WO2005115998A1 - TYROSINE DERIVATIVES SUBSTITUTED BY ALKANOYLAS hPPARα & hPPARϜ ANGONISTS - Google Patents

TYROSINE DERIVATIVES SUBSTITUTED BY ALKANOYLAS hPPARα & hPPARϜ ANGONISTS Download PDF

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WO2005115998A1
WO2005115998A1 PCT/CN2005/000147 CN2005000147W WO2005115998A1 WO 2005115998 A1 WO2005115998 A1 WO 2005115998A1 CN 2005000147 W CN2005000147 W CN 2005000147W WO 2005115998 A1 WO2005115998 A1 WO 2005115998A1
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phenyl
propionic acid
ethoxy
methyl
oxazol
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PCT/CN2005/000147
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Chinese (zh)
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Song Li
Xinbo Zhou
Cuifang Lin
Lili Wang
Cheng Xu
Chengmai Ruan
Junhai Xiao
Zhibing Zheng
Hongying Liu
Yunde Xie
Wu Zhong
Hao Cui
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Beijing Molecule Science And Technology Co., Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Thiazolidinediones such as troglitazone and rosiglitazone have been clinically shown to enhance insulin action and reduce serum glucose in patients with type II diabetes.
  • Thiazolidinedione has been reported as a potent and selective activator of PPARy and directly binds to the PPAR gamma receptor (J. M. Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)).
  • one aspect of the invention relates to a compound of formula I, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof,
  • Y is H, halogen
  • a further aspect of the invention relates to the use of a compound of formula I according to the invention for the manufacture of a medicament for the treatment or prevention of a hPPAR Y and / or hPPAR a mediated disease, risk factor or condition.
  • n is an integer from 1-4;
  • the compounds of formula I of the present invention have stereocenters.
  • a single enantiomer of a compound of formula I can be prepared using reactants in all possible steps in the form of a single enantiomer, or Prepared in the presence of a reaction, or It is prepared by resolving a mixture of stereoisomers by a conventional method.
  • Some preferred methods include resolution using microorganisms, resolution of diastereomeric salts with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc., or resolution with Diastereomeric salts such as brae ine, cinchona alkaloids and their derivatives.
  • compounds of the general formula I are useful in the treatment or prevention of hPPAR ⁇ and / or hPPAR ct-mediated diseases, risk factors or conditions.
  • the hPPAR v and / or hPPAR oc-mediated diseases, risk factors or conditions include hyperglycemia, dyslipidemia, and type II diabetes including related diabetic dyslipidemia, type I diabetes , Hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesterolemia, hypertension, cardiovascular diseases including atherosclerosis, suffering from diseases such as obesity, anorexia, greed Regulation of appetite and food absorption in patients with anorexia and anorexia nervosa.
  • the compounds of the present invention are particularly useful in the treatment or prevention of hyperglycemia, dyslipidemia, and type II diabetes, including related diabetic dyslipidemia.
  • compositions of the present invention can be used both by themselves and in the form of their pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts of the compounds of formula I include conventional salts with pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, as well as acid addition salts of quaternary ammonium.
  • suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid , Citric acid, navic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluene Salts formed from sulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid, and the like.
  • the invention also includes active metabolites of the compounds of the invention.
  • the compounds of the present invention can be used either alone or in the form of pharmaceutical compositions.
  • the pharmaceutical composition of the present invention comprises an effective amount of a compound of formula I of the present invention, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof, and one or more suitable pharmaceutically acceptable carriers.
  • the pharmaceutical carriers according to the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, zoster ring fat, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, sorbic acid Potassium acid, a mixture of partially glycerides of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, Polyvinylpyrrolidone, cellulose shield, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inner, ventricle, sternum Intracranial and intracranial injection or infusion, or medication with the aid of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • Diluents used in capsule preparations generally include lactose and dried corn starch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweeteners, fragrances, or colorants may be added to the above oral preparation forms.
  • Example 5 (2S) -3- ⁇ 4- [2- (5-methyl-2-phenyl-1,3-poxazol-4-yl) -ethoxy] -phenyl ⁇ -2 -[3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid
  • the 3- (4-methoxy-phenyl) -propane Replace the acid with 3- (4-trifluoromethyl-phenyl) -propionic acid to obtain (2S) -3- ⁇ 4- [2- (5-methyl-2 -phenyl-1, 3 as a white solid) -Oxazolyl-4-yl) -ethoxy] -phenyl ⁇ -2- [3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid, mp: 159-161 ° C .
  • Example 12 (2S)-3- ⁇ 4- [2- (5-methyl-2 -phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl ⁇ -2- (2-o-trifluoromethyl- Phenyl-acetylamino) -propionic acid was prepared in a similar manner to that in Example 1.
  • Example 38 (28) -3- ⁇ 3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl ⁇ -2- (3-phenyl-butyrylamino) -propionic acid
  • the GAL4DNA binding region was linked to pB4-tk-luc to form PB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4DNA binding site).
  • PRL-CMV-Rluc was used as an internal standard to correct transfection efficiency and endogenous effects.
  • 293-T cells were seeded into a 48-well plate with a cell density of 2-4 x 10 4 cells / well and the culture medium was 10% defatted fetal calf serum (FCS) without phenol red and antibiotic-free 1640 medium. After 48 hours, the culture medium was replaced with 5% defatted FCS without phenol red and antibiotic-free 1640 medium, and then two subtypes of pM-hPPAR / GAL4, pB4-RES-tk-luc, and pRL-CMV- The three Rluc plasmids were co-transfected into 293-T cells and administered after 24 hours. The intensity of luciferase was measured 24 hours after administration. 0.2% 0 DMS0 was used as a blank control.
  • Example 8 8.2 3.9 9.01
  • Example 9 26.9 12.8 10.45
  • Example 10 23.1 11 11.51
  • Example 11 21.7 10.3
  • Example 6 23.9 17.1 0.058
  • Example 7 11.8 8.4
  • Example 8 12.2 8.7 1.19
  • Example 9 12.4 8.9 0.021
  • Example 10 6.2 4.4 0.24
  • Example 11 13.7 9.8

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides compounds of the general formula (I), racemic mixtures, optical isomers, pharmaceutically acceptable salts, solvates and pharmaceutical compositions thereof. The definitions of substituents in the general formula (I) are the same as the definitions of claims. The present invention also relates to the preparation for the compounds of the general formula (I) and the usage thereof for the preparation of a medicament, which is used for treating hyperglycemia, lipidosis lipaemia and NIDDM (type II) diabetes.

Description

作为 hPPAR α和 hPPAR γ激动剂的烷 酰基取代的酪氨酸衍生物 技术领域  Alkanoyl substituted tyrosine derivatives as hPPAR α and hPPAR γ agonists Technical Field
本发明涉及酪氨酸衍生物或其药学上可接受的盐或溶剂化物， 它们的制备方法， 含有它们的药物組合物以及它们作为过氧化物酶 体增殖因子活化受体 （筒称 PPAR)的激动剂、 尤其是对 PPAR y和 PPAR a显示出激动作用的双重激动剂用于治疗和 /或预防糖尿病和 高脂血症等代谢疾病的用途。 背景技术  The present invention relates to tyrosine derivatives or pharmaceutically acceptable salts or solvates thereof, methods for their preparation, pharmaceutical compositions containing them, and their use as peroxisome proliferator-activated receptors (PPAR) Use of an agonist, especially a dual agonist exhibiting an agonistic effect on PPARy and PPARa, for the treatment and / or prevention of metabolic diseases such as diabetes and hyperlipidemia. Background technique
过氧化物酶体增殖因子活化受体（简称为 PPAR)是与糖皮质 激素受体、 维甲酸受体和甲状腺素受体等同属于核内受体超家族 的配体依赖型转录因子。迄今为止，人们已经发现三种 PPAR亚型： α、 γ和 δ (也称 β和 NUC1 ) 。 它们是被不同的基因编码的。 而 且， PPAR y还存在 2种同工型 PPAR y 和 2。 这 2种蛋白盾的区 别在于它们的 NH2-末端的 30个氨基酸，它们是启动子的交替使用 和 nRNA 的差异剪接的结果（Vidal- Puig， J. Cl in. Inves t. , 97: 2553-2561, 1996)。 Peroxisome proliferator-activated receptor (PPAR for short) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, which is equivalent to the glucocorticoid receptor, retinoic acid receptor and thyroxine receptor. To date, three PPAR isoforms have been discovered: α, γ, and δ (also known as β and NUC1). They are encoded by different genes. Moreover, there are two isoforms PPAR y and 2 of PPAR y. The two protein shields differ by their 30 amino acids at the NH 2 -terminus, which are the result of alternate promoter use and differential splicing of nRNA (Vidal- Puig, J. Cl in. Inves t., 97: 2553 -2561, 1996).
PPAR α主要在对脂类有极高分解代谢活性的组织如棕色脂肪 组织和肝脏中表达，其次是在肾、心脏、骨骼肌中。（Endocnno logy, 1995, 137， 354)。 它能正控制或负控制与脂肪酸代谢和胞内输送 有关的基因（例如酰基 CoA合成酶、脂肪酸结合蛋白质和脂蛋白脂 肪酶）以及与胆固醇和中性脂质的代谢有关的载脂蛋白（AI , Al l , CI I I)基因的表达。 PPAR Y主要存在于脂肪组织中，也少量存在于 骨骼肌、 肝脏、 结肠、 视网膜、 免疫系统中。 最近研究结果也提 示其高度表达于巨噬细胞， 包括动脉粥样硬化的泡沫细胞中。 其 中， PPAR Y 2主要是在脂肪组织中专一性表达的， 而 PPAR Y 则在 各种组织中均有发现， 其中在肾、 肠和心脏表达最高。 PPARy主 要调节涉及脂肪细胞分化以及胰岛素敏感性基因的表达（L Lipid. Res. , 1996, 37， 907)。 PPAR α is mainly expressed in tissues with extremely high catabolic activity on lipids such as brown adipose tissue and liver, followed by kidney, heart, and skeletal muscle. (Endocnno logy, 1995, 137, 354). It can positively or negatively control genes related to fatty acid metabolism and intracellular transport (such as acyl CoA synthetase, fatty acid binding protein and lipoprotein lipase) and apolipoprotein (AI) related to cholesterol and neutral lipid metabolism , Al l, CI II) gene expression. PPAR Y is mainly found in adipose tissue, but also in small amounts in skeletal muscle, liver, colon, retina, and immune system. Recent results also suggest that it is highly expressed in macrophages, including atherosclerotic foam cells. Among them, PPAR Y 2 is mainly expressed exclusively in adipose tissue, while PPAR Y is expressed in It is found in various tissues, with the highest expression in the kidney, intestine, and heart. PPARy mainly regulates adipocyte differentiation and expression of insulin-sensitive genes (L Lipid. Res., 1996, 37, 907).
PPAR δ以神经细胞为中心在生物体内各组织中普遍表达。 目 前， 关于 PPAR δ的生理学意义还不清楚。  PPAR δ is commonly expressed in various tissues in the body with nerve cells as the center. At present, the physiological significance of PPAR δ is unclear.
噻唑烷二酮类药物如曲格列酮、 罗格列酮在临床上显示可增 强 Π型糖尿病患者的胰岛素作用， 降低血清葡萄糖。 已报道噻唑 烷二酮为 PPARy的有效和选择性的激活剂， 并直接结合到 PPAR γ受体（J. M. Lehmann 等， J. Biol. Chem. 12953-12956 , 270 (1995))。  Thiazolidinediones such as troglitazone and rosiglitazone have been clinically shown to enhance insulin action and reduce serum glucose in patients with type II diabetes. Thiazolidinedione has been reported as a potent and selective activator of PPARy and directly binds to the PPAR gamma receptor (J. M. Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)).
贝特类 (fibrates)药物一向被广泛用作高脂血症的治疗药, 可降低血清甘油三酯（ 20-50 % ) 、 LDL ( 10-15% ) ， 并增加 HDL ( 10-15% )。实验表明， fibrates对血清脂质的作用是通过 PPAR ct的激活作用介导的， 例如可参见， B, Staels等， Curr. Pharm. Des.， 1-14， 3 (1), (1997)。 PPAR ot的激活引起增加脂肪酸分解代谢 和降低肝脏中脂肪酸再次合成（引起甘油三酯合成和 VLDL 产生 / 分泌减少）的酶的转录。此外， PPARot激活降低 apoC- III的产生。 apoC-III (LPL活性的抑制剂）产生的减少增加了 VLDL的清除（ J. Auwerx等， Atherosclerosis, J59-S37, 124 (Suppl), (1996) )。  Fibrates have been widely used as a treatment for hyperlipidemia, which can reduce serum triglycerides (20-50%), LDL (10-15%), and increase HDL (10-15%). . Experiments have shown that the effect of fibrates on serum lipids is mediated by the activation of PPAR ct. See, for example, B, Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPAR ot causes transcription of enzymes that increase fatty acid catabolism and decrease fatty acid resynthesis in the liver (causing reduced triglyceride synthesis and reduced VLDL production / secretion). In addition, PPARot activation reduces apoC-III production. Decreased production of apoC-III (an inhibitor of LPL activity) increases clearance of VLDL (J. Auwerx et al., Atherosclerosis, J59-S37, 124 (Suppl), (1996)).
现有技术的研究结果表明，具有对 PPAR γ和 PPAR α两者的双 重激动作用的药物在降低糖尿病伴有的其他异常、 尤其是升高甘 油三酯中可具有附加的益处， 例如可参见 US5478852 , WO98/0533L 发明内容  The results of research in the prior art indicate that drugs with dual agonistic effects on both PPAR γ and PPAR α may have additional benefits in reducing other abnormalities associated with diabetes, especially in increasing triglycerides, see for example US5478852 , WO98 / 0533L Summary of the Invention
本发明的目的是寻找并开发具有 PPAR γ和 PPAR α激动活性 的小分子化合物， 所述化合物可用来治疗 hPPARv和 /或 hPPARct 介导的疾病、 危险因子或病症。 本发明人经研究发现， 下列通式 I的化合物具有对 PPAR y和 PPAR a激动活性，从而可用于预防和 /或治疗与 PPAR Y和 PPAR a有关的疾病或症状， 如糖尿病或高血 糖症。 本发明进一步发现， 通式 I化合物还具有良好的降血脂作 用。 The object of the present invention is to find and develop small molecule compounds with PPARγ and PPARα agonistic activity, which compounds can be used to treat hPPARv and / or hPPARct-mediated diseases, risk factors or disorders. The inventor found through research that the following formula The compounds of I have agonistic activity on PPARy and PPARa, and thus can be used to prevent and / or treat diseases or symptoms related to PPARY and PPARa, such as diabetes or hyperglycemia. The present invention further finds that the compound of the general formula I also has a good hypolipidemic effect.
因此， 本发明的一方面涉及式 I化合物， 其消旋体、 旋光异 构体或其药学上可接受的盐或溶剂化物，  Therefore, one aspect of the invention relates to a compound of formula I, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000005_0001
Figure imgf000005_0001
其中：  among them:
1^和112各自独立地选自 H， d-C4直链或支链烷基； 1 ^ and 11 2 are each independently selected from H, dC 4 straight or branched alkyl;
Ar选自芳香碳环或杂环， 其中的环为单环、 双环或三环； 每个 环为 5 - 6元环， 杂环中包括 1 - 4个选自下面的杂原子： 0, S， N; 环上无取代或被 1 - 5个选自下面的取代基取代： 卤素， 硝基， 羟基， 羟曱基， 三氟甲基， 三氟甲氧基， d - C6直链或支链烷基， C2 - C6直链或支链烯基， d - C4烷氧基， C2 - C4链烯氧基， 苯氧基， 苄氧基， 羧基或氨基； Ar is selected from aromatic carbocyclic or heterocyclic rings, wherein the rings are monocyclic, bicyclic, or tricyclic; each ring is a 5-6 membered ring, and the heterocyclic ring includes 1-4 heteroatoms selected from the following: 0, S , N; ring unsubstituted or substituted by 1 to 5 substituents selected from: halogen, nitro, hydroxy, hydroxyfluorenyl, trifluoromethyl, trifluoromethoxy, d-C 6 linear or Branched alkyl, C 2 -C 6 straight or branched alkenyl, d-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, carboxyl or amino;
Y为 H, 卤素；  Y is H, halogen;
n是 1-4的整数；  n is an integer from 1-4;
m为 0或 1 ,  m is 0 or 1,
o 0  o 0
为 CH2、 0、 S、 、、 0 ϋ CH 2 , 0, S,, 0 0
X S 、 s基团。 XS, s groups.
本发明的另一方面涉及包含本发明化合物的药物组合物， 其 含有至少一种通式 I化合物的消旋体或旋光异构体或其药学上可 接受的盐或溶剂化物以及一或多种药用载体或赋形剂。  Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, comprising at least one racemate or optical isomer of a compound of formula I Pharmaceutical carrier or excipient.
本发明的另一方面涉及制备通式 I化合物或者其药学上可接 受的盐或溶剂化物的方法。 Another aspect of the invention relates to the preparation of a compound of formula I or a pharmaceutically acceptable Accepted salt or solvate method.
本发明的另一方面涉及制备通式 I化合物或者其药学上可接 受的盐或溶剂化物的中间体。  Another aspect of the invention relates to an intermediate for the preparation of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
本发明的再一方面涉及本发明通式 I化合物用于制备治疗或 预防 hPPAR Y和 /或 hPPAR a介导的疾病、 危险因子或病症的药物 的用途。  A further aspect of the invention relates to the use of a compound of formula I according to the invention for the manufacture of a medicament for the treatment or prevention of a hPPAR Y and / or hPPAR a mediated disease, risk factor or condition.
所述的 hPPAR y和 /或 hPPAR a介导的疾病、 危险因子或病症 包括高血糖症、 脂代谢障碍脂血症、 Π型糖尿病包括相关的糖尿 病性脂代谢障碍脂血症、 I型糖尿病、高甘油三酯血症、 X综合征、 胰岛素抗性、 心力衰竭、 高脂血症、 高胆固醇血症、 高血压、 心 血管疾病包括动脉粥样硬化以及患有如肥胖症、 厌食症、 贪食症 和神经性厌食症患者的食欲和食物吸收的调节。  The hPPAR y and / or hPPAR a-mediated diseases, risk factors or conditions include hyperglycemia, dyslipidemia, dyslipidemia, type II diabetes including related diabetic dyslipidemia, type I diabetes, Hypertriglyceridemia, Syndrome X, Insulin resistance, Heart failure, Hyperlipidemia, Hypercholesterolemia, Hypertension, Cardiovascular diseases including atherosclerosis and suffering from diseases such as obesity, anorexia, bulimia Regulation of Appetite and Food Absorption in Patients with Anorexia and Anorexia Nervosa
具体来说， 在本发明的一个实施方案中, 本发明涉及通式 I 化合物， 其消旋体、 旋光异构体或其药学上可接受的盐或溶剂化 物，  Specifically, in one embodiment of the present invention, the present invention relates to a compound of general formula I, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000006_0001
Figure imgf000006_0001
I  I
其中：  among them:
1^和112各自独立地选自 H, d-C4直链或支链烷基； 1 ^ and 11 2 are each independently selected from H, dC 4 straight or branched alkyl;
Ar选自芳香碳环或杂环， 其中的环为单环、 双环或三环； 每 个环为 5 一 6元环， 杂环中包括 1 - 4个选自下面的杂原子： 0, S， N; 环上无取代或被 1 - 5个选自下面的取代基取代： 卤素， 硝基， 羟基， 羟甲基， 三氟甲基， 三氟甲氧基， d - C6直链或支 链烷基， C2 - C6直链或支链烯基， d - C4烷氧基， C2 - C4链浠氧 基， 苯氧基， 苄氧基， 羧基或氨基； Ar is selected from aromatic carbocyclic or heterocyclic rings, wherein the rings are monocyclic, bicyclic, or tricyclic; each ring is a 5 to 6 membered ring, and the heterocyclic ring includes 1-4 heteroatoms selected from the following: 0, S , N; unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d-C 6 linear or Branched alkyl, C 2 -C 6 straight or branched alkenyl, d-C 4 alkoxy, C 2 -C 4 chain alkoxy Group, phenoxy, benzyloxy, carboxyl or amino;
Y为 H, 卤素；  Y is H, halogen;
n是 1-4的整数；  n is an integer from 1-4;
m为 0或 1,  m is 0 or 1,
n 0  n 0
。、、 II  . ,, II
X为 CH2、 0、 S、 s 、 S基团。 在本发明的一个优选实施方案中， 通式 I 化合物为通式 II 所代表的 S构型异构体， 或其药学上可接受的盐或溶剂化物， X is a CH 2 , 0, S, s , S group. In a preferred embodiment of the present invention, the compound of the general formula I is an S configuration isomer represented by the general formula II, or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000007_0001
Figure imgf000007_0001
其中：  among them:
连接于 C00I 的碳原子为 S构型；  The carbon atom attached to C00I is in the S configuration;
^和 R2各自独立地选自 H, CH3; ^ And R 2 are each independently selected from H, CH 3 ;
Ar选自芳香碳环或杂环， 其中的环为是单环、 双环或三环； 每个环为 5 -6元环， 杂环中包括 1 -4个选自下面的杂原子： 0, S, N; 环上无取代或被 1 一 5个选自下面的取代基取代： 卤素， 硝基， 羟基， 羟甲基， 三氟甲基， 三氟甲氧基， d- (6直链或支 链烷基， C2- C6直链或支链烯基， d- C4烷氧基， C2- C4链烯氧 基， 苯氧基， 苄氧基， 羧基或氨基； Ar is selected from aromatic carbocyclic or heterocyclic rings, wherein the rings are monocyclic, bicyclic or tricyclic; each ring is a 5-6 membered ring, and the heterocyclic ring includes 1-4 heteroatoms selected from the following: 0, S, N; unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d- ( 6 linear Or branched alkyl, C 2 -C 6 straight or branched alkenyl, d- C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, carboxyl or amino;
Y为 H, Br;  Y is H, Br;
n是 1-4的整数；  n is an integer from 1-4;
m为 0或 1, X为 CH2、 0、 S,
Figure imgf000008_0001
m is 0 or 1, X is CH 2 , 0, S,
Figure imgf000008_0001
优选的本发明化合物及其相应的化学结构如下所示: 对应的实 结构 The preferred compounds of the invention and their corresponding chemical structures are shown below: Corresponding real structures
化学名称 m. p.。C 施例编号  Chemical name m. P. C Example number
(2S)-2- [3-(4-曱氧基  (2S) -2- [3- (4-Methoxy
- 苯 基）- 丙 酰 氨  -Phenyl)-propionamide
基]- 3- {4-[2-(5-甲基  Group]-3- {4- [2- (5-methyl
实施例 1 osn 158-159 Example 1 osn 158-159
- 2 -苯基 -1, 3- p恶唑- 4-
Figure imgf000008_0002
-2 -phenyl-1, 3- p oxazole-4-
Figure imgf000008_0002
团  Group
基）-乙氧基] -苯基 } - 丙酸  ) -Ethoxy] -phenyl} -propionic acid
(2S) - 3- {4-[2-（5- 甲  (2S)-3- {4- [2- (5- A
基 -2-苯基- 1， 3-喁唑  Phenyl-2-phenyl-1,3-oxazole
-4-基）-乙氧基] -苯  -4-yl) -ethoxy] -benzene
实施例 2 160-161 基}-2-(3-苯基 -丁酰Example 2 160-161yl) -2- (3-phenyl-butyryl
Figure imgf000008_0003
Figure imgf000008_0003
氨基） -丙酸  Amino) -propionic acid
(2S)- 2- [3- (3-甲氧基 (2S)-2- [3- (3-methoxy
- 苯基 ） - 丙 酰 氨  -Phenyl)-Propionamide
基]- 3- {4- [2- (5 -甲基  Base]-3- {4- [2- (5- -methyl
实施例 3 178-180 Example 3 178-180
- 2 -苯基 -1， 3-嚙唑- 4-
Figure imgf000008_0004
-2-phenyl-1,3-pyrazole-4
Figure imgf000008_0004
基）-乙氧基]-苯基 } - 丙酸  ) -Ethoxy] -phenyl}-propionic acid
(2S) -2- [3- (2-曱氧基 (2S) -2- [3- (2-Methoxy
- 苯基） - 酰 氨  -Phenyl)-Amide
实施例 4 178-179 基 ]- 3- {4-[2- (5-曱基
Figure imgf000008_0005
Example 4 178-179 group]-3- {4- [2- (5-fluorenyl
Figure imgf000008_0005
- 2 -苯基 -1， 3-喁唑 -4- 基） -乙氧基] -苯基 } - 丙酸 -2 -phenyl-1,3-oxazole-4- ) -Ethoxy] -phenyl} -propionic acid
(2S)-3- {4- [2- (5- 甲 (2S) -3- {4- [2- (5- A
基 -2-苯基- 1, 3-噁唑  Phenyl-2-phenyl-1,3-oxazole
- 4-基）-乙氧基] -苯  -4-yl) -ethoxy] -benzene
实施例 159-161 基 }- 2- [3- (4-三氟甲Example 159-161 based}-2- [3- (4-trifluoromethyl
Figure imgf000009_0001
Figure imgf000009_0001
基-苯基)- 酰氨基] - 丙酸  -Phenyl) -acylamino]-propionic acid
(2S)-3- {4- [2- (5- 曱  (2S) -3- {4- [2- (5- 曱
基 -2-苯基 -1, 3-恶唑  Phenyl-2-phenyl-1,3-oxazole
实施例 6 -4-基） -乙氧基] -苯 130-131
Figure imgf000009_0002
Example 6-4-yl) -ethoxy] -benzene 130-131
Figure imgf000009_0002
基 }- 2- (2-曱基 -3 -苯  }-2- (2-fluorenyl -3 -benzene
基 -丙酰氨基） -丙酸  -Propionylamino) -propionic acid
(2S)-3- {4- [2- (5- 甲  (2S) -3- {4- [2- (5- A
基 -2-苯基- 1, 3 -喁唑  Phenyl-2-phenyl-1,3-oxazole
-4-基）-乙氧基] -苯  -4-yl) -ethoxy] -benzene
实施例 7
Figure imgf000009_0003
167-168 基}- 3-苯基-丙酰氨 Example 7
Figure imgf000009_0003
167-168 group}-3-phenyl-propionamide
基） -丙酸  ) -Propionic acid
(2S)-3-{4-[2-(5- 甲 (2S) -3- {4- [2- (5- A
基 -2-苯基 -1, 3 恶唑  Phenyl-2-phenyl-1,3 oxazole
- 4-基） -乙氧基] -苯  -4-yl) -ethoxy] -benzene
实施例 8 198-199 基}-2- (2-五氟苯基-
Figure imgf000009_0004
Example 8 198-199 group} -2- (2-pentafluorophenyl-
Figure imgf000009_0004
乙酰氨基）-丙酸 (2S) -2- [2- (2-甲氧基 Acetamino) -propionic acid (2S) -2- [2- (2-methoxy
- 苯 基）- 乙 酰 氨  -Phenyl) -acetamide
基]- 3-{4- [2-(5-甲基 Group]-3- {4- [2- (5-methyl
Figure imgf000010_0001
Figure imgf000010_0001
实施例 9 -2-苯基- 1, 3-喁唑 -4- 165-166 基） -乙氧基] -苯基 } - 丙酸  Example 9-2-phenyl-1,3-oxazole-4- 165-166) -ethoxy] -phenyl} -propionic acid
(2S) -2- [2- (2-氯-苯 (2S) -2- [2- (2-chloro-benzene
基 ）- 乙 酰 氨  ) -Acetamido
基] -3- {4-[2-(5-甲基
Figure imgf000010_0002
Yl] -3- {4- [2- (5-methyl
Figure imgf000010_0002
实施例 10 - 2-苯基- 1， 3-噁唑 - 4- 188-189 基）-乙氧基] -苯基 } - 丙酸 Example 10-2-Phenyl-1, 3-oxazole-4-188-189yl) -ethoxy] -phenyl} -propionic acid
(2S)-2- [2-(4-氯-苯 (2S) -2- [2- (4-chloro-benzene
基 ）- 乙 酰 氨  ) -Acetamido
基] -3-{4- [2-(5-曱基 Base] -3- {4- [2- (5-fluorenyl
Figure imgf000010_0003
Figure imgf000010_0003
实施例 11 -2-苯基 -1, 3-喁唑 -4- 168-170 基）-乙氧基] -苯基 } - 丙酸 Example 11 2-Phenyl-1,3-oxazole-4-168-170yl) -ethoxy] -phenyl} -propionic acid
(2S)-3-{4-[2-(5- 甲 (2S) -3- {4- [2- (5- A
基- 2-苯基 -1， 3-喁唑  2-phenyl-1,3-oxazole
-4-基）-乙氧基] -苯 -4-yl) -ethoxy] -benzene
Figure imgf000010_0004
Figure imgf000010_0004
实施例 12 基}- 2-(2-邻-三氟曱 154-156 基 -苯基 -乙酰氨基） - 丙酸 (2S)-3- {4- [2- (5- 甲 Example 12 Amino}-2- (2-o-trifluorofluorene 154-156-phenyl-acetylamino) -propionic acid (2S) -3- {4- [2- (5- A
基- 2-苯基- 1， 3 恶唑  2-phenyl-1,3 oxazole
-4-基） -乙氧基] -苯 -4-yl) -ethoxy] -benzene
Figure imgf000011_0001
Figure imgf000011_0001
实施例 I3 基} -2- (2-对-三氟甲 169-170 Example I 3 -based} -2- (2-p-trifluoromethyl 169-170
基-苯基-乙酰氨基） - 丙酸  -Phenyl-acetylamino)-propionic acid
(2S)-3-{4-[2-(5- 甲 (2S) -3- {4- [2- (5- A
基 -2-苯基- 1， 3-喁唑  Phenyl-2-phenyl-1,3-oxazole
-4-基）-乙氧基] -苯  -4-yl) -ethoxy] -benzene
实施例 I4 基}-2- [2- (3-三氟曱
Figure imgf000011_0002
Example I 4 -based} -2- [2- (3-trifluorofluorene
Figure imgf000011_0002
172-173 基-苯基）-乙酰氨基] - 丙酸  172-173-phenyl-phenyl) -acetylamino]-propionic acid
(2S)-2-[2-(2, 3 -二 (2S) -2- [2- (2, 3 -two
氟-苯基）-乙酰氨  Fluoro-phenyl) -acetamide
基]- 3-{4- [2- (5-甲基  Group]-3- {4- [2- (5-methyl
实施例 15 - 2-苯基- 1, 3-喁唑- 4-
Figure imgf000011_0003
179-180 Example 15-2-Phenyl-1, 3-oxazole-4
Figure imgf000011_0003
179-180
基）-乙氧基] -苯基 } - 丙酸  ) -Ethoxy] -phenyl} -propionic acid
(2S) -2- [2- (3, 4 -二 (2S) -2- [2- (3, 4 -Tue
氟-苯基） -乙酰氨  Fluoro-phenyl) -acetamide
基] -3-{4-[2-(5-甲基  Group] -3- {4- [2- (5-methyl
实施例 16 - 2-苯基- 1， 3-喁唑- 4-
Figure imgf000011_0004
Example 16-2-Phenyl-1,3-oxazole-4
Figure imgf000011_0004
172-173 基） -乙氧基]-苯基 } - 丙酸 (2S)-3- {4- [2- (5- 甲 172-173yl) -ethoxy] -phenyl} -propionic acid (2S) -3- {4- [2- (5- A
基 -2-苯基 -1, 3- p恶唑  Phenyl-2-phenyl-1, 3-p oxazole
-4-基） -乙氧基] -苯
Figure imgf000012_0001
-4-yl) -ethoxy] -benzene
Figure imgf000012_0001
实施例 17 137-138 Example 17 137-138
基} -2-苯基-乙酰氨基  } -2-phenyl-acetylamino
-丙酸  -Propionic acid
(2S)-3-{4-[2-(5- 曱 (2S) -3- {4- [2- (5- 曱
基- 2 -苯基 -1, 3-'恶唑  -2 -phenyl-1,3-'oxazole
-4 -基） -乙氧基] -苯  -4 -yl) -ethoxy] -benzene
实旅例 18 163 - 164 Travel Examples 18 163-164
基} -2- (2-对甲苯氧基
Figure imgf000012_0002
Yl) -2- (2-p-tolyloxy
Figure imgf000012_0002
-乙酰氨基） -丙酸  -Acetamino) -propionic acid
(2S)-3- {4- [2- (5- 甲 (2S) -3- {4- [2- (5- A
基 -2-苯基- 1, 3-噁唑  Phenyl-2-phenyl-1,3-oxazole
-4 -基） -乙氧基]-苯  -4 -yl) -ethoxy] -benzene
实施例 19Example 19
Figure imgf000012_0003
124 - 126 基}- 2- [2- (萘- 1-基氧
Figure imgf000012_0003
124-126 base}-2- [2- (naphthalene-1 -yloxy
基） -乙酰氨基] -丙酸  ) -Acetamino] -propionic acid
(2S)-3- {4- [2- (5- 甲 (2S) -3- {4- [2- (5- A
基- 2 -苯基 -1, 3 恶唑  -2 -phenyl-1, 3 oxazole
-4 -基） -乙氧基] -苯 -4 -yl) -ethoxy] -benzene
Figure imgf000012_0004
Figure imgf000012_0004
实施例 20 基}- 2- [2- (2-硝基-苯 184 - 186 Example 20 Base}-2- [2- (2-nitro-benzene 184-186
氧基） -乙酰氨基] -丙  (Oxy) -acetylamino] -propane
酸 (2S) -2- [2- (3-曱氧基 acid (2S) -2- [2- (3-Methoxy
-苯氧基）-乙酰氨  -Phenoxy) -acetamide
基] -3- {4- [2- (5-甲基  Yl] -3- {4- [2- (5-methyl
实施例 21 -2-苯基- 1, 3-噁唑 -4-
Figure imgf000013_0001
137― 138 基） -乙氧基] -苯基 } - 丙酸 Example 21-2-phenyl-1,3-oxazole-4-
Figure imgf000013_0001
137― 138 group) -ethoxy] -phenyl} -propionic acid
(2S)-2- [2- (4-氟-苯 (2S) -2- [2- (4-fluoro-benzene
氧 基 ）- 乙 酰 氨  Oxo) -acetamido
基] -3-{4- [2- (5-甲基  Yl] -3- {4- [2- (5-methyl
实施例 22 -2-苯基 -1, 3-喁唑 -4-
Figure imgf000013_0002
132 - 134 基） -乙氧基]-苯基 } - 丙酸 Example 22-2-phenyl-1,3-oxazole-4-
Figure imgf000013_0002
132-134 group) -ethoxy] -phenyl}-propionic acid
(2S)-3- {4- [2- (5- 曱 (2S) -3- {4- [2- (5- 曱
基 -2-苯基 -1, 3 恶唑  Phenyl-2-phenyl-1,3 oxazole
-4 -基） -乙氧基] -苯  -4 -yl) -ethoxy] -benzene
实施例 23
Figure imgf000013_0003
114 - 116 基 }- 2- (2-苯氧基-乙 Example 23
Figure imgf000013_0003
114-116 yl)-2- (2-phenoxy-ethyl
酰氨基） -丙酸  Amido)-propionic acid
(2S)-3- {4- [2- (5- 曱 (2S) -3- {4- [2- (5- 曱
基 -2-苯基 -1, 3 恶唑  Phenyl-2-phenyl-1,3 oxazole
-4 -基） -乙氧基] -苯  -4 -yl) -ethoxy] -benzene
实施例 24 181 - 182 基} -2- [2- (4-硝基-苯Example 24 181-182 groups} -2- [2- (4-nitro-benzene
Figure imgf000013_0004
Figure imgf000013_0004
氧基-乙酰氨基） -丙酸 (2S)-3- {4- [2- (5- 甲 Oxy-acetylamino) -propionic acid (2S) -3- {4- [2- (5- A
基 -2-苯基- 1, 3 恶唑  Phenyl-2-phenyl-1,3 oxazole
-4 -基） -乙氧基] -苯  -4 -yl) -ethoxy] -benzene
实施例 25
Figure imgf000014_0001
192 - 194 基}-2-(2-邻甲苯氧基 Example 25
Figure imgf000014_0001
192-194 yl) -2- (2-o-tolyloxy
-乙酰氨基） -丙酸  -Acetamino) -propionic acid
(2S)-3-{4-[2-(5- 甲 (2S) -3- {4- [2- (5- A
基- 2-苯基- 1， 3 -喁唑  2-phenyl-1,3-oxazole
-4 -基） -乙氧基] -苯  -4 -yl) -ethoxy] -benzene
实施例 26
Figure imgf000014_0002
183 - 185 基}- 2-U- (萘 -2-基 Example 26
Figure imgf000014_0002
183-185 group}-2-U- (naphthalene-2-yl
氧）-乙酰氨基〗 -丙酸  (Oxygen) -acetylamino-propionic acid
(2S)- 2- [2- (4-氯-苯 (2S)-2- [2- (4-chloro-benzene
硫基） -乙酰氨基】 -3  Thio) -acetylamino] -3
实施例 27 -{4- [2- (5-甲基- 2-苯 164 - 166 基- 1， 3-噁唑 -4-基） -
Figure imgf000014_0003
Example 27-{4- [2- (5-Methyl-2-benzene 164-166-1, 3-oxazol-4-yl)-
Figure imgf000014_0003
乙氧基]-苯基 } -丙酸  Ethoxy] -phenyl} -propionic acid
(2S)-2- [2- 氧基  (2S) -2- [2-oxy
-苯硫基）-乙酰氨  -Phenylthio) -acetamide
基] -3- {4- [2- (5-甲基  Yl] -3- {4- [2- (5-methyl
实施例 28 -2-苯基- 1, 3- p恶唑- 4- 156 - 158
Figure imgf000014_0004
Example 28-2-phenyl-1,3-poxazole-4-4-156-158
Figure imgf000014_0004
基） -乙氧基]-苯基 } - 丙酸  ) -Ethoxy] -phenyl}-propionic acid
(2S)-2- [2- (8-氯-萘 (2S) -2- [2- (8-chloro-naphthalene
- 1-基硫基） -乙酰氨  -1-ylthio) -Acetylamine
实施例 29 138 - 140 基] -3- {4- [2- (5-甲基 Example 29 138-140 group] -3- {4- [2- (5-methyl
-2-苯基- 1, 3-嚅唑- 4-
Figure imgf000014_0005
基）-乙氧基] -苯基 } - 丙酸 -2-phenyl-1,3-oxazole-4
Figure imgf000014_0005
) -Ethoxy] -phenyl} -propionic acid
(2S)-3-{3-溴 -4- [2- (5-甲基 -2-苯基- 1, 3- 喁唑 -4-基）-乙氧基] - 实施例 30 苯基 }- 2-[2-(2-甲氧 194-195 (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy]-Example 30 Phenyl} -2- [2- (2-Methoxyl 194-195
基-苯基) -乙酰氨基] - 丙酸  -Phenyl) -acetylamino]-propionic acid
(2S)-3-{3-溴 -4- [2- (5 -甲基 - 2-苯基 -1, 3- 喁唑 -4-基） -乙氧基] - 实施例 31 189-190 (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy]-Example 31 189-190
苯基 }- 2-苯基乙酰氨  Phenyl}-2-phenylacetamide
基 -丙酸  Propyl-propionic acid
(2S)-3-{3-溴 -4-[2- (5-甲基 -2-苯基- 1, 3- 噁唑 -4-基） -乙氧基] - 实施例 32 苯基 }-2-[3-(4-甲氧 195-196 (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy]-Example 32 Phenyl} -2- [3- (4-methoxyl 195-196
基-苯基) -丙酰氨基] - 丙酸  -Phenyl) -propionamido]-propionic acid
(2S)-3-{3-溴 -4-[2- (5-甲基- 2-苯基 -l，3- 实施例 33 190-191 p恶唑 -4-基）-乙氧基] - 苯基 }-(3-苯基-丙酰
Figure imgf000015_0001
氨基） -丙酸 (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-l, 3- Example 33 190-191 poxazol-4-yl) -ethoxy] -Phenyl}-(3-phenyl-propionyl
Figure imgf000015_0001
Amino) -propionic acid
(2S)-3-{3-溴 -4- [2- 础 （5-曱基 -2-苯基 (2S) -3- {3-bromo-4- [2-base (5-fluorenyl-2-phenyl
-1， 3-嚙唑 -4-基） -乙 -1, 3-pyrazol-4-yl) -B
Figure imgf000016_0001
Figure imgf000016_0001
氧 基 ] - 苯  Oxo]-benzene
实施例 34 178-180 基 }- 2- [3- (2-曱氧基- 苯基） -丙酰氨基] -丙 Example 34 178-180 group}-2- [3- (2-Methoxy-phenyl) -propionamido] -propion
酸  Sour
(2S)-3-{3-溴 -4-[2- 础 （5-甲基 -2-苯基 (2S) -3- {3-bromo-4- [2-base (5-methyl-2-phenyl
-1, 3 恶唑- 4-基） -乙  -1, 3 oxazole-4-yl) -B
实施例 35 氧基] -苯基 }- 2-理论
Figure imgf000016_0002
195-196 Example 35 Oxy] -phenyl}-2-theory
Figure imgf000016_0002
195-196
[3-（3-甲氧基-苯基) - 丙酰氨基] -丙酸  [3- (3-methoxy-phenyl) -propionamido] -propionic acid
(2S)-3-{3-溴 -4- [2- (5 -甲基 -2-苯基- 1， 3- p恶唑 -4-基）-乙氧基] - 实施例 36 苯基 }- 2-[3-(4-三氟
Figure imgf000016_0003
214-216 甲基-苯基）-丙酰氨 (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-poxazol-4-yl) -ethoxy]-Example 36 Phenyl }-2- [3- (4-trifluoro
Figure imgf000016_0003
214-216 methyl-phenyl) -propionamide
基] -丙酸 (2S)-3-{3-溴 - 4- [2- 理论（5-曱基- 2-苯基 Propyl] -propionic acid (2S) -3- {3-Bromo-4- [2-theory (5-fluorenyl-2-phenyl
-1， 3- p恶唑- 4-基） -乙 -1,3-poxazole-4yl) -B
Figure imgf000017_0001
Figure imgf000017_0001
实施例 37 氧基] -苯基 } -2- (2 -甲 164-166 基 -3-苯基-丙酰氨 Example 37 Oxy] -phenyl} -2- (2-methyl 164-166yl-3-phenyl-propionamido
基）-丙酸  ) -Propionic acid
(2S)-3-{3-溴 -4-〖2- 础 （5-甲基 -2-苯基 (2S) -3- {3-bromo-4- 〖2-basic (5-methyl-2-phenyl
- 1, 3-P恶唑 -4-基） -乙  -1, 3-P oxazole-4-yl) -B
实施例 38
Figure imgf000017_0002
165-167 氧基] -苯基 } -2- (3-苯 Example 38
Figure imgf000017_0002
165-167oxy] -phenyl} -2- (3-benzene
基-丁酰氨基）-丙酸  -Butyrylamino) -propionic acid
(2S)-3-{3-溴一4-[2- 理论（5-甲基 -2-苯基 (2S) -3- {3-bromo-4- [2- theory (5-methyl-2-phenyl
- 1, 3 恶唑- 4 -基） -乙 -1, 3 oxazole-4 -yl) -B
Figure imgf000017_0003
Figure imgf000017_0003
实施例 39 氧基] -苯基 } -2- (2-邻 202― 204 甲苯氧基-乙酰氨基) - 丙酸 Example 39 Oxy] -phenyl} -2- (2-o-202-204 tolyloxy-acetylamino)-propionic acid
(2S)-3-{3-溴 -4- [2- (5 -曱基 -2-苯基- 1， 3- 实施例 40 喁唑- 4-基） -乙氧基] - 171― 173
Figure imgf000017_0004
(2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1, 3-, Example 40 oxazol-4-yl) -ethoxy]-171- 173
Figure imgf000017_0004
苯基 }- 2- (2-苯硫基- 乙酰氨基） -丙酸  Phenyl}-2- (2-phenylthio-acetylamino) -propionic acid
本发明通式 I化合物或其药用盐或溶剂化物， The compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to the present invention,
Figure imgf000018_0001
Figure imgf000018_0001
I  I
其中 R2， Ar， X， Y, m,n的定义同通式 I: 可由式 III化合物 Wherein R 2 , Ar, X, Y, m, n have the same definition as the general formula I:
Figure imgf000018_0002
Figure imgf000018_0002
III  III
其中 Y， n, R的定义同通式 I， Ph为苯基;  Where Y, n, R have the same definition as I, and Ph is phenyl;
与式 X化合物进行反应得
Figure imgf000018_0003
Reaction with a compound of formula X
Figure imgf000018_0003
X  X
其中 Ar， X， R2, m的定义同通式 I。 Wherein, the definitions of Ar, X, R 2 and m are the same as those of the general formula I.
上述反应的原料之一式 III化合物可按以下方法制备：  A compound of formula III, one of the starting materials for the above reaction, can be prepared by the following method:
1) 由市售可得的苯甲酰胺与式 IV化合物进行反应， 环合得 到式 V化合物。 式 V化合物再经四氢锂铝 （LiAlH4)还原， 得到 式 VI化合物。其中的式 IV化合物的制备可参见： Chem. Phar. Bull.1) A commercially available benzamide is reacted with a compound of formula IV to cyclize to obtain a compound of formula V. The compound of formula V is then reduced by lithium aluminum hydride (LiAlH 4 ) to obtain a compound of formula VI. The preparation of compounds of formula IV can be found in: Chem. Phar. Bull.
(1986), 34 (7), 2840-51; J. Med. Chem. (1992), 35 (14),(1986), 34 (7), 2840-51; J. Med. Chem. (1992), 35 (14),
2617-26。
Figure imgf000019_0001
2617-26.
Figure imgf000019_0001
IV V VI IV V VI
2)使其中 Y和 n的定义同通式 I的式 VII化合物，特别优选 其中丫=^或者！1= 1、 Y = Br并且 Br位于羟基邻位的式 VII化合 物先与 ΟΗ (其中 的定义同通式 I, 优选 = (¾)、 二氯亚砜 反应， 接着与 B0C20反应， 得到 VIII的化合物， 其中， U和 n 的定义同通式 I。 所述的 n-l、 Y = Br并且 Br位于羟基邻位的式 VII化合物可由酪氨酸与溴素反应制得，
Figure imgf000019_0002
2) Compounds of formula VII in which Y and n have the same definitions as in formula I, and particularly preferably in which y = ^ or! 1 = 1, Y = Br and Br is ortho to the hydroxyl group of the compound of formula VII first reacted with Η (wherein the definition is the same as the general formula I, preferably = (¾), dichlorosulfoxide, and then with B0C 2 0 to obtain VIII A compound of formula VII, wherein U and n have the same definition as the general formula I. The compound of formula VII where nl, Y = Br and Br is located adjacent to the hydroxyl group can be prepared by reacting tyrosine with bromine,
Figure imgf000019_0002
VII VIII  VII VIII
3)使步骤 1)得到的式 VI化合物与步骤 2)得到的式 VIII 化合物反应，得到其中 Ί,！！和！^的定义同通式 I的式 IX化合物，  3) The compound of formula VI obtained in step 1) is reacted with the compound of formula VIII obtained in step 2) to obtain Ί! !! with! ^ Is defined as a compound of formula IX of formula I,
Figure imgf000019_0003
Figure imgf000019_0003
IX  IX
接着使式 IX化合物用三氟乙酸脱保护基， 即得到其中 Y， η 和^的定义同通式 I的式 III化合物，  Then, the compound of formula IX is deprotected with trifluoroacetic acid to obtain a compound of formula III wherein Y, η and ^ have the same definitions as those of formula I,
Figure imgf000019_0004
Figure imgf000019_0004
III 就另一个原料式 X化合物来说，对于通式 I中 m-0或 X=C的 化合物， 其可由市售获得； 对于通式 I中 X=0或 S的化合物， 其 可由市售获得或参照文献 (Patel,V. F. ,Andis,S,Li,et al, J Org Chem 1997, 62 (25)： 8868-8874; D'Arcangelis, Samuel T, Cowan, Dwaine 0， Tetrahedron letter, 1996, 37 (17) : 2931-2934 )才艮道III For another raw material compound of formula X, for compounds of general formula I m-0 or X = C, it can be obtained commercially; for compounds of general formula I, X = 0 or S, it can be obtained commercially References (Patel, VF, Andis, S, Li, et al, J Org Chem 1997, 62 (25): 8868-8874; D'Arcangelis, Samuel T, Cowan, Dwaine 0, Tetrahedron letter, 1996, 37 (17 ): 2931-2934)
。、、 , II . ,,, II
的方法制备； 对于通式 I中 X= s 、 S的化合物， 其可由市售 获得或由 X=S的化合物按照常规方法 （见 《实用精细有机合成手 册》 ， 段行信编， 化学工业出版社（ 2000 ) ， P385-386 )制得。 For the compounds of X = s and S in the general formula I, they can be obtained from the market or can be obtained from the compounds of X = S according to the conventional method (see "Handbook of Practical Fine Organic Synthesis", edited by Duan Xingxin, Chemical Industry Press ( 2000), P385-386).
如果需要， 通式 I化合物可转化成另一种形式的通式 I化合 物， 例如， Ri-d- 直链或支链烷基的通式 I化合物在碱金属氢 氧化物的作用下， 得到 R^H的通式 I化合物。  If desired, a compound of general formula I can be converted into another form of a compound of general formula I, for example, a compound of general formula I of Ri-d- linear or branched alkyl group under the action of an alkali metal hydroxide to obtain R ^ H Compound of Formula I.
更具体地， 通式 I化合物的合成反应方案详见下列反应路线 和描述 =  More specifically, the synthetic reaction scheme of the compound of general formula I is detailed in the following reaction scheme and description:
反应步骤一：  Reaction step one:
Figure imgf000020_0001
式 IV的化合物与苯甲酰胺（购自北京化学试剂公司）在甲苯 中回流反应 6 - 30小时。 浓缩， 柱分离 （洗脱剂： 正己烷 /乙酸乙 酯系统） ， 得到棕色油状的式 V化合物。 式 V化合物和四氢锂铝 (LiAlH4, 购自天津市环威精细化工有限公司）室温下于乙醚中， 混合搅拌 1一 24小时。 依次小心滴加水、 氢氧化钠水溶液及无水 硫酸镁搅拌 0.1 - 1小时。 过滤， 滤液浓缩， 柱分离 （洗脱剂： 正 己烷 /乙酸乙酯系统） ， 得到白色固体的式 VI的化合物。 这里所 使用的硅胶为常规柱层析用硅胶， 颗粒度 10 - 40μιη。 纯化后得 到化合物 VI。
Figure imgf000020_0001
The compound of formula IV is reacted with benzamide (purchased from Beijing Chemical Reagent Company) in toluene at reflux for 6-30 hours. Concentrated and separated by column (eluent: n-hexane / ethyl acetate system) to obtain the compound of formula V as a brown oil. The compound of formula V and lithium aluminum hydride (LiAlH 4 , purchased from Tianjin Huanwei Fine Chemical Co., Ltd.) were mixed in ether at room temperature for 1 to 24 hours. Carefully add water, sodium hydroxide aqueous solution and anhydrous magnesium sulfate in this order and stir for 0.1-1 hour. Filtration, concentration of the filtrate, and column separation (eluent: n-hexane / ethyl acetate system) gave the compound of Formula VI as a white solid. The silica gel used here is silica gel for general column chromatography, and the particle size is 10-40 μm. After purification To compound VI.
反应步骤二:
Figure imgf000021_0001
其中 Y， n， 的定义同通式 I。 Reaction step two:
Figure imgf000021_0001
Wherein Y, n, have the same definition as the general formula I.
式 VII的化合物， 特别优选 Y = H或 n= 1、 Y = Br并且 Br位 于羟基邻位的式 VII化合物先与 (优选！ -CHJ、 二氯亚砜 混合回流 1一 10小时， 浓缩。 得到的残留物接着与 B0C20在无水 乙腈中三乙胺中催化下， 室温搅拌 1-8小时， 浓缩。 加二氯甲烷 溶解， 依次用旒酸氢钠水溶液、 饱和碳酸钠水溶液、 饱和氯化钠 水溶液洗， 干燥。 浓缩， 乙醚重结晶， 得到白色固体的式 VIII 的化合物。 其中 n=l、 Y = Br (Br位于羟基邻位） 的式 VII的化 合物， 可由酪氨酸与溴素在冰醋酸中 -20 - 110°C反应 0.5-48 小时制得。 Y、 η同通式 I的定义。 The compound of formula VII is particularly preferably a compound of formula VII in which Y = H or n = 1, Y = Br, and Br is ortho to the hydroxyl group, and is first mixed with (preferably! -CHJ, dichlorosulfoxide and refluxed for 1-10 hours, and concentrated.) The residue was then stirred with B0C 2 0 in triethylamine in anhydrous acetonitrile, stirred at room temperature for 1-8 hours, and concentrated. Dichloromethane was added to dissolve, followed by aqueous sodium hydrogen acetate solution, saturated sodium carbonate aqueous solution, and saturated chlorine. Wash with sodium hydroxide solution and dry. Concentrate and recrystallize from ether to obtain a compound of formula VIII as a white solid. Wherein n = 1 and Y = Br (Br is at the hydroxyl ortho position), the compound of formula VII can be selected from tyrosine and bromine. It is prepared by reacting in glacial acetic acid at -20-110 ° C for 0.5-48 hours. Y, η have the same definitions as those of general formula I.
反应步骤三:  Reaction step three:
Figure imgf000021_0002
Figure imgf000021_0002
111 其中 Y， η， ^的定义同通式 I。  111 wherein Y, η, ^ have the same definition as the general formula I.
将化合物 VI与式化合物 VIII在有机溶剂如 THF中， 在 -20 °C- 150°C (如 20°C)温度下， 在三苯膦和偶氮二羧酸酯如偶氮二 羧酸二乙酯存在下，按 Mitsunobu型方法反应 1-40小时。浓缩， 再经硅胶柱层析（洗脱剂： 正己烷 /乙酸乙酯系统）， 得到化合物 IX。 化合物 IX与三氟乙酸在有机溶剂如二氯甲烷中 -20°C- 40°C 反应 1 - 40小时。 反应液用氢氧化钠水溶液中和， 有机层千燥。 浓缩， 得到的粗品经硅胶柱层析（洗脱剂： 氯仿 /曱醇系统）， 得 到化合物 III。 Compound VI and compound VIII in an organic solvent such as THF at a temperature of -20 ° C to 150 ° C (e.g. 20 ° C) at a temperature of triphenylphosphine and an azodicarboxylic acid ester such as azodi In the presence of diethyl carboxylate, the reaction is carried out for 1-40 hours according to the Mitsunobu type method. It was concentrated and then subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate system) to obtain compound IX. Compound IX is reacted with trifluoroacetic acid in an organic solvent such as dichloromethane at -20 ° C to 40 ° C for 1 to 40 hours. The reaction solution was neutralized with an aqueous sodium hydroxide solution, and the organic layer was dried. After concentration, the obtained crude product was subjected to silica gel column chromatography (eluent: chloroform / methanol system) to obtain compound III.
反应步驟四:  Reaction step four:
Figure imgf000022_0001
其中 Y， n, R1? R2, m、 x和 Ar的定义同通式 I。
Figure imgf000022_0001
Wherein Y, n, R 1 to R 2 , m, x and Ar have the same definitions as in Formula I.
将化合物 III和化合物 X在非极性溶剂， 例如二氯甲烷中， 于室温在无或脱水剂如 DCC或 CDI存在下反应 0.1 - 20小时， 或 者先将式 ΠΙ化合物与二氯亚砜 0 一 80°C反应 0.5 - 10小时， 浓缩后将得到的残留物于- 20 - 40°C下， 在非质子性溶剂如二氯 甲烷中三乙胺催化下反应 0.1-20小时。 将按上述方法反应得到 的反应液水洗、 干燥、 浓缩， 得到的粗品经硅胶柱层析（洗脱剂： 石油醚 /乙酸乙酯系统） ， 即得到化合物 I。  The compound III and the compound X are reacted in a non-polar solvent such as dichloromethane at room temperature in the absence of a dehydrating agent such as DCC or CDI for 0.1-20 hours, or the compound of the formula III and dichlorosulfoxide The reaction is performed at 80 ° C for 0.5 to 10 hours. After concentration, the obtained residue is reacted at -20 to 40 ° C for 0.1 to 20 hours under the aprotic solvent such as triethylamine in dichloromethane. The reaction solution obtained by the above method was washed with water, dried, and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate system) to obtain compound I.
如果需要， 通式 I化合物可转化成另一种形式的通式 I的化 合物， 如 = d-C4直链或支链的烷基的通式 I化合物在碱金属氢 氧化物的作用下室温或回流反应 0.1-40 小时， 经后处理得到 If desired, the compound of general formula I can be converted into another form of compound of general formula I, such as = dC 4 linear or branched alkyl compound of general formula I under the action of an alkali metal hydroxide at room temperature or reflux 0.1-40 hours reaction time
=H的通式 I化合物。  = H Compound of Formula I.
本领域技术人员应该认识到本发明式 I 化合物存在立体中 心。 当需要式 I化合物为单一的对映体时， 可以使用在所有可能 的步骤中均处于单一对映异构体形式的反应物来制备， 或者在单 一对映异构体形式的试剂或催化剂的存在下进行反应来制备， 或 者通过常规方法拆分立体异构体混合物来制备。 一些优选的方法 包括使用微生物进行拆分， 拆分与手性酸如扁桃酸、 樟脑磺酸、 酒石酸、 乳酸等任何可使用的酸形成的非对映异构体的盐， 或者 拆分与手性碱如番木鳖碱（brae ine)、金鸡纳树生物碱及其衍生物 等形成的非对映异构体的盐。 常用的方法见 Jaques 等人编辑的 " Enant iomers , Raceraates and Resolut ion ，， (Wi ley Interscience, 1981)。 更具体地， 式 I的化合物可以通过用手性 胺、 氨基酸、 由氨基酸衍生的氨基醇进行处理而转化成非对映异 构酰胺的 1: 1的混合物； 可以使用常规的反应条件将酸转化成酰 胺； 非对映异构体可以通过分级结晶或色谱法进行分离， 式 I化 合物的立体异构体可以通过水解纯的非对映异构酰胺来制备。 Those skilled in the art will recognize that the compounds of formula I of the present invention have stereocenters. When a single enantiomer of a compound of formula I is required, it can be prepared using reactants in all possible steps in the form of a single enantiomer, or Prepared in the presence of a reaction, or It is prepared by resolving a mixture of stereoisomers by a conventional method. Some preferred methods include resolution using microorganisms, resolution of diastereomeric salts with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc., or resolution with Diastereomeric salts such as brae ine, cinchona alkaloids and their derivatives. Common methods are described in "Enant iomers, Raceraates and Resolution," edited by Jaques et al. (Wi ley Interscience, 1981). More specifically, compounds of formula I can be prepared by chiral amines, amino acids, amino alcohols derived from amino acids It is converted to a 1: 1 mixture of diastereomeric amides by treatment; the acid can be converted to an amide using conventional reaction conditions; Stereoisomers can be prepared by hydrolysis of pure diastereomeric amides.
根据本发明， 通式 I化合物可用于治疗或预防 hPPAR γ和 /或 hPPAR ct介导的疾病、 危险因子或病症。 所述的 hPPAR v和 /或 hPPAR oc介导的疾病、危险因子或病症包括有高血糖症、脂代谢障 碍脂血症、 Π型糖尿病包括相关的糖尿病性脂代谢障碍脂血症、 I 型糖尿病、 高甘油三酯血症、 X综合征、 胰岛素抗性、 心力衰竭、 高脂血症、 高胆固醇血症、 高血压、 心血管疾病包括动脉粥样硬 化、 患有如肥胖症、 厌食症、 贪食症和神经性厌食症患者的食欲 和食物吸收的调节。 本发明化合物特别适用于治疗或预防高血糖 症、 脂代谢障碍脂血症、 Π型糖尿病包括相关的糖尿病性脂代谢 障碍脂血症。  According to the present invention, compounds of the general formula I are useful in the treatment or prevention of hPPAR γ and / or hPPAR ct-mediated diseases, risk factors or conditions. The hPPAR v and / or hPPAR oc-mediated diseases, risk factors or conditions include hyperglycemia, dyslipidemia, and type II diabetes including related diabetic dyslipidemia, type I diabetes , Hypertriglyceridemia, syndrome X, insulin resistance, heart failure, hyperlipidemia, hypercholesterolemia, hypertension, cardiovascular diseases including atherosclerosis, suffering from diseases such as obesity, anorexia, greed Regulation of appetite and food absorption in patients with anorexia and anorexia nervosa. The compounds of the present invention are particularly useful in the treatment or prevention of hyperglycemia, dyslipidemia, and type II diabetes, including related diabetic dyslipidemia.
本发明化合物既可以其本身也可以其药学上可接受的盐或溶 剂化物的形式使用。 式 I化合物的药学上可接收的盐包括与药学 上可接受的无机酸或有机酸或者无机碱或有机碱形成的常规盐以 及季铵的酸加成盐。合适的酸加成盐的例子包括与盐酸、氢溴酸、 硫酸、 磷酸、 硝酸、 高氯酸、 富马酸、 乙酸、 丙酸、 琥珀酸、 羟 基乙酸、 甲酸、 乳酸、 马来酸、 酒石酸、 柠檬酸、 朴酸、 丙二酸、 羟基马来酸、 苯乙酸、 谷氨酸、 苯甲酸、 水杨酸、 富马酸、 甲苯 磺酸、 甲磺酸、 萘 -2-磺酸、 苯磺酸、 羟基萘甲酸、 氢碘酸、 苹果 酸、 鞣酸等形成的盐。 其它的酸， 如草酸， 虽然其本身并非药学 上可接受的， 但可以用于制备用作中间体的盐， 以获得本发明化 合物及其药学上可接受的盐。 合适的碱加成盐的例子包括与钠、 锂、 钾、 鎂、 铝、 钙、 锌、 N，N， -二苄基乙二胺、 氯代普鲁卡因、 胆碱、 二乙醇胺、 乙二胺、 N-甲基葡糖胺和普鲁卡因形成的盐。 本文中涉及到本发明化合物时， 包括式 I化合物及其药学上可接 受的盐或溶剂化物。 The compounds of the present invention can be used both by themselves and in the form of their pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts of the compounds of formula I include conventional salts with pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, as well as acid addition salts of quaternary ammonium. Examples of suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid , Citric acid, navic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluene Salts formed from sulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid, and the like. Other acids, such as oxalic acid, although not per se pharmaceutically acceptable, can be used to prepare salts for use as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable salts. Examples of suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N, N, -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethyl Salt formed by diamine, N-methylglucamine and procaine. Reference to a compound of the invention herein includes a compound of formula I and a pharmaceutically acceptable salt or solvate thereof.
本发明还包括本发明化合物的前药,该前药一经给药， 即在 体内通过代谢过程进行化学转化， 变成具有活性的药物。 通常， 这类前药是本发明化合物的功能性衍生物， 其在体内容易转化成 所需的式（1)的化合物。例如， 在 "Des ign Of Prodrugs" , Η. Bund Saard, El sevier 编辑 （ 1985 ) 中描述了选择和制备适宜前药衍 生物的常规方法。  The present invention also includes a prodrug of the compound of the present invention. Once the prodrug is administered, it is chemically transformed in the body through a metabolic process to become an active drug. Generally, such prodrugs are functional derivatives of the compounds of the present invention, which are easily converted into the desired compound of formula (1) in vivo. For example, in "Design Of Prodrugs", Η. Bund Saard, El sevier (ed. 1985), a conventional method for selecting and preparing suitable prodrug derivatives is described.
本发明还包括本发明化合物的活性代谢产物。  The invention also includes active metabolites of the compounds of the invention.
本发明化合物既可单独也可以药物组合物的形式使用。 本发 明的药物组合物包含有效剂量的本发明式 I化合物、 其消旋体、 旋光异构体、 或其可药用盐或溶剂化物以及一种或多种适宜的可 药用载体。 本发明所述的药用载体包括但不限于： 离子交换剂， 氧化铝， 硬脂酸铝， 卵癬脂， 血清蛋白如人血白蛋白， 緩冲物质 如磷酸盐， 甘油， 山梨酸， 山梨酸钾， 饱和植物脂肪酸的部分甘 油酯混合物， 水， 盐或电解质， 如硫酸鱼精蛋白， 磷酸氢二钠， 磷酸氢钾， 氯化钠， 锌盐， 胶态氧化硅， 三硅酸鎂， 聚乙烯吡咯 烷酮， 纤维素物盾， 聚乙二醇， 羧甲基纤维素钠， 聚丙烯酸酯， 蜂蜡， 羊毛脂。  The compounds of the present invention can be used either alone or in the form of pharmaceutical compositions. The pharmaceutical composition of the present invention comprises an effective amount of a compound of formula I of the present invention, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof, and one or more suitable pharmaceutically acceptable carriers. The pharmaceutical carriers according to the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, zoster ring fat, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, sorbic acid Potassium acid, a mixture of partially glycerides of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, Polyvinylpyrrolidone, cellulose shield, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
本发明化合物的药物组合物可以以下面的任意方式施用： 口 服， 喷雾吸入， 直肠用药， 鼻腔用药， 颊部用药， 局部用药， 非 肠道用药， 如皮下、 静脉、 肌内、 腹膜内、 鞘内、 心室内、 胸骨 内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、 腹膜内或静脉内给药方式。 The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Inner, ventricle, sternum Intracranial and intracranial injection or infusion, or medication with the aid of an explant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.
当口服用药时，本发明化合物可制成任意口服可接受的制剂 形式，包括但不限于片剂、 胶嚢、 水溶液或水悬浮液。 其中，片剂 使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬 脂酸镁。 胶嚢制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。 水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合 使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香 剂或着色剂。  When administered orally, the compounds of the present invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carriers used for tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added. Diluents used in capsule preparations generally include lactose and dried corn starch. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweeteners, fragrances, or colorants may be added to the above oral preparation forms.
当局部用药时，特别是治疗局部外敷容易达到的患面或器官， 如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将 本发明化合物制成不同的局部用药制剂形式，具体说明如下：  When applied topically, especially for the treatment of affected surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be made into different topical preparations according to different affected surfaces or organs. The form is described as follows:
当眼部局部施用时，本发明化合物可配制成一种微粉化悬浮 液或溶液的制剂形式，所使用载体为等渗的一定 pH 的无菌盐水， 其中可加入或不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化 合物制成膏剂形式如凡士林膏。  When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution formulation, and the carrier used is isotonic sterile saline of a certain pH, with or without a preservative such as benzyl chloride Alkoxide. For ophthalmic use, the compounds can also be formulated in the form of a paste such as vaseline.
当皮肤局部施用时，本发明化合物可制成适当的软膏、洗剂或 霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。 软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡 士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂 可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯， 吐温 60，十六烷酯蜡，十六碳烯芳醇， 2-辛基十二烷醇，苄醇和水。  When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax and water; carriers that can be used in lotions or creams include, but are not limited to: Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
本发明化合物还可以无菌注射制剂形式用药，包括无菌注射 水或油悬浮液或无菌注射溶液。 其中，可使用的载体和溶剂包括 水、林格氏溶液和等渗氯化钠溶液。 另外，灭菌的非挥发油也可用 作溶剂或悬浮介质，如单甘油酯或二甘油酯。  The compounds of the invention can also be administered in the form of sterile injectable preparations, including sterile injectable water or oil suspensions or sterile injectable solutions. Among them, carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized non-volatile oils can be used as solvents or suspension media, such as monoglycerides or diglycerides.
另外需要指出，本发明化合物的使用剂量和使用方法取决于 诸多因素，包括患者的年龄、 体重、 性别、 自然健康状况、 营养状 况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程度 以及诊治医师的主观判断。优选的使用剂量介于 0. 01 - 100mg/kg 体重 /天， 其中最优剂量在 5mg/kg-10mg/kg体重 /天。 具体实施方式 In addition, it should be noted that the dosage and method of use of the compounds of the present invention depend on many factors, including the age, weight, sex, natural health status, nutritional status of the patient Conditions, the strength of the compound's activity, the time taken, the metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100 mg / kg body weight / day, and the optimal dosage is between 5 mg / kg and 10 mg / kg body weight / day. detailed description
下面的实施例是本发明优选的说明性优选方案，对本发明不构 成任何限制。  The following examples are preferred illustrative preferred embodiments of the present invention and do not constitute any limitation to the present invention.
化合物熔点由 RY- 1 型熔点仪测定， 温度未经校正。 ^ NMR 光谱由 Bruker ARX 400型或 US Var ian Ul i ty Inova 600 型核 磁仪测定。 FAB质谱由 Zabspect高分辨磁质谱仪测定。 制备实施例 1 : 2- (5-甲基 -2-苯基- 1， 3-噁唑 -4-基）-乙醇（中 间体 1 )  The melting point of the compound was determined by a RY-1 melting point apparatus, and the temperature was not corrected. ^ NMR spectra were measured with Bruker ARX 400 or US Varian Ul Inty Inova 600 NMR. FAB mass spectrometry was measured by Zabspect high-resolution magnetic mass spectrometer. Preparation Example 1: 2- (5-methyl-2-phenyl-1,3-oxazole-4-yl) -ethanol (intermediate 1)
将 4-溴- 3-氧-戊酸甲酯 ( 23. 2g， 0. l lmol ) 和苯甲酰胺 ( 20. lg, 0. 17mo l ) 溶于 160mL甲苯中， 加热回流， 用分水器除 去反应生成的水， 反应 9小时。 浓缩， 将得到的粗产物经硅胶柱 层析（正己烷： 乙酸乙酯 =6: 1 ) ， 得到 5. 6g浅棕色油状 2- (5- 甲基- 2 -苯基 -1， 3 -喁唑 -4-基）-乙酸甲酯， 收率 22 %。  Dissolve 4-bromo-3-oxo-valeric acid methyl ester (23.2 g, 0.1 l mol) and benzamide (20 lg, 0.17 mol) in 160 mL of toluene, heat to reflux, and use a water separator The water produced by the reaction was removed, and the reaction was carried out for 9 hours. Concentrated, the obtained crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 5.6 g of 2- (5-methyl-2-phenyl-1, 3 -fluorene as a light brown oil. Azol-4-yl) -methyl acetate, yield 22%.
将 2- (5-甲基 -2-苯基 -1， 3-喁唑- 4-基） -乙酸甲酯 （2. 3g， l Ommol ) 溶于 16mL乙醚， 0°C下滴加至 LiAlH4 ( 0. 38g, l Ommol ) 在乙醚中的混悬液 4mL中。 室温搅拌过夜。 反应液依次小心加入 0. 4raL水、 0. 4mL的 15%NaOH水溶液、 1. 2mL水及一勺无水硫酸镁。 过滤，滤液浓缩，得到 1. 6g 2-（5-甲基- 2-苯基 -1， 3 -噁唑 -4-基） - 乙醇， 其为淡黄色固体， 收率 80 %。 Dissolve methyl 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -acetate (2.3 g, 10 mmol) in 16 mL of ether, and add dropwise to LiAlH at 0 ° C. 4 (0. 38 g, 10 mmol) in 4 mL of a suspension in ether. Stir overnight at room temperature. The reaction solution was carefully added sequentially with 0.4raL of water, 0.4mL of a 15% NaOH aqueous solution, 1.2mL of water, and a spoonful of anhydrous magnesium sulfate. Filtration and concentration of the filtrate gave 1.6 g of 2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethanol as a pale yellow solid with a yield of 80%.
MS [M] +=231. 2 m/e;  MS [M] + = 231. 2 m / e;
^-NMR (400MHz, CDC13) δ 7. 99 - 7. 78 (m, 2H) , 7. 43 一 7. 42 (m, 3H) , 3. 94 (t, 2H)， 2. 74 (t， 2H) , 2. 34 (s， 3H)。 制备实施例 2A: (2S) -2-叔丁氧羰基氨基 -3- (4-羟基-苯基） - 丙酸甲酯 （中间体 2A) ^ -NMR (400MHz, CDC1 3 ) δ 7. 99-7. 78 (m, 2H), 7. 43-7. 42 (m, 3H), 3. 94 (t, 2H), 2. 74 (t , 2H), 2. 34 (s, 3H). Preparation Example 2A: (2S) -2-tert-butoxycarbonylamino-3- (4-hydroxy-phenyl) -methyl propionate (Intermediate 2A)
0°C下， 将二氯亚砜 ( 8mL, 0. llmmol ) 滴加至含 L-酪氨酸 ( 17.9g， 0.1匪01)的甲醇（1001^)溶液中。 回流 3小时。 浓缩。 加入三乙胺 ( 15mL) 、 乙腈 （150mL) , 再滴加 B0C20 ( 23.3mL, 0· llmmol )。 室温搅拌 1.5小时。 浓缩， 加二氯甲烷（ 200mL )溶 解， 依次用 1M硫酸氢钠水溶液（ 200mL) 、 少量饱和碳酸钠水溶 液及水洗， 有机相无水硫酸镁干燥。 浓缩， 得到（2S)- 2-叔丁氧羰 基氨基 -3- (4-羟基-苯基） -丙酸甲酯 （26. Og, 90% ) ， 其为白色 固体。 At 0 ° C, dichlorosulfoxide (8mL, 0.11mmol) was added dropwise to a methanol (1001 ^) solution containing L-tyrosine (17.9g, 0.1mg01). Reflux for 3 hours. concentrate. Triethylamine (15 mL) and acetonitrile (150 mL) were added, and then BOC 2 0 (23.3 mL, 0.11 mmol) was added dropwise. Stir at room temperature for 1.5 hours. Concentrate, add dichloromethane (200mL) to dissolve, wash with 1M aqueous sodium hydrogen sulfate solution (200mL), a small amount of saturated aqueous sodium carbonate solution and water, and dry the organic phase with anhydrous magnesium sulfate. Concentrated to give (2S) -2-tert-butoxycarbonylamino-3- (4-hydroxy-phenyl) -propionic acid methyl ester (26.0 g, 90%) as a white solid.
MS [M] +=295.4 m/e;  MS [M] + = 295.4 m / e;
'H-NMR (400MHz, CDC13) δ 6.98 - 6.90 (m, 2H)， 6.78 一 6.73 (m, 2H)， 4.60— 4.50 (m, 1H)， 3.70 (s， 3H) , 3.08— 2.93 (m， 2H)， 1.45 (s， 9H)。 制备实施例 2B: (2S)- 3- (3-溴- 4-羟基-苯基) -2-叔丁氧羰基 氨基-丙酸甲酯 （中间体 2B) 'H-NMR (400MHz, CDC1 3 ) δ 6.98-6.90 (m, 2H), 6.78-6.73 (m, 2H), 4.60—4.50 (m, 1H), 3.70 (s, 3H), 3.08— 2.93 (m , 2H), 1.45 (s, 9H). Preparation Example 2B: (2S) -3- (3-Bromo-4-hydroxy-phenyl) -2-tert-butoxycarbonylamino-propionic acid methyl ester (Intermediate 2B)
0°C下， 将含溴素（0.9g， 5.5mmol )的冰醋酸溶液（8mL)滴加 至 L-酪氨酸（1.0g， 5.5mmol )与冰醋酸的混浊液（lOmL) 中。 室 温过夜。 过滤， 烘干滤饼， 得到 1.7g黄色固体， 直接用于下一步 反应。  At 0 ° C, a glacial acetic acid solution (8 mL) containing bromine (0.9 g, 5.5 mmol) was added dropwise to a turbid solution (10 mL) of L-tyrosine (1.0 g, 5.5 mmol) and glacial acetic acid. Room temperature overnight. Filtration and drying of the filter cake gave 1.7 g of a yellow solid, which was used directly in the next reaction.
按照上述制备实施例 2A中所述方法进行反应，得到的粗产物 经硅胶柱层析 （石油醚：乙酸乙酯 =4: 1 ) ， 得 0.8g 白色固体状 (2S) -3- (3-溴 -4-羟基-苯基） -2-叔丁氧羰基氨基-丙酸甲酯， 收 率 38·6%。  The reaction was performed according to the method described in the above Preparation Example 2A, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 0.8 g of (2S) -3- (3- Bromo-4-hydroxy-phenyl) -2-tert-butoxycarbonylamino-propionic acid methyl ester, yield 38.6%.
MS [M] +=374.4 ra/e;  MS [M] + = 374.4 ra / e;
'H-NMR (400MHz, DMS0-d6) δ 7.37 (d, 1H)， 7.10 - 7.05 (dd, 2H)， 3.56 (s, 3H) , 3.52 - 2.50 (m, 1H)， 2.80 一 2.65 (m， 2H), 1.45 (s, 9H) 制备实施例 3A: (23)-2-氨基-3-{4-[2-（5-甲基-2-苯基 -1， 3_P恶唑 -4-基)-乙氧基] -苯基 } -丙酸甲酯 （中间体 3A) 'H-NMR (400MHz, DMS0-d 6 ) δ 7.37 (d, 1H), 7.10-7.05 (dd, 2H), 3.56 (s, 3H), 3.52-2.50 (m, 1H), 2.80-2.65 (m, 2H), 1.45 (s, 9H) Preparation Example 3A: (23) -2-amino-3- {4- [2- (5-methyl-2-phenyl-1, 3- Poxazole -4 -yl) -ethoxy] -phenyl} -methyl propionate (Intermediate 3A)
将中间体 1( 10. lg, 0.05mol )、中间体 2 ( 14.7g， 0.05mol )、 三苯基磷 (14.41g, 0.055 mol) 溶于干燥的四氢呋喃 （180mL) ， 滴加含 40%DIAD的甲苯溶液（ 74mL, 0· 14mmol ) 。 室温搅拌 20 小时。浓缩，残留物经硅胶柱层析纯化（石油醚：乙酸乙酯 =3: 1), 得 16· 8g 浅黄色油状（2S) -2-叔丁氧羰基氨基 -3- {4- [2- (5-甲基 -2-苯基 -1, 3-p恶唑 -4-基）-乙氧基] -苯基 } -丙酸甲酯， 收率 67%。  Intermediate 1 (10 lg, 0.05 mol), Intermediate 2 (14.7 g, 0.05 mol), and triphenyl phosphorus (14.41 g, 0.055 mol) were dissolved in dry tetrahydrofuran (180 mL), and 40% DIAD was added dropwise. Of toluene solution (74mL, 0.14mmol). Stir at room temperature for 20 hours. After concentration, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 16.8 g of (2S) as a pale yellow oily 2-tert-butoxycarbonylamino-3- {4- [2- (5-Methyl-2-phenyl-1,3-poxazole-4-yl) -ethoxy] -phenyl} -methyl propionate, yield 67%.
将（2S) -2-叔丁氧羰基氨基- 3- {4- [2- (5-甲基- 2-苯基 -1, 3- 喁唑- 4-基）-乙氧基] -苯基 } -丙酸甲酯 （16.8g， 0.035mol) 、 三 氟乙酸（34mL) 、 二氯甲烷（ 340mL)混合室温搅拌过夜。 用 0.5 %氢氧化钠水溶液调 PH值至中性，有机层无水^ ^酸钠干燥。浓缩， 残留物经硅胶柱层析纯化 （氯仿：甲醇 -80: 1 ) ， 得 10.6g浅棕色 油状（2S) - 2-氨基- 3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑- 4-基） -乙 氧基] -苯基 } -丙酸 酯，.收率 80%。  The (2S) -2-tert-butoxycarbonylamino-3-{4- [2- (5-methyl-2-phenyl-1,3-oxazole-4 -yl) -ethoxy] -benzene Methyl} -propionate (16.8 g, 0.035 mol), trifluoroacetic acid (34 mL), and dichloromethane (340 mL) were mixed and stirred at room temperature overnight. The pH value was adjusted to neutral with a 0.5% sodium hydroxide aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (chloroform: methanol-80: 1) to obtain 10.6 g of (2S)-2-amino- 3- {4- [2- (5-methyl-2- Phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -propionate, yield 80%.
MS [M] +=380.4 m/e;  MS [M] + = 380.4 m / e;
'H-NMR (400MHz, DMS0-d6) δ 7.92 - 7.89 (m， 2H)， 7.52 - 7.45 (m， 3H)， 7.07 (d, 2H) , 6.83 (d, 2H)， 4.17 (t， 2H) , 3.56 (s， 3H)， 3.51 - 3.42 (m, 1H) , 2.93 (t， 2H)， 2.80 - 2.67 (m, 2H), 2.36 (s, 3H)， 1.75 (s， 2H)。 制备实施例 3B: (2S)- 2-氛基 -3-{3-溴-4-[2-（5-甲基-2-苯 基 -1, 3-p恶唑- 4-基）-乙氧基]-苯基 } -丙酸甲酯 （中间体 3B) 'H-NMR (400MHz, DMS0-d 6 ) δ 7.92-7.89 (m, 2H), 7.52-7.45 (m, 3H), 7.07 (d, 2H), 6.83 (d, 2H), 4.17 (t, 2H ), 3.56 (s, 3H), 3.51-3.42 (m, 1H), 2.93 (t, 2H), 2.80-2.67 (m, 2H), 2.36 (s, 3H), 1.75 (s, 2H). Preparation Example 3B: (2S)-2-amino-3- {3-bromo-4- [2- (5-methyl-2-phenyl-1, 3-poxazole-4-yl)- Ethoxy] -phenyl} -methyl propionate (Intermediate 3B)
按照与制备中间体 3A相似的方法， 用中间体 2B替代中间体 2A, 得到 （23)-2-氨基-3-{3-溴-4-[2-(5-甲基-2-苯基-1, 3-噁 唑- 4-基)―乙氧基] -苯基 } -丙酸甲酯。 MS [M] +=459. 4 ra/e; Following a similar method to preparing intermediate 3A, replacing intermediate 2A with intermediate 2B gave (23) -2-amino-3- {3-bromo-4- [2- (5-methyl-2-phenyl) -1,3-oxazole-4-yl) -ethoxy] -phenyl} -methyl propionate. MS [M] + = 459. 4 ra / e;
^-NMR (400MHz, DMS0-d6) δ 7. 92 - 7. 89 (m, 2H)， 7. 52 一 7. 48 (m， 3H) , 7. 37 (d, 1H)， 7. 10 - 7. 05 (dd, 2H)， 4. 25 (t, 2H) , 3. 56 (s， 3H) , 3. 52— 2. 50 (m， 1H) , 2. 94 (t， 2H) , 2. 80 - 2. 65 (m， 2H) , 2. 38 (s, 3H)， 1. 76 (s， 2H)。 实施例 1 : (2S) - 2- [3- (4-甲 氧基-苯基） -丙 酰氨 基] -3- {4- [2- (5-甲基- 2-苯基 -1， 3 -喁唑 -4-基) -乙氧基] -苯基 } - 丙酸 ^ -NMR (400MHz, DMS0-d 6 ) δ 7. 92-7. 89 (m, 2H), 7. 52-7. 48 (m, 3H), 7. 37 (d, 1H), 7. 10 -7. 05 (dd, 2H), 4. 25 (t, 2H), 3. 56 (s, 3H), 3. 52— 2. 50 (m, 1H), 2. 94 (t, 2H), 2. 80-2. 65 (m, 2H), 2. 38 (s, 3H), 1. 76 (s, 2H). Example 1: (2S)-2- [3- (4-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazolyl-4-yl) -ethoxy] -phenyl} -propionic acid
3-（4-甲氧基-苯基） -丙酸（0. 38g, 2. l lmmol)和二氯亚砜 2mL 混合回流 3h。 蒸除二氯亚砜， 残留物用 4mL二氯甲烷溶解。 在另 一反应瓶中， 将中间体 3A (0. 8g , 2. llmmol) , 三乙胺（0. 23g， 3- (4-methoxy-phenyl) -propionic acid (0.38 g, 2. l mmol) and dichlorosulfoxide 2 mL were mixed under reflux for 3 h. Dichlorosulfoxide was distilled off, and the residue was dissolved in 4 mL of dichloromethane. In another reaction flask, intermediate 3A (0.8 g, 2.11 mmol), triethylamine (0.23 g,
2. 32腿 ol)溶于 5mL二氯甲烷中， 滴加上述溶液。 滴毕， 室温搅拌 过夜。 浓缩， 粗品经硅胶柱层析分离（石油醚： 乙酸乙酯 =3: 1) , 得白色固体（2 S) -2- [ 3- (4-甲氧基-苯基) -丙酰氨基 3- {4- [2- (5- 甲基 -2-苯基- 1， 3 -噁唑 -4-基） -乙氧基] -苯基 } -丙酸甲酯（0. 34g， 30%)。 2. 32 legs ol) was dissolved in 5 mL of dichloromethane, and the above solution was added dropwise. After dripping, stir at room temperature overnight. Concentrated, the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain a white solid (2 S) -2- [3- (4-methoxy-phenyl) -propionamido 3 -{4- [2- (5-methyl-2-phenyl-1, 3 -oxazol-4-yl) -ethoxy] -phenyl}-methyl propionate (0.34g, 30% ).
将（2S) -2- [3- (4 -甲氧基-苯基) -丙酰氨基 3- {4- [2- (5-甲基 -2-苯基 -1， 3- p恶唑 -4-基） -乙氧基] -苯基 } -丙酸甲酯溶于 5mLTHF 中， 加入 2mL IN氢氧化锂溶液， 室温搅拌 2h。 向反应液中加入 2N盐酸调 PH值至酸性。 CHC13萃取， 有机层干燥。 过滤， 浓缩， 得白色固体（280mg， 85%)。 mp: 158-159 °C 0 (2S) -2- [3- (4-methoxy-phenyl) -propionamido 3- {4- [2- (5-methyl-2-phenyl-1,3-poxazole -4-yl) -ethoxy] -phenyl} -methyl propionate was dissolved in 5 mL of THF, 2 mL of a lithium hydroxide solution was added, and the mixture was stirred at room temperature for 2 h. 2N hydrochloric acid was added to the reaction solution to adjust the pH to acidic. It was extracted with CHC1 3 and the organic layer was dried. Filtered and concentrated to give a white solid (280 mg, 85%). mp: 158-159 ° C 0
MS [M] +=528. lm/e, MS [M] + = 528. Lm / e,
'H-NMR (400MHz, DMS0-d6) δ 8. 12 (d, 1H， J=7. 8Hz) , 7. 92 - 7. 90 (m, 2H)， 7. 51— 7. 48 (m， 3H) , 7. 07 - 7. 03 (m, 4H) , 6. 83 - 6. 80 (m, 4H)， 4. 38 - 4. 35 (m, 1H) , 4. 15 (t, 2H， J=6. 4Hz) ,'H-NMR (400MHz, DMS0-d 6 ) δ 8. 12 (d, 1H, J = 7.8 Hz), 7. 92-7. 90 (m, 2H), 7. 51- 7. 48 (m , 3H), 7. 07-7. 03 (m, 4H), 6. 83-6. 80 (m, 4H), 4. 38-4. 35 (m, 1H), 4. 15 (t, 2H , J = 6.4 Hz),
3. 69 (s, 3H) , 2. 96 - 2. 89 (m, 3H) , 2. 79 - 2. 73 (m, 1H)， 2. 63 (t, 2H, J=7. 5Hz)， 2. 35 - 2. 30 (m, 5H)。 实施例 2: (2S)- 3-{4- [2-(5-甲基 -2-苯基 -1， 3-喁唑 -4- 基)-乙氧基〗 -苯基 } -2- (3-苯基 -丁酰氨基) -丙酸 3. 69 (s, 3H), 2. 96-2. 89 (m, 3H), 2. 79-2. 73 (m, 1H), 2. 63 (t, 2H, J = 7.5 Hz), 2. 35-2. 30 (m, 5H). Example 2: (2S)-3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy〗 -phenyl} -2- (3-phenyl-butyrylamino) -propionic acid
按照与实施例 1类似的方法，将其中的 3-(4 -甲氧基-苯基） - 丙酸替换为 3-苯基-丁酸-基， 得白色固体状（2S)- 3- {4- [2- (5-甲 基- 2-苯基- 1， 3-喁唑 -4-基） -乙氧基] -苯基 } -2- (3-苯基-丁酰氨 基） -丙酸， mp:160-161°C。  According to a method similar to that in Example 1, 3- (4-methoxy-phenyl) -propionic acid was replaced with 3-phenyl-butyric acid-yl group to obtain (2S)-3- { 4- [2- (5-Methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (3-phenyl-butyrylamino)- Propionic acid, mp: 160-161 ° C.
MS [M+H]+=512. lm/e.  MS [M + H] + = 512. Lm / e.
1HNMR (400MHz, DMSO) δ 8.18 - 8.13(m, 1H)， 7.91 - 7.89 (ra, 2H)， 7.51 - 7.45 (m, 3H)， 7.26 - 7.10 (m, 6H) , 7.11 - 7.02 (d, 1H， J=8.8Hz), 6.88 - 6.79 (m, 2H) , 4.38 - 4.33 (m, 1H), 4.16(t, 2H， J=6.6Hz) , 3.06 - 2.89 (ra, 4H) , 2.78 - 2.69 (m: 1H)， 2.35 - 2.30 (ra, 5H)， 1.07 (d, 1H， J=8.0Hz) , 0.98 (d, 1H, J=8.0Hz)。 实施例 3 : (2S)- 2-[3-(3-甲氧基-苯基） -丙酰氨 基〗 -3- {4- [2- (5-甲基- 2-苯基 -1， 3-喁唑 -4-基) -乙氧基] -苯基 } - 丙酸 1HNMR (400MHz, DMSO) δ 8.18-8.13 (m, 1H), 7.91-7.89 (ra, 2H), 7.51-7.45 (m, 3H), 7.26-7.10 (m, 6H), 7.11-7.02 (d, 1H , J = 8.8Hz), 6.88-6.79 (m, 2H), 4.38-4.33 (m, 1H), 4.16 (t, 2H, J = 6.6Hz), 3.06-2.89 (ra, 4H), 2.78-2.69 ( m : 1H), 2.35-2.30 (ra, 5H), 1.07 (d, 1H, J = 8.0Hz), 0.98 (d, 1H, J = 8.0Hz). Example 3: (2S)-2- [3- (3-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
按照与实施例 1类似的方法， 将其中的 3-(4-甲氧基-苯基) - 丙酸替换为 3-（3-甲氧基-苯基）-丙酸， 得白 色固体状 (2S) -2- [3- (3-甲氧基-苯基) -丙酰氨基] -3- {4- [2- (5-甲基- 2- 苯基- 1， 3-P恶唑 -4-基） -乙氧基] -苯基 }-丙酸， mp: 178-180°C。  According to a method similar to that in Example 1, 3- (4-methoxy-phenyl) -propionic acid was replaced with 3- (3-methoxy-phenyl) -propionic acid to obtain a white solid ( 2S) -2- [3- (3-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1,3-Poxazole -4-yl) -ethoxy] -phenyl} -propionic acid, mp: 178-180 ° C.
MS [M] +=528. lm/e.  MS [M] + = 528. Lm / e.
'H-NMR (400MHz, DMS0-d6) δ 8.00 (d, 1H， J=8.1Hz) , 7.91 一 7.89 (ra, 2H)， 7.51 - 7.45 (m， 3H) , 7.14 - 7.06 (m, 3H) , 6.82 - 6.80 (m, 2H) , 6.72 - 6.71 (m, 3H) , 4.40 - 4.36 (m， 1H) , 4.16 (t， 2H， J=6.5Hz), 3.70 (s， 3H) , 2.96 - 2.89 (m, 3H) , 2.80 - 2.68 (m, 3H) , 2.38 - 2.34 (m, 5H)。 实施例 4 : (2S)- 2- [3- (2-甲氧基 -苯基）-丙酰氨 基] -3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑- 4 -基) -乙氧基] -苯基 } - 丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 8.00 (d, 1H, J = 8.1Hz), 7.91-7.89 (ra, 2H), 7.51-7.45 (m, 3H), 7.14-7.06 (m, 3H ), 6.82-6.80 (m, 2H), 6.72-6.71 (m, 3H), 4.40-4.36 (m, 1H), 4.16 (t, 2H, J = 6.5Hz), 3.70 (s, 3H), 2.96- 2.89 (m, 3H), 2.80-2.68 (m, 3H), 2.38-2.34 (m, 5H). Example 4: (2S)-2- [3- (2-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole-4 -yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 3- (2-甲氧基-苯基）-丙酸， 得白色固体状 (2S) -2- [ 3- (2-甲氧基-苯基） -丙酰氨基] -3- {4- [2- (5-甲基 -2- 苯基 -1， 3-喁唑 -4-基） -乙氧基]-苯基 }-丙酸， mp: 178-179°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 3- (2-methoxy-phenyl) -propionic acid to obtain a white solid (2S) -2- [3- (2-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid, mp: 178-179 ° C.
MS [M] +=528. lm/e.  MS [M] + = 528. Lm / e.
JH-NMR (400MHz, DMS0-d6) δ 8.00 (d, 1H, J=8.1Hz) , 7.91-7.89 (m， 2H)， 7.51-7.45 (m, 3H) , 7.14-7.06 (m, 3H) , 6.82-6.80 (m, 2H) , 6.72-6.71 (ra, 3H) , 4.40-4.36 (m, 1H)， 4.16 (t， 2H, J=6.5Hz), 3.70(s, 3H)， 2.96-2.89 (m， 3H)， 2.80-2.68 (m, 3H) , 2.38-2.34 (m, 5H)。 实施例 5: (2S)-3- {4- [2- (5-甲基 -2-苯基 -l，3-p恶唑 -4- 基) -乙氧基] -苯基 } -2- [ 3- (4-三氟甲基-苯基) -丙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 3- (4-三氟甲基-苯基） -丙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2 -苯基 -1， 3 -喁唑 -4-基) -乙氧基] -苯 基 } -2- [3- (4-三氟甲基-苯基） -丙酰氨基]-丙酸， mp: 159-161°C。 J H-NMR (400MHz, DMS0-d 6 ) δ 8.00 (d, 1H, J = 8.1Hz), 7.91-7.89 (m, 2H), 7.51-7.45 (m, 3H), 7.14-7.06 (m, 3H ), 6.82-6.80 (m, 2H), 6.72-6.71 (ra, 3H), 4.40-4.36 (m, 1H), 4.16 (t, 2H, J = 6.5Hz), 3.70 (s, 3H), 2.96- 2.89 (m, 3H), 2.80-2.68 (m, 3H), 2.38-2.34 (m, 5H). Example 5: (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-poxazol-4-yl) -ethoxy] -phenyl} -2 -[3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid Using a preparation method similar to that in Example 1, the 3- (4-methoxy-phenyl) -propane Replace the acid with 3- (4-trifluoromethyl-phenyl) -propionic acid to obtain (2S) -3- {4- [2- (5-methyl-2 -phenyl-1, 3 as a white solid) -Oxazolyl-4-yl) -ethoxy] -phenyl} -2- [3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid, mp: 159-161 ° C .
MS [M] +=566. lm/e.  MS [M] + = 566. Lm / e.
'H-NMR (400MHz, DMS0-d6) δ 7.89 (d, 2H) , 7.57 - 7.48 (m， 5H)， 7.47 (d, 2H)， 7.33 (d, 2H)， 6.75 (d， 2H) , 4.30 - 4.29 (m, 1H), 4.13 (t， 2H， J=6.0) , 2.91 - 2.81 (m， 6H)， 2.40 - 2.34 (m, 5H)。 'H-NMR (400MHz, DMS0-d 6 ) δ 7.89 (d, 2H), 7.57-7.48 (m, 5H), 7.47 (d, 2H), 7.33 (d, 2H), 6.75 (d, 2H), 4.30-4.29 (m, 1H), 4.13 (t, 2H, J = 6.0), 2.91-2.81 (m, 6H), 2.40-2.34 (m, 5H).
(2S) -3- {4- [2- (5-甲基 -2-苯基- 1， 3-噁唑 -4 基) -乙氧基] -苯基 } -2- (2-甲基- 3-苯基-丙酰氨基) -丙酸 (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole-4 ) -Ethoxy] -phenyl} -2- (2-methyl-3-phenyl-propionamido) -propionic acid
采用与实施例 1类似的制备方法， 将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-甲基- 3-苯基-丙酸， 得白 色固体状 (2S) -3- {4- [2- (5-甲基 -2-苯基- 1， 3 -喁唑 -4-基) -乙氧基] -苯 基} -2- (2-甲基 -3-苯基-丙酰氨基）-丙酸， mp: 130- 131。C。  Using a preparation method similar to that in Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2-methyl-3-phenyl-propionic acid to obtain a white solid (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazolyl-4-yl) -ethoxy] -phenyl} -2- (2-methyl-3 -Phenyl-propionamido) -propionic acid, mp: 130-131. C.
MS [M] +=512m/e.  MS [M] + = 512m / e.
'H-NMR (400MHz, DMS0-d6) δ 7. 91-7. 89 (ra, 2H) , 7. 52- 7. 49 (m, 3H) , 7. 24-7. 02 (m, 4H)， 6. 89 (d, 1H， J=8. 5Hz) , 6. 77-6. 68 (m, 2H)， 4. 14-4. 11 (m， 4H) , 3. 04-2. 89 (m, 5H )， 2. 54—2. 52 (m, 1H) , 2. 46-2. 38 (m, 1H)， 2. 34 (s， 3H) , 0. 80 (q, 3H, J=6. 6Hz)。 实施例 7： (2S) - 3- {4- [2- (5-甲基 -2-苯基- 1， 3-喁唑- 4- 基) -乙氧基] -苯基 } - 3- (苯基-丙酰氨基) -丙酸  'H-NMR (400MHz, DMS0-d6) δ 7. 91-7. 89 (ra, 2H), 7. 52- 7. 49 (m, 3H), 7. 24-7. 02 (m, 4H) , 6. 89 (d, 1H, J = 8.5 Hz), 6. 77-6. 68 (m, 2H), 4. 14-4. 11 (m, 4H), 3. 04-2. 89 ( m, 5H), 2. 54—2.52 (m, 1H), 2. 46-2. 38 (m, 1H), 2. 34 (s, 3H), 0.8 (q, 3H, J = 6. 6Hz). Example 7: (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -3 (Phenyl-propionamido) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 3-苯基 -丙酸（购自北京化学试剂公司） ， 得白 色固体的（2S) -3- {4- [2- (5-甲基- 2-苯基 -1， 3 -喁唑 -4 -基) -乙氧 基] -苯基 } - 3- (苯基-丙酰氨基）-丙酸， mp: 167-168 °C。  A similar preparation method as in Example 1 was used, and 3- (4-methoxy-phenyl) -propionic acid was replaced with 3-phenyl-propionic acid (purchased from Beijing Chemical Reagent Company) to obtain a white solid (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole-4-yl) -ethoxy] -phenyl} -3- (phenyl- Propionylamino) -propionic acid, mp: 167-168 ° C.
MS [M] +=498. 2ra/e.  MS [M] + = 498. 2ra / e.
'H-NMR (400MHz, DMS0-d6) δ 8. 15 (d, 1H, J-8. 1Hz) , 7. 92 - 7. 90 (m, 2H)， 7. 50 - 7. 48 (m, 3H) , 7. 22 - 7. 13 (m, 2H) , 7. 13 - 7. 07 (m, 5H)， 6. 81 (d， 2H， J=8. 4Hz) , 4. 37 - 4. 35 (m, 1H)， 4. 15 (t， 2H， J=6. 5Hz) , 3. 59 (t, 1H, J=6. 5Hz) , 2. 93 - 2. 89 (ra, 3H) , 2. 73 - 2. 69 (ra, 2H) , 2. 38 - 2. 35 (m, 5H)。 实施例 8 : (2S) -3- {4- [2- (5-甲基- 2-苯基 -1， 3-"恶唑 -4- 基） -乙氧基] -苯基 } -2- (2-五氟苯基-乙酰氨基） -丙酸  'H-NMR (400MHz, DMS0-d6) δ 8. 15 (d, 1H, J-8. 1Hz), 7. 92-7. 90 (m, 2H), 7. 50-7. 48 (m, 3H), 7. 22-7. 13 (m, 2H), 7. 13-7. 07 (m, 5H), 6. 81 (d, 2H, J = 8.4 Hz), 4. 37-4. 35 (m, 1H), 4. 15 (t, 2H, J = 6.5 Hz), 3.59 (t, 1H, J = 6.5 Hz), 2. 93-2. 89 (ra, 3H), 2. 73-2. 69 (ra, 2H), 2. 38-2. 35 (m, 5H). Example 8: (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3- "oxazol-4-yl) -ethoxy] -phenyl} -2 -(2-pentafluorophenyl-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基）-丙酸替换为 2-(2-五氟苯基）-乙酸， 得白 色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基 -1, 3-喁唑- 4-基） -乙氧基] -苯 基 } -2- (2-五氟苯基-乙酰氨基)-丙酸， mp: 198-199°C。 Using a similar preparation method as in Example 1, the 3- (4-methoxy-benzene Group) -propionic acid was replaced with 2- (2-pentafluorophenyl) -acetic acid to obtain (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3 -Oxazole- 4-yl) -ethoxy] -phenyl} -2- (2-pentafluorophenyl-acetamino) -propionic acid, mp: 198-199 ° C.
MS [M] +=574.3m/e.  MS [M] + = 574.3m / e.
'H-NMR (400MHz, DMS0-d6) δ 12.69 (brs, 1H) , 8.45 (d, 1H, J=8.1Hz), 7.92-7.90 (m , 2H) , 7.50-7.47 (m, 3H)， 7.11-7.09 (d, 2H, J=8.6Hz) , 6.83-6.82 (d, 2H, J=8.6Hz) , 4.35 (m， 1H), 4.18 (t， 2H， J=6.7Hz) , 3.60-2.8 Km, 4H)， 2.35 'H-NMR (400MHz, DMS0-d6) δ 12.69 (brs, 1H), 8.45 (d, 1H, J = 8.1Hz), 7.92-7.90 (m, 2H), 7.50-7.47 (m, 3H), 7.11 -7.09 (d, 2H, J = 8.6Hz), 6.83-6.82 (d, 2H, J = 8.6Hz), 4.35 (m, 1H), 4.18 (t, 2H, J = 6.7Hz), 3.60-2.8 Km , 4H), 2.35
(s， 3H)。 实施例 9 : (2S)- 2- [2- (2-甲氧基-苯基） -乙酰氨 基] -3- {4- [2- (5-甲基- 2 -苯基 -1， 3-p恶唑- 4 -基） -乙氧基] -苯基 } - 丙酸 (s, 3H). Example 9: (2S)-2- [2- (2-methoxy-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2 -phenyl-1, 3 -p oxazole-4 -yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-(2 -甲氧基-苯基）-乙酸， 得白色固体状 (2S) -2- [2- (2-甲氧基-苯基） -乙酰氨基] -3- {4- [2- (5-甲基- 2- 苯基- 1， 3-嚙唑 -4-基） -乙氧基] -苯基 }-丙酸， mp: 165-166°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2-methoxy-phenyl) -acetic acid to obtain a white solid ( 2S) -2- [2- (2-methoxy-phenyl) -acetamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-pyrazole-4 -Yl) -ethoxy] -phenyl} -propionic acid, mp: 165-166 ° C.
MS [M] +=514.3m/e.  MS [M] + = 514.3m / e.
'H-NMR (400MHz, DMS0-d6) δ 12.50(brs, 1H) , 7.91— 7.90 (m, 3H)， 7.50 ― 7.46 (m, 3H)， 7.15 一 7.06 (m， 3H) , 6.97 一 6.96 (m, 1H), 6.86 — 6.75 (ra, 4H) , 4.40 (m， 1H) , 4.17 (t， 2H, J=6.4Hz)， 3.65 (s, 3H) , 3.35 (s， 2H) , 2.99 - 2.91 (m， 3H), 2.89 ― 2.76 (m, 1H), 2.35 (s， 3H)。 实 施 例 10 ： (2S) -2- [2- (2-氯 -苯基）- 乙 酰氨 基] -3- {4- [2- (5-曱基 -2-苯基 -1， 3 -喁唑 -4 -基) -乙氧基] -苯基 } - 丙酸  'H-NMR (400MHz, DMS0-d6) δ 12.50 (brs, 1H), 7.91— 7.90 (m, 3H), 7.50 ― 7.46 (m, 3H), 7.15-7.06 (m, 3H), 6.97-6.96 ( m, 1H), 6.86 — 6.75 (ra, 4H), 4.40 (m, 1H), 4.17 (t, 2H, J = 6.4Hz), 3.65 (s, 3H), 3.35 (s, 2H), 2.99-2.91 (m, 3H), 2.89 ― 2.76 (m, 1H), 2.35 (s, 3H). Example 10: (2S) -2- [2- (2-chloro-phenyl) -acetylamino] -3- {4- [2- (5-fluorenyl-2-phenyl-1, 3 -fluorene Azole-4 -yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基) -丙酸替换为 2- (2-氯-苯基) -乙酸（购自北京化学试剂公司）， 得白色固体状（2S) -2- [2- (2-氯-苯基） -乙酰氨基] -3- {4- [2- (5- 曱基 -2-苯基 -1, 3-"恶唑 -4-基） -乙氧基] -苯基 } -丙酸， mp: 188-189 °C。 Using a similar preparation method as in Example 1, the 3- (4-methoxy-benzene Group) -propionic acid was replaced with 2- (2-chloro-phenyl) -acetic acid (purchased from Beijing Chemical Reagent Company) to obtain (2S) -2- [2- (2-chloro-phenyl)- Acetamino] -3- {4- [2- (5-fluorenyl-2-phenyl-1, 3- "oxazol-4-yl) -ethoxy] -phenyl} -propionic acid, mp: 188-189 ° C.
MS [M] +=518. 3m/e.  MS [M] + = 518. 3m / e.
'H-NMR (400MHz, DMS0-d6) δ 12. 64 (brs, 1H) , 8. 27 (d, 1H, J=8. 2Hz) , 7. 93 - 7. 90 (m, 2H) , 7. 51— 7. 47 (ra, 3H) , 7. 34 ― 7. 32 (m, 5H)， 6. 84 ― 6. 81 (ra, 2H) , 4. 42 - 4. 39 (m, 1H) , 4. 18 - 4. 17 (t, 2H, J=6. 6Hz)， 3. 55 - 2. 77 (m， 4H) , 2. 36 (s, 'H-NMR (400MHz, DMS0-d6) δ 12. 64 (brs, 1H), 8. 27 (d, 1H, J = 8.2 Hz), 7. 93-7. 90 (m, 2H), 7 51— 7. 47 (ra, 3H), 7. 34 ― 7. 32 (m, 5H), 6. 84 ― 6. 81 (ra, 2H), 4. 42-4. 39 (m, 1H) , 4. 18-4. 17 (t, 2H, J = 6.6 Hz), 3. 55-2. 77 (m, 4H), 2. 36 (s,
3H)。 实 施例 11 ： (2S) -2- [2- (4-氯 -苯基）- 乙 酰氨 基] -3- {4- [2- (5-甲基- 2-苯基- 1, 3-噁唑 -4 -基) -乙氧基] -苯基 } - 丙酸 3H). Example 11: (2S) -2- [2- (4-chloro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxan Azole-4 -yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基) -丙酸替换为 2- (4-氯-苯基） -乙酸（购自北京化学试剂公司）， 得白色固体状 (2S) -2- [2- (4-氯-苯基) -乙酰氨基] -3- {4- [2- (5- 甲基- 2-苯基- 1， 3 -噁唑 -4-基） -乙氧基] -苯基 } -丙酸， mp: 168-170°C。 A preparation method similar to that in Example 1 was used, and 3- (4-methoxy-phenyl) -propionic acid was replaced with 2- (4-chloro-phenyl) -acetic acid (purchased from Beijing Chemical Reagent Company). (2S) -2- [2- (4-chloro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3- Oxazol-4-yl) -ethoxy] -phenyl} -propionic acid, mp : 168-170 ° C.
MS [M] +=518. 2m/e.  MS [M] + = 518. 2m / e.
'H-NMR (400MHz, DMS0-d6) δ 8. 28 (d, 1H, J=8. 0Hz) , 7. 90 (m, 2H)， 7. 52 - 7. 47 (m, 3H) , 7. 28 - 7. 25 (m, 2H) , 7. 13 - 7. 05 (m, 6H) , 6. 80 - 6. 78 (d, 2H， J=8. 6Hz) , 4. 37 (m, 1H)， 4. 16 (t, 2H， J=6. 6Hz) , 3. 01 - 2. 75 (m, 4H)， 2. 35 (s, 3H) 0 实施例 12 : (2S) - 3- {4- [2- (5-甲基 -2 -苯基 -1， 3-喁唑- 4- 基) -乙氧基] -苯基 } -2- (2-邻-三氟甲基-苯基-乙酰氨基) -丙酸 采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基) -丙酸替换为 2- (2-邻-三氟甲基-苯基) -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑 -4-基) -乙氧基] -苯 基 } -2- (2-邻-三氟甲基 -苯基 -乙酰氨基） -丙酸， mp: 154- 156。 (。 'H-NMR (400MHz, DMS0-d6) δ 8. 28 (d, 1H, J = 8.0 Hz), 7. 90 (m, 2H), 7. 52-7. 47 (m, 3H), 7 . 28-7. 25 (m, 2H), 7. 13-7. 05 (m, 6H), 6. 80-6. 78 (d, 2H, J = 8.6 Hz), 4. 37 (m, 1H), 4. 16 (t, 2H, J = 6.6 Hz), 3. 01-2. 75 (m, 4H), 2. 35 (s, 3H) 0 Example 12: (2S)-3- {4- [2- (5-methyl-2 -phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o-trifluoromethyl- Phenyl-acetylamino) -propionic acid was prepared in a similar manner to that in Example 1. The 3- (4-methoxy-benzene) Group) -propionic acid was replaced with 2- (2-o-trifluoromethyl-phenyl) -acetic acid to obtain (2S) -3- {4- [2- (5-methyl-2-benzene -1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o-trifluoromethyl-phenyl-acetamino) -propionic acid, mp: 154-156 . (.
MS [M] +=552. 2m/e. MS [M] + = 552. 2m / e.
'H-NMR (400MHz, DMS0-d6) δ 12. 67 (brs, 1H)， 8. 41 (d, 1H, J=8. 8Hz)， 7. 93 - 7. 89 (in, 2H)， 7. 62 ― 7. 35 (m, 4H) , 7. 21 - 7. 12 (m, 3H) , 6. 86 - 6. 84 (ra, 2H) , 4. 40 (m, 1H) , 4. 17 (t, 2H) , 3. 03 - 2. 76 (m, 4H)， 2. 37 (s, 3H)。 实施例 13 : (2S) -3- {4- [2- (5-甲基 -2-苯基- 1, 3- "恶唑- 4- 基） -乙氧基] -苯基 } -2- (2-对-三氟甲基-苯基-乙酰氨基) -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12. 67 (brs, 1H), 8. 41 (d, 1H, J = 8.8 Hz), 7. 93-7. 89 (in, 2H), 7. 62 ― 7. 35 (m, 4H), 7. 21-7. 12 (m, 3H), 6. 86-6. 84 (ra, 2H), 4. 40 (m, 1H), 4. 17 (t, 2H), 3. 03-2. 76 (m, 4H), 2. 37 (s, 3H). Example 13: (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3- "oxazole-4-yl) -ethoxy] -phenyl} -2 -( 2 -p-trifluoromethyl-phenyl-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2- (2 -对 -三氟甲基-苯基) -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基- 1， 3 恶唑 -4-基)一乙氧基〗 -苯 基 } - 2- (2-对 -三氟甲基-苯基-乙酰氨基）-丙酸， mp: 169-170。 ( 。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2-p-trifluoromethyl-phenyl) -acetic acid to obtain white (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3oxazol-4-yl) monoethoxy-phenyl}-2- (2- P-trifluoromethyl-phenyl-acetamino) -propionic acid, mp: 169-170. (.
MS [M] +=552. 2m/e. MS [M] + = 552. 2m / e.
'H-NMR (400MHz, DMS0-d6) δ 12. 78 (brs， 1H)， 8. 45 (d, 1H: J=8. 2Hz) , 7. 91 - 7. 90 (m， 2H) , 7. 58 - 7. 47 (m, 5H) , 7. 34 - 7. 32 (d, 2H， J=8. 8Hz) , 7. 09 - 7. 06 (d, 2H, J=8. 5Hz) , 4. 37 (m， 1H) , 4. 16 (t, 2H, J=6. 6Hz)， 3. 50 (q, 2H)， 3. 01 - 2. 75 (m. 4H) , 2. 36 (s， 3H)。 实施例 14 : (2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑- 4- 基) -乙氧基] -苯基 } -2- [2 - (3-三氟甲基-苯基) -乙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2- (3 -三氟甲基-苯基）-乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基- 1， 3-喁唑 -4 -基） -乙氧基〗 -苯 基 } -2- [2- (3-三氟甲基-苯基） -乙酰氨基] -丙酸 mp: 172- 173°C。 MS [M]+=552.2m/e. 'H-NMR (400MHz, DMS0-d 6 ) δ 12. 78 (brs, 1H), 8. 45 (d, 1H: J = 8. 2Hz), 7. 91-7. 90 (m, 2H), 7. 58-7. 47 (m, 5H), 7. 34-7. 32 (d, 2H, J = 8.8 Hz), 7. 09-7. 06 (d, 2H, J = 8.5 Hz) , 4. 37 (m, 1H), 4. 16 (t, 2H, J = 6.6 Hz), 3. 50 (q, 2H), 3. 01-2. 75 (m. 4H), 2. 36 (s, 3H). Example 14: (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (3-trifluoromethyl-phenyl) -acetamido] -propionic acid was prepared by a method similar to that in Example 1, and 3- (4-methoxy-phenyl) -propionic acid was replaced therein. Is 2- (3-trifluoromethyl-phenyl) -acetic acid to give (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole) as a white solid -4 -yl group) -ethoxy group -phenyl group} -2- [2- (3-trifluoromethyl-phenyl) -acetylamino] -propionic acid mp: 172-173 ° C. MS [M] + = 552.2m / e.
'H-N R (400MHz, DMS0-d6) δ 12.59 (brs, 1H)， 8.39 (d, 1H J=8.1Hz), 7.93 - 7.90 (m， 2H) , 7.55 - 7.36 (m， 7H) , 7.07 - 7.05 (d， 2H)， 6.78 - 6.76 (d, 2H, J=8.7Hz) , 4.38 (m, 1H), 4.17 (t， 3H, J=6.6Hz), 3.52 (m, 2H) , 3.01 - 2.77 (m, 4H) , 2.36 (s， 3H)。 实施例 15: (2S) -2- [2- (2, 3-二氟-苯基） -乙酰氨 基] -3- {4- [2- (5-甲基- 2 -苯基 -1， 3-p恶唑 -4-基) -乙氧基] -苯基 } - 丙酸 'HN R (400MHz, DMS0-d 6 ) δ 12.59 (brs, 1H), 8.39 (d, 1H J = 8.1Hz), 7.93-7.90 (m, 2H), 7.55-7.36 (m, 7H), 7.07- 7.05 (d, 2H), 6.78-6.76 (d, 2H, J = 8.7Hz), 4.38 (m, 1H), 4.17 (t, 3H, J = 6.6Hz), 3.52 (m, 2H), 3.01-2.77 (m, 4H), 2.36 (s, 3H). Example 15: (2S) -2- [2- (2,3-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-poxazole-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-(2, 3-二氟-苯基） -乙酸， 得白色固体状 (2S) -2- [2- (2, 3-二氟-苯基） -乙酰氨基] -3- {4- [2- (5-甲基- 2- 苯基- 1， 3- p恶唑- 4-基）-乙氧基] -苯基 }-丙酸， mp: 179-180°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2, 3-difluoro-phenyl) -acetic acid to obtain a white solid (2S) -2- [2- (2, 3-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl- 2-phenyl-1, 3-p-oxazine Azole-4-yl) -ethoxy] -phenyl} -propionic acid, mp: 179-180 ° C.
MS [M] +=520.2m/e. MS [M] + = 520.2m / e.
'H-NMR (400MHz, DMS0- ) δ 12.60 (brs, 1H) , 8.34 (d， 1H: J=8.1Hz), 7.93 - 7.90 (m， 2H) , 7.51 ― 7.47 (m, 3H)， 7.22 - 6.95 (m, 5H)， 6.89 - 6.81(d, 1H)， 4.38 (m, 1H)， 4.18 (t, 2H， J=6.6Hz)， 2.51 (s, 2H) , 3.02 - 2.77 (m, 4H) , 2.36 (s， 'H-NMR (400MHz, DMS0-) δ 12.60 (brs, 1H), 8.34 (d, 1H: J = 8.1Hz), 7.93-7.90 (m, 2H), 7.51 ― 7.47 (m, 3H), 7.22- 6.95 (m, 5H), 6.89-6.81 (d, 1H), 4.38 (m, 1H), 4.18 (t, 2H, J = 6.6Hz), 2.51 (s, 2H), 3.02-2.77 (m, 4H) , 2.36 (s,
3H)。 实施例 16 : (2S) -2- [2- (3, 4-二氟-苯基）-乙酰氨 基] -3- {4- [2- (5-甲基 -2-苯基- 1， 3-喁唑 -4-基)-乙氧基] -苯基 } - 丙酸 3H). Example 16: (2S) -2- [2- (3,4-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3-(4-甲氧基-苯 基）-丙酸替换为 2- (3， 4 -二氟-苯基）-乙酸， 得白色固体状 (2S) -2- [2- (3， 4-二氟-苯基） -乙酰氨基] -3- {4- [2- (5-甲基 -2- 苯基 -1， 3 -噁唑 -4-基） -乙氧基] -苯基 }-丙酸， mp: 172-173°C。 MS [M] +=520.3m/e. Using a preparation method similar to that in Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (3,4-difluoro-phenyl) -acetic acid to obtain a white solid (2S) -2- [2- (3,4-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid, mp: 172-173 ° C. MS [M] + = 520.3m / e.
aH-NMR (400MHz, DMS0-d6) δ 12.71(brs, 1H), 8.26(d, 1H， J=8.3Hz)? 7.92 - 7.90 (m, 2H)， 7.52 ― 7.46 (m, 3H) , 7.30 - 7.14 (m, 2H), 7.07 - 7.05 (d, 1H, J=8.60Hz), 6.97 - 6.77 (d, 2H, J=8.8Hz) , 4.37 - 4.34 (m， 1H) , 4.16 (t, 2H， J=6.6Hz) ,aH-NMR (400MHz, DMS0-d 6 ) δ 12.71 (brs, 1H), 8.26 (d, 1H, J = 8.3Hz) ? 7.92-7.90 (m, 2H), 7.52 ― 7.46 (m, 3H), 7.30 -7.14 (m, 2H), 7.07-7.05 (d, 1H, J = 8.60Hz), 6.97-6.77 (d, 2H, J = 8.8Hz), 4.37-4.34 (m, 1H), 4.16 (t, 2H , J = 6.6Hz),
3.41(q, 2H, J=4.3Hz) , 3.01 - 2.89 (ra, 3H) , 2.81 - 2.75 (m, 1H)， 2.35 (s, 3H)。 实施例 17: (2S) - 3-{4-[2-(5-甲基- 2-苯基 -1，3-喁唑- 4- 基) -乙氧基] -苯基 } -2-苯基-乙酰氨基-丙酸 3.41 (q, 2H, J = 4.3Hz), 3.01-2.89 (ra, 3H), 2.81-2.75 (m, 1H), 2.35 (s, 3H). Example 17: (2S)-3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- Phenyl-acetamino-propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基) -丙酸替换为 2-苯基 -乙酸（购自北京化学试剂公司） ， 得白 色固体状（2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-"恶唑 -4-基） -乙氧 基] -苯基 }- 2-苯基 -乙酰氨基-丙酸， mp: 137- 138°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2-phenyl-acetic acid (purchased from Beijing Chemical Reagent Company) to obtain a white solid ( 2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3- "oxazol-4-yl) -ethoxy] -phenyl} -2-phenyl-acetyl Amino-propionic acid, mp: 137-138 ° C.
MS [M]+=484.3ra/e. MS [M] + = 484.3ra / e.
^- MR (400MHz, DMS0-d6) δ 8.23 (d, 1H， J=8.2Hz) , 7.91 (m, 2H)， 7.48 (m， 2H), 7.21 - 7.07 (m, 2H)， 6.79 (ra, 2H) ,^-MR (400MHz, DMS0-d 6 ) δ 8.23 (d, 1H, J = 8.2Hz), 7.91 (m, 2H), 7.48 (m, 2H), 7.21-7.07 (m, 2H), 6.79 (ra , 2H),
4.37 (m， 1H)， 4.18 (t, 2H， J=6.6Hz) , 3.38 (m, 2H)， 3.03 - 2.90 (ra, 3H)， 2.80 (m， 1H) , 2.36 (s, 3H)。 实施例 18: (23)-3-{4-[2-（5-曱基-2-苯基-1，3-喁唑-4- 基)-乙氧基] -苯基 } -2- (2-对甲苯氧基-乙酰氨基) -丙酸 4.37 (m, 1H), 4.18 (t, 2H, J = 6.6Hz), 3.38 (m, 2H), 3.03-2.90 (ra, 3H), 2.80 (m, 1H), 2.36 (s, 3H). Example 18: (23) -3- {4- [2- (5-fluorenyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-p-tolyloxy-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3-(4-甲氧基-苯 基） -丙酸替换为 2-(2-对甲苯氧基）-乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基- 1, 3 恶唑- 4-基） -乙氧基〗 -苯 基 }- 2-(2-对甲苯氧基-乙酰氨基）-丙酸， mp: 163 - 164°C。  Using a preparation method similar to that in Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2-p-tolyloxy) -acetic acid to obtain (2S) -3- {4- [2- (5-Methyl-2-phenyl-1, 3 oxazole-4-yl) -ethoxy] -phenyl} -2- (2-p-tolyloxy- Acetamino) -propionic acid, mp: 163-164 ° C.
MS [M] +=514.2m/e, MS [M] + = 514.2m / e,
aH-NMR (400MHz, DMS0-d6) δ 12.65 (brs, 1H) , 8.06 (d, 1H， J=8.2Hz), 7.92 - 7.90 (m， 2H) , 7.52 - 7.45 (m， 3H) , 7.10 - 7.03 (m, 4H), 6.82 - 6.73 (m, 4H) , 4.49 - 4.36 (ra, 3H)， 4.18 (t, 2H， J=6.6Hz) , 3.05 - 3.00 (m, 1H)， 2.93 - 2.87 (m, 3H), 2.35 (s， 3H), 2.21 (s, 3H)。 实施例 19: (2S)-3-{4- [2-(5-甲基- 2-苯基 -1， 3 恶唑- 4- 基)-乙氧基] -苯基 } -2- [2- (萘 -1-基氧基) -乙酰氨基] -丙酸 aH-NMR (400MHz, DMS0-d 6 ) δ 12.65 (brs, 1H), 8.06 (d, 1H, J = 8.2Hz), 7.92-7.90 (m, 2H), 7.52-7.45 (m, 3H), 7.10-7.03 (m, 4H), 6.82-6.73 (m, 4H), 4.49-4.36 (ra, 3H), 4.18 (t, 2H, J = 6.6Hz), 3.05-3.00 (m, 1H), 2.93-2.87 (m, 3H), 2.35 (s, 3H), 2.21 (s, 3H). Example 19: (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3 oxazole-4-yl) -ethoxy] -phenyl} -2- [ 2- (naphthalene-1-yloxy) -acetylamino] -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-[2- (萘- 1-基氧基）] -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基 -1， 3 恶唑 -4 -基）―乙氧基] -苯 基} -2- [2- (萘- 1 -基氧基） -乙酰氨基] -丙酸， rap: 124 - 126。C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- [2- (naphthalene-1-yloxy)]-acetic acid to obtain white (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3 oxazole-4 -yl) -ethoxy] -phenyl} -2- [2- (Naphthalene-1 -yloxy) -acetamido] -propionic acid, rap: 124-126. C.
MS [M]+=550.2m/e, MS [M] + = 550.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 8.17 (m, 2H)， 7.93 - 7.81 (m, 3H), 7.51 - 7.45 (m， 6H) , 7.36 - 7.29 (m, 1H), 7.13 - 7.10 (ra, 2H)， 6.81 - 6.75 (m, 3H)， 4.76 - 4.65 (m， 2H) , 4.56 - 4.52 (m, 1H), 4.21 (t， 2H, 1=6.6Hz)， 3.09 - 2.89 (m， 4H) , 2.35 (s， 3H), 2.14 (s, 3H)。 实施例 20: (2S)-3-{4- [2- (5-甲基 -2-苯基 -1, 3-p恶唑 -4- 基) -乙氧基〗 -苯基 } -2- [2- (2 -硝基 -苯氧基) -乙酰氨基] -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 8.17 (m, 2H), 7.93-7.81 (m, 3H), 7.51-7.45 (m, 6H), 7.36-7.29 (m, 1H), 7.13-7.10 (ra, 2H), 6.81-6.75 (m, 3H), 4.76-4.65 (m, 2H), 4.56-4.52 (m, 1H), 4.21 (t, 2H, 1 = 6.6Hz), 3.09-2.89 (m , 4H), 2.35 (s, 3H), 2.14 (s, 3H). Example 20: (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-poxazole-4-yl) -ethoxy group-phenyl group -2 -[2- (2-nitro-phenoxy) -acetylamino] -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-(2 -硝基-苯氧基） -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基- 1， 3 恶唑 -4 -基） -乙氧基] -苯 基 }- 2- [2- (2-硝基-苯氧基） -乙酰氨基] -丙酸， mp: 184 - 1860Co Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2-nitro-phenoxy) -acetic acid to obtain a white solid ( 2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3 oxazole-4 -yl) -ethoxy] -phenyl}-2- [2- (2- Nitro-phenoxy) -acetamino] -propionic acid, mp: 184-186 0 C o
MS [M] +=545.2m/e, MS [M] + = 545.2m / e,
aH-NMR (400MHz, DMS0-d6) δ 12.81 (brs, 1H), 8.10 (d, 1H， J=8.2Hz), 7.92— 7.90 (m， 3H) , 7.56— 7.45 (ra, 4H) , 7.12 - 7.03 (m， 4H), 6.83 - 6.82 (m， 2H)， 4.70 (s， 2H)， 4.47 (m， 1H), 4.16 (t， 2H, J=6.6Hz) , 3.06 - 2.76 (m.4H)， 2.36 (s，aH-NMR (400MHz, DMS0-d 6 ) δ 12.81 (brs, 1H), 8.10 (d, 1H, J = 8.2Hz), 7.92— 7.90 (m, 3H), 7.56— 7.45 (ra, 4H), 7.12 -7.03 (m, 4H), 6.83-6.82 (m, 2H), 4.70 (s, 2H), 4.47 (m, 1H), 4.16 (t, 2H, J = 6.6Hz), 3.06-2.76 (m.4H), 2.36 (s,
3H)。 实施例 21: (2S)-2-[2-(3-甲氧基 -苯氧基）-乙酰氨 基] -3- {4- [2- (5-甲基- 2-苯基 -1， 3 -喁唑 -4-基) -乙氧基] -苯基 } - 丙酸 3H). Example 21: (2S) -2- [2- (3-methoxy-phenoxy) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazolyl-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-(3-甲氧基-苯氧基） -乙酸， 得白色固体状 (2S) -2- [2- (3-甲氧基-苯氧基) -乙酰氨基] -3- {4- [2- (5-甲基 -2 -苯基 -1， 3-p恶唑 -4-基） -乙氧基] -苯基 }-丙酸， mp: 137 - 138 Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (3-methoxy-phenoxy) -acetic acid to obtain a white solid (2S) -2- [2- (3-methoxy-phenoxy) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-p Azole-4-yl) -ethoxy] -phenyl} -propionic acid, mp: 137-138
°C。 ° C.
MS [M] +=530.2m/e, MS [M] + = 530.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 12.80 (brs, 1H)， 8.10 (d, 1H, J=8.0Hz), 7.92— 7.90 (m， 2H)， 7.51 - 7.47 (m, 3H) , 7.15 - 7.07 (m， 3H)， 6.81 - 6.79 (d, 2H， J=8.5Hz) , 6.53 - 6.41 (m, 3H), 4.43 (m， 1H), 4.16 (t， 2H, J=6.6Hz)， 3.70 (s, 3H) , 3.04 - 2.90 (m， 4H) , 2.35 (s， 3H)。 实施例 22 : (2S)-2- [2- (4-氟 -苯氧基）-乙酰氨 基] -3- {4- [2- (5-甲基 -2 -苯基 -1， 3-喁唑 -4 -基) -乙氧基] -苯基 } - 丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12.80 (brs, 1H), 8.10 (d, 1H, J = 8.0Hz), 7.92— 7.90 (m, 2H), 7.51-7.47 (m, 3H), 7.15-7.07 (m, 3H), 6.81-6.79 (d, 2H, J = 8.5Hz), 6.53-6.41 (m, 3H), 4.43 (m, 1H), 4.16 (t, 2H, J = 6.6Hz) , 3.70 (s, 3H), 3.04-2.90 (m, 4H), 2.35 (s, 3H). Example 22: (2S) -2- [2- (4-fluoro-phenoxy) -acetylamino] -3- {4- [2- (5-methyl-2 -phenyl-1, 3- Oxazole-4 -yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法， 将其中的 3-(4-甲氧基-苯 基） -丙酸替换为 2-(4-氟-苯氧基）-乙酸， 得白色固体状 (2S) -2- [2- (4-氟-苯氧基)一乙酰氨基] -3- {4- [2- (5-曱基 -2-苯 基- 1， 3- p恶唑 -4 -基） -乙氧基] -苯基 }-丙酸， mp: 132 - 134°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (4-fluoro-phenoxy) -acetic acid to obtain a white solid (2S ) -2- [2- (4-fluoro-phenoxy) monoacetamido] -3- {4- [2- (5-fluorenyl-2-phenyl-1,3-poxazole-4- ) -Ethoxy] -phenyl} -propionic acid, mp: 132-134 ° C.
MS [M]+=518.2m/e, MS [M] + = 518.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 12.60 (brs, 1H) , 8.06 (d, 1H, J=8.2Hz), 7.91 - 7.89 (m, 2H) , 7.51 - 7.46 (m， 3H)， 7.10 一 7.04 (m， 4H)， 6.89 - 6.80 (m, 4H)， 4.50 - 4.43 (ra, 3H) , 4.19 - 4.16 (t， 2H, J=6.6Hz) , 3.06 ― 2.87 (m, 4Hz)， 2.34 (s， 3H)。 实施例 23: (2S)- 3- {4- [2- (5-甲基- 2-苯基 -1, 3-喁唑 -4- 基） -乙氧基〗 -苯基 } -2- (2-苯氧基-乙酰氨基） -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12.60 (brs, 1H), 8.06 (d, 1H, J = 8.2Hz), 7.91-7.89 (m, 2H), 7.51-7.46 (m, 3H), 7.10 -7.04 (m, 4H), 6.89-6.80 (m, 4H), 4.50-4.43 (ra, 3H), 4.19-4.16 (t, 2H, J = 6.6Hz), 3.06-2.87 (m, 4Hz), 2.34 (s, 3H). Example 23: (2S)-3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy group -phenyl group -2- ( 2 -phenoxy-acetamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基）-丙 酸替换为 2-苯氧基-乙 酸， 得白 色 固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基 -1， 3-喁唑 -4-基) -乙氧基] -苯 基 } -2- (2-苯氧基 -乙酰氨基） -丙酸， mp: 114 - 116°C；。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2-phenoxy-acetic acid to obtain (2S) -3- {4 as a white solid -[2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-phenoxy-acetylamino) -propane Acid, mp: 114-116 ° C ;.
MS [M]+=500.2m/e, MS [M] + = 500.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 8.09 (d, 1H), 7.89 (m, 2H) , 7.47 (m, 3H), 7.26— 7.20 (m， 2H) , 7.10 (d, 2H) , 6.90 - 6.80 (m， 5H), 4.48 — 4.44 (m, 3H) , 4.16 (t， 2H, J=6.6Hz)， 3.08 一 2.85 (m， 4H), 2.35 (s, 3H)。 实施例 24: (2S) -3- - [2- (5-甲基- 2-苯基- 1, 3-喁唑 -4- 基)-乙氧基] -苯基 } -2- [2- (4-硝基-苯氧基-乙酰氨基) -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 8.09 (d, 1H), 7.89 (m, 2H), 7.47 (m, 3H), 7.26— 7.20 (m, 2H), 7.10 (d, 2H), 6.90-6.80 (m, 5H), 4.48 — 4.44 (m, 3H), 4.16 (t, 2H, J = 6.6Hz), 3.08-2.85 (m, 4H), 2.35 (s, 3H). Example 24: (2S) -3--[2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2 -(4-nitro-phenoxy-acetamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基- 苯基） -丙酸替换为 2-（4-硝基-苯氧基） -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-曱基- 2-苯基 -1, 3 -喁唑 -4-基) -乙氧基] -苯 基 }-2- [2-(4-硝基-苯氧基 -乙酰氨基） -丙酸， mp: 181 - 182°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (4-nitro-phenoxy) -acetic acid to obtain a white solid ( 2S) -3- {4- [2- (5-fluorenyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (4 -Nitro-phenoxy-acetylamino) -propionic acid, mp: 181-182 ° C.
MS [M] +=545.2m/e, MS [M] + = 545.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 8.36 (d, 1H， J=8.2Hz) , 8.16 - 8.14 (d, 2H)， 7.91 - 7.89 (m, 2H) , 7.51 - 7.46 (m, 3H) , 7.10 (d, 2H), 7.01 (d, 2H, J=9.2Hz) , 7.00 - 6.80 (d, 2H) , 4.65 (s， 2H)， 4.46 (m, 1H) , 4.15 (t, 2H， J=6.6Hz) , 3.08 - 2.93 (m, 3H), 2.35 (s， 3H)。 实施例 25: (23)-3-{4-[2-（5-甲基-2-苯基-1，3-喁唑-4- 基) -乙氧基] -苯基 } -2- (2-邻甲苯氧基-乙酰氨基） -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 8.36 (d, 1H, J = 8.2Hz), 8.16-8.14 (d, 2H), 7.91-7.89 (m, 2H), 7.51-7.46 (m, 3H ), 7.10 (d, 2H), 7.01 (d, 2H, J = 9.2Hz), 7.00-6.80 (d, 2H), 4.65 (s, 2H), 4.46 (m, 1H), 4.15 (t, 2H, J = 6.6Hz), 3.08-2.93 (m, 3H), 2.35 (s, 3H). Example 25: (23) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o-tolyloxy-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-(2-邻甲苯氧基）-乙酸， 得白色固体状 (2S) -3- {4- [2- (5-曱基 -2 -苯基 -1， 3 -噁唑 -4-基) -乙氧基] -苯 基 }-2-(2-邻甲苯氧基-乙酰氨基）-丙酸， mp: 192 - 194° ( 。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (2-o-tolyloxy) -acetic acid to obtain a white solid (2S) -3- {4- [2- (5-fluorenyl-2 -phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o-tolyloxy -Acetamino) -propionic acid, mp: 192-194 ° (.
MS [M]+=514.2m/e， MS [M] + = 514.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 12.87 (brs， 1H)， 7.96 - 7.90 (m, 3H), 7.50 - 7.48 (ra, 3H) , 7.10 - 7.03 (m， 4H)， 6.84 一 6.81 (m, 3H), 6.71 - 6.69 (m, 1H)， 4.51 - 4.41 (m, 3H) , 4.19 - 4.16 (t, 2H, J=6.6Hz)， 3.06 - 2.90 (m， 4H) , 2.35 (s， 3H) , 2.13 (s, 3H)。 实施例 26: (2S)- 3- {4- [2- (5-甲基- 2-苯基- 1， 3-喁唑- 4- 基)-乙氧基] -苯基 } -2- [2- (萘 -2-基氧) -乙酰氨基] -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12.87 (brs, 1H), 7.96-7.90 (m, 3H), 7.50-7.48 (ra, 3H), 7.10-7.03 (m, 4H), 6.84-6.81 (m, 3H), 6.71-6.69 (m, 1H), 4.51-4.41 (m, 3H), 4.19-4.16 (t, 2H, J = 6.6Hz), 3.06-2.90 (m, 4H), 2.35 (s , 3H), 2.13 (s, 3H). Example 26: (2S)-3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (naphthalene-2-yloxy) -acetylamino] -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2- [2- (萘 -2-基氧）] -乙酸， 得白色固体状 (2S) -3- {4- [2- (5-甲基- 2-苯基- 1， 3-喁唑- 4-基） -乙氧基] -苯 基} -2- [2- (萘- 2-基氧） -乙酰氨基〗-丙酸， mp: 183 - 185°C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- [2- (naphthalene-2-yloxy)]-acetic acid to obtain a white solid (2S) -3- {4- [2- (5-Methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (Naphthalene-2-yloxy) -acetamino acid-propionic acid, mp: 183-185 ° C.
MS [M]+=550.4m/e, MS [M] + = 550.4m / e,
'H-NMR (400MHz, DMS0-d6) δ 12.81 (brs, 1H)， 8.22-8.20 (d, 1H， J=8.0Hz), 7.93— 7.91 (d, 2H， J=6.4Hz) , 7.84 - 7.82 (d, 2H, J=8.0Hz) , 7.74 - 7.72 (d, 2H, J=8.0Hz) , 7.51— 7.43 (m, 4H), 7.36 - 7.32 (t， 1H)， 7.22 - 7.20 (d, 2H， J=8.8Hz) , 7.10— 7.08 (d, 2H， J=8.4Hz) , 6.79— 6.73 (d, 2H, J=8.4Hz) , 4.61 (s， 2H)， 4.51 (m, 1H)， 4.12 (t， 2H, J=6.6Hz) , 3.07 - 2.89 (m, 4H), 2.35 (s， 3H)。 实施例 27 : (2S)- 2 - [2- (4-氯-苯硫基）-乙酰氨 基] -3- {4- [2- (5-甲基 -2 -苯基 -1， 3-喁唑 -4-基) -乙氧基] -苯基 } - 丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12.81 (brs, 1H), 8.22-8.20 (d, 1H, J = 8.0Hz), 7.93— 7.91 (d, 2H, J = 6.4Hz), 7.84- 7.82 (d, 2H, J = 8.0Hz), 7.74-7.72 (d, 2H, J = 8.0Hz), 7.51- 7.43 (m, 4H), 7.36-7.32 (t, 1H), 7.22-7.20 (d, 2H, J = 8.8Hz), 7.10—7.08 (d, 2H, J = 8.4Hz), 6.79— 6.73 (d, 2H, J = 8.4Hz), 4.61 (s, 2H), 4.51 (m, 1H), 4.12 (t, 2H, J = 6.6Hz), 3.07-2.89 (m, 4H), 2.35 (s, 3H). Example 27: (2S)-2-[2- (4-chloro-phenylthio) -acetylamino] -3- {4- [2- (5-methyl-2 -phenyl-1, 3- Oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3- (4-甲氧基-苯 基） -丙酸替换为 2-（4-氯-苯硫基） -乙酸， 得白色固体状 (2S) -2- [2- (4-氯-苯硫基） -乙酰氨基] -3- {4- [2- (5-甲基- 2-苯 基- 1， 3-噁唑 -4-基） -乙氧基] -苯基 }-丙酸， mp: 164 - 166。C。  Using a preparation method similar to Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (4-chloro-phenylthio) -acetic acid to obtain a white solid (2S ) -2- [2- (4-Chloro-phenylthio) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl ) -Ethoxy] -phenyl} -propionic acid, mp: 164-166. C.
MS [M] += 550.2m/e, MS [M] + = 550.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 8.03 (d, 1H) , 7.91 ― 7.90 (m, 2H), 7.49 一 7.48 (m， 3H) , 7.30 - 7.27 (m， 4H) , 7.02 — 7.00 (d, 2H， J=8.8Hz), 6.75 — 6.73 (d, 2H, J=8.2Hz) , 4.20 一 4.13 (m， 3H), 3.01 - 2.81 (m， 4H) , 2.35 (s, 3H)。 实施例 28: (2S)-2-[2-(4-甲氧基 -苯硫基）-乙酰氨 基] -3- {4- [2- (5-甲基 -2-苯基 -1， 3 -喁唑 -4-基)-乙氧基] -苯基 } - 丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 8.03 (d, 1H), 7.91 ― 7.90 (m, 2H), 7.49-7.48 (m, 3H), 7.30-7.27 (m, 4H), 7.02 — 7.00 (d, 2H, J = 8.8Hz), 6.75 — 6.73 (d, 2H, J = 8.2Hz), 4.20-4.13 (m, 3H), 3.01-2.81 (m, 4H), 2.35 (s, 3H). Example 28: (2S) -2- [2- (4-methoxy-phenylthio) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazolyl-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法，将其中的 3-(4-甲氧基-苯 基） -丙酸替换为 2- (4-甲氧基 -苯硫基）-乙酸， 得白色固体状 (2S) -2- [2- (4-甲氧基-苯硫基） -乙酰氨基 ] -3- {4- [2- (5-甲基 - 2-苯基- 1， 3-噁唑 -4-基）-乙氧基] -苯基 }-丙酸， mp: 156 - 158 Using a preparation method similar to that in Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (4-methoxy-phenylthio) -acetic acid to obtain a white solid (2S) -2- [2- (4-methoxy-phenylthio) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid, mp: 156-158
。C。 . C.
MS [M]+= 546.2ra/e, MS [M] + = 546.2ra / e,
^-NMR (400MHz, DMS0-d6) δ 12.71 (brs, 1H) , 8.28 (d, 1H, J=8.0Hz) , 7.92— 7.90 (m， 2H) , 7.52— 7.47 (m， 3H)， 7.17 - 7.13 (m, 1H)， 7.07 — 7.05 (m， 2H) ,■ 6.87 - 6.70 (m， 5H)， 4.71 (m, 1H), 4.14 (m, 1H) , 3.70 (s， 3H) , 3.65 (s， 2H)， 2.98 - 2.78 (m， 4H), 2.35 (s， 3H)。 实施例 29: (2S)-2-[2-(8-氯-萘- 1-基硫基） -乙酰氨 基] -3- {4~ [2- (5-甲基 -2 -苯基 -1， 3-噁唑 -4-基) -乙氧基] -苯基 } - 丙酸 ^ -NMR (400MHz, DMS0-d 6 ) δ 12.71 (brs, 1H), 8.28 (d, 1H, J = 8.0Hz), 7.92— 7.90 (m, 2H), 7.52— 7.47 (m, 3H), 7.17 -7.13 (m, 1H), 7.07 — 7.05 (m, 2H), ■ 6.87-6.70 (m, 5H), 4.71 (m, 1H), 4.14 (m, 1H), 3.70 (s, 3H), 3.65 ( s, 2H), 2.98-2.78 (m, 4H), 2.35 (s, 3H). Example 29: (2S) -2- [2- (8-chloro-naphthalene-1-ylthio) -acetylamino] -3- {4 ~ [2- (5-methyl-2 -phenyl- 1,3-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid
采用与实施例 1类似的制备方法， 将其中的 3-(4-甲氧基-苯 基） -丙酸替换为 2-（8-氯-萘 -1 -基硫基） -乙酸， 得白色固体状 (2S) -2- [2- (8-氯-蔡 -1-基硫基)一乙酰氨基] -3- {4- [2- (5-甲基 -2-苯基- 1， 3-p恶唑 -4-基）-乙氧基] -苯基 }-丙酸， mp: 138 - 140 Using a preparation method similar to that in Example 1, replacing 3- (4-methoxy-phenyl) -propionic acid with 2- (8-chloro-naphthalene-1 -ylthio) -acetic acid to obtain white (2S) -2- [2- (8-chloro-Cai-1-ylthio) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-poxazole-4-yl) -ethoxy] -phenyl} -propionic acid, mp: 138-140
。C。 . C.
MS [M] += 600.2m/e, MS [M] + = 600.2m / e,
'H-NMR (400MHz, DMS0-d6) δ 12.70 (brs, 1H), 8.36 (d, 1H, J=8.0Hz), 7.92 - 7.85 (m， 3H) , 7.72 (d, 1H, J=7.8Hz) , 7.60 (d, 1H, J=7.3Hz) , 7.52 - 7.33 (m， 6H)， 7.06 - 7.04 (d, 2H， 8.5Hz), 6.75 — 6.73 (d， 2H, J=8.5Hz) , 4.43 — 4.38 (ra, 1H)， 4.14 (t， 2H, J=6.5Hz), 3.73 (s, 2H)， 2.99 - 2.79 (m, 4H)， 2.35 (s， 3H)。 实施例 30: (2S)- 3- {3-溴- 4- [2- (5 -甲基 -2-苯基- 1, 3-P恶唑 -4-基) -乙氧基] -苯基 } -2- [2- (2-甲氧基-苯基) -乙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的中间体 3 A替换为 中间体 3B, 3- (4-甲氧基-苯基) -丙酸替换为 2- (2-甲基-苯基) - 乙酸 （购自北京化学试剂公司） ， 得白色固体状（2S)-3-{3 -溴 -4- [2- (5-甲基 -2-苯基 -1， 3-喁唑- 4-基） -乙氧基] -苯 基 }-2-[2-（2-甲氧基 -苯基）-乙酰氨基] -丙酸， mp: 194-195°C。 'H-NMR (400MHz, DMS0-d 6 ) δ 12.70 (brs, 1H), 8.36 (d, 1H, J = 8.0Hz), 7.92-7.85 (m, 3H), 7.72 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 7.3Hz), 7.52-7.33 (m, 6H), 7.06-7.04 (d, 2H, 8.5Hz), 6.75 — 6.73 (d, 2H, J = 8.5Hz), 4.43 — 4.38 (ra, 1H), 4.14 (t, 2H, J = 6.5Hz), 3.73 (s, 2H), 2.99-2.79 (m, 4H), 2.35 (s, 3H). Example 30: (2S)-3- {3-bromo- 4- [2- (5-methyl-2-phenyl-1, 3-Poxazol-4-yl) -ethoxy] -benzene Group} -2- [2- (2-methoxy-phenyl) -acetamino] -propionic acid Using a preparation method similar to that in Example 1, the intermediate 3 A was replaced by the intermediate 3B, 3- (4-methoxy-phenyl) -propionic acid was replaced with 2- (2-methyl-phenyl) -acetic acid (purchased from Beijing Chemical Reagent Company) to obtain (2S) -3- {3-as a white solid Bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (2-methoxy -Phenyl) -acetylamino] -propionic acid, mp: 194-195 ° C.
MS [M] +=592.2m/e. MS [M] + = 592.2m / e.
2H-NMR (400MHz,DMSO) δ 12.76 (brs, 1H) , 8.08 (d, 1H, J=8.0Hz), 7.93 - 7.91 (ra, 2H) , 7.53 - 7.48 (m, 3H) , 7.41 - 7.40(s, 1H)， 7.15 - 7.10 (ra, 2H) , 7.03 - 6.73 (m, 6H)， 4.40 (m, 1H)， 4.25 (t, 2H， J=6.6Hz) , 3.63(s, 3H) , 3.35 (s, 2H)， 3.02 - 2.75 (m, 4H), 2.39 (s, 3H)。 实施例 31: (23)-3-{3-溴-4-[2-（5-甲基-2-苯基-1， 3 -喁唑 -4-基） -乙氧基] -苯基 } -2-苯基乙酰氨基-丙酸 2 H-NMR (400MHz, DMSO) δ 12.76 (brs, 1H), 8.08 (d, 1H, J = 8.0Hz), 7.93-7.91 (ra, 2H), 7.53-7.48 (m, 3H), 7.41-7.40 (s, 1H), 7.15-7.10 (ra, 2H), 7.03-6.73 (m, 6H), 4.40 (m, 1H), 4.25 (t, 2H, J = 6.6Hz), 3.63 (s, 3H), 3.35 (s, 2H), 3.02-2.75 (m, 4H), 2.39 (s, 3H). Example 31: (23) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl } -2-phenylacetamino-propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B, 3- (4-甲氧基-苯基) -丙酸替换为 2-苯基 -乙酸（购自 北京化学试剂公司），得白色固体状（2S)-3-{3-溴 -4-[2-(5-甲基 -2-苯基- 1， 3 -喁唑 -4-基） -乙氧基] -苯基 } -2 -苯基乙酰氨基-丙 酸， mp: 189-190。C。  Using a preparation method similar to Example 1, the intermediate 3A was replaced by intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced by 2-phenyl-acetic acid (purchased from Beijing Chemical Reagent Company) to obtain (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy as a white solid ] -Phenyl} -2-phenylacetamido-propionic acid, mp: 189-190. C.
MS [M] +=563.2m/e，MS [M] + = 563.2m / e,
H-NMR (400MHz, DMS0-d6) δ 12.74(brs, 1H) , 8.20 (d, 1H， J=8.0), 7.93(m, 2H) , 7.52 - 7.46 (ra, 3H) , 7.40 - 7.39 (m, 1H), 7.20 - 7.07 (m, 6H) , 6.99 - 6.97 (d, 1H, J=8.5Hz), 4.38 一 4.33 (m, 1H), 4.25(t, 2H， J=6.3Hz)， 3.41(q, 2H)， 3.02 - 2.93(m, 3H), 2.80 - 2.75 (m, 1H) , 2.38 (s, 3H)。 实施例 32: (23)-3-{3-溴-4-[2-(5-甲基-2-苯基-1，3-喁唑 - 4 -基) -乙氧基] -苯基 } -2- [3- (4-甲氧基-苯基) -丙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3- (4-甲氧基 -苯基)-丙酸替换为（4-甲氧基-苯基）丙 酸，得白色固体状（2S) -3- {3-溴 -4- [2- (5-甲基- 2-苯基 -1, 3-"恶唑 -4 -基) -乙氧基〗 -苯基 } -2_ [ 3- (4 -甲氧基-苯基） 丙酰氨基] -丙 酸， mp: 195-196C。 H-NMR (400MHz, DMS0-d 6 ) δ 12.74 (brs, 1H), 8.20 (d, 1H, J = 8.0), 7.93 (m, 2H), 7.52-7.46 (ra, 3H), 7.40-7.39 ( m, 1H), 7.20-7.07 (m, 6H), 6.99-6.97 (d, 1H, J = 8.5Hz), 4.38-4.33 (m, 1H), 4.25 (t, 2H, J = 6.3Hz), 3.41 (q, 2H), 3.02-2.93 (m, 3H), 2.80-2.75 (m, 1H), 2.38 (s, 3H). Example 32: (23) -3- {3-Bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl } -2- [3- (4-methoxy-phenyl) -propionamido] -propionic acid was prepared by a method similar to that in Example 1, and intermediate 3A was replaced by intermediate 3B, 3- ( 4-methoxy-phenyl) -propionic acid was replaced with (4-methoxy-phenyl) propionic acid to obtain (2S) -3- {3-bromo-4- [2- (5- Methyl-2-phenyl-1,3- "oxazole- 4 -yl) -ethoxy〗 -phenyl} -2 _ [3- (4-methoxy-phenyl) propionamido]- Propionic acid, mp: 195-196C.
MS [M] +=608. Om/e. MS [M] + = 608. Om / e.
'H-NMR (400MHz, DMS0-d6) δ 12.60(s, 1H)， 8.08 (d, 1H, J=7.9Hz), 7.91 - 7.90 (m, 2H) , 7.50 - 7.46 (m, 3H) , 7.40(s, 1H, J=2.0Hz) , 7.13 - 7. ll(m, 1H)， 7.02 (d, 3H, J=7.3Hz) , 6.77 (d, 2H， J=8.8Hz) , 4.41 - 4.35 (m, 1H)， 4.25 (t, 2H, J=6.2Hz), 3.70(s, 3H), 2.99 - 2.92 (m, 3H) , 2.78 — 2.73 (m， 1H), 2.67 (t, 2H, J=7.6Hz) , 2.36 - 2.29 (m, 5H)。 实施例 33: (2S)-3-{3-溴 -4- [2-（5-曱基 -2-苯基 -1, 3-p恶唑'H-NMR (400MHz, DMS0-d 6 ) δ 12.60 (s, 1H), 8.08 (d, 1H, J = 7.9Hz), 7.91-7.90 (m, 2H), 7.50-7.46 (m, 3H), 7.40 (s, 1H, J = 2.0Hz), 7.13-7. ll (m, 1H), 7.02 (d, 3H, J = 7.3Hz), 6.77 (d, 2H, J = 8.8Hz), 4.41-4.35 (m, 1H), 4.25 (t, 2H, J = 6.2Hz), 3.70 (s, 3H), 2.99-2.92 (m, 3H), 2.78 — 2.73 (m, 1H), 2.67 (t, 2H, J = 7.6Hz), 2.36-2.29 (m, 5H). Example 33: (2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1, 3-poxazole
- 4-基) -乙氧基〗 -苯基 } - (3-苯基-丙酰氨基) -丙酸 -4-yl) -ethoxy〗 -phenyl}-(3-phenyl-propionamido) -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3- (4-甲氧基 -苯基)-丙酸替换为 3-苯基-丙酸（购自 北京化学试剂公司），得白色固体状（2S)- 3-{3-渙 -4-[2-（5-甲基 -2-苯基- 1， 3-喁唑 -4-基) -乙氧基] -苯基 } - (3-苯基 -丙酰氨基) - 丙酸， mp: 190-191°Co Using a preparation method similar to Example 1, the intermediate 3A was replaced with intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced with 3-phenyl-propionic acid (purchased from Beijing). Chemical Reagents Co., Ltd.), (2S) -3- {3-fluoren-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy as a white solid [] Phenyl]-(3-phenyl-propionamido)-propionic acid, mp: 190-191 ° C o
MS [M] +=578. Om/e. MS [M] + = 578. Om / e.
^-NMR (400MHz, DMS0-d6) δ 8.15 (d, 1H， J=8.1Hz) , 7.92^ -NMR (400MHz, DMS0-d 6 ) δ 8.15 (d, 1H, J = 8.1Hz), 7.92
- 7.90(m, 2H)， 7.50― 7.48 (m, 3H)， 7.22 - 7.13 (m， 2H)， 7.13 - 7.07 (m, 5H)， 6.81 (d, 2H, J=8.4Hz) , 4.37 - 4.35 (m, 1H) , 4.15 (t, 2H, J=6.5Hz)， 3.59 (t, 1H, J=6.5Hz)， 2.93 - 2.89 (m, 3H)， 2.73 - 2.69 (m, 2H)， 2.38 - 2.35 (m， 5H)。 实施例 34: (2S)- 3- {3-溴 -4- [2- (5-甲基- 2-苯基 -1， 3-喁唑-7.90 (m, 2H), 7.50― 7.48 (m, 3H), 7.22-7.13 (m, 2H), 7.13-7.07 (m, 5H), 6.81 (d, 2H, J = 8.4Hz), 4.37-4.35 (m, 1H), 4.15 (t, 2H, J = 6.5Hz), 3.59 (t, 1H, J = 6.5Hz), 2.93-2.89 (m, 3H), 2.73-2.69 (m, 2H), 2.38- 2.35 (m, 5H). Example 34: (2S)-3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazole
- 4 -基) -乙氧基] -苯基 } - 2- [ 3- (2-甲氧基-苯基) -丙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3-(4-曱氧基-苯基) -丙酸替换为 3- (2-甲氧基-苯基) - 丙酸， 得白色固体状（2S)-3-{3-溴 -4-[2-（5-曱基- 2-苯基- 1, 3- 喵唑- 4-基) -乙氧基] -苯基 } -2- [ 3- (2-甲氧基-苯基) -丙酰氨基] - 丙酸， mp: 178-180°C。 -4 -yl) -ethoxy] -phenyl}-2- [3- (2-methoxy-phenyl) -propionamido] -propanoic acid was prepared in a similar manner to that in Example 1, where Intermediate 3A was replaced by Intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced by 3- (2-methoxy-phenyl) -propionic acid to obtain a white solid (2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1,3-methylazole-4-yl) -ethoxy] -phenyl} -2- [3- (2-methoxy-phenyl) -propionamido] -propionic acid, mp: 178-180 ° C.
MS [M]+=608. Om/e. MS [M] + = 608. Om / e.
JH-NMR (400MHz, DMSO-d6) δ 12.60(s, 1H) , 8.05 (d, 1H， J=8.0Hz), 7.91-7.89 (m, 2H)， 7.51 - 7.46 (m, 3H) , 7.41 - 7.39 (m, 1H)， 7.17 - 7.00 (m, 4H) , 6.92 - 6.90 (m, 1H)， 6.80 J H-NMR (400MHz, DMSO-d 6 ) δ 12.60 (s, 1H), 8.05 (d, 1H, J = 8.0Hz), 7.91-7.89 (m, 2H), 7.51-7.46 (m, 3H), 7.41- 7.39 (m, 1H), 7.17-7.00 (m, 4H), 6.92-6.90 (m, 1H), 6.80
- 6.77 (m, 1H), 4.40 - 4.34 (m, 1H) , 4.23(t, 2H, J=6.3Hz) ,-6.77 (m, 1H), 4.40-4.34 (m, 1H), 4.23 (t, 2H, J = 6.3Hz),
3.74 (s, 3H)， 2.98 - 2.92 (m, 3H) , 2.79 — 2.64 (m， 3H) , 2.36 ― 2.28 (m, 5H)。 实施例 35: (2S) -3- {3-溴 -4- [2- (5-甲基 -2-苯基- 1， 3-噁唑 -4-基) -乙氧基] -苯基 } -2- [3- (3-甲氧基-苯基) -丙酰氨基] -丙酸 采用与实施例 1类似的制备方法，将其中的中间体 3 A替换为 中间体 3B， 3- (4-甲氧基-苯基)-丙酸替换为 3-(3-曱氧基-苯基) - 丙酸，得白色固体（2S) -3- {3-溴- 4- [2- (5-甲基- 2-苯基 -1， 3 -喁唑 - 4 -基） -乙氧基] -苯基 } -2- [ 3- (3-甲氧基-苯基） -丙酰氨基〗 -丙 酸， rap: 195-196°C0 3.74 (s, 3H), 2.98-2.92 (m, 3H), 2.79 — 2.64 (m, 3H), 2.36 ― 2.28 (m, 5H). Example 35: (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl } -2- [3- (3-methoxy-phenyl) -propionamido] -propionic acid was prepared in a manner similar to that in Example 1, and intermediate 3 A was replaced by intermediate 3B, 3- (4-methoxy-phenyl) -propionic acid was replaced with 3- (3-methoxy-phenyl) -propionic acid to obtain (2S) -3- {3-bromo-4- [2- (5-methyl- 2-phenyl-1, 3-oxazole-4 -yl) -ethoxy] -phenyl} -2- [3- (3-methoxy-phenyl) -propionyl Amino-propionic acid, rap: 195-196 ° C 0
MS [M]+=608. Om/e. MS [M] + = 608. Om / e.
!H-NMR (400MHz, DMS0-d6) δ 12.62(s, 1H), 8.01 (d, 1H, J=8.0Hz), 7.91 - 7.89 (m, 2H) , 7.51 - 7.46(m, 3H) , 7.40 (d, 1H, J=2.0Hz) , 7.14 - 7.10 (m, 2H) , 7.01 (d, 1H, J=8.5Hz) , 6.72 一 6.68(m， 3H), 4.41 - 4.36 (m, 1H)， 4.23(t, 2H, J=6.5Hz) , 3.69 (s, 3H), 2.86 - 2.92 (ra, 3H) , 3.00 - 2.92 (m, 3H)， 2.79 一 2.67 (m， 3H), 2.37 ― 2.33 (m, 5H)。 实施例 36: (2S)- 3-{3-溴- 4- [2- (5-甲基- 2-苯基 -1， 3-喁唑 -4 -基) -乙氧基] -苯基 } -2- [3- (4-三氟甲基-苯基) -丙酰氨基] -丙 酸 ! H-NMR (400MHz, DMS0-d 6 ) δ 12.62 (s, 1H), 8.01 (d, 1H, J = 8.0Hz), 7.91-7.89 (m, 2H), 7.51-7.46 (m, 3H), 7.40 (d, 1H, J = 2.0Hz), 7.14-7.10 (m, 2H), 7.01 (d, 1H, J = 8.5Hz), 6.72-6.68 (m, 3H), 4.41-4.36 (m, 1H) , 4.23 (t, 2H, J = 6.5Hz), 3.69 (s, 3H), 2.86-2.92 (ra, 3H), 3.00-2.92 (m, 3H), 2.79-2.67 (m, 3H), 2.37-2.33 (m, 5H). Example 36: (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl } -2- [3- ( 4 -trifluoromethyl-phenyl) -propionamido] -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3- (4-甲氧基-苯基) -丙酸替换为 3-(4-三氟甲基-苯 基） -丙酸（购自 Aldrich 公司） ， 得白色固体状（2S)-3-{3-溴 -4- [2- (5-甲基 -2-苯基 -1， 3- p恶唑 -4-基） -乙氧基 ] -苯 基} -2- [ 3- (4-三氟甲基-苯基） -丙酰氨基] -丙酸， mp: 214-216 °C。
Figure imgf000047_0001
Using a preparation method similar to Example 1, the intermediate 3A was replaced by the intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced by 3- ( 4 -trifluoromethyl-benzene ) -Propionic acid (purchased from Aldrich) to obtain (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-poxazole) as a white solid -4-yl) -ethoxy] -phenyl} -2- [3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid, mp: 214-216 ° C.
Figure imgf000047_0001
^-NMR (400MHz, DMSO - d6) δ 12. 74 (s, 1H) , 8. 20 (d, 1H， J=8. 1Hz) , 7. 91 - 7. 89 (m, 2H)， 7. 56 (d, 2H， J=7. 9Hz) , 7. 51 一 7. 47 (m， 3H) , 7. 40 (d, 1H， J=2. 0Hz) , 7. 33 (d, 2H， J=7. 9Hz) , 7. 13 - 7. 11 (ra, H) , 7. 02 (d, 1H, J=8. 5Hz) , 4. 40 - 4. 34 (m, 1H)， 4. 22 (t, 2H, J=6. 5Hz) , 2. 95 - 2. 92 (m, 3H) , 2. 81 - 2. 79 (ra, 3H)， 2. 40 - 2. 37 (m, 5H)。 实施例 37: (2S) -3- {3 -溴- 4- [2- (5-曱基 -2-苯基- 1, 3 -喁唑 -4 -基） -乙氧基] -苯基 } - 2- (2-甲基 -3-苯基 -丙酰氨基) -丙酸 ^ -NMR (400MHz, DMSO-d 6 ) δ 12. 74 (s, 1H), 8. 20 (d, 1H, J = 8.1 Hz), 7. 91-7. 89 (m, 2H), 7 56 (d, 2H, J = 7.9 Hz), 7.51-7.47 (m, 3H), 7.40 (d, 1H, J = 2.0 Hz), 7.33 (d, 2H, J = 7.9 Hz), 7. 13-7. 11 (ra, H), 7. 02 (d, 1H, J = 8.5 Hz), 4. 40-4. 34 (m, 1H), 4. 22 (t, 2H, J = 6.5 Hz), 2. 95-2. 92 (m, 3H), 2. 81-2. 79 (ra, 3H), 2. 40-2. 37 (m, 5H ). Example 37: (2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1,3-oxazole-4-yl) -ethoxy] -phenyl }-2- (2-methyl-3-phenyl-propionamido) -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3 A替换为 中间体 3B， 3- (4-甲氧基 -苯基) -丙酸替换为 2-甲基- 3-苯基-丙 酸，得白色固体状（2S) -3- {3-溴 -4- [2- (5-甲基- 2-苯基- 1, 3- 唑 -4-基） -乙氧基] -苯基 } -2- (2-甲基 -3-苯基-丙酰氨基） -丙酸， mp: 164-166 °C。  Using a preparation method similar to Example 1, the intermediate 3 A was replaced with the intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced with 2-methyl-3-phenyl- Propionic acid to give (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-azole-4-yl) -ethoxy]-as a white solid Phenyl} -2- (2-methyl-3-phenyl-propionamido) -propionic acid, mp: 164-166 ° C.
MS [M] +=592. lm/e. MS [M] + = 592. Lm / e.
'H-NM (400MHz, DMS0-d6) δ 12. 66 (s, 1H)， 8. 00 (d, 1H, J=8. 0Hz) , 7. 91 — 7. 89 (m， 2H) , 7. 50 - 7. 47 (m， 3H) , 7. 40 - 7. 36 (m, H) , 7. 23 - 6. 97 (ra, 7H) , 4. 37 - 4. 35 (m, 1H) , 4. 22 (t, 2H, J=6. 3Hz) , 3. 01 - 2. 89 (m, 3H) , 2. 86 - 2, 75 (m， 2H) , 2. 44 - 2. 36 (m, 5H)， 0. 92 - 0. 82 (m， 3H)。 实施例 38: (28) -3- {3-溴-4- [2- (5-甲基-2-苯基-1， 3-喁唑 -4 -基) -乙氧基] -苯基 } -2- (3-苯基-丁酰氨基) -丙酸 'H-NM (400MHz, DMS0-d 6 ) δ 12. 66 (s, 1H), 8. 00 (d, 1H, J = 8. 0Hz), 7. 91 — 7. 89 (m, 2H), 7. 50-7. 47 (m, 3H), 7. 40-7. 36 (m, H), 7. 23-6. 97 (ra, 7H), 4. 37-4. 35 (m, 1H ), 4. 22 (t, 2H, J = 6.3 Hz), 3. 01-2. 89 (m, 3H), 2. 86-2, 75 (m, 2H), 2. 44-2. 36 (m, 5H), 0.92-0.82 (m, 3H). Example 38: (28) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl } -2- (3-phenyl-butyrylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B, 3-（4 -甲氧基-苯基) -丙酸替换为 3-苯基-丁酸， 得白 色固体状（2S) -3- {3 -渙- 4- [2- (5-甲基 -2-苯基- 1， 3 -喁唑 -4 -基） - 乙氧基] -苯基 } - 2- (3-苯基 -丁酰氨基） -丙酸， mp: 165-167 °C。 MS [M] =592. Ora/e. Using a preparation method similar to that in Example 1, the intermediate 3A was replaced with the intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced with 3-phenyl-butyric acid to obtain a white solid. (2S) -3- {3 -fluorene- 4- [2- (5-methyl-2-phenyl-1,3-oxazole-4 -yl) -ethoxy] -phenyl}-2 -(3-phenyl-butyrylamino) -propionic acid, mp: 165-167 ° C. MS [M] = 592. Ora / e.
'H-NMR (400MHz, DMS0-d6) δ 12.57 (s, 1H), 8.11 - 8.08 (ra: 1H), 7.91 - 7.88 (m, 2H) , 7.50 - 7.46 (m, 3H) , 7.43 - 7.38 (m， 1H), 7.25 - 7.21 (m， 2H)， 7.16 - 6.98 (m, 5H)， 4.38 - 4.35 (m, 1H), 4.23(m, 2H) , 3.06 - 2.89 (ra, 4H)， 2.78 - 2.72 (m, 1H)， 2.36 - 2.23 (m， 5H) , 1.07 - 0.98 (ra, 3H)。 实施例 39: (2S) -3- {3-溴 -4- [2- (5-甲基- 2-苯基 -1， 3-噁唑 - 4-基) -乙氧基] -苯基 } -2- (2-邻甲苯氧基-乙酰氨基) -丙酸 'H-NMR (400MHz, DMS0-d 6 ) δ 12.57 (s, 1H), 8.11-8.08 (ra : 1H), 7.91-7.88 (m, 2H), 7.50-7.46 (m, 3H), 7.43-7.38 (m, 1H), 7.25-7.21 (m, 2H), 7.16-6.98 (m, 5H), 4.38-4.35 (m, 1H), 4.23 (m, 2H), 3.06-2.89 (ra, 4H), 2.78 -2.72 (m, 1H), 2.36-2.23 (m, 5H), 1.07-0.98 (ra, 3H). Example 39: (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazole-4-yl) -ethoxy] -phenyl } -2- (2-o-tolyloxy-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3- (4-甲氧基 -苯基)-丙酸替换为 2-(2-邻甲苯氧基) - 乙酸， 得白色固体状（2S)-3-{3-溴- 4- [2-(5-曱基 -2-苯基- 1， 3- 喁唑- 4-基) -乙氧基] -苯基 } -2- (2-邻甲苯氧基 -乙酰氨基) -丙酸， mp: 202 204°C。 O  Using a preparation method similar to Example 1, the intermediate 3A was replaced by the intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced by 2- (2-o-tolyloxy)- Acetic acid to give (2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1,3-oxazole-4-4-yl) -ethoxy]-as a white solid Phenyl} -2- (2-o-tolyloxy-acetylamino) -propionic acid, mp: 202 204 ° C. O
^-NMR (400MHz, DMS0-d6) δ 12.85 (brs, 1H), 7.97-7.89 (m， 3H), 7.49 - 7.40 (m， 3H) , 7.15 ― 6.99 (m, 4H)， 6.83 - 6.79 (m， 1H), 6.70— 6.68 (d, 1H, J=8.1Hz) , 4.50 - 4.39 (m, 3H)， 4.26 - 4.23 (t， 2H, J=6.6Hz) , 3.05 - 2.92 (m, 4H)， 2.37 (s， 3H), 2.13 (s， 3H)。 实施例 40: (2S) -3- {3-溴 -4- [2- (5-甲基- 2-苯基 -1， 3-p恶唑 -4-基)一乙氧基] -苯基 } -2- (2-苯硫基-乙酰氨基) -丙酸 ^ -NMR (400MHz, DMS0-d 6 ) δ 12.85 (brs, 1H), 7.97-7.89 (m, 3H), 7.49-7.40 (m, 3H), 7.15 ― 6.99 (m, 4H), 6.83-6.79 ( m, 1H), 6.70— 6.68 (d, 1H, J = 8.1Hz), 4.50-4.39 (m, 3H), 4.26-4.23 (t, 2H, J = 6.6Hz), 3.05-2.92 (m, 4H) , 2.37 (s, 3H), 2.13 (s, 3H). Example 40: (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-poxazol-4-yl) monoethoxy] -benzene } -2- (2-phenylthio-acetylamino) -propionic acid
采用与实施例 1类似的制备方法，将其中的中间体 3A替换为 中间体 3B， 3- (4-甲氧基-苯基） -丙酸替换为 2-(2-苯硫基）-乙酸， 得白色固体状（2S)-3-{3-溴 -4-[2-（5-甲基- 2 -苯基 - 1， 3-嗝唑- 4- 基）-乙氧基] -苯基 }-2- (2-苯硫基 -乙酰氨基） -丙酸， mp: 171 - 173°C。 MS [M] +=595. 2m/e, Using a preparation method similar to Example 1, the intermediate 3A was replaced by intermediate 3B, and 3- (4-methoxy-phenyl) -propionic acid was replaced by 2- (2-phenylthio) -acetic acid (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -benzene as a white solid } -2- (2-phenylthio-acetylamino) -propionic acid, mp: 171-173 ° C. MS [M] + = 595. 2m / e,
'H-NMR (400MHz, DMSO-d6) δ 7. 91 - 7. 90 (m， 2H) , 7. 50 一 7. 38 (m, 4H)， 7. 27 — 7. 08 (m， 6H)， 6. 97 一 6. 95 (d, 1H, J=8. 2Hz) , 4. 35 (m, 1H) , 4. 23 (t， 2H, J=6. 6Hz) , 3. 61 (m, 2H)， 3. 01 - 2. 93 (m， 3H) , 3. 01 - 2. 93 (m， 3H) , 2. 82 - 2. 78 (m， 1H) , 2. 38 (s, 3H)。 实施例 41： 激活人 PPAR α和 PPAR γ的活性测定 'H-NMR (400MHz, DMSO-d 6 ) δ 7. 91-7. 90 (m, 2H), 7. 50-7. 38 (m, 4H), 7. 27 — 7. 08 (m, 6H ), 6. 97 to 6. 95 (d, 1H, J = 8.2 Hz), 4. 35 (m, 1H), 4. 23 (t, 2H, J = 6.6 Hz), 3. 61 (m , 2H), 3. 01-2. 93 (m, 3H), 3. 01-2. 93 (m, 3H), 2. 82-2. 78 (m, 1H), 2. 38 (s, 3H ). Example 41: Determination of the activity of activating human PPAR α and PPAR γ
对化合物在 293- Τ细胞中瞬时转染的功能效应进行筛选， 以 测定它们激活 PPAR亚型的能力。采用预先建立嵌合受体系统比较 受体亚型对相同的靶基因转录活性的影响，以 Rluc作为内标减少 内源性影响。将人 PPAR ex和 PPAR γ配体结合域各自与酵母转录因 子 GAL4DNA结合域融合。再连接到哺乳动物的表达载体 pM上，构 建 pM-hPPAR a /GAL4和 pM-PPAR γ /GAL4 两种质粒。 把 GAL4DNA 结合区与 pB4- tk-luc 连接， 构成 PB4-RES- tk-luc (—个含有 GAL4DNA 结合位点的萤火虫荧光素酶的报告基因 ） 。 以 pRL-CMV-Rluc作为内标校正转染效率以及内源性影响。  Functional effects of transient transfection of compounds in 293-T cells were screened to determine their ability to activate PPAR isoforms. A pre-established chimeric receptor system was used to compare the effect of receptor subtypes on the transcriptional activity of the same target genes, and Rluc was used as an internal standard to reduce endogenous effects. The human PPAR ex and PPAR γ ligand binding domains were each fused to the yeast transcription factor GAL4 DNA binding domain. Then it was ligated to mammalian expression vector pM to construct two plasmids, pM-hPPAR a / GAL4 and pM-PPAR γ / GAL4. The GAL4DNA binding region was linked to pB4-tk-luc to form PB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4DNA binding site). PRL-CMV-Rluc was used as an internal standard to correct transfection efficiency and endogenous effects.
将 293-T细胞接种入 48孔板， 细胞密度为 2-4 χ 104个 /孔， 培养液为 10%脱脂胎牛血清 （FCS ) 的无酚红无抗生素的 1640培 养基。 48小时后，将培养液更换为 5%脱脂 FCS的无酚红无抗生素 的 1640 培养基， 然后分别把两种亚型的 pM- hPPAR/GAL4、 pB4- RES-tk- luc和 pRL-CMV-Rluc三种质粒共转染到 293-T细胞 中， 24小时后给药， 给药后 24小时检测荧光素酶的强度。 以 0. 2 %0DMS0作为空白对照。 部分本发明化合物对 PPARa的激动作用（ 10 μΜ)及其 EC 化合物 光子数（ xlO4) 与对照組相比增长的倍数 EC50 ( μΜ ) 对照 2.1 293-T cells were seeded into a 48-well plate with a cell density of 2-4 x 10 4 cells / well and the culture medium was 10% defatted fetal calf serum (FCS) without phenol red and antibiotic-free 1640 medium. After 48 hours, the culture medium was replaced with 5% defatted FCS without phenol red and antibiotic-free 1640 medium, and then two subtypes of pM-hPPAR / GAL4, pB4-RES-tk-luc, and pRL-CMV- The three Rluc plasmids were co-transfected into 293-T cells and administered after 24 hours. The intensity of luciferase was measured 24 hours after administration. 0.2% 0 DMS0 was used as a blank control. The agonistic effect of some of the compounds of the present invention on PPARa (10 μΜ) and the number of photons (xlO 4 ) of the EC compound compared to the control group EC 50 (μΜ) Control 2.1
实施例 3 7.4 3.5 Example 3 7.4 3.5
实施例 6 17.2 8.2 9.15 实施例 7 30 14.3 Example 6 17.2 8.2 9.15 Example 7 30 14.3
实施例 8 8.2 3.9 9.01 实施例 9 26.9 12.8 10.45 实施例 10 23.1 11 11.51 实施例 11 21.7 10.3 Example 8 8.2 3.9 9.01 Example 9 26.9 12.8 10.45 Example 10 23.1 11 11.51 Example 11 21.7 10.3
实施例 14 6.4 3 Example 14 6.4 3
实施例 15 23. δ 11.3 Example 15 23.δ 11.3
实施例 20 9.9 4.7 Example 20 9.9 4.7
实施例 23 17.5 8.3 Example 23 17.5 8.3
实施例 24 19.9 9.5 Example 24 19.9 9.5
实施例 25 16.4 7.8 Example 25 16.4 7.8
实施例 26 12.1 5.8 Example 26 12.1 5.8
实施例 28 4.6 2.2 Example 28 4.6 2.2
部分本发明化合物对 PPAR y的激动作用（ 10 μΜ)及其 EC 化合物 光子数（ χΐο4) 与对照組相比增长的倍数 EC5o (μΜ) 对照 1.4 The agonistic effect of some compounds of the present invention on PPAR y (10 μM) and the number of photons (χΐο 4 ) of EC compounds compared to the control group EC 5 o (μΜ) Control 1.4
实施例 3 2.1 1.5 Example 3 2.1 1.5
实施例 6 23.9 17.1 0.058 实施例 7 11.8 8.4 Example 6 23.9 17.1 0.058 Example 7 11.8 8.4
实施例 8 12.2 8.7 1.19 实施例 9 12.4 8.9 0.021 实施例 10 6.2 4.4 0.24 实施例 11 13.7 9.8 Example 8 12.2 8.7 1.19 Example 9 12.4 8.9 0.021 Example 10 6.2 4.4 0.24 Example 11 13.7 9.8
实施例 14 ― ― Embodiment 14 ― ―
实施例 15 11.9 8.5 Example 15 11.9 8.5
实施例 20 20 14.3 Example 20 20 14.3
实施例 23 4.1 2.9 Example 23 4.1 2.9
实施例 24 4.1 2.9 Example 24 4.1 2.9
实施例 25 12.5 8.9 Example 25 12.5 8.9
实施例 26 16.2 11.6 Example 26 16.2 11.6
实施例 28 18.1 12.9 Example 28 18.1 12.9

Claims

Figure imgf000052_0001
Figure imgf000052_0001
1. 通式 ( I )化合物， 其消旋体、 旋光异构体或其药学上可 接受的盐或溶剂化物， 1. a compound of general formula (I), a racemate, an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000052_0002
Figure imgf000052_0002
I  I
其中：  among them:
1^和112各自独立地选自 H, d-C4的直链或支链烷基；1 ^ and 11 2 are each independently selected from H, dC 4 linear or branched alkyl;
Ar选自芳香碳环或杂环，其中的环可以是单环、默环或三环； 每个环为 5 - 6元环， 杂环中包括 1 - 4个选自下面的杂原子： 0, S, N; 环上无取代或被 1 - 5个选自下面的取代基取代： 卤素， 硝基， 羟基， 羟甲基， 三氟甲基， 三氟甲氧基， Ct- (：6直链或支 链烷基， C2- C6直链或支链烯基， d - 04烷氧基， C2- C4链烯氧 基， 苯氧基， 苄氧基， 羧基或氨基； Ar is selected from aromatic carbocyclic or heterocyclic rings, wherein the rings may be monocyclic, silent or tricyclic; each ring is a 5-6 membered ring, and the heterocyclic ring includes 1-4 heteroatoms selected from the following: 0 , S, N; unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, Ct- (: 6 Straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, d-0 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, carboxyl or amino ;
Y为 H， 卤素；  Y is H, halogen;
n是 1-4的整数；  n is an integer from 1-4;
m为 0或 1,  m is 0 or 1,
π 0  π 0
、、。 0 ,,. 0
X为 CH2、 0、 s、 s 、 s基团。 X is a CH 2 , 0, s, s , or s group.
2. 权利要求 1的化合物，其为通式 II表示的 S构型异构体, 2. The compound according to claim 1, which is an S configuration isomer represented by the general formula II,
Figure imgf000053_0001
Figure imgf000053_0001
I I  I I
其中：  among them:
连接于 COORi的碳原子为 S构型；  The carbon atom attached to COORi is in the S configuration;
^和 R2各自独立地选自 H， CH3; ^ And R 2 are each independently selected from H, CH 3 ;
Ar选自芳香碳环或杂环，其中的环可以是单环、双环或三环; 每个环为 5 - 6元环， 杂环中包括 1 - 4个选自下面的杂原子： 0， S, N; 环上无取代或被 1 - 5个选自下面的取代基取代： 卤素， 硝基， 羟基， 羟甲基， 三氟甲基， 三氟甲氧基， d - (^直链或支 链烷基， C2 - C6直链或支链烯基， d - C4烷氧基， C2 - C4链烯氧 基， 苯氧基， 苄氧基， 羧基或氨基； Ar is selected from aromatic carbocyclic or heterocyclic rings, wherein the rings may be monocyclic, bicyclic or tricyclic; each ring is a 5-6 membered ring, and the heterocyclic ring includes 1-4 heteroatoms selected from the following: 0, S, N; unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, methylol, trifluoromethyl, trifluoromethoxy, d-(^ straight chain Or branched alkyl, C 2 -C 6 straight or branched alkenyl, d-C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, carboxyl or amino;
Y为 H, Br;  Y is H, Br;
n是 1-4的整数；  n is an integer from 1-4;
m为 0或 1，  m is 0 or 1,
π 0  π 0
、、。 0 ϋ ,,. 0 ϋ
X为 CH2、 0、 S、 s 、 s基团， X is a CH 2 , 0, S, s, s group,
或其药学上可接受的盐或溶剂化物。  Or a pharmaceutically acceptable salt or solvate thereof.
3. 权利要求 1或 2的化合物， 其选自： 3. A compound according to claim 1 or 2 selected from:
(2S) -2- [3- (4-甲氧基-苯基） -丙酰氨基] -3- {4- [2- (5-甲基 - 2-苯基 -1， 3-噁唑- 4-基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [3- (4-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -3- {4- [2- (5-甲基- 2-苯基 -1 , 3-恶唑- 4-基）一乙氧基] - 苯基 } -2- (3-苯基 -丁酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole-4-yl) -ethoxy] -phenyl} -2- (3-benzene -Butyrylamino) -propionic acid;
(2S) -2- [3- (3-甲氧基-苯基) -丙酰氨基] -3- {4- [2- (5-甲基 - 2-苯基- 1， 3-噁唑 -4-基) -乙氧基] -苯基 } -丙酸； (2S) -2- [3- (3-methoxy-phenyl) -propionamido] -3- {4- [2- (5-methyl -2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [3- (2-曱氧基-苯基） -丙酰氨基] -3 - {4- [2- (5-甲基 - 2-苯基- 1, 3- p恶唑 -4-基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [3- (2-Methoxy-phenyl) -propionamido] -3-{4- [2- (5-Methyl-2-phenyl-1, 3-p-oxazine Azole-4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2 -苯基 -1， 3-喁唑 -4-基） -乙氧基] - 苯基 } -2- [ 3- (4-三氟甲基-苯基) -丙酰氨基〗 -丙酸；  (2S) -3- {4- [2- (5-methyl-2 -phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -2- [3- ( 4-trifluoromethyl-phenyl) -propionamido-propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-噁唑 -4-基）一乙氧基〗 - 苯基 } -2 - (2-甲基- 3-苯基-丙酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) monoethoxy- -phenyl} -2-(2-methyl -3-phenyl-propionamido) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基- 1， 3-喁唑 -4 -基） -乙氧基] - 苯基 } -3-苯基 丙酰氨基） -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -3-phenylpropionyl Amino) -propionic acid;
(2S) -3- {4- [2- (5-甲基- 2 -苯基 -1， 3-喁唑- 4-基） -乙氧基] - 苯基 } -2- (2-五氟苯基-乙酰氨基） -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-penta Fluorophenyl-acetylamino) -propionic acid;
(2S) -2- [2- (2-甲氧基-苯基） -乙酰氨基] -3 - {4- [2- (5-曱基 - 2 -苯基 -1， 3-噁唑 -4-基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (2-methoxy-phenyl) -acetylamino] -3- {4- [2- (5-fluorenyl-2-phenyl-1,3-oxazole- 4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (2 -氯-苯基) -乙酰氨基] -3- {4- [2- (5-甲基 -2- 苯基- 1， 3-噁唑 -4-基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (2-chloro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole-4- ) -Ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (4 -氯-苯基)一乙酰氨基] -3- {4- [2- (5-甲基- 2- 苯基 -1， 3-噁唑 -4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (4-chloro-phenyl) monoacetamido] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole-4- ) -Ethoxy] -phenyl} -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑- 4-基） -乙氧基] - 苯基 } -2- (2-邻-三氟曱基-苯基-乙酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o -Trifluorofluorenyl-phenyl-acetamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基- 1， 3-喁唑- 4-基） -乙氧基] - 苯基 } -2- (2-对-三氟甲基-苯基-乙酰氨基) -丙酸； (2S) -3- {4- [2- ( 5 -methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-p -Trifluoromethyl-phenyl-acetamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基- 2-苯基- 1, 3-喁唑- 4 -基） -乙氧基] - 苯基 } -2- [2- (3-三氟曱基-苯基) -乙酰氨基] -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole-4 -yl) -ethoxy] -phenyl} -2- [2- ( 3-trifluorofluorenyl-phenyl) -acetamino] -propionic acid;
(2S) -2- [2— (2， 3—二氟-苯基）―乙酰氨基] -3- {4- [2- (5-甲基 - 2 -苯基 -1， 3-噁唑 -4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (2, 3-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (3, 4-二氟-苯基） -乙酰氨基] -3- {4- [2- (5-甲基 -2-苯基- 1， 3 -嗝唑 -4 -基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (3,4-difluoro-phenyl) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole -4 -yl) -ethoxy] -phenyl} -propionic acid;
(2S) -3- {4- [2- (5-甲基- 2 -苯基 -1， 3-喁唑- 4-基）一乙氧基] - 苯基 } -2-苯基-乙酰氨基-丙酸； (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) monoethoxy]- Phenyl} -2-phenyl-acetamino-propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1 , 3-喁唑 -4-基） -乙氧基] - 苯基 } -2- (2-对甲苯氧基-乙酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-p Tolyloxy-acetylamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3 恶唑 -4-基） -乙氧基] - 苯基 } -2- [2- (萘 -1-基氧基) -乙酰氨基] -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3 oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (naphthalene -1-yloxy) -acetamino] -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1, 3-噁唑 -4-基） -乙氧基〗 - 苯基 } -2- [2- (2-硝基-苯氧基) -乙酰氨基] -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy]-phenyl} -2- [2- ( 2-nitro-phenoxy) -acetamino] -propionic acid;
(2S) -2- [2- (3-甲氧基-苯氧基） -乙酰氨基] -3- {4- [2- (5-甲 基 -2-苯基 -1， 3-噁唑- 4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (3-methoxy-phenoxy) -acetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazole -4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (4 -氟-苯氧基） -乙酰氨基 ] - 3- {4- [2- (5-甲基 -2-苯基- 1， 3-噁唑 -4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (4-Fluoro-phenoxy) -acetamino]-3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole-4 -Yl) -ethoxy] -phenyl} -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1, 3 -噁唑 -4-基） -乙氧基] - 苯基 } -2- (2-苯氧基-乙酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1, 3-oxazole-4-yl) -ethoxy] -phenyl} -2- (2-benzene Oxy-acetylamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基- 1， 3-噁唑 -4-基） -乙氧基] - 苯基 } -2- [2- (4-硝基-苯氧基-乙酰氨基) -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [2- ( 4-nitro-phenoxy-acetamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3-喁唑 -4-基） -乙氧基] - 苯基 } -2- (2-邻甲苯氧基-乙酰氨基） -丙酸;  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-o Toluyl-acetylamino) -propionic acid;
(2S) -3- {4- [2- (5-甲基 -2-苯基 -1， 3 恶唑 -4-基） -乙氧基] - 苯基 } -2- [2- (萘- 2-基氧） -乙酰氨基] -丙酸；  (2S) -3- {4- [2- (5-methyl-2-phenyl-1,3 oxazol-4-yl) -ethoxy] -phenyl} -2- [2- (naphthalene -2-yloxy) -acetylamino] -propionic acid;
(2S) -2- [2- (4-氯-苯硫基） -乙酰氨基 ] -3- {4- [2- (5-甲基 -2 -苯基 -1， 3-喁唑 -4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (4-chloro-phenylthio) -acetylamino] -3- {4- [2- (5-methyl-2 -phenyl-1, 3-oxazole-4 -Yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (4-甲氧基-苯硫基）一乙酰氨基] -3- {4- [2- (5 -甲 基- 2-苯基 -1， 3-嚙唑- 4-基) -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (4-methoxy-phenylthio) monoacetylamino] -3- {4- [2- (5-methyl-2-phenyl-1,3-pyrazole -4-yl) -ethoxy] -phenyl} -propionic acid;
(2S) -2- [2- (8-氯-萘 -1-基硫基） -乙酰氨基] -3- {4- [2- (5 - 甲基 -2-苯基 -1， 3 -噁唑 -4 -基） -乙氧基] -苯基 } -丙酸；  (2S) -2- [2- (8-chloro-naphthalen-1-ylthio) -acetylamino] -3- {4- [2- (5 -methyl-2-phenyl-1, 3- Oxazole-4 -yl) -ethoxy] -phenyl} -propionic acid;
(2S) -3- {3-溴- 4 - [2- (5-曱基- 2-苯基- 1， 3-P恶唑- 4 -基） -乙氧 基] -苯基 } -2- [2- (2-甲氧基-苯基)一乙酰氨基] -丙酸；  (2S) -3- {3-bromo-4-[2- (5-fluorenyl-2-phenyl-1,3-Poxazole-4-yl) -ethoxy] -phenyl} -2 -[2- (2-methoxy-phenyl) monoacetylamino] -propionic acid;
(2S) -3- {3-溴- 4- [2- (5-甲基 -2-苯基 -1, 3 -喁唑 -4-基) -乙氧 基] -苯基 } -2-苯基乙酰氨基-丙酸； (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1, 3-oxazol-4-yl) -ethoxy Phenyl] -phenyl} -2-phenylacetamino-propionic acid;
(2S) -3- {3 -溴 -4- [2- (5 -甲基 -2-苯基 -1， 3-喁唑 -4-基） -乙氧 基] -苯基 } -2- [ 3- (4-甲氧基-苯基) -丙酰氨基] -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [3- (4-methoxy-phenyl) -propionamido] -propionic acid;
(2S) -3- {3-溴 -4- [2- (5-甲基 -2-苯基 -1， 3-喁唑 -4-基) -乙氧 基] -苯基 } - ( 3-苯基-丙酰氨基） -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl}-(3 -Phenyl-propionamido) -propionic acid;
(2S) -3- {3-溴- 4- [2- (5 -甲基 -2 -苯基 -1， 3-喁唑 -4-基）-乙氧 基] -苯基 } -2- [ 3- (2-甲氧基-苯基) -丙酰氨基] -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- [3- (2-methoxy-phenyl) -propionamido] -propionic acid;
(23) -3- {3-溴-4- [2-（5-甲基-2-苯基-1， 3 -喁唑 -4 -基) -乙氧 基〗 -苯基 } -2- [3- (3-甲氧基-苯基) -丙酰氛基] -丙酸；  (23) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazole-4 -yl) -ethoxy〗 -phenyl} -2- [3- (3-methoxy-phenyl) -propanoyl] -propionic acid;
(2S) -3- {3-溴 -4- [2- (5 -甲基 -2-苯基 -1， 3 -喁唑 -4-基） -乙氧 基〗 -苯基 } -2- [ 3- (4-三氟甲基-苯基) -丙酰氨基] -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy〗 -phenyl} -2- [3- (4-trifluoromethyl-phenyl) -propionamido] -propionic acid;
(2S) -3- {3 -溴- 4- [2- (5-甲基- 2-苯基- 1， 3-喁唑- 4-基） -乙氧 基] -苯基 } -2- (2-曱基- 3-苯基-丙酰氨基) -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (2-fluorenyl-3-phenyl-propionamido) -propionic acid;
(23) -3- {3-溴-4- [2- (5-甲基-2-苯基-1， 3-噁唑 -4-基） -乙氧 基] -苯基 } -2- (3-苯基-丁酰氨基) -丙酸；  (23) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy] -phenyl} -2- (3-phenyl-butyrylamino) -propionic acid;
(2S) -3- {3-溴 -4- [2- (5-甲基 -2 -苯基 -1， 3- p恶唑- 4-基） -乙氧 基] -苯基 } -2- (2-邻甲苯氧基-乙酰氨基） -丙酸；  (2S) -3- {3-bromo-4- [2- (5-methyl-2-phenyl-1,3-poxazole-4-yl) -ethoxy] -phenyl} -2 -(2-o-tolyloxy-acetamino)-propionic acid;
(2S) -3- {3 -溴- 4- [2- (5-曱基 -2-苯基 -1， 3-喁唑- 4 -基） -乙氧 基〗 -苯基 } -2- (2-苯硫基 -乙酰氨基） -丙酸；  (2S) -3- {3-bromo-4- [2- (5-fluorenyl-2-phenyl-1,3-oxazol-4-yl) -ethoxy group-phenyl group} -2- (2-phenylthio-acetylamino) -propionic acid;
或其药学上可接受的盐或溶剂化物。  Or a pharmaceutically acceptable salt or solvate thereof.
4. 药物组合物， 其含有权利要求 1-3任一项的化合物， 其消 旋体、 旋光异构体、 或其药学上可接受的盐或溶剂化物以及至少 一种药学上可接受的载体。 4. A pharmaceutical composition comprising a compound according to any one of claims 1-3, a racemate, an optical isomer, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier .
5. 权利要求 1所述化合物的制备方法， 其包括： 5. The method for preparing a compound according to claim 1, comprising:
使式 I I I化合物
Figure imgf000057_0001
Make a compound of formula III
Figure imgf000057_0001
III  III
其中 Y， n， 的定义同权利要求 1;  Wherein Y, n, are defined as in claim 1;
与式 X化合物进行反应，
Figure imgf000057_0002
Reacting with a compound of formula X,
Figure imgf000057_0002
X  X
其中 Ar, X， R2， m的定义同权利要求 1; Where Ar, X, R 2 , m are defined as in claim 1;
得到通式 I化合物，  To give compounds of general formula I,
Figure imgf000057_0003
Figure imgf000057_0003
I  I
其中 Rl5 R2, Ar, X， Y, m和 n的定义同权利要求 1。 Wherein R l5 R 2 , Ar, X, Y, m and n are defined as in claim 1.
6. 权利要求 5的方法， 其中的式 III化合物可按以下方法制 备: 6. The method of claim 5, wherein the compound of formula III can be prepared as follows:
1)使式 IV化合物与苯甲酰胺进行反应， 环合得到式 V化合 物， 式 V化合物再经四氢锂铝还原， 得到式 VI化合物；
Figure imgf000057_0004
IV V VI 1) reacting a compound of formula IV with benzamide to obtain a compound of formula V by cyclization, and then reducing the compound of formula V by lithium tetrahydro lithium aluminum to obtain a compound of formula VI;
Figure imgf000057_0004
IV V VI
2 M吏其中 Y和 n的定义同权利要求 1的式 VII化合物先与其 中 Ri定义同通式 I的 ROH和二氯亚砜反应， 接着与 B0C20反应， 得到 VIII的化合物， 其中 Y， ！！和^的定义同权利要求 1;
Figure imgf000058_0001
2. Wherein the definition of Y and n is the same as the compound of formula VII in claim 1, first react with ROH and dichlorosulfoxide in which the definition of Ri is the same as the general formula I, and then react with BOC 2 0 to obtain the compound of VIII, wherein !! !! And ^ have the same definition as in claim 1;
Figure imgf000058_0001
VII VIII  VII VIII
3)使步骤 1)得到的式 VI化合物与步骤 2)得到的式 VIII 化合物反应， 得到其中 Υ, η和 1^定义同权利要求 1的式 IX化合 物，  3) reacting the compound of formula VI obtained in step 1) with the compound of formula VIII obtained in step 2) to obtain a compound of formula IX in which Υ, η and 1 ^ are as defined in claim 1,
Figure imgf000058_0002
Figure imgf000058_0002
IX  IX
接着使式 IX化合物用三氟乙酸脱保护基， 得到其中 Y， η和 的定义同权利要求 1的式 III化合物，  The compound of formula IX is then deprotected with trifluoroacetic acid to obtain a compound of formula III in which Y, η and have the same definitions as in claim 1,
Figure imgf000058_0003
Figure imgf000058_0003
III  III
7. 权利要求 5所述的方法， 其进一步包括：  7. The method of claim 5, further comprising:
使其中 ^-^ 直链或支链烷基的通式 I化合物和碱金属氢 氧化物反应， 得到 = H的通式 I化合物。  A compound of the general formula I in which a ^-^ linear or branched alkyl group is reacted with an alkali metal hydroxide to obtain a compound of the general formula I = H.
8. 权利要求 1 的化合物用于制备治疗 hPPARc和 hPPARy介 导的疾病、 危险因子或病症的药物的用途。 8. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of hPPARc and hPPARy-mediated diseases, risk factors or conditions.
9. 权利要求 8的用途， 其中所述疾病、 危险因子或病症为高 血糖症、 脂代谢障碍脂血症或 Π型糖尿病包括相关的糖尿病性脂 代谢障碍脂血症。 9. The use of claim 8, wherein the disease, risk factor or condition is hyperglycemia, dyslipidemia, or type II diabetes including related diabetic dyslipidemia.
10. 式 III化合物
Figure imgf000059_0001
10. Compound of formula III
Figure imgf000059_0001
III  III
其中 Y, n， I 的定义同权利要求 1,  Where Y, n, I have the same meaning as in claim 1,
PCT/CN2005/000147 2004-05-24 2005-02-02 TYROSINE DERIVATIVES SUBSTITUTED BY ALKANOYLAS hPPARα & hPPARϜ ANGONISTS WO2005115998A1 (en)

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