任一项所述的药物组合物，其中所述药物组合物为口服制剂、直肠给药制剂、肠胃外给药制剂或局部给药制剂。 The pharmaceutical composition according to any one of claims 10 to 13, wherein the pharmaceutical composition is an oral preparation, a rectal administration preparation, a parenteral administration preparation or a topical preparation.

15. 如权利要求 1-8中任一项所述的化合物或其药学上可接受的盐或权利要求 10至 13中任一项所述的药物组合物在制备用于治疗和 /或预防 PPAR γ受体相关的疾病的药物中的应用。 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 10 to 13 for use in the preparation and/or prevention of PPAR The use of drugs for gamma receptor-related diseases.

16. 如权利要求 15 所述的应用，其中所述疾病选自糖尿病、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症。 16. The use according to claim 15, wherein the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.

17. 如权利要求 16 所述的应用，其中所述疾病为糖尿病或血糖异常升高相关疾病。 17. The use according to claim 16, wherein the disease is diabetes or a disease associated with elevated blood sugar abnormalities.

18. —种治疗和 /或预防哺乳动物 PPAR γ受体相关的疾病的方法，包括将治疗和 /或预防有效量的权利要求 1-8中任一所述的化合物或其药学上可接受的盐或权利要求 10至 13中任一项所述的药物组合物给予需要的哺乳动物。 18. A method of treating and/or preventing a PPAR gamma receptor-associated disease in a mammal, comprising administering a therapeutically and/or prophylactically effective amount of a compound of any of claims 1-8, or a pharmaceutically acceptable thereof The salt or the pharmaceutical composition of any one of claims 10 to 13 is administered to a mammal in need thereof.

19. 如权利要求 18 所述的方法，其中所述疾病选自糖尿病'、血糖异常升高相关疾病、脂质紊乱、代谢综合症、心血管疾病、冠状动脉疾病、高血胆固醇和肥胖症。 19. The method according to claim 18, wherein the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.

20. 如权利要求 19 所述的方法，其中所述疾病为糖尿病或血糖异常升高相关疾病。 20. The method according to claim 19, wherein the disease is diabetes or a disease associated with elevated blood sugar abnormalities.

21. 如权利要求 18至 20中任一项所述的方法，其中进一步包括将其他的降血糖药物与权利要求 1至 8中任一项所述的化合物或其盐或权利要求 10至 13中任一项所述的药物组合物同时或顺序地给予需要的哺乳动物。 The method according to any one of claims 18 to 20, further comprising the other hypoglycemic agent and the compound according to any one of claims 1 to 8 or a salt thereof or in claims 10 to 13. The pharmaceutical composition of any of the above is administered to a mammal in need thereof simultaneously or sequentially.