CN115572223A - 一种苯丙酸衍生物及其用途 - Google Patents
一种苯丙酸衍生物及其用途 Download PDFInfo
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- CN115572223A CN115572223A CN202211264163.1A CN202211264163A CN115572223A CN 115572223 A CN115572223 A CN 115572223A CN 202211264163 A CN202211264163 A CN 202211264163A CN 115572223 A CN115572223 A CN 115572223A
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- Prior art keywords
- alkyl
- substituted
- unsubstituted
- oxy
- phenyl
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- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 title description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
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- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 19
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 19
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- 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 4
- -1 3- (4- ((2- (4-ethylphenoxy) benzyl) oxy) phenyl) propanoic acid Chemical compound 0.000 claims description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 45
- 229910052717 sulfur Inorganic materials 0.000 claims description 35
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 22
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
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- 125000005842 heteroatom Chemical group 0.000 claims description 16
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 14
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 14
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 14
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
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- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 7
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 7
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 claims description 7
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 claims description 7
- 239000004913 cyclooctene Substances 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
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- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 7
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 7
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- 150000003852 triazoles Chemical class 0.000 claims description 7
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 claims description 6
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- JOKNYDGDJBLSHN-UHFFFAOYSA-N 3-[4-[(2-phenoxyphenyl)methoxy]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1OCC1=CC=CC=C1OC1=CC=CC=C1 JOKNYDGDJBLSHN-UHFFFAOYSA-N 0.000 claims description 3
- QJDQMJCZLVXQRF-UHFFFAOYSA-N 3-[4-[[2-(2-methylphenyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound CC1=CC=CC=C1C1=CC=CC=C1COC1=CC=C(CCC(O)=O)C=C1 QJDQMJCZLVXQRF-UHFFFAOYSA-N 0.000 claims description 3
- VJRNDSQCSFWPFE-UHFFFAOYSA-N 3-[4-[[2-(3-methylphenyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound CC1=CC=CC(C=2C(=CC=CC=2)COC=2C=CC(CCC(O)=O)=CC=2)=C1 VJRNDSQCSFWPFE-UHFFFAOYSA-N 0.000 claims description 3
- PRAXVMOBNOHQJB-UHFFFAOYSA-N 3-[4-[[2-(4-methylphenyl)phenyl]methoxy]phenyl]propanoic acid Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1COC1=CC=C(CCC(O)=O)C=C1 PRAXVMOBNOHQJB-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明提供式（I）表示的化合物及其生理学可接受盐，其中各个符号如说明书中所定义。所述化合物或其盐在体内代谢后具有GPR120受体调节作用，引起GLP‑1分泌增加。并且作为胰岛素促分泌素或预防或治疗糖尿病、代谢综合征、及其相关疾病等的药物是有用的
Description
技术领域
本发明涉及一类苯丙酸衍生物、其制备方法及含有该化合物的药物或药物组合物以及其作为治疗剂特别是作为GPR120受体激动剂在预防或治疗糖尿病、代谢综合征、及其相关疾病等的药物的用途。
背景技术
糖尿病是一种能量代谢疾病，主要分为1型糖尿病(胰岛素依赖型糖尿病)和2型糖尿病(非-胰岛素依赖型糖尿病)。目前全球约有5.37亿糖尿病患者，平均每10个人中就有1位患病。其中2型糖尿病患者约占糖尿病患者总数的90～95％。
糖尿病可以通过饮食调节和锻炼治疗。当这些不能缓解症状时，需要进行药物治疗。目前糖尿病的药物治疗方法包括：双胍类如二甲双胍，能够减少肝脏中葡萄糖的形成；磺酰脲类如格列本脲，能够刺激胰腺β细胞分泌更多的胰岛素；噻唑烷二酮类如匹格列酮，通过激活氧化物酶体增殖物激活受体γ(PPAR-γ)增强胰岛素的生物效用；α-葡萄糖苷酶抑制剂如阿卡波糖，能够抑制肠道内葡萄糖的生成；胰高血糖素样肽-1(GLP-1)类似物如利拉鲁肽，能够促进胰腺的β细胞分泌胰岛素；二肽基肽酶IV(DPP-IV)抑制剂如西格列汀，能够抑制体内GLP-1的降解。但是，现有的治疗糖尿病的方法都有一定的缺陷。例如胰岛素注射剂和磺酰脲类，可能引起低血糖和体重增加副作用；二甲双胍类、α-葡萄糖苷酶抑制剂和GLP-1类似物可能引起胃肠道副作用；PPAR-γ激动剂可能引起体重增加和水肿副作用；DPP-IV抑制剂可能引起咽上部炎、头疼和感染副作用。针对多个领域的研究正在进行，以期为市场带来更有效的新型降血糖药物。
游离脂肪酸受体(FFAR)是近几年去孤儿化的G蛋白偶联受体(GPCRs)。目前已确定的游离脂肪酸受体有G蛋白偶联受体40(GPR40)家族，包括GPR40(也称游离脂肪酸受体1，FFA1)、GPR41(也称也称游离脂肪酸受体3，FFA3)、GPR43(也称游离脂肪酸受体2，FFA2)以及其它家族的GPR84、GPR120。近年来，以G蛋白偶联受体120(GPR120)为代表的游离脂肪酸受体在糖尿病治疗领域受到广泛关注。GPR120又称游离脂肪酸受体4(free fat acidreceptors，FFA4)是G蛋白偶联受体家族(GPCRs)的成员之一，与GPCRs具有相似的跨膜结构。
GPR120在体内参与调节多种生理功能，①促进胰高血糖素样肽(GLP-1)、葡萄糖依赖性促胰岛素分泌肽(GIP)和胆囊收缩素(CCK)的分泌。激活GPR120能够通过PLC-β/IP3通路增加响应细胞内Ca2+浓度，促使L细胞分泌GLP-1，K细胞分泌GIP，I细胞分泌CCK；②促进葡萄糖转运，增加胰岛素敏感性。激活GPR120能够通过Gαq/11/PI3K/AKT/GLUT4通路促进脂肪细胞对葡萄糖的摄取；因此，激活GPR120可以通过多条通路调节血糖。
本发明涉及结构新颖的苯丙酸衍生物，该类化合物具有GPR120激动活性，因此所述通式(I)化合物及其药用盐潜在的用于治疗或者预防糖尿病及相关疾病是有效的。
发明内容
本发明所要解决的技术问题是提供一种苯丙酸衍生物以及上述衍生物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
本发明目的的技术方案是：一种苯丙酸衍生物，具有下述通式(I)：
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
X为O、S或NR，其中，R为取代或未取代的C1-C6烷基、取代或未取代的C3-C10碳环；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R5、R6、R7和R8相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
作为优选，其是通式(II)所示的化合物或其可药用的盐：
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
X为O或S；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R6和R7相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
作为优选，其是通式(III)所示的化合物或其可药用的盐：
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-；
R6和R7相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
优选化合物选自但不限于下列化合物：
3-(4-((2-苯氧苄基)氧)苯基)丙酸；
3-(4-((2-(临-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(间-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(对-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(4-乙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-丙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-异丙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3,5-二甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯-4-甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯-4-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-溴-2-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氟-2-甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氯-2-甲基苯氧)苄基)氧)苯基)丙酸。
所述通式(I)所示的化合物、其可药用的盐在制备GPR120激动剂中的用途。
所述的盐为盐酸盐、磷酸盐、硫酸盐、碳酸盐、硝酸盐、柠檬酸盐、酒石酸盐、马来酸盐、琥珀酸盐、磺酸盐、对甲苯磺酸盐、甲磺酸盐、苯甲酸盐、富马酸盐。
所述的药物组合物表示含有一种或多种本发明通式(I)所述化合物或其可药用的盐联合一种或多种治疗糖尿病药物与其他化学组分的混合物，其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收，利于活性成分在生物体内发挥生物活性，降低副作用。
所述的药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
所述的治疗糖尿病药物，包括胰岛素、胰岛素类似物、促进胰岛β细胞分泌胰岛素的药物、促进外周组织增加葡萄糖利用的药物、抑制肠道葡萄糖吸收的药物、胰岛素增敏剂、促进葡萄糖代谢的药物或者抑制肾脏葡萄糖重吸收的药物等，其优选实例包括胰岛素、胰岛素类似物、格列苯脲、格列喹酮、格列齐特、格列吡嗪、格列美脲、瑞格列奈、那格列奈、二甲双胍、苯乙双胍、环格列酮、罗格列酮、吡格列酮、利拉鲁肽、艾塞那肽、利司那肽、阿必鲁肽、阿卡波糖、伏格波糖、米格列醇、沙格列汀、西格列汀、维格列汀、利格列汀、阿格列汀、曲格列汀、达格列净、卡格列净、艾格列净、Ipragliflozin、Luseogliflozin以及Tofogliflozin等。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，所述的药物还包括药学上可以接受的载体如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体或润滑剂。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可通过口服、注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮肉、皮下、静脉、粘膜组织，或是被其他物质混合或包裹后导入机体等。
所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。
所述代谢综合征及其相关疾病为蛋白质、脂肪、碳水化合物等物质代谢发生紊乱的病理状态，包括肥胖(Després J P,Lemieux I,Alméras N.Abdominal obesity and themetabolic syndrome[M]Overweight and the Metabolic Syndrome.Springer US,2006:137-152)、高血糖(Grundy S M,Cleeman J I,Daniels S R,et al.Diagnosis andmanagement of the metabolic syndrome[J].Circulation,2005,112(17):2735-2752)、血脂异常(Charlton M.Obesity,hyperlipidemia,and metabolic syndrome[J].LiverTransplantation,2009,15(S2))、高血黏(Irace C,Scavelli F,Carallo C,et al.Plasmaand blood viscosity in metabolic syndrome[J].Nutrition,Metabolism andCardiovascular Diseases,2009,19(7):476-480)、高尿酸(Yoo T W,Sung K C,Shin H S,et al.Relationship between serum uric acid concentration and insulinresistance and metabolic syndrome[J].Circulation Journal,2005,69(8):928-933)、高脂肪肝(Marchesini G,Bugianesi E,Forlani G,et al.Nonalcoholic fatty liver,steatohepatitis,and the metabolic syndrome[J].Hepatology,2003,37(4):917-923)和高胰岛素血症(Han T S,Williams K,Sattar N,et al.Analysis of obesity andhyperinsulinemia in the development of metabolic syndrome:San Antonio HeartStudy[J].Obesity,2002,10(9):923-931；Grundy S M,Brewer H B,Cleeman J I,etal.Definition of metabolic syndrome[J].Circulation,2004,109(3):433-438)等，但不限于举例范围。
发明的详细说明
除非另有说明，否则说明书和权利要求书中的的术语具有下述含义。
“C1-C4烷基”可以提及例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。
“C1-C6烷基”可以提及如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等。
“C3-C8碳环”可以提及例如环丙烷、环丁烷、环戊烷、环己烷等饱和碳环；环丁烯、环戊烯、环己烯等不饱和碳环及苯环等芳香碳环。
“杂环”可以提及例如5-10元杂环，构成杂环的原子除了含有碳原子外，还含有一种或两种选自N、S、O的1至4个杂原子，优选5-10元非芳香杂环或5-10元芳香杂环等。具体地，非芳香杂环例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等；芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等。
“杂环基”可以提及例如5-10元(单环、双环或三环)杂环基，构成杂环的原子除了含有碳原子外，还含有一种或两种选自N、S、O的1至4个杂原子，优选5-10元非芳香杂环或5-10元芳香杂环等。具体地，非芳香杂环例如四氢呋喃、四氢吡喃、吡咯烷基、噁唑烷基、咪唑烷基、哌啶基、哌嗪基、吗啉基等；芳香杂环例如噻吩基、呋喃基、吡啶基、噻唑基、嘧啶基、吡唑基、咪唑基等。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本发明化合物的合成方法。
可如方案一所示制备式(I)的化合物。
化合物(VI)可以通过将通式(VI)表示的化合物和通式(V)表示的化合物(分别简称化合物VI和化合物V)在碱的存在下反应制备，得到的化合物IV进一步在碱存在下水解反应，得到化合物(I)。
化合物(I)可以通过将通式(IV)表示的化合物和通式(V)表示的化合物在碱和缩合剂的存在下反应制备得到。
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
X为O、S或NR，其中，R为取代或未取代的C1-C6烷基、取代或未取代的C3-C10碳环；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R5、R6、R7和R8相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
L表示离去基团，可以提及例如Cl、Br、I、任选卤代的C1-C6烷基磺酰基氧基(例如，甲磺酰基氧基、乙磺酰基氧基、三氯甲磺酰基)、任选具有取代基的的C6-C10芳基磺酰基氧基(例如，苯基磺酰基氧基、对甲苯磺酰基氧基，间-硝基苯磺酰基氧基等)等；
W为取代或未取代的C1-C6烷基，“取代”指基团中的一个或多个氢原子，优选为最多5个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
作为所述的碱包括无机碱和有机碱，所述的无机碱可以提及例如，碱金属碳酸盐类例如碳酸钠、碳酸钾、碳酸铯等；碱金属碳酸氢盐类例如碳酸氢钾等；碱金属氢氧化物例如氢氧化锂、氢氧化钠、氢氧化钾等；所述的无机碱可以提及例如三乙胺、吡啶、二甲基吡啶、正丁基锂、叔丁基钾等。
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
本实施例的苯丙酸衍生物3-(4-((2-苯氧苄基)氧)苯基)丙酸(编号I-1)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.29g(1.11mmol)化合物IV-1和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-1。
熔点:110-112℃.收率:62％1H NMR(500MHz,DMSO-d6)δ12.04(s,1H),7.55(dd,J＝7.6,1.7Hz,1H),7.41–7.31(m,3H),7.19(td,J＝7.5,1.1Hz,1H),7.15–7.07(m,3H),7.00–6.95(m,2H),6.90(dd,J＝8.2,1.2Hz,1H),6.87–6.82(m,2H),5.06(s,2H),2.73(t,J＝7.6Hz,2H),2.46(t,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.07,157.32,156.95,154.54,133.42,130.33,129.98,129.50,128.47,124.19,123.59,119.22,118.42,114.84,64.79,35.81,29.79；HRMS(ES+)for C22H20O4(M+Na)+:calcd 371.1259；found,371.1266.
实施例2
本实施例的苯丙酸衍生物3-(4-((2-(临-甲苯基)苄基)氧)苯基)丙酸(编号I-2)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-2和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-2
熔点:84-86℃.收率:68％1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),7.54(dd,J＝7.6,1.7Hz,1H),7.34–7.25(m,2H),7.21(d,J＝1.8Hz,1H),7.16–7.03(m,4H),6.94–6.87(m,2H),6.85(dd,J＝8.1,1.2Hz,1H),6.65(dd,J＝8.2,1.1Hz,1H),5.12(s,2H),2.74(t,J＝7.6Hz,2H),2.49–2.43(m,2H),2.17(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.24,157.20,155.37,154.46,133.54,131.97,130.48,130.02,129.68,129.33,127.91,127.22,124.56,123.29,119.42,116.82,115.01,65.06,35.99,29.97,16.14；HRMS(ES+)for C23H22O4(M+Na)+:calcd 385.1416；found,385.1415.
实施例3
本实施例的苯丙酸衍生物3-(4-((2-(间-甲苯基)苄基)氧)苯基)丙酸(编号I-3)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-3和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-3
熔点:105-107℃.收率:65％1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),7.55(dd,J＝7.6,1.7Hz,1H),7.35(td,J＝7.8,1.8Hz,1H),7.25(t,J＝7.8Hz,1H),7.22–7.15(m,1H),7.15–7.08(m,2H),6.94(dd,J＝7.2,1.4Hz,1H),6.90(dd,J＝8.2,1.1Hz,1H),6.88–6.83(m,2H),6.80(d,J＝2.0Hz,1H),6.76(dd,J＝8.1,2.5Hz,1H),5.06(s,2H),2.73(t,J＝7.6Hz,2H),2.47(t,J＝7.6Hz,2H),2.27(s,3H)；13CNMR(125MHz,DMSO-d6)δ174.23,157.46,157.11,154.75,140.17,133.58,130.47,130.14,129.67,128.59,124.48,124.27,119.38,119.12,115.62,115.01,64.93,35.98,29.96,21.40；HRMS(ES+)for C23H22O4(M+Na)+:calcd385.1416；found,385.1423.
实施例4
本实施例的苯丙酸衍生物3-(4-((2-(对-甲苯基)苄基)氧)苯基)丙酸(编号I-4)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-4和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-4
熔点:72-74℃.收率:67％1H NMR(500MHz,DMSO-d6)δ12.06(s,1H),7.53(dd,J＝7.6,1.7Hz,1H),7.31(td,J＝7.8,1.8Hz,1H),7.20–7.13(m,3H),7.11(dd,J＝9.0,6.9Hz,2H),6.92–6.85(m,4H),6.83(dd,J＝8.2,1.1Hz,1H),5.07(s,2H),2.73(t,J＝7.6Hz,2H),2.50–2.43(m,2H),2.27(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.27,157.14,155.24,155.04,133.57,132.95,130.84,130.40,130.04,129.68,128.22,123.92,118.87,118.67,115.00,64.92,36.00,29.97,20.71；HRMS(ES+)for C23H22O4(M+Na)+:calcd 385.1416；found,385.1421.
实施例5
本实施例的苯丙酸衍生物3-(4-((2-(4-乙基苯氧)苄基)氧)苯基)丙酸(编号I-5)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-5和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-5
熔点:70-72℃.收率:71％1H NMR(500MHz,DMSO-d6)δ7.54(dd,J＝7.6,1.7Hz,1H),7.32(td,J＝7.8,1.8Hz,1H),7.24–7.18(m,2H),7.15(td,J＝7.5,1.1Hz,1H),7.13–7.07(m,2H),6.92–6.88(m,2H),6.88–6.81(m,3H),5.07(s,2H),2.73(t,J＝7.6Hz,2H),2.58(q,J＝7.6Hz,2H),2.46(d,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H)；13C NMR(125MHz,DMSO-d6)δ173.27,156.16,154.23,138.32,132.59,129.43,129.06,128.66,127.31,122.99,117.83,114.04,63.95,35.01,28.99,26.88,15.19；HRMS(ES+)for C24H24O4(M+Na)+:calcd399.1572；found,399.1576.
实施例6
本实施例的苯丙酸衍生物3-(4-((2-(4-丙基苯氧)苄基)氧)苯基)丙酸(编号I-6)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-6和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-6
熔点:61-63℃.收率:69％1H NMR(500MHz,DMSO-d6)δ12.03(s,1H),7.50(dd,J＝7.6,1.7Hz,1H),7.28(td,J＝7.8,1.8Hz,1H),7.17–7.09(m,3H),7.09–7.03(m,2H),6.89–6.84(m,2H),6.84–6.79(m,3H),5.04(s,2H),2.70(t,J＝7.6Hz,2H),2.49–2.41(m,4H),1.59–1.45(m,2H),0.84(t,J＝7.3Hz,3H)；13C NMR(125MHz,DMSO-d6)δ174.08,156.99,155.00,137.50,133.41,130.24,130.04,129.88,129.50,128.15,123.82,118.69,118.54,114.86,64.79,36.77,35.83,29.81,24.46,13.88；HRMS(ES+)for C22H20O4(M+Na)+:calcd413.1729；found,413.1731.
实施例7
本实施例的苯丙酸衍生物3-(4-((2-(4-异丙基苯氧)苄基)氧)苯基)丙酸(编号I-7)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-7和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-7
熔点:73-75℃.收率:67％1H NMR(500MHz,DMSO-d6)δ12.07(s,1H),7.54(dd,J＝7.6,1.7Hz,1H),7.32(td,J＝7.8,1.8Hz,1H),7.27–7.20(m,2H),7.16(dd,J＝7.5,1.1Hz,1H),7.12–7.08(m,2H),6.93–6.88(m,2H),6.88–6.83(m,3H),5.07(s,2H),2.93–2.82(m,1H),2.73(t,J＝7.6Hz,2H),2.47(t,J＝7.6Hz,2H),1.18(d,J＝6.9Hz,6H)；13C NMR(125MHz,DMSO-d6)δ174.25,157.15,155.33,155.12,143.90,133.57,130.42,130.05,129.66,128.34,128.15,124.01,118.93,118.68,115.02,64.94,36.00,33.21,29.98,24.46；HRMS(ES+)for C25H26O4(M+Na)+:calcd 413.1729；found,413.1728.
实施例8
本实施例的苯丙酸衍生物3-(4-((2-(2-氟苯氧)苄基)氧)苯基)丙酸(编号I-8)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-8和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-8
熔点:83-85℃.收率:68％1H NMR(500MHz,DMSO-d6)δ7.56(dd,J＝7.6,1.8Hz,1H),7.42–7.34(m,1H),7.34–7.30(m,1H),7.25–7.19(m,2H),7.17(d,J＝7.5Hz,1H),7.12(dd,J＝8.7,2.8Hz,3H),6.89(d,J＝8.6Hz,2H),6.79(d,J＝8.1Hz,1H),5.15(s,2H),2.74(t,J＝7.6Hz,2H),2.48(t,J＝7.8Hz,2H)；13C NMR(125MHz,DMSO-d6)δ179.01,161.88,159.79,157.62,148.44,138.37,135.21,134.87,134.43,132.16,130.59,128.82,126.88,122.42,122.28,121.68,119.77,69.61,40.75,34.73；HRMS(ES+)for C22H19FO4(M+Na)+:calcd389.1165；found,389.1167.实施例9
本实施例的苯丙酸衍生物3-(4-((2-(3-氟苯氧)苄基)氧)苯基)丙酸(编号I-9)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-9和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-9
熔点:86-88℃.收率:71％1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),7.59(dd,J＝7.6,1.7Hz,1H),7.43–7.34(m,2H),7.25(td,J＝7.5,1.2Hz,1H),7.12–7.07(m,2H),7.02(dd,J＝8.2,1.2Hz,1H),6.94(td,J＝8.5,2.5Hz,1H),6.85–6.75(m,4H),5.04(s,2H),2.73(t,J＝7.6Hz,2H),2.46(t,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.24,164.29,162.34,159.20,157.04,153.91,133.64,131.74,131.66,130.81,130.40,129.65,129.08,125.18,120.27,114.99,114.08,110.38,110.21,105.88,105.68,64.95,35.98,29.96；HRMS(ES+)for C22H19FO4(M+Na)+:calcd 389.1165；found,389.1169.
实施例10
本实施例的苯丙酸衍生物3-(4-((2-(4-氟苯氧)苄基)氧)苯基)丙酸(编号I-10)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-10和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-10
熔点:90-92℃.收率:74％1H NMR(500MHz,DMSO-d6)δ7.57(dd,J＝7.6,1.7Hz,1H),7.35(td,J＝7.8,1.8Hz,1H),7.25–7.16(m,3H),7.15–7.10(m,2H),7.08–7.00(m,2H),6.88(d,J＝8.4Hz,3H),5.09(s,2H),2.75(t,J＝7.6Hz,2H),2.48(t,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.16,159.42,157.52,157.01,155.08,153.37,133.49,130.47,130.08,129.56,128.20,124.12,120.48,118.65,116.76,114.89,64.87,35.88,29.86；HRMS(ES+)for C22H19FO4(M+Na)+:calcd 389.1165；found,389.1164.
实施例11
本实施例的苯丙酸衍生物3-(4-((2-(2-氯苯氧)苄基)氧)苯基)丙酸(编号I-11)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-11和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-11
熔点:90-92℃.收率:72％1H NMR(500MHz,DMSO-d6)δ12.07(s,1H),7.57(ddd,J＝7.6,4.1,1.6Hz,2H),7.39–7.29(m,2H),7.23–7.15(m,2H),7.14–7.09(m,2H),7.04(dd,J＝8.3,1.5Hz,1H),6.90–6.85(m,2H),6.76(d,J＝8.1Hz,1H),5.12(s,2H),2.74(t,J＝7.6Hz,2H),2.46(d,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ173.43,156.27,153.74,151.42,132.79,130.34,129.71,129.33,128.85,128.42,126.89,124.97,123.91,123.47,120.32,116.76,114.20,64.06,35.16,29.15；HRMS(ES+)for C22H19ClO4(M+Na)+:calcd 405.0870；found,405.0874.
实施例12
本实施例的苯丙酸衍生物3-(4-((2-(3-氯苯氧)苄基)氧)苯基)丙酸(编号I-12)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-12和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-12
熔点:64-67℃.收率:63％1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),7.59(dd,J＝7.6,1.7Hz,1H),7.46–7.30(m,2H),7.26(td,J＝7.5,1.2Hz,1H),7.16(dd,J＝8.0,2.0Hz,1H),7.12–7.07(m,2H),7.02(dd,J＝8.1,1.1Hz,1H),6.98(t,J＝2.2Hz,1H),6.95–6.90(m,1H),6.84–6.79(m,2H),5.04(s,2H),2.73(t,J＝7.6Hz,2H),2.46(t,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.23,158.80,157.02,153.89,134.36,133.62,131.83,130.89,130.47,129.64,129.14,125.25,123.48,120.35,118.15,116.85,114.99,64.97,35.96,29.95；HRMS(ES+)for C22H19ClO4(M+Na)+:calcd 405.0870；found,405.0872.
实施例13
本实施例的苯丙酸衍生物3-(4-((2-(4-氯苯氧)苄基)氧)苯基)丙酸(编号I-13)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-13和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-13
熔点:93-95℃.收率:68％1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),7.57(dd,J＝7.6,1.7Hz,1H),7.43–7.34(m,3H),7.22(td,J＝7.5,1.2Hz,1H),7.12–7.07(m,2H),7.01–6.93(m,3H),6.86–6.80(m,2H),5.04(s,2H),2.73(t,J＝7.6Hz,2H),2.50–2.43(m,2H)；13CNMR(125MHz,DMSO-d6)δ174.24,157.07,156.58,154.34,133.62,130.74,130.30,129.66,128.87,127.42,124.86,120.10,119.79,115.00,64.97,35.98,29.97；HRMS(ES+)forC22H19ClO4(M+Na)+:calcd 405.0870；found,405.0873.
实施例14
本实施例的苯丙酸衍生物3-(4-((2-(2,4-二甲基苯氧)苄基)氧)苯基)丙酸(编号I-14)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-14和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-14
熔点:105-105℃.收率:57％1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),7.52(dd,J＝7.6,1.7Hz,1H),7.25(td,J＝7.8,1.8Hz,1H),7.14–7.10(m,3H),7.07(td,J＝7.5,1.1Hz,1H),7.01(dd,J＝8.2,2.2Hz,1H),6.95–6.89(m,2H),6.78(d,J＝8.2Hz,1H),6.58(dd,J＝8.3,1.1Hz,1H),5.14(s,2H),2.75(t,J＝7.6Hz,2H),2.51–2.45(m,2H),2.26(s,3H),2.11(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.12,157.10,155.66,151.80,133.62,133.39,132.35,130.20,129.76,129.54,129.14,128.15,126.65,122.70,119.77,115.87,114.87,64.91,35.87,29.85,20.62,15.92；HRMS(ES+)for C24H24O4(M+Na)+:calcd 399.1572；found,399.1573.
实施例15
本实施例的苯丙酸衍生物3-(4-((2-(3,5-二甲基苯氧)苄基)氧)苯基)丙酸(编号I-15)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-15和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-15
熔点:88-90℃.收率:61％1H NMR(500MHz,DMSO-d6)δ7.53(dd,J＝7.7,1.8Hz,1H),7.30(td,J＝7.8,1.8Hz,1H),7.13(dd,J＝15.9,7.9Hz,4H),6.91–6.86(m,2H),6.85–6.79(m,2H),6.71(dd,J＝8.2,2.7Hz,1H),5.08(s,2H),2.74(t,J＝7.6Hz,2H),2.52–2.44(m,2H),2.18(s,6H)；13C NMR(125MHz,DMSO-d6)δ173.44,156.34,154.33,137.72,132.75,130.93,130.29,129.50,129.16,128.85,127.35,122.97,119.30,117.80,115.34,114.21,64.11,35.19,29.17,19.11,18.23；HRMS(ES+)for C24H24O4(M+Na)+:calcd 399.1572；found,399.1573.
实施例16
本实施例的苯丙酸衍生物3-(4-((2-(2,4-二氟苯氧)苄基)氧)苯基)丙酸(编号I-16)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-16和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-16
熔点:87-89℃.收率:63％1H NMR(500MHz,DMSO-d6)δ12.10(s,1H),7.55(dd,J＝7.6,1.8Hz,1H),7.47(ddd,J＝11.5,8.8,3.0Hz,1H),7.32(td,J＝7.8,1.8Hz,1H),7.22(dt,J＝9.2,4.6Hz,1H),7.18–7.08(m,4H),6.93–6.88(m,2H),6.77(d,J＝8.2Hz,1H),5.16(s,2H),2.74(t,J＝7.6Hz,2H),2.47(d,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.29,159.58,157.73,157.64,157.11,155.31,154.91,154.81,152.93,152.83,140.05,133.60,130.48,130.15,129.70,127.08,123.96,123.49,116.27,114.98,112.64,112.46,106.38,106.18,105.99,64.81,36.00,29.97；HRMS(ES+)for C22H18F2O4(M+Na)+:calcd 407.1071；found,407.1072.
实施例17
本实施例的苯丙酸衍生物3-(4-((2-(2,4-二氯苯氧)苄基)氧)苯基)丙酸(编号I-17)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-17和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-17
熔点:66-68℃.收率:61％1H NMR(500MHz,DMSO-d6)δ12.10(s,1H),7.73(d,J＝2.6Hz,1H),7.58(dd,J＝7.6,1.8Hz,1H),7.41(dd,J＝8.8,2.6Hz,1H),7.35(td,J＝7.8,1.8Hz,1H),7.21(td,J＝7.5,1.2Hz,1H),7.13–7.08(m,2H),7.02(d,J＝8.8Hz,1H),6.88–6.81(m,3H),5.10(s,2H),2.73(t,J＝7.6Hz,2H),2.52–2.44(m,2H)；13C NMR(125MHz,DMSO-d6)δ174.17,156.90,154.11,151.52,133.50,130.66,130.39,130.23,129.55,129.09,128.53,127.84,125.45,124.66,121.76,118.03,114.84,64.75,35.87,29.85；HRMS(ES+)for C22H18Cl2O4(M+Na)+:calcd 439.0480；found,439.0483.
实施例18
本实施例的苯丙酸衍生物3-(4-((2-(2-氯-4-甲基苯氧)苄基)氧)苯基)丙酸(编号I-18)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-18和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-18
熔点:71-73℃.收率:67％1H NMR(500MHz,DMSO-d6)δ12.07(s,1H),7.54(dd,J＝7.6,1.8Hz,1H),7.40(d,J＝2.1Hz,1H),7.29(td,J＝7.8,1.7Hz,1H),7.19–7.09(m,4H),6.99(d,J＝8.3Hz,1H),6.92–6.87(m,2H),6.67(d,J＝8.2Hz,1H),5.14(s,2H),3.33(s,2H),2.74(t,J＝7.6Hz,2H),2.47(d,J＝7.6Hz,1H),2.30(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.26,157.12,155.01,149.63,135.76,133.60,131.29,130.33,130.00,129.71,127.26,124.71,123.82,121.59,116.71,115.03,64.84,36.00,29.98,20.48；HRMS(ES+)for C23H21ClO4(M+Na)+:calcd 419.1026；found,419.1027.
实施例19
本实施例的苯丙酸衍生物3-(4-((2-(2-氯-4-氟苯氧)苄基)氧)苯基)丙酸(编号I-19)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-19和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-19
熔点:97-99℃.收率:65％1H NMR(500MHz,DMSO-d6)δ12.07(s,1H),7.60(dd,J＝8.4,3.1Hz,1H),7.56(dd,J＝7.5,1.7Hz,1H),7.32(td,J＝7.8,1.7Hz,1H),7.25(td,J＝8.5,3.0Hz,1H),7.20–7.10(m,4H),6.89(d,J＝8.6Hz,2H),6.72(d,J＝8.2Hz,1H),5.14(s,2H),2.74(t,J＝7.6Hz,2H),2.47(d,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ174.26,159.53,157.59,157.10,154.90,148.67,133.62,130.53,130.15,129.68,127.37,125.91,124.13,122.82,118.34,118.13,116.86,116.22,116.03,115.01,64.90,36.00,29.98；HRMS(ES+)for C22H18ClFO4(M+Na)+:calcd 423.0775；found,423.0773.
实施例20
本实施例的苯丙酸衍生物3-(4-((2-(4-溴-2-氯苯氧)苄基)氧)苯基)丙酸(编号I-20)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-20和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-20
熔点:90-92℃.收率:71％1H NMR(500MHz,DMSO-d6)δ12.09(s,1H),7.84(d,J＝2.4Hz,1H),7.58(dd,J＝7.6,1.7Hz,1H),7.53(dd,J＝8.7,2.4Hz,1H),7.36(td,J＝7.8,1.8Hz,1H),7.22(td,J＝7.5,1.2Hz,1H),7.13–7.08(m,2H),6.95(d,J＝8.8Hz,1H),6.88–6.82(m,3H),5.09(s,2H),2.73(t,J＝7.6Hz,2H),2.47(t,J＝7.6Hz,2H)；13C NMR(125MHz,DMSO-d6)δ173.99,156.72,153.82,151.85,133.33,132.88,131.82,130.51,130.08,129.37,127.74,125.49,124.57,121.87,118.03,115.91,114.66,64.58,35.70,29.67；HRMS(ES+)for C22H18BrClO4(M+Na)+:calcd 482.9975；found,482.9982.
实施例21
本实施例的苯丙酸衍生物3-(4-((2-(4-氟-2-甲基苯氧)苄基)氧)苯基)丙酸(编号I-21)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-12和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-21
熔点:97-99℃.收率:66％1H NMR(500MHz,DMSO-d6)δ7.53(dd,J＝7.6,1.8Hz,1H),7.27(td,J＝7.8,1.8Hz,1H),7.18(dd,J＝9.4,3.2Hz,1H),7.15–7.07(m,3H),7.04(td,J＝8.6,3.2Hz,1H),6.95–6.91(m,1H),6.91–6.87(m,2H),6.61(dd,J＝8.3,1.1Hz,1H),5.13(s,2H),2.73(t,J＝7.6Hz,2H),2.47(dd,J＝15.4,7.7Hz,2H),2.15(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.32,159.81,157.90,157.18,155.65,150.38,133.63,132.10,130.53,130.07,129.69,126.90,123.20,121.49,118.34,118.16,116.10,114.99,114.34,114.15,65.06,36.15,30.03,16.18；HRMS(ES+)for C23H21FO4(M+Na)+:calcd 403.1322；found,403.1324.
实施例22
本实施例的苯丙酸衍生物3-(4-((2-(4-氯-2-甲基苯氧)苄基)氧)苯基)丙酸(编号I-22)经2步反应合成，反应式如下。
将0.2g(1.11mmol)化合物V溶于15ml N,N-二甲基甲酰胺中，加入0.30g(1.11mmol)化合物IV-22和0.31g(2.22mmol)碳酸钾，常温反应过夜后过滤，浓缩。将粗品溶于5ml甲醇、5ml四氢呋喃和5ml甲醇中，加入0.18(4.44mmol)氢氧化钠，常温反应2小时后加1mol/L的盐酸调节至pH为2至3，乙酸乙酯萃取，旋蒸后得粗产品，硅胶柱层析分离，乙酸乙酯：石油醚(4:1)洗脱得化合物I-22
熔点:90-92℃.收率:58％1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),7.55(dd,J＝7.6,1.7Hz,1H),7.39(d,J＝2.7Hz,1H),7.31(td,J＝7.8,1.8Hz,1H),7.24(dd,J＝8.7,2.7Hz,1H),7.15(td,J＝7.5,1.1Hz,1H),7.11(d,J＝8.6Hz,2H),6.91–6.85(m,2H),6.83(d,J＝8.7Hz,1H),6.73(dd,J＝8.2,1.1Hz,1H),5.09(s,2H),2.73(t,J＝7.6Hz,2H),2.47(t,J＝7.6Hz,2H),2.17(s,3H)；13C NMR(125MHz,DMSO-d6)δ174.28,157.14,154.96,153.64,133.56,131.59,131.40,130.69,130.21,129.68,127.97,127.57,123.85,120.59,117.42,114.96,65.03,36.00,29.96,15.98；HRMS(ES+)for C23H21ClO4(M+Na)+:calcd419.1026；found,419.1030.
实施例23
本发明中化合物的体外GPR120激动活性的测定：
将稳定转染人GPR120的CHO细胞以10×105个/mL的浓度悬浮于生长培养基中，以每孔20000个细胞的密度接种于96孔板中，置于37℃、5％CO2培养箱中培养24h。轻轻吸弃培养孔中的培养基，用Hank's平衡盐溶液(HBSS，每孔100μL)洗孔。然后将细胞在含有荧光钙指示剂Fluo-4AM(2.5μg/mL)、0.1％无脂肪酸牛血清白蛋白和丙磺舒(2.5mM)的HBSS中37℃孵育60分钟。然后将细胞在HBSS中清洗3次，并在进行测试之前平衡10分钟。将溶解在二甲基亚砜(DMSO)中的测试配体稀释在不同浓度的HBSS中，并加入到含有Fluo-4AM的细胞中，使用FlexStation3分子设备测量细胞内Ca2+浓度。受试化合物的GPR120激动活性见表1。
表1：化合物对GPR120受体的激动活性
通式(I)所示化合物的体外GPR120激动活性结果表明，苯丙酸衍生物具有较好的体外激动活性，作为GPR120受体激动剂，用于治疗或者预防糖尿病及相关疾病是有效的。
实施例24
含活性剂I-11的片剂：
按常规方法将原辅料混合，制粒，干燥，压片。
Claims (9)
1.权利要求通式（I）所示的化合物或其可药用的盐：
（I）
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
X为O、S或NR，其中，R为取代或未取代的C1-C6烷基、取代或未取代的C3-C10碳环；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R5、R6、R7和R8相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
2.根据权利要求1所述的通式（I）的化合物或其可药用的盐，其是通式（II）所示的化合物或其可药用的盐：
（II）
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
X为O或S；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代的C1-C6烷基-CO-；
R6和R7相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
3.根据权利要求2所述的通式（II）的化合物或其可药用的盐，其是通式（III）所示的化合物或其可药用的盐：
（III）
其中：
A环为C3-C10碳环、杂环、稠杂环；所述的碳环是环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、苯环；所述的杂环是吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、三氮唑、吡啶、嘧啶、吡嗪、哒嗪、呋喃、吡咯、噻吩、哌嗪、吗啉、哌啶、四氢呋喃、四氢吡咯、四氢噻唑；所述的稠杂环是苯环并杂环或杂环并杂环，如喹啉、异喹啉、四氢喹啉、四氢异喹啉、吲哚、二氢吲哚、嘌呤等；
R1、R2、R3和R4相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-；
R6和R7相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基；
R9、R10、和R11相同或不同，并各自为H、D、F、Cl、Br、CN、CF3、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷基-O-、取代或未取代C1-C6烷基-S(O)n-、NH2、NH(C1-C4烷基)、N(C1-C4烷基)2、CONH2、CONH(C1-C4烷基)、CON(C1-C4烷基)2、C3-C10碳环、含碳原子及1-4个选自N、O、S及S(O)n的杂原子的3至10元杂环基。
4.根据权利要求1-3所定义的通式（I）化合物及其可药用盐，该化合物选自，但不限于举例范围：
3-(4-((2-苯氧苄基)氧)苯基)丙酸；
3-(4-((2-(临-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(间-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(对-甲苯基)苄基)氧)苯基)丙酸；
3-(4-((2-(4-乙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-丙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-异丙基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(3,5-二甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2,4-二氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯-4-甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(2-氯-4-氟苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-溴-2-氯苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氟-2-甲基苯氧)苄基)氧)苯基)丙酸；
3-(4-((2-(4-氯-2-甲基苯氧)苄基)氧)苯基)丙酸。
5.根据权利要求1-4中任意一项所述通式（I）所示的化合物、其可药用的盐在制备GPR120激动剂中的用途。
6.一种药物组合物，所述药物组合物含有治疗有效剂量的根据权利要求1-4中任意一项所述通式（I）所示的化合物、其可药用的盐及一种或多种治疗糖尿病药物。
7.权利要求1-4所述的通式（I）化合物、其可药用盐或权利要求6所述的药物组合物在制备预防或治疗糖尿病、代谢综合征、及其相关疾病的药物中的用途。
8.权利要求7中所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，所述的药物还包括药学上可以接受的载体如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体或润滑剂。
9.权利要求7中所述的预防或治疗糖尿病、代谢综合征、及其相关疾病的药物，其特征在于，该药物可制成注射剂、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂多种形式。
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