CN115536638A - 一种三氮唑类化合物及其应用 - Google Patents
一种三氮唑类化合物及其应用 Download PDFInfo
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- CN115536638A CN115536638A CN202210977610.1A CN202210977610A CN115536638A CN 115536638 A CN115536638 A CN 115536638A CN 202210977610 A CN202210977610 A CN 202210977610A CN 115536638 A CN115536638 A CN 115536638A
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- -1 Triazole compound Chemical class 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims abstract 6
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 claims abstract 6
- 125000003118 aryl group Chemical group 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 69
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 50
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 125000005842 heteroatom Chemical group 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 24
- 125000001624 naphthyl group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
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- 150000002367 halogens Chemical group 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
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- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 150000005840 aryl radicals Chemical class 0.000 claims description 5
- 230000027455 binding Effects 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
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- 230000003281 allosteric effect Effects 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- 229940126027 positive allosteric modulator Drugs 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000003566 oxetanyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 1
- XIPUIGPNIDKXJU-UHFFFAOYSA-N [CH]1CC1 Chemical compound [CH]1CC1 XIPUIGPNIDKXJU-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 12
- 230000008848 allosteric regulation Effects 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 89
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- 102000006419 Glucagon-Like Peptide Receptors Human genes 0.000 description 33
- 108010083749 Glucagon-Like Peptide Receptors Proteins 0.000 description 33
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 27
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 13
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- 229940079593 drug Drugs 0.000 description 8
- 235000019260 propionic acid Nutrition 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
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Abstract
本发明公开了一种三氮唑类化合物及其应用。本发明具体提供了一种如式I所示的化合物或其药学上可接受的盐。本发明的三氮唑类化合物具有较佳的GLP‑1R别构调节活性。
Description
技术领域
本发明涉及一种三氮唑类化合物及其应用。
背景技术
胰高血糖素样肽受体(GLP-1R)是B型G蛋白偶联受体(G protein-coupledreceptor,GPCR)家族成员之一,也是一种广为人知的2型糖尿病(Type 2 diabetesmellitus,T2DM)药物靶点。当人体摄入营养物质时,肠道会分泌胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1),此多肽与GLP-1R高度特异性结合使其活化,刺激胰岛素的分泌,抑制胰高血糖素的产生,使餐后血糖含量保持稳定。临床研究发现大多数T2DM患者的病因是靶细胞对胰岛素的敏感性降低(胰岛素抵抗),导致胰岛素相对不足。目前靶向GLP-1R的药物都是GLP-1的多肽类似物,如Exenatide、Liraglutide、Semaglutide、Albiglutide、Dulaglutide、Lixisenatide等,这类药物与GLP-1R特异性结合并使其活化,以此提高其胰岛素敏感性。由于GLP-1R靶向药物刺激胰岛素分泌是血糖浓度依赖型的,所以不会像其他降糖药一样有低血糖的风险,同时兼具减肥、降压、改善血脂等效果。此外,另有研究表明,GLP-1R还与非酒精性脂肪变性肝炎(NASH)、帕金森综合征(Parkinson’sdisease)、阿尔兹海默症(Alzheimer’s disease)有关,目前研发GLP-1R靶向药物是许多新药研发机构的研究热点。
目前生物大分子GLP-1R多肽药物不方便口服,批准使用的仅有Novo Nordisk公司的Semeglutide可以和胃吸收促进剂N-[8-(2-羟基苯甲酰氨基)]辛酸钠(SNAC)联合使用,然而这个技术并不完美,至少有两个缺陷:1.每天都需要在空腹状态下使用并且需要尽量少的液体送服,但是这种口服方式的服用剂量远大于每周一次的可注射剂量;2.糖尿病患者一般都患有其他疾病,相应地会服用其他药物,而SNAC有可能增加其他药物的吸收,从而带来潜在的风险。
目前有两种小分子激活GLP-1R的策略,即直接寻找GLP-1R激动剂和寻找GLP-1R正向别构调节剂(positive allosteric modulators,PAMs)。前者直接利用小分子激活GLP-1R,各大公司也相继报道了许多有成药潜力的化合物,如Pfizer公司的PF06882961、EliLilly公司的LY-3502970等,但尚未有小分子激动剂通过临床并获得FDA的批准。后者GLP-1R PAMs的策略是利用小分子作用在内源性配体(GLP-1)结合位点之外的另一位点,并提高内源性配体与GLP-1R结合的活性,也是近年来药物研发领域的新方向。与激动剂相比,GLP-1R PAMs具有很多优势(CN101565408A):更接近生理状态、更安全、更精细地调控信号。
2019年,Andrija Smelcerovic等人总结报道了多个小分子GLP-1R PAMs(ChemMedChem 2019,14,514–521),如Boc 5、BETP等,但是这些化合物因为成药性差等多方面原因并未通过临床实验。2020年,Sanofi公司通过高通量筛选并进行多维结构优化得到了活性较好的化合物19(J.Med.Chem.2020,63,2292-2307),该化合物有效提高了GLP-1代谢产物GLP-1(9-36)NH2与GLP-1R结合的活性,但是该化合物还需进一步优化才能进行临床研究。2020年,Eli Lilly公司通过高通量筛选并进行结构优化得到了高活性的小分子LSN3160440,并利用该小分子进行了结构的解析,提供了全新的GLP-1R别构位点,但是尚未有该化合物的临床研究。
发明内容
本发明所要解决的技术问题是现有技术的GLP-1R别构调节剂的种类少的问题,提供了一种三氮唑类化合物及其应用。该类化合物具有较佳的GLP-1R别构调节活性。
本发明提供了一种如式I所示的化合物或其药学上可接受的盐:
L1为化学键、C1-C6亚烷基或-C1-C6亚烷基-C3-C6亚环烷基-;
R1为C6-C10芳基、5-10元杂芳基、被1个、2个或3个R1-1取代的C6-C10芳基或被1个、2个或3个R1-2取代的5-10元杂芳基;所述的5-10元杂芳基和被1个、2个或3个R1-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2为C1-C6烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、被1个、2个或3个R2-1取代的C1-C6烷基、被1个、2个或3个R2-3取代的3-10元杂环烷基、被1个、2个或3个R2-4取代的C6-C10芳基或被1个、2个或3个R2-2取代的5-10元杂芳基;所述的3-10元杂环烷基和所述的被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;所述的5-10元杂芳基和被1个、2个或3个R2-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
L2为C1-C6亚烷基;L3为C1-C6亚烷基;
R2-1独立地为-CN、-OH、-N(R2-1-1R2-1-2)、-NHC(=O)-R2-1-3、-O-S(=O)2-R2-1-5、-C(=O)-NH-R2-1-6、-(OCH2CH2)n-OH、3-10元杂环烷基、C6-C10芳基、被1个、2个或3个R2-1-8取代的3-10元杂环烷基或被1个、2个或3个R2-1-7取代的C6-C10芳基;所述3-10元杂环烷基和所述的被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2-1-1和R2-1-2独立地为氢、C1-C6烷基、C6-C10芳基或被1个、2个或3个C6-C10芳基取代的C1-C6烷基;
R2-1-3独立地为-N(R2-1-3-1R2-1-3-2)、C1-C6烷基或被1个、2个或3个C6-C10芳基取代的C1-C6烷基;R2-1-3-1和R2-1-3-2独立地为氢、C1-C6烷基或C3-C6环烷基;
R2-1-5和R2-1-6独立地为C6-C10芳基或被1个、2个或3个R2-1-5-1取代的C6-C10芳基;R2 -1-5-1独立地为C1-C6烷基;
n为1、2或3;
R2-1-8独立地为氧代(=O)或-C(=O)-R2-1-8-1;R2-1-8-1独立地为5-10元杂芳基;所述的5-10元杂芳基中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2-3为-OH;
R2-2为-NH2;
在某一方案中,所述的如式I所示的化合物或其药学上可接受的盐里,某些基团的定义如下所述,其余基团的定义如其他任一方案所述(下文简称“在某一方案中”):所述的如式I所示的化合物的药学上可接受的盐可为三氟乙酸盐。
在某一方案中,L1中,所述C1-C6亚烷基可为-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2-、-C(CH3)2CH2-或-CH(C(CH3)3)-;优选为-CH2-、-CH2CH2-、-C(CH3)2-、-C(CH3)2CH2-或-CH(C(CH3)3)-。
在某一方案中,L1中,所述-C1-C6亚烷基-C3-C6亚环烷基-中的-C1-C6亚烷基-可为-C1-C3亚烷基-;优选为-亚甲基-。
在某一方案中,L1中,所述-C1-C6亚烷基-C3-C6亚环烷基-中的-C3-C6亚环烷基-可为-C3-C4亚环烷基-。
在某一方案中,R1中,所述5-10元杂芳基和所述被1个、2个或3个R1-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子选自N,所述的杂原子的数量为1个。
在某一方案中,R1-1中,所述卤素可为氟、氯、溴或碘;优选为氯。
在某一方案中,R1-1中,所述C1-C6烷基可为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如甲基。
在某一方案中,R1-1中,所述C1-C6烷氧基可为C1-C4烷氧基;优选为甲氧基或乙氧基;例如甲氧基。
在某一方案中,R1-2-1中,所述C1-C6烷基可为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如叔丁基。
在某一方案中,R1-2中,所述卤素可为氟、氯、溴或碘;优选为氯。
在某一方案中,R1-2中,所述C1-C6烷基可为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如甲基。
在某一方案中,R1-2中,所述C1-C6烷氧基可为C1-C4烷氧基;优选为甲氧基或乙氧基;例如甲氧基。
在某一方案中,L2中,所述C1-C6亚烷基可为C1-C3亚烷基;优选为-CH2-。
在某一方案中,L3中,所述C1-C6亚烷基可为C1-C3亚烷基;优选为-CH2CH2-。
在某一方案中,R2中,所述的5-10元杂芳基和被1个、2个或3个R2-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子可为N。
在某一方案中,R2中,所述的C1-C6烷基和被1个、2个或3个R2-1取代的C1-C6烷基里C1-C6烷基可为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在某一方案中,R2-1-1中,所述C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1-2中,所述C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1-3中,所述的C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1-3中,所述的被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C6-C10芳基可为苯基或萘基,优选为苯基。
在某一方案中,R2-1-3-1中,所述C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1-3-2中,所述C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1-3-1中,所述C3-C6环烷基可为环丙基、环丁基、环戊基或环己基,例如环丙基。
在某一方案中,R2-1-3-2中,所述C3-C6环烷基可为环丙基、环丁基、环戊基或环己基,例如环丙基。
在某一方案中,R2-1-5中,所述C6-C10芳基和被1个、2个或3个R2-1-5-1取代的C6-C10芳基里的C6-C10芳基可为苯基或萘基,优选为苯基。
在某一方案中,R2-1-6中,所述C6-C10芳基和被1个、2个或3个R2-1-5-1取代的C6-C10芳基里的C6-C10芳基可为苯基或萘基,优选为苯基。
在某一方案中,R2-1-5-1中,所述C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1中,所述的C6-C10芳基和被1个、2个或3个R2-1-7取代的C6-C10芳基里C6-C10芳基可为苯基或萘基,优选为苯基。
在某一方案中,R2-1-7-1中,所述C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,R2-1中,所述3-10元杂环烷基和被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N和S;所述的杂原子的数量独立地为1个或2个。
在某一方案中,R2-1中,所述3-10元杂环烷基和被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”优选为5-6元杂环烷基。
在某一方案中,R2中,所述的3-10元杂环烷基和被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子选自O;所述的杂原子的数量为1个。
在某一方案中,R2中,所述的3-10元杂环烷基和被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”优选为4-6元杂环烷基。
在某一方案中,R2中,所述的C6-C10芳基和被1个、2个或3个R2-4取代的C6-C10芳基里C6-C10芳基可为苯基或萘基,优选为苯基。
在某一方案中,R2-4中,所述的被1个、2个或3个R2-4-2取代的C1-C6烷基里的C1-C6烷基可为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
在某一方案中,如式I所示的化合物为如下任一结构:
在某一方案中,如式I所示的化合物的药学上可接受的盐为如下任一结构:
本发明还提供了一种药物组合物,其包括物质A和至少一种药用辅料;所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐。
在某一方案中,所述的物质A可为治疗有效量的物质A。
本发明还提供了一种物质B在制备GLP-1R正向别构调节剂中的应用;
所述物质B为:
(1)上述的如式I所示的化合物或其药学上可接受的盐;或者,
(2)上述的药物组合物。
在某一方案中,所述的GLP-1R正向别构调节剂可调节GLP-1(9-36)NH2与GLP-1R的结合。
本发明还提供了一种物质B在制备治疗和/或预防与GLP-1R相关的疾病的药物中的应用;
所述物质B为:
(1)上述的如式I所示的化合物或其药学上可接受的盐;或者,
(2)上述的药物组合物。
在某一方案中,所述与GLP-1R相关的疾病可为代谢性疾病、帕金森综合征、阿尔兹海默症或非酒精性脂肪性肝炎;所述代谢性疾病优选为2型糖尿病、胰岛素抵抗或肥胖。
本发明还提供了一种物质B在制备药物中的应用;
所述物质B为:
(1)上述的如式I所示的化合物或其药学上可接受的盐;或者,
(2)上述的药物组合物;
所述的药物为用于治疗以下一种或多种疾病的药物:代谢性疾病、帕金森综合征、阿尔兹海默症和非酒精性脂肪性肝炎。
在某一方案中,所述代谢性疾病优选为2型糖尿病、胰岛素抵抗或肥胖。
如无特别说明,本发明所用术语具有如下含义:
术语“药学上可接受”是指相对无毒、安全、适合于患者使用。
术语“药学上可接受的盐”是指化合物与药学上可接受的酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物接触的方式获得碱加成盐。当化合物中含有相对碱性的官能团时,可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物接触的方式获得酸加成盐。具体可参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,Camille G.Wermuth,2011,2nd Revised Edition)。
基团末端的“-”是指该基团通过该位点与分子其余部分相连。例如,CH3-C(=O)-是指乙酰基。
术语“卤素”是指氟、氯、溴或碘。
术语“氧代”是指=O,氧原子替代同一碳原子上的两个氢(也即,以羰基替代亚甲基);或者砜基、或亚砜基替代硫。
术语“烷基”是指具有指定碳原子数(例如,C1-C6)的、直链或支链的、饱和的一价烃基。烷基包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
术语“亚烷基”为二价基团,其通过两个单键与分子其余部分相连,其余定义同术语“烷基”。
术语“烷氧基”是指基团RX-O-,RX的定义同术语“烷基”。烷氧基包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基等。
术语“芳基”是指具有指定碳原子数(例如,C6-C10)的、环状的、不饱和的一价烃基,其为单环或多环(例如,2个或3个),为多环时,单环之间共用两个原子和一根键,且至少一个环具有芳香性。芳基通过具有芳香性的环或不具有芳香性的环与分子其余部分相连。芳基包括但不限于:苯基、萘基、等。
术语“杂环烷基”是指具有指定环原子数(例如,3-10元)的、指定杂原子数(例如,1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、饱和的一价基团,其为单环。杂环烷基通过碳原子或杂原子与分子其余部分相连。杂环烷基包括但不限于: 等。
术语“杂芳基”是指具有指定环原子数(例如,5-10元)的、指定杂原子数(例如,1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价基团,其为单环或多环,单环之间共用两个原子和一根键,且每个环均具有芳香性。杂芳基通过碳原子或杂原子与分子其余部分相连;杂芳基通过具有杂原子的环或不具有杂原子的环与分子其余部分相连;杂芳基通过具有芳香性的环或不具有芳香性的环与分子其余部分相连。杂芳基包括但不限于: 等。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的量。治疗有效量将根据化合物种类、疾病种类、疾病的严重度、患者的年龄等变化,但可由本领域技术人员视情况调整。
术语“药用辅料”是指除活性药物成分以外,包含在药物制剂中的所有物质,一般分为赋形剂和附加剂两大类。具体可参见《中华人民共和国药典(2020年版)》、Handbook ofPharmaceutical Excipients(Paul J Sheskey,Bruno C Hancock,Gary P Moss,David JGoldfarb,2020,9th Edition)。
术语“治疗”是指消除病因或缓解症状。
术语“预防”是指降低发生疾病的风险。
术语“患者”是指需要接受治疗或预防疾病的任何动物,通常是哺乳动物,例如人类。哺乳动物包括但不限于:牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的三氮唑类化合物具有较佳的GLP-1R别构调节活性。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
化合物1的合成:
3-(4-(丙-2-炔基-1-基氨基)苯甲酰胺基)酸。
向100mL梨形瓶中依次加入对氨基苯甲酰-beta-丙氨酸(6.24g,30mmol,1equiv.),溴代丙炔(3.57g,30mmol,1equiv.),K2CO3(5g,36mmol,1.2equiv.)和DMF(50mL),常温下搅拌过夜。LC-MS检测反应结束后,将混合物用水(50mL)稀释,用稀盐酸(1M)将体系的pH调节至4-5,然后水相用EA(50mL×3)萃取,再用LiCl溶液(1M,100mL×3)洗涤,饱和食盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过柱层析(DCM:MeOH=95:5),得到白色固体(4.4g,61%产率)。
1H NMR(400MHz,CDCl3)δ7.59(d,J=8.7Hz,2H),6.67–6.60(m,3H),4.71(d,J=2.4Hz,2H),3.98(s,1H),3.70(q,J=6.0Hz,2H),2.69(t,J=6.0Hz,2H),2.48(t,J=2.4Hz,1H).
MS(ESI,m/z):计算值C13H15N2O3:247.2735[M+H]+,实测值:247.01。
化合物2的合成:
氟磺酰叠氮的甲基叔丁基醚溶液。
向250mL圆柱形塑料瓶中加入叠氮钠(1.96g,30mmol,1equiv.)、蒸馏水(60mL)和MTBE(60mL),快速搅拌冰浴。将1-(氟磺酰基)-2,3-二甲基-1H-咪唑三氟甲磺酸盐(11.1g,36mL,1.2equiv.)完全溶解在MeCN(4mL)中,将得到的粘稠溶液快速加入剧烈搅拌的混合液中,冰水浴下剧烈搅拌10分钟,然后将混合液倒入200mL分液漏斗中,室温下进行相分离,留取含产物的有机相于塑料瓶中,置于阴凉的试剂柜中12h,用塑料移液管除去静置期间产生的红色残留水相得到无色有机相即FSO2N3/MTBE溶液,通过19F NMR测定浓度和产率后可直接使用。
19F NMR(376MHz)δ61.531.
化合物3的合成:
3-(4-((1-(2,2-二甲基-1-苯基丙基)-1H-1,2,3-三唑-4-基)甲基)氨基苯甲酰胺基丙酸。
向带有磁子的20mL圆柱形玻璃瓶子中依次加入2,2-二甲基-1-苯丙烷-1-胺(163mg,1mmol,1equiv.)、KHCO3(670μL,4mmol,4equiv.,3M水溶液)和DMF(2mL),搅拌均匀后缓慢加入FSO2N3(2.05mL,1mmol,1equiv.,489mM的MTBE溶液,根据“化合物2的合成”制得),搅拌30分钟后经LC-MS检测反应完毕。向反应体系中加入化合物1(246mg,1mmol,1equiv,根据“化合物1的合成”制得)后,取抗坏血酸钠(198mg,1mmol,1equiv.)溶于水(1mL)中,与硫酸铜(100μL,0.1mmol,0.1equiv.,1M水溶液)混合,溶液由蓝色先变为棕褐色,搅拌后变为浅黄色,混合均匀后加入反应体系中,反应12小时。LC-MS检测反应结束后,先向反应体系加水(10mL)稀释,然后用EA(20mL×3)萃取,合并有机相,再用LiCl溶液(1M,100mL×3)洗涤,饱和食盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过柱层析(DCM:MeOH=95:5),得到淡黄色油状液体(150mg,57%产率)。
1H NMR(400MHz,DMSO-d6)δ:8.25(s,1H),8.15(t,J=5.5Hz,1H),7.60(td,J=5.6,2.6Hz,4H),7.41-7.26(m,3H),6.61(d,J=8.4Hz,2H),5.74(s,1H),5.58(s,1H),5.17(d,J=2.1Hz,2H),3.48(q,J=6.5Hz,2H),2.59(t,J=6.9Hz,2H),0.94(s,9H);
13C NMR(126MHz,DMSO-d6)δ:171.27,166.42,151.12,140.89,129.37,128.78,127.97,126.18,121.49,112.97,73.37,57.33,54.88,35.86,35.34,33.96,26.82.
HRMS(ESI,m/z):计算值C24H29N5O3:436.2343[M+H]+,实测值:436.2339.
实施例2
化合物4的合成:
3-(4-((1-((4-氯苯基)环丙基)甲基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ:8.10(t,J=5.5Hz,1H),7.91(s,1H),7.57(d,J=8.7Hz,2H),7.26(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),6.56(d,J=8.7Hz,2H),5.11(s,2H),4.54(s,2H),3.66-3.21(m,2H),2.58(t,J=7.0Hz,2H),1.20–1.12(m,2H),1.03–0.82(m,2H).
13C NMR(126MHz,DMSO-d6)δ:171.19,166.44,151.68,141.71,140.50,131.31,130.40,128.76,128.19,124.59,121.05,112.58,57.57,57.23,54.93,35.32,33.96,25.53,12.40.
HRMS(ESI,m/z):计算值C23H24ClN5O3:454.1640[M+H]+,实测值:454.1638.
实施例3
化合物5的合成:
3-(4-((1-(7-甲基-1,2,3,4-四氢萘-1-基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.71(s,1H),7.68(d,J=8.6Hz,2H),7.17–7.07(m,1H),6.91(d,J=8.6Hz,2H),6.65(s,1H),5.90(t,J=6.0Hz,1H),5.21(s,2H),3.63(t,J=6.7Hz,2H),3.02–2.77(m,2H),2.68(t,J=6.7Hz,2H),2.34–2.23(m,2H),2.21(s,3H),1.87(p,J=6.3Hz,2H).
13C NMR(126MHz,CD3OD)δ173.97,171.05,138.14,136.89,134.59,131.40,131.29,130.82,130.72,126.06,125.26,116.59,61.69,59.26,37.64,35.81,32.97,30.21,21.81,21.62.
HRMS(ESI,m/z):计算值C24H28N5O3:434.2187[M+H]+,实测值:434.2183.
实施例4
化合物6的合成:
3-(4-((1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.80(d,J=8.4Hz,1H),7.69(d,J=8.6Hz,2H),7.42(d,J=9.2Hz,1H),7.16(t,J=7.5Hz,1H),7.09(t,J=7.5Hz,1H),6.92(d,J=8.6Hz,2H),6.83(d,J=11.0Hz,2H),5.02(s,2H),4.73(s,2H),3.58(t,J=6.8Hz,2H),2.60(t,J=6.8Hz,2H),1.46(s,6H).
13C NMR(126MHz,CD3OD)δ173.67,171.07,152.11,143.88,139.85,130.83,127.26,126.95,125.24,124.37,123.32,121.87,121.31,120.86,116.60,113.83,61.89,58.99,38.68,37.60,35.72,27.73.
HRMS(ESI,m/z):计算值C25H29N6O3:461.2296[M+H]+,实测值:461.2293.
实施例5
化合物7的合成:
3-(4-((1-(1-(叔丁氧羰基)-1H-吲哚-5-基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.20(d,J=8.7Hz,1H),8.14-8.10(m,2H),7.82(dd,J1=8.9Hz,J2=2.2Hz,1H),7.79(d,J=3.8Hz,1H),7.55(d,J=8.7Hz,2H),6.81(d,J=3.8Hz,1H),6.53(d,J=8.7Hz,2H),5.62(s,1H),5.26(s,2H),3.49(q,J=6.6Hz,2H),2.63(t,J=6.6Hz,2H),1.63(s,9H).
13C NMR(126MHz,DMSO-d6)δ171.29,166.45,151.65,148.82,143.08,134.08,132.04,130.77,128.74,128.15,123.09,121.04,116.85,115.63,112.85,112.56,107.65,84.40,57.22,54.93,35.32,34.02,27.64.
HRMS(ESI,m/z):计算值C26H29N6O5:505.2194[M+H]+,实测值:505.2195.
实施例5
化合物8的合成:
3-(4-((1-((1H-吲哚-5-基)甲基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.10(s,1H),8.08(t,J=5.6Hz,1H),7.58–7.53(m,3H),7.41–7.32(m,2H),7.10(dd,J1=8.4Hz,J2=1.7Hz,1H),6.55(d,J=8.6Hz,2H),6.44(t,J=2.5Hz,1H),5.64(s,2H),5.59(s,2H),5.12(s,2H),3.54–3.37(m,2H),2.56(t,J=7.0Hz,2H).
13C NMR(126MHz,DMSO-d6)δ:171.28,166.42,151.69,142.13,135.61,128.76,127.71,126.29,126.19,124.41,121.46,121.04,120.27,112.58,111.78,101.29,57.33,53.81,35.31,33.93,30.73.
HRMS(ESI,m/z):计算值C22H23N6O3:419.1826[M+H]+,实测值:419.1823.
实施例7
化合物9的合成:
3-(4-((1-(2-(7-甲氧基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.10–8.06(m,2H),7.54(d,J=87Hz,2H),7.11(d,J=8.0Hz,1H),6.99(d,J=2.5Hz,1H),6.91(t,J=7.7Hz,1H),6.64(d,J=7.7Hz,1H),6.53(d,J=8.7Hz,2H),5.62(s,2H),5.11(s,2H),4.60(t,J=7.3Hz,2H),3.88(s,3H),3.44(q,J=6.7Hz,2H),3.23(t,J=7.3Hz,2H),2.56(t,J=7.0Hz,2H).
13C NMR(126MHz,DMSO-d6)δ171.21,166.39,151.67,146.15,141.71,128.72,128.43,126.19,124.65,122.81,120.98,119.08,112.53,111.04,110.47,101.62,57.28,55.04,50.05,35.28,33.93,26.06.
HRMS(ESI,m/z):计算值C24H27N6O4:463.2088[M+H]+,实测值:463.2086.
实施例8
化合物10的合成:
3-(4-((1-(2-(萘-1-基)丙烷-2-基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.92(dd,J=13.4,8.3Hz,2H),7.84(d,J=6.2Hz,1H),7.62–7.52(m,4H),7.40(t,J=7.5Hz,1H),7.22(t,J=7.8Hz,1H),7.09(d,J=8.4Hz,1H),6.67(d,J=8.6Hz,2H),5.13(s,2H),3.54(t,J=6.7Hz,2H),2.59(t,J=6.7Hz,2H),2.23(s,6H).
13C NMR(126MHz,CD3OD)δ173.87,171.22,154.09,145.41,140.10,137.26,132.43,132.11,131.56,130.78,128.13,127.37,126.94,126.57,125.85,125.72,123.80,115.57,67.47,59.15,37.55,35.80,31.50.
HRMS(ESI,m/z):计算值C26H28N5O3:458.2187[M+H]+,实测值:458.2181.
实施例9
化合物11的合成:
3-(4-((1-(2-(5,7-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.53(d,J=8.6Hz,2H),7.39(s,1H),7.12(d,J=1.8Hz,1H),6.91(d,J=1.8Hz,1H),6.61(d,J=8.6Hz,2H),5.08(s,2H),4.53(t,J=6.5Hz,2H),3.55(t,J=6.8Hz,2H),3.28(t,J=6.5Hz,2H),2.59(t,J=6.8Hz,2H),1.81(s,3H).
13C NMR(101MHz,CD3OD)δ173.81,171.21,153.98,144.52,139.28,138.14,130.78,130.72,127.82,126.98,126.55,125.29,123.78,121.53,115.57,111.39,107.96,59.08,54.11,37.58,35.83,27.85,11.48.
HRMS(ESI,m/z):计算值C24H25Cl2N6O3:515.1360[M+H]+,实测值:515.1360.
实施例10
化合物12的合成:
3-(4-((1-(2-(4-氯苯基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)甲基)氨基苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(500MHz,DMSO-d6)δ8.05(t,J=5.6Hz,1H),7.55(s,1H),7.52(d,J=8.7Hz,2H),7.36(s,4H),6.52(d,J=8.7Hz,2H),5.63(s,1H),5.05(s,2H),4.51(s,2H),3.41(q,J=7.0Hz,2H),2.53(t,J=7.0Hz,2H),1.27(s,6H).
13C NMR(126MHz,DMSO-d6)δ171.12,166.31,151.64,144.61,141.15,131.13,128.69,128.16,128.11,125.59,120.96,112.50,60.08,57.13,35.25,33.91,26.19.
HRMS(ESI,m/z):计算值C23H26ClN5O3:456.1797[M+H]+,实测值:456.1793.
实施例11
化合物13的合成:
3-(4-((1-(2-(萘-2-基)乙基)-1H-1,2,3-三唑-4-基)甲基)氨基)苯甲酰胺基)丙酸。
以与化合物3类似的方式制备。
1H NMR(500MHz,DMSO-d6)δ8.07(s,2H),7.86(d,J=7.5Hz,1H),7.84(d,J=8.4Hz,1H),7.80(d,J=7.5Hz,1H),7.66(s,1H),7.53(d,J=8.6Hz,2H),7.50–7.43(m,2H),7.37(dd,J1=8.4Hz,J2=1.8Hz,1H),6.53(d,J=8.6Hz,2H),5.64(s,1H),5.09(s,2H),4.69(t,J=7.3Hz,2H),3.42(q,J=7.0Hz,2H),3.31(t,J=7.3Hz,2H),2.53(t,J=7.0Hz,2H).
13C NMR(126MHz,DMSO-d6)δ171.16,166.35,151.63,141.76,135.22,133.02,131.89,128.71,127.93,127.52,127.39,127.18,127.02,126.14,125.62,124.72,121.01,112.53,57.23,50.36,35.82,35.25,33.91.
HRMS(ESI,m/z):计算值C25H26N5O3:444.2030[M+H]+,实测值:444.2027.
实施例12
化合物14的合成:
3-(1-叠氮-2-甲基丙烷-2-基)-1H吲哚。
向带有磁子的20mL圆柱形玻璃瓶子中依次加入2-(1H-吲哚-3-基)-2-甲基丙烷-1-胺(188mg,1mmol,1equiv.)、KHCO3(670μL,4mmol,4equiv.,3M水溶液)和DMF(2mL),搅拌均匀后缓慢加入FSO2N3(2.05mL,1mmol,1equiv.,489mM的MTBE溶液,根据“化合物2的合成”制得),搅拌30分钟后经LC-MS检测反应完毕。先向反应体系加水(10mL)稀释,然后用EA(20mL×3)萃取,合并有机相,再用LiCl溶液(1M,100mL×3)洗涤,饱和食盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过柱层析(PE:DCM=90:10),得到无色油状液体(197mg,92%产率)。
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.79(d,J=7.4Hz,1H),7.38(d,J=8.2Hz,1H),7.26–7.21(m,1H),7.18–7.12(m,1H),6.99(d,J=1.5Hz,1H),3.64(s,2H),1.53(s,6H).
13C NMR(101MHz,CDCl3)δ137.21,125.56,121.92,121.79,121.29,120.76,119.35,111.74,62.13,36.98,26.28.
化合物15的合成:
3-(2-叠氮乙基)-4,6-二氯-2-甲基-1H-吲哚。
以与化合物14类似的方式制备。
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.14(s,1H),7.06(s,0H),3.51(t,J=7.1Hz,2H),3.16(t,J=7.1Hz,2H),2.39(s,3H).
13C NMR(126MHz,CDCl3)δ136.64,134.68,126.78,125.39,123.78,120.96,109.33,108.45,53.04,24.86,11.70.
化合物16的合成:
(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)(苯基)甲醇。
向带有磁子的20mL圆柱形玻璃瓶子中依次加入化合物14(107mg,0.5mmol,1equiv,根据“化合物14的合成”制得)、1-苯基-2-丙炔-1-醇(66mg,0.5mmol,1equiv.)和DMF(2mL),搅拌溶解,取抗坏血酸钠(99mg,0.5mmol,1equiv.)溶于水(1mL)中,与硫酸铜(50μL,0.05mmol,0.1equiv.,1M水溶液)混合,溶液油蓝色先变为棕褐色,搅拌后变为浅黄色,混合均匀后加入反应体系中,反应12小时。LC-MS检测反应结束后,先向反应体系加水(10mL)稀释,然后用EA(20mL×3)萃取,合并有机相,再用LiCl溶液(1M,100mL×3)洗涤,饱和食盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物通过柱层析(DCM:MeOH=95:5),得到白色固体(126mg,74%产率)。
1H NMR(400MHz,CD3OD)δ7.76(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.32-7.21(m,3H),7.21-7.12(m,3H),7.09-7.04(m,1H),6.81(s,1H),6.56(s,1H),5.76(s,1H),4.66(q,J=13.6Hz,2H),3.38(s,1H),1.43(d,J=16.1Hz,6H).
13C NMR(126MHz,CD3OD)δ152.39,144.67,139.71,130.18,129.46,128.28,127.16,124.82,124.28,123.23,121.79,121.30,120.83,113.85,70.63,61.72 38.62,27.78,27.66.
HRMS(ESI,m/z):计算值C21H23N4O:347.1866[M+H]+,实测值:347.1863.
实施例13
化合物17的合成:
1-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)-N-苄基-N-甲基甲胺。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.88(d,J=7.8Hz,1H),7.42(d,J=7.8Hz,1H),7.32-7.25(m,3H),7.22-7.17(m,1H),7.16-7.11(m,3H),6.89(s,1H),6.72(s,1H),4.81(s,2H),3.50(s,2H),3.29(s,2H),2.01(s,3H),1.52(s,6H).
13C NMR(126MHz,CD3OD)δ144.18,139.88,139.77,131.26,130.22,129.21,127.37,126.54,124.40,123.37,121.94,121.49,120.97,113.93,62.29,61.76,59.18,52.33,42.65,38.86,27.92.
HRMS(ESI,m/z):计算值C23H28N5:374.2339[M+H]+,实测值:374.2337.
实施例14
化合物18的合成:
步骤一:
与化合物1合成方法类似,向100mL梨形瓶中依次加入1-(2-呋喃甲酰基)哌嗪盐酸盐(2.06g,10mmol,1equiv.),溴代丙炔(1.18g,10mmol,1equiv.),K2CO3(1.66g,12mmol,1.2equiv.)和DMF(20mL),常温下搅拌过夜。LC-MS检测反应结束后,将混合物用水(50mL)稀释,用稀盐酸(1M)将体系的pH调节至4-5,然后水相用EA(50mL×3)萃取,再用LiCl溶液(1M,100mL×3)洗涤,饱和食盐水(100mL)洗涤,经Na2SO4干燥,过滤并浓缩得到粗产物,直接进行步骤二反应。
步骤二:
(4-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)哌嗪-1-基(呋喃-2-基)甲酮。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.72(dd,J1=1.8Hz,J2=0.8Hz,1H),7.43(s,1H),7.21(d,J=1.8Hz,1H),7.06(dd,J1=3.5Hz,J2=0.8Hz,1H),7.01(d,J=1.8Hz,1H),6.62(dd,J1=3.5Hz,J2=1.8Hz,1H),4.72(t,J=6.5Hz,2H),3.79(s,4H),3.65(s,2H),3.48(t,J=6.5Hz,2H),2.45(t,J=5.1Hz,4H),2.02(s,3H).
13C NMR(126MHz,CD3OD)δ161.77,149.10,146.84,144.68,139.27,138.12,127.85,126.70,126.61,125.48,121.62,118.60,113.29,111.39,108.14,54.07,54.01,31.55,27.72,25.07,11.78.
HRMS(ESI,m/z):计算值C23H25Cl2N6O2:487.1411[M+H]+,实测值:487.1406.
实施例15
化合物19的合成:
2-(2-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲氧基)乙氧基)乙烷-1-醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,CDCl3)δ9.57(s,1H),7.14(s,1H),7.01(s,1H),6.92(s,1H),4.62(t,J=6.3Hz,2H),4.53(s,2H),3.74(s,2H),3.62–3.55(m,4H),3.53(d,J=4.5Hz,2H),3.35(t,J=6.3Hz,2H),1.78(s,3H).
13C NMR(126MHz,CDCl3)δ136.99,136.19,126.24,124.69,123.90,123.15,120.28,109.74,106.18,72.47,70.27,69.34,64.13,61.47,52.27,26.25,10.59.
HRMS(ESI,m/z):计算值C18H23Cl2N4O3:413.1142[M+H]+,实测值:413.1136.
实施例16
化合物20的合成:
(4-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)苯基)硼酸。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.83(d,J=7.9Hz,1H),7.74(d,J=7.4Hz,1H),7.48(d,J=7.9Hz,2H),7.45(d,J=8.0Hz,1H),7.18(t,J=7.6Hz,1H),7.11(t,J=7.6Hz,1H),7.08(s,1H),6.89(s,1H),4.74(s,2H),1.49(s,6H).
13C NMR(126MHz,CD3OD)δ148.53,139.83,136.28,136.00,130.57,127.33,126.35,124.39,123.59,123.35,121.98,121.50,120.90,113.80,61.97,38.68,27.72.
HRMS(ESI,m/z):计算值C20H22BN4O2:361.1830[M+H]+,实测值:361.1828.
实施例17
化合物21的合成:
(4-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)苯基)甲醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.87(d,J=8.0Hz,1H),7.52(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,1H),7.36(d,J=8.0Hz,2H),7.19(t,J=7.7Hz,1H),7.15-7.10(m,2H),6.94(s,1H),4.82(s,2H),4.61(s,2H),1.54(s,6H).
13C NMR(126MHz,CD3OD)δ148.53,143.67,139.90,131.43,129.28,127.41,127.34,124.42,123.38,123.35,122.01,121.58,120.89,113.80,65.67,62.04,38.76,27.77.
HRMS(ESI,m/z):计算值C21H23N4O:347.1866[M+H]+,实测值:347.1864.
实施例18
化合物22的合成:
4-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)丁腈。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.68(s,1H),7.25(s,1H),7.00(s,1H),4.47(t,J=6.9Hz,2H),3.27(t,J=6.9Hz,2H),2.65(t,J=7.4Hz,2H),2.47(t,J=7.1Hz,2H),1.96(s,3H),1.82(p,J=7.4Hz,2H).
13C NMR(126MHz,DMSO-d6)δ145.12,136.70,136.42,124.53,123.96,123.13,122.32,120.38,119.02,109.62,105.97,51.14,25.72,24.90,23.94,15.76,10.53.
HRMS(ESI,m/z):计算值C17H18Cl2N5:362.0934[M+H]+,实测值:362.0931.
实施例19
化合物23的合成:
4-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)-3-丁醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.37(s,1H),7.21(d,J=1.7Hz,1H),7.00(d,J=1.7Hz,1H),4.64(t,J=6.7Hz,2H),3.69(td,J1=7.4Hz,J2=3.8Hz,1H),3.44(t,J=6.7Hz,2H),2.77(qd,J1=7.4Hz,J2=3.8Hz,2H),2.01(s,3H),1.52-1.32(m,2H).0.97(t,J=7.4Hz,3H).
13C NMR(101MHz,CD3OD)δ146.76,139.39,138.22,127.86,126.63,125.53,125.48,121.57,111.38,108.23,74.10,54.01,34.74,31.23,27.89,11.62,11.13.
HRMS(ESI,m/z):计算值C17H21Cl2N4O:367.1687[M+H]+,实测值:367.1084.
实施例20
化合物24的合成:
N-((1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)甲基)-2-苯乙酰胺。
以与化合物16类似的方式制备。
原料:CAS:174271-37-5,合成的参照文献:Agrofoglio,Luigi A.;Becker,Hubert F.;Biteau,Nicolas G.;Lambry,Jean-Christophe;Myllykallio,Hannu;Roy,Vincent.Bioorganic and Medicinal Chemistry,2021,46,116351。
1H NMR(400MHz,CD3OD)δ7.80(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.32-7.20(m,5H),7.17(M,1H),7.10(m,1H),6.86(s,1H),6.79(s,1H),4.72(s,2H),4.26(s,2H),3.45(s,2H),1.44(s,6H).
13C NMR(126MHz,CD3OD)δ174.63,146.10,139.86,137.53,130.94,130.43,128.77,127.28,125.43,124.28,123.29,121.91,121.48,120.81,113.83,61.91,44.47,38.59,36.41,27.73.
HRMS(ESI,m/z):计算值C23H26N5O:388.2132[M+H]+,实测值:388.2127.
实施例21
化合物25的合成:
2-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)丁烷-2-胺。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.81(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.19-7.14(td,J1=7.5Hz,J2=1.2Hz,1H),7.10(td,J1=7.5Hz,J2=1.2Hz,1H),6.89(s,1H),6.71(s,1H),4.74(s,2H),1.65(q,J=7.4Hz,2H),1.51(s,6H),1.28(s,3H),0.64(t,J=7.4Hz,3H).
13C NMR(101MHz,CD3OD)δ155.10,139.84,127.46,124.31,123.82,123.27,121.97,121.58,120.84,113.76,62.00,53.46,38.82,37.78,28.32,27.82,9.61.
HRMS(ESI,m/z):计算值C18H26N5:312.2183[M+H]+,实测值:312.2181.
实施例22
化合物26的合成:
1-环丙基-3-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)脲。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.45(s,1H),7.22(d,J=1.8Hz,1H),7.01(d,J=1.8Hz,1H),4.66(t,J=6.7Hz,2H),4.36(s,2H),3.44(t,J=6.6Hz,2H),2.45(tt,J1=7.0Hz,J2=3.6Hz,1H),1.98(s,3H),0.71(td,J1=7.0Hz,J2=4.8Hz,2H),0.49-0.42(m,2H).
13C NMR(126MHz,CD3OD)δ162.58,139.41,138.30,127.89,126.64,125.46,125.20,121.57,111.41,108.18,59.19,54.12,37.00,27.92,23.99,19.23,11.56,8.33.
HRMS(ESI,m/z):计算值C18H21Cl2N6O:407.1148[M+H]+,实测值:407.1844.
实施例23
化合物27的合成:
4-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)硫代吗啉1,1-二氧化物。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.41(s,1H),7.20(d,J=1.7Hz,1H),6.99(d,J=1.7Hz,1H),4.70(t,J=6.5Hz,2H),3.74(s,2H),3.45(t,J=6.5Hz,2H),3.08–3.03(m,4H),2.88–2.84(m,4H),1.99(s,3H).
13C NMR(101MHz,CD3OD)δ139.37,138.24,127.95,126.68,125.53,121.69,111.46,108.19,54.16,53.02,52.13,50.71,27.74,11.74.
HRMS(ESI,m/z):计算值C18H22Cl2N5O2S:442.0866[M+H]+,实测值:442.0860.
实施例24
化合物28的合成:
1-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)脲。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),7.77(s,1H),7.28(d,J=1.8Hz,1H),7.06(d,J=1.8Hz,1H),6.33(s,1H),5.51(s,1H),4.51(t,J=7.1Hz,2H),4.17(d,J=5.1Hz,2H),3.33–3.28(m,2H),2.03(s,3H).
13C NMR(101MHz,DMSO-d6)δ158.58,145.97,136.74,136.58,124.54,123.96,123.16,122.52,119.04,109.66,105.95,51.13,34.92,25.78,10.61.
HRMS(ESI,m/z):计算值C15H17Cl2N6O:367.0835[M+H]+,实测值:367.0832.
实施例25
化合物29的合成:
2-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲氧基)乙烷-1-醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.56(s,1H),7.17(d,J=1.7Hz,1H),6.96(d,J=1.7Hz,1H),4.63(t,J=6.7Hz,2H),4.55(s,2H),3.67–3.62(m,2H),3.52–3.48(m,2H),3.40(t,J=6.7Hz,2H),1.96(s,3H).
13C NMR(126MHz,CD3OD)δ139.25,138.12,127.76,126.52,126.19,125.34,121.50,111.36,108.01,73.53,65.55,62.93,54.04,27.86,11.58.
HRMS(ESI,m/z):计算值C16H18Cl2N4O2:369.0880[M+H]+,实测值:369.0874.
实施例26
化合物30的合成:
2-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)乙基4-甲基苯磺酸酯。
以与化合物16类似的方式制备。
1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),7.75–7.70(m,3H),7.45(d,J=8.0Hz,2H),7.28(d,J=1.7Hz,1H),7.06(d,J=1.7Hz,1H),4.48(t,J=7.0Hz,2H),4.21(t,J=6.5Hz,2H),3.27(t,J=7.0Hz,2H),2.92(t,J=6.5Hz,2H),2.41(s,3H),1.99(s,3H).
13C NMR(126MHz,DMSO-d6)δ144.97,141.90,136.70,136.52,132.23,130.17,127.59,124.51,123.93,123.12,122.90,119.02,109.65,105.91,69.58,51.16,25.73,25.14,21.13,10.56.
HRMS(ESI,m/z):计算值C22H23Cl2N4O3S:493.0862[M+H]+,实测值:493.0863.
实施例27
化合物31的合成:
4-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)丁醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.30(s,1H),7.22(d,J=1.7Hz,1H),7.01(d,J=1.7Hz,1H),4.65(t,J=6.6Hz,2H),3.58(t,J=6.6Hz,2H),3.44(t,J=6.6Hz,2H),2.66(t,J=7.5Hz,2H),1.98(s,3H),1.72-1.61(m,2H),1.59-1.49(m,2H).
13C NMR(126MHz,CD3OD)δ139.35,138.16,127.85,126.64,125.45,124.66,121.56,111.37,108.24,63.36,54.02,33.77,27.90,27.85,26.76,11.58.
HRMS(ESI,m/z):计算值C17H21Cl2N4O:367.1087[M+H]+,实测值:367.1084.
实施例28
化合物32的合成:
4-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)(羟基)甲基)苯甲酸甲酯。
以与化合物16类似的方式制备。
原料:合成参考文献:Petrone,David A.;Isomura,Mayuko;Franzoni,Ivan;Simon L.;Carreira,Erick M.Journal of the AmericanChemical Society,2018,140,13,4697-4704。
1H NMR(400MHz,DMSO-d6)δ10.95(d,J=2.6Hz,1H),7.92(d,J=8.1Hz,2H),7.82(d,J=8.1Hz,1H),7.39(d,J=8.3Hz,3H),7.13–7.05(m,2H),7.03–6.95(m,2H),5.83–5.78(m,1H),4.64(s,2H),3.85(s,3H),1.35(d,J=12.3Hz,6H).
13C NMR(126MHz,DMSO-d6)δ166.18,149.94,149.30,137.13,129.07,128.32,126.57,124.97,122.80,122.38,120.80,120.12,119.47,118.47,111.92,67.39,67.30,59.04,52.08,36.14,26.23,26.19.
HRMS(ESI,m/z):计算值C23H25N4O3:405.1921[M+H]+,实测值:405.1915.
实施例29
化合物33的合成:
3-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)氧杂环丁烷-3-醇。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),7.89(s,1H),7.28(d,J=1.7Hz,1H),7.06(d,J=1.7Hz,1H),6.39(s,1H),4.80(d,J=6.2Hz,2H),4.67(d,J=6.2Hz,2H),4.54(t,J=7.0Hz,2H),3.36–3.27(m,2H),2.00(s,3H).
13C NMR(126MHz,DMSO-d6)δ150.23,136.69,136.54,124.51,123.97,123.13,121.99,119.02,109.61,105.91,83.73,70.39,51.20,25.73,10.53.
HRMS(ESI,m/z):计算值C16H17Cl2N4O2:367.0723[M+H]+,实测值:367.0721.
实施例30
化合物34的合成:
6-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)吡啶-3-胺。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ10.94(d,J=2.0Hz,1H),8.26(s,1H),7.84(m,2H),7.69(dd,J1=8.4Hz,J2=2.0Hz,1H),7.40(d,J=8.4Hz,1H),7.13–7.07(m,2H),7.03(t,J=7.0Hz,1H),6.49(s,1H),6.08(s,2H),4.66(s,2H),1.40(s,6H).
13C NMR(126MHz,DMSO-d6)δ159.80,145.24,144.48,137.61,134.61,125.52,122.73,121.29,120.82,120.62,120.15,118.90,112.36,59.80,36.52,26.71.
HRMS(ESI,m/z):计算值C19H21N6:333.1822[M+H]+,实测值:333.1816.
实施例31
化合物35的合成:
3-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)咪唑并[1,2-b]哒嗪。
以与化合物16类似的方式制备。
1H NMR(500MHz,DMSO-d6)δ10.92(s,1H),8.49(d,J=4.4Hz,1H),8.28–8.19(m,1H),7.97–7.89(m,2H),7.43(d,J=8.1Hz,1H),7.26(dd,J1=9.0Hz,J2=4.4Hz,1H),7.14(t,J=7.5Hz,1H),7.06(t,J=7.5Hz,1H),7.00(d,J=2.4Hz,1H),4.83(s,2H),1.43(s,6H).
13C NMR(126MHz,DMSO-d6)δ144.08,137.26,134.97,131.19,125.98,125.06,122.63,122.15,120.89,120.21,119.35,118.57,117.00,111.90,59.16,36.32,26.22.
HRMS(ESI,m/z):计算值C20H20N7:358.1775[M+H]+,实测值:358.1771.
实施例32
化合物36的合成:
3-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)-N-苯基丙酰胺。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.90(s,1H),7.79(d,J=8.0Hz,1H),7.56(d,J=7.3Hz,2H),7.38(d,J=8.0Hz,1H),7.30–7.23(m,3H),7.09(t,J=7.6Hz,1H),7.04–6.98(m,3H),4.60(s,2H),2.85(t,J=7.5Hz,2H),2.59(t,J=7.5Hz,2H),1.31(s,6H).
13C NMR(126MHz,DMSO-d6)δ170.14,144.98,139.23,137.14,128.65,125.01,123.01,122.79,122.17,120.81,120.14,119.77,119.03,118.42,111.90,59.04,36.01,26.17,21.03.
HRMS(ESI,m/z):计算值C23H26N5O:388.2132[M+H]+,实测值:388.2128.
实施例33
化合物37的合成:
N-((1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)甲基)乙酰胺。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.48(s,1H),7.22(d,J=1.7Hz,1H),7.01(d,J=1.7Hz,1H),4.66(t,J=6.7Hz,2H),4.37(s,2H),3.44(t,J=6.7Hz,2H),1.99(s,3H),1.96(s,3H).
13C NMR(101MHz,CD3OD)δ173.98,139.43,138.25,127.91,126.66,125.47,121.58,111.40,108.18,54.13,36.39,27.91,23.28,11.53.
HRMS(ESI,m/z):计算值C16H18Cl2N5O:366.0883[M+H]+,实测值:366.0880.
实施例34
化合物38的合成:
N-叔丁氧羰基-2-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)乙氨。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.42(s,1H),7.22(d,J=1.7Hz,1H),7.02(d,J=1.7Hz,1H),4.65(t,J=6.7Hz,2H),3.44(t,J=6.7Hz,2H),3.27(t,J=6.8Hz,2H),2.82(t,J=6.8Hz,2H),2.00(s,3H),1.44(s,9H).
13C NMR(126MHz,CD3OD)δ139.42,138.20,127.92,126.66,125.49,121.59,111.44,108.27,80.95,54.08,42.00,29.59,27.93,27.84,11.57.
化合物39的合成:
2-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)乙铵三氟乙酸盐。
向带有磁子的20mL圆柱形玻璃瓶子中加入化合物38(153mg,0.35mmol,1equiv,根据“化合物38的合成”制得),溶于DCM(2mL)中,向溶液中加入三氟乙酸(2mL),混合物在室温下搅拌1小时。LC-MS检测反应结束后,将混合物蒸发干燥,加入少许甲苯再次将混合体系蒸发干燥后,得到浅黄色固体(150mg,95%产率)。
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.01(s,2H),7.88(s,1H),7.30(d,J=1.8Hz,1H),7.05(d,J=1.8Hz,1H),4.51(t,J=7.1Hz,2H),3.31(t,J=7.1Hz,2H),3.10–3.03(m,2H),2.91(t,J=7.7Hz,2H),2.05(s,3H).
19F NMR(376MHz,DMSO-d6)δ-73.70.
13C NMR(126MHz,DMSO-d6)δ142.53,136.77,136.54,124.53,123.93,123.17,122.92,119.03,109.73,105.88,51.23,38.46,25.76,23.42,10.62.
HRMS(ESI,m/z):计算值C15H18Cl2N5:338.0934[M-CF3COO-]+,实测值:338.0930.
实施例35
化合物40的合成:
N-叔丁氧羰基-2-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)丙氨。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.33(s,1H),7.22(d,J=1.7Hz,1H),7.02(d,J=1.7Hz,1H),4.65(t,J=6.6Hz,2H),3.45(t,J=6.6Hz,2H),3.04(t,J=6.9Hz,2H),2.66(t,J=7.6Hz,2H),1.98(s,3H),1.75(p,J=7.1Hz,2H),1.46(s,9H).
13C NMR(126MHz,CD3OD)δ138.22,127.91,126.69,125.50,124.74,121.60,111.41,108.28,80.78,54.05,41.37,31.72,29.64,27.93,24.24,11.56.
化合物41的合成:
2-(1-(2-(4,6-二氯-2-甲基-1H-吲哚-3-基)乙基)-1H-1,2,3-三唑-4-基)丙铵三氟乙酸盐。
以与化合物39类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),7.95(s,2H),7.72(s,1H),7.29(d,J=1.8Hz,1H),7.04(d,J=1.8Hz,1H),4.50(t,J=6.9Hz,2H),3.30(t,J=6.9Hz,2H),2.83(m,2H),2.66(t,J=7.5Hz,2H),2.00(s,3H),1.86(p,J=7.6Hz,2H).
19F NMR(376MHz,DMSO-d6)δ-73.87.
13C NMR(126MHz,DMSO-d6)δ145.55,136.79,136.52,124.53,123.96,123.17,122.23,119.03,109.74,105.98,51.18,38.43,27.00,25.81,21.99,10.57.
HRMS(ESI,m/z):计算值C16H20Cl2N5:352.1090[M-CF3COO-]+,实测值:352.1086.
实施例36
化合物42的合成:
(R)-N-((1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)甲基)-2,3-二氢-1H-茚-1-胺。
以与化合物16类似的方式制备。
1H NMR(500MHz,CD3OD)δ7.80(d,J=8.0Hz,1H),7.39-7.36(m,1H),7.25-7.20(m,3H),7.19-7.16(m,1H),7.14(t,J=7.6Hz,1H),7.09(t,J=7.6Hz,1H),6.88(d,J=5.6Hz,2H),4.75(s,2H),4.03-3.98(m,1H),3.82-3.71(m,2H),3.05-2.96(m,1H),2.83-2.73(m,1H),2.28-2.19(m,1H),2.16(s,1H),1.84-1.74(m,1H),1.48(d,J=3.4Hz,6H).
13C NMR(126MHz,CD3OD)δ145.95,139.84,129.75,128.20,127.35,126.65,126.16,125.82,124.30,123.27,121.91,121.49,120.84,113.84,63.64,61.91,38.71,33.89,32.04,27.91,27.88.
HRMS(ESI,m/z):计算值C24H27N5:386.2339[M+H]+,实测值:386.2333.
实施例37
化合物43的合成:
3-(2-甲基-1-(4-(甲基磺酰基)苯基)-1H-1,2,3-三唑-1-基)丙烷-2-基)-1H吲哚。
以与化合物16类似的方式制备。
1H NMR(400MHz,CD3OD)δ7.89(d,J=8.4Hz,2H),7.83(d,J=8.0Hz,1H),7.76(d,J=8.4Hz,2H),7.44(d,J=8.0Hz,1H),7.32(s,1H),7.18(t,J=7.6Hz,1H),7.10(t,J=7.6Hz,1H),6.92(s,1H),4.80(s,2H),3.11(s,3H),1.52(s,6H).
13C NMR(126MHz,CD3OD)δ146.77,141.86,139.84,137.87,129.90,127.87,127.37,124.89,124.42,123.37,122.01,121.46,120.91,113.83,62.16,45.16,38.74,27.76.
HRMS(ESI,m/z):计算值C21H23N4O2S:395.1536[M+H]+,实测值:395.1530.
实施例38
化合物44的合成:
4-(1-(2-(1H-吲哚-3-基)-2-甲基丙基)-1H-1,2,3-三唑-4-基)喹啉。
以与化合物16类似的方式制备。
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.90(d,J=4.5Hz,1H),8.04(dd,J1=14.4Hz,J2=8.5Hz,2H),7.90–7.84(m,2H),7.79(t,J=7.6Hz,1H),7.67(d,J=4.5Hz,1H),7.62(t,J=7.6Hz,1H),7.46(d,J=8.1Hz,1H),7.13(t,J=7.5Hz,1H),7.09(d,J=2.5Hz,1H),7.04(t,J=7.5Hz,1H),4.82(s,2H),1.49(s,6H).
13C NMR(126MHz,DMSO-d6)δ150.22,148.32,142.09,137.17,135.69,129.64,129.51,127.14,125.89,125.07,125.04,124.56,122.72,120.98,120.11,119.93,119.32,118.65,111.97,59.46,36.44,26.34.
HRMS(ESI,m/z):计算值C23H22N5:368.1870[M+H]+,实测值:368.1865.
效果实施例:
由GLP-1(9-36)NH2和小分子引起的GLP-1R介导的激动活性cAMP细胞活性实验如下:
GLP-1R介导的cAMP信号通路的激动活性通过基于细胞的功能分析检测,应用HTRF(均相时间分辨)cAMP检测试剂盒(Cisbio,货号62AM4PEC)检测细胞内cAMP水平。该方法的原理基于均相时间分辨技术,由细胞产生的天然cAMP和d2标记的cAMP与铕标记的抗cAMP抗体竞争结合。该特异性信号与标准品或样品中的cAMP浓度成反比。
本实验采用的细胞系为稳定表达人源GLP-1R的中国仓鼠卵巢细胞系(DiscoverX,货号95-0062C2)。GLP-1R稳转细胞系培养在含有10%胎牛血清(Cellgro,货号35-081-CV)和800μg/mL G418(Invivogen,货号ant-gn-5)的Ham’s F12培养基(Cellfro,货号10-080-CV)中。细胞接种在10cm细胞培养皿培养箱中,条件设定为5%CO2、37℃静置培养48小时。
当细胞融合至80%~90%时,细胞解离液(Sigma,货号C5914-100ML)消化细胞后,用1%透析胎牛血清(Gibco,货号26400044)的Ham’s F12培养基重悬细胞,对细胞悬液计数以确定细胞个数和细胞存活率,用1%透析胎牛血清的Ham’s F12培养基调整细胞浓度至5×105个每毫升。向384浅孔板(Thermo/Nunc,货号264706)递送细胞,每个孔加入的细胞悬液体积为5μL,细胞数量为2500个。
用含有0.1%BSA(Sigma Aldrich,货号A7030)的HBSS(Hyclone,货号SH30268.01)缓冲液来稀释溶于DMSO(Sigma-Aldirich,货号D2438)中的测试化合物和溶解于无菌的去离子水中的GLP-1(9-36)-酰胺得到4×药物缓冲液。先将2.5μL稀释的不同浓度的4×测试化合物缓冲液加入到384浅孔板的细胞悬液中,室温孵育10分钟。再将2.5μL稀释好的固定亚阈值浓度(EC20,20%最大效应浓度)的4×GLP-1(9-36)-酰胺缓冲液加入到384浅孔板的细胞悬液中,GLP-1(9-36)-酰胺作用终浓度为1μM,室温孵育15至20分钟。孵育结束后,将5μL d2标记的cAMP和5μL抗cAMP抗体(两者分别用细胞裂解缓冲液以1:20稀释)分别加入到384浅孔板中,在室温下避光孵育60分钟。在60分钟后应用EnVision多功能酶标仪(PerkinElmer)使用330nM激发及615和665nM发光来读取HTRF信号变化。将原始数据转换成cAMP浓度(详见检测试剂盒说明书),将测试小分子的实验结果归一化至%BETP响应值,最后通过GraphPad Prism 7软件对数据进行非线性回归分析生成剂量反应曲线并确定化合物的EC50和EMAX(参考J.Med.Chem.2020,63,2292-2307;ACS Chem Biol 2021,16(11),2444-2452.),结果显示于表1。
表1 GLP-1R稳转细胞系中各化合物的活性
Claims (10)
1.一种如式I所示的化合物或其药学上可接受的盐:
L1为化学键、C1-C6亚烷基或-C1-C6亚烷基-C3-C6亚环烷基-;
R1为C6-C10芳基、5-10元杂芳基、被1个、2个或3个R1-1取代的C6-C10芳基或被1个、2个或3个R1-2取代的5-10元杂芳基;所述的5-10元杂芳基和被1个、2个或3个R1-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2为C1-C6烷基、3-10元杂环烷基、C6-C10芳基、5-10元杂芳基、被1个、2个或3个R2-1取代的C1-C6烷基、被1个、2个或3个R2-3取代的3-10元杂环烷基、被1个、2个或3个R2-4取代的C6-C10芳基或被1个、2个或3个R2-2取代的5-10元杂芳基;所述的3-10元杂环烷基和所述的被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;所述的5-10元杂芳基和被1个、2个或3个R2-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
L2为C1-C6亚烷基;L3为C1-C6亚烷基;
R2-1独立地为-CN、-OH、-N(R2-1-1R2-1-2)、-NHC(=O)-R2-1-3、-O-S(=O)2-R2-1-5、-C(=O)-NH-R2-1-6、-(OCH2CH2)n-OH、3-10元杂环烷基、C6-C10芳基、被1个、2个或3个R2-1-8取代的3-10元杂环烷基或被1个、2个或3个R2-1-7取代的C6-C10芳基;所述3-10元杂环烷基和所述的被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2-1-1和R2-1-2独立地为氢、C1-C6烷基、C6-C10芳基或被1个、2个或3个C6-C10芳基取代的C1-C6烷基;
R2-1-3独立地为-N(R2-1-3-1R2-1-3-2)、C1-C6烷基或被1个、2个或3个C6-C10芳基取代的C1-C6烷基;R2-1-3-1和R2-1-3-2独立地为氢、C1-C6烷基或C3-C6环烷基;
R2-1-5和R2-1-6独立地为C6-C10芳基或被1个、2个或3个R2-1-5-1取代的C6-C10芳基;R2-1-5-1独立地为C1-C6烷基;
n为1、2或3;
R2-1-8独立地为氧代(=O)或-C(=O)-R2-1-8-1;R2-1-8-1独立地为5-10元杂芳基;所述的5-10元杂芳基中,所述的杂原子独立地选自N、O和S中的一种或多种,所述的杂原子的数量独立地为1个、2个或3个;
R2-3为-OH;
R2-2为-NH2;
2.如权利要求1所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,其满足如下条件中的一个或多个:
(1)所述的如式I所示的化合物的药学上可接受的盐为三氟乙酸盐;
(2)L1中,所述C1-C6亚烷基为-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-、-C(CH3)2-、-C(CH3)2CH2-或-CH(C(CH3)3)-;优选为-CH2-、-CH2CH2-、-C(CH3)2-、-C(CH3)2CH2-或-CH(C(CH3)3)-;
(3)L1中,所述-C1-C6亚烷基-C3-C6亚环烷基-中的-C1-C6亚烷基-为-C1-C3亚烷基-;优选为-亚甲基-;
(4)L1中,所述-C1-C6亚烷基-C3-C6亚环烷基-中的-C3-C6亚环烷基-为-C3-C4亚环烷基-;
(6)R1中,所述5-10元杂芳基和所述被1个、2个或3个R1-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子选自N,所述的杂原子的数量为1个;
(7)R1-1中,所述卤素为氟、氯、溴或碘;优选为氯;
(8)R1-1中,所述C1-C6烷基为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如甲基;
(9)R1-1中,所述C1-C6烷氧基为C1-C4烷氧基;优选为甲氧基或乙氧基;例如甲氧基;
(10)R1-2-1中,所述C1-C6烷基为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如叔丁基;
(11)R1-2中,所述卤素为氟、氯、溴或碘;优选为氯;
(12)R1-2中,所述C1-C6烷基为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;例如甲基;
(13)R1-2中,所述C1-C6烷氧基为C1-C4烷氧基;优选为甲氧基或乙氧基;例如甲氧基;
(14)L2中,所述C1-C6亚烷基为C1-C3亚烷基;优选为-CH2-;
(15)L3中,所述C1-C6亚烷基为C1-C3亚烷基;优选为-CH2CH2-;
(16)R2中,所述的5-10元杂芳基和被1个、2个或3个R2-2取代的5-10元杂芳基里的“5-10元杂芳基”中,所述的杂原子为N;
(17)R2中,所述的C1-C6烷基和被1个、2个或3个R2-1取代的C1-C6烷基里C1-C6烷基为C1-C4烷基;优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;
(18)R2-1-1中,所述C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(19)R2-1-2中,所述C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(22)R2-1-3中,所述的C1-C6烷基和被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(23)R2-1-3中,所述的被1个、2个或3个C6-C10芳基取代的C1-C6烷基里的C6-C10芳基为苯基或萘基,优选为苯基;
(24)R2-1-3-1中,所述C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(25)R2-1-3-2中,所述C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(26)R2-1-3-1中,所述C3-C6环烷基为环丙基、环丁基、环戊基或环己基,例如环丙基;
(27)R2-1-3-2中,所述C3-C6环烷基为环丙基、环丁基、环戊基或环己基,例如环丙基;
(28)R2-1-5中,所述C6-C10芳基和被1个、2个或3个R2-1-5-1取代的C6-C10芳基里的C6-C10芳基为苯基或萘基,优选为苯基;
(29)R2-1-6中,所述C6-C10芳基和被1个、2个或3个R2-1-5-1取代的C6-C10芳基里的C6-C10芳基为苯基或萘基,优选为苯基;
(30)R2-1-5-1中,所述C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(31)R2-1中,所述的C6-C10芳基和被1个、2个或3个R2-1-7取代的C6-C10芳基里C6-C10芳基为苯基或萘基,优选为苯基;
(32)R2-1-7-1中,所述C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基;
(33)R2-1中,所述3-10元杂环烷基和被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子独立地选自N和S;所述的杂原子的数量独立地为1个或2个;
(34)R2-1中,所述3-10元杂环烷基和被1个、2个或3个R2-1-8取代的3-10元杂环烷基里的“3-10元杂环烷基”为5-6元杂环烷基;
(35)R2中,所述的3-10元杂环烷基和被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”中,所述的杂原子选自O;所述的杂原子的数量为1个;
(36)R2中,所述的3-10元杂环烷基和被1个、2个或3个R2-3取代的3-10元杂环烷基里的“3-10元杂环烷基”为4-6元杂环烷基;
(37)R2中,所述的C6-C10芳基和被1个、2个或3个R2-4取代的C6-C10芳基里C6-C10芳基为苯基或萘基,优选为苯基;
(38)R2-4中,所述的被1个、2个或3个R2-4-2取代的C1-C6烷基里的C1-C6烷基为C1-C3烷基;优选为甲基、乙基、正丙基或异丙基;例如甲基。
3.如权利要求2所述的如式I所示的化合物或其药学上可接受的盐,其特征在于,其满足如下条件中的一个或多个:
7.一种药物组合物,其特征在于,其包括物质A和至少一种药用辅料;所述的物质A为如权利要求1~6中任一项所述的如式I所示的化合物或其药学上可接受的盐。
8.一种物质B在制备GLP-1R正向别构调节剂中的应用;
所述物质B为:
(1)如权利要求1~6中任一项如式I所示的化合物或其药学上可接受的盐;或者,
(2)如权利要求7所述的药物组合物;
例如,所述的GLP-1R正向别构调节剂可调节GLP-1(9-36)NH2与GLP-1R的结合。
9.一种物质B在制备治疗和/或预防与GLP-1R相关的疾病的药物中的应用;
所述物质B为:
(1)如权利要求1~6中任一项如式I所示的化合物或其药学上可接受的盐;或者,
(2)如权利要求7所述的药物组合物;
例如,所述与GLP-1R相关的疾病可为代谢性疾病、帕金森综合征、阿尔兹海默症或非酒精性脂肪性肝炎;所述代谢性疾病优选为2型糖尿病、胰岛素抵抗或肥胖。
10.一种物质B在制备药物中的应用;
所述物质B为:
(1)如权利要求1~6中任一项如式I所示的化合物或其药学上可接受的盐;或者,
(2)如权利要求7所述的药物组合物;
所述的药物为用于治疗以下一种或多种疾病的药物:代谢性疾病、帕金森综合征、阿尔兹海默症和非酒精性脂肪性肝炎;
例如,所述代谢性疾病优选为2型糖尿病、胰岛素抵抗或肥胖。
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