CN116693416A - 一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 - Google Patents
一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN116693416A CN116693416A CN202310661008.1A CN202310661008A CN116693416A CN 116693416 A CN116693416 A CN 116693416A CN 202310661008 A CN202310661008 A CN 202310661008A CN 116693416 A CN116693416 A CN 116693416A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- dmso
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Aryloxy aminobenzoic acid derivative Chemical class 0.000 title claims abstract description 186
- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- 150000001875 compounds Chemical class 0.000 claims abstract description 201
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 4
- 230000020477 pH reduction Effects 0.000 claims abstract description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 43
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 102100038495 Bile acid receptor Human genes 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 20
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 claims description 19
- 230000002829 reductive effect Effects 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 235000010290 biphenyl Nutrition 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 6
- 229960005274 benzocaine Drugs 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 206010008635 Cholestasis Diseases 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 abstract description 2
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 abstract description 2
- 229940043259 farnesol Drugs 0.000 abstract description 2
- 229930002886 farnesol Natural products 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 abstract description 2
- 230000009435 amidation Effects 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- 150000005338 nitrobenzoic acids Chemical class 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 58
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 53
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 50
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 44
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 40
- 241000699670 Mus sp. Species 0.000 description 34
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 30
- 210000004185 liver Anatomy 0.000 description 29
- 229960001601 obeticholic acid Drugs 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 26
- 230000000694 effects Effects 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 210000002966 serum Anatomy 0.000 description 18
- 150000002632 lipids Chemical class 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 10
- 239000011734 sodium Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ZAYYSJVSIXZJNE-UHFFFAOYSA-N 4-(4-propanoylphenoxy)butanoic acid Chemical group CCC(=O)C1=CC=C(OCCCC(O)=O)C=C1 ZAYYSJVSIXZJNE-UHFFFAOYSA-N 0.000 description 5
- CROYTYSPZWBOAG-UHFFFAOYSA-N 5-(4-acetylphenoxy)pentanoic acid Chemical compound CC(=O)C1=CC=C(OCCCCC(O)=O)C=C1 CROYTYSPZWBOAG-UHFFFAOYSA-N 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 5
- 230000001270 agonistic effect Effects 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 235000009200 high fat diet Nutrition 0.000 description 5
- 229940118019 malondialdehyde Drugs 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- FNHIEZKOCYDCOH-UHFFFAOYSA-N 4-(4-acetylphenoxy)butanoic acid Chemical compound CC(=O)C1=CC=C(OCCCC(O)=O)C=C1 FNHIEZKOCYDCOH-UHFFFAOYSA-N 0.000 description 4
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 4
- 102000016938 Catalase Human genes 0.000 description 4
- 108010053835 Catalase Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- 206010067125 Liver injury Diseases 0.000 description 4
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000001789 adipocyte Anatomy 0.000 description 4
- 210000000593 adipose tissue white Anatomy 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 231100000753 hepatic injury Toxicity 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- JYEGGFMXLMBMPD-UHFFFAOYSA-N 4-(4-phenylmethoxyphenoxy)butanoic acid Chemical compound C1=CC(OCCCC(=O)O)=CC=C1OCC1=CC=CC=C1 JYEGGFMXLMBMPD-UHFFFAOYSA-N 0.000 description 3
- SBRAJDSNLRABGN-UHFFFAOYSA-N 4-(4-tert-butylphenoxy)butanoic acid Chemical compound CC(C)(C)C1=CC=C(OCCCC(O)=O)C=C1 SBRAJDSNLRABGN-UHFFFAOYSA-N 0.000 description 3
- ROEWDSOBRSEWBI-UHFFFAOYSA-N 4-naphthalen-2-yloxybutanoic acid Chemical compound C1=CC=CC2=CC(OCCCC(=O)O)=CC=C21 ROEWDSOBRSEWBI-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 230000002262 irrigation Effects 0.000 description 3
- 238000003973 irrigation Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 3
- AMBYTOJMLCFQTC-UHFFFAOYSA-N 5-(4-ethylphenoxy)pentanoic acid Chemical compound CCC1=CC=C(OCCCCC(O)=O)C=C1 AMBYTOJMLCFQTC-UHFFFAOYSA-N 0.000 description 2
- ZCJHJELVOVDWOP-UHFFFAOYSA-N 5-(4-tert-butylphenoxy)pentanoic acid Chemical compound CC(C)(C)C1=CC=C(OCCCCC(O)=O)C=C1 ZCJHJELVOVDWOP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- TWLLPUMZVVGILS-UHFFFAOYSA-N Ethyl 2-aminobenzoate Chemical compound CCOC(=O)C1=CC=CC=C1N TWLLPUMZVVGILS-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 108010052090 Renilla Luciferases Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000005417 aminobenzoic acid derivatives Chemical class 0.000 description 2
- 150000005415 aminobenzoic acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000003855 cell nucleus Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 201000010063 epididymitis Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000006372 lipid accumulation Effects 0.000 description 2
- 230000000512 lipotoxic effect Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000011118 potassium hydroxide Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000007863 steatosis Effects 0.000 description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000003934 vacuole Anatomy 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- ORUNWRBEMLXXLJ-UHFFFAOYSA-N 4-(4-ethylphenoxy)butanoic acid Chemical compound CCC1=CC=C(OCCCC(O)=O)C=C1 ORUNWRBEMLXXLJ-UHFFFAOYSA-N 0.000 description 1
- KZLLSSGOPIGKDO-UHFFFAOYSA-N 4-methyl-2-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 KZLLSSGOPIGKDO-UHFFFAOYSA-N 0.000 description 1
- XXHOTMZGOUFFSL-UHFFFAOYSA-N 5-(4-phenylmethoxyphenoxy)pentanoic acid Chemical compound C1=CC(OCCCCC(=O)O)=CC=C1OCC1=CC=CC=C1 XXHOTMZGOUFFSL-UHFFFAOYSA-N 0.000 description 1
- QRRSIFNWHCKMSW-UHFFFAOYSA-N 5-methyl-2-nitrobenzoic acid Chemical compound CC1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 QRRSIFNWHCKMSW-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Polymers C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 108070000005 Bile acid receptors Proteins 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- 238000013234 NASH mouse model Methods 0.000 description 1
- 238000013231 NASH rodent model Methods 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 1
- OROMVXLWBWNXIW-UHFFFAOYSA-N ethyl 2-amino-5-methylbenzoate Chemical compound CCOC(=O)C1=CC(C)=CC=C1N OROMVXLWBWNXIW-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 150000004780 naphthols Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于衍生物及其合成领域，具体公开一种芳氧氨基苯甲酸类衍生物及其制备方法和应用。提供了如式（I）所示衍生物，制备时以硝基苯甲酸类化合物为原料，经过酰胺化、还原、酸化等多步化学反应，制备得到芳氧氨基苯甲酸类衍生物。此外，本发明还公开式（I）所示衍生物或其药学上可接还原受的盐、或其药物组合物作为法尼醇X受体（FXR）调节剂，用于预防和/治疗FXR介导和/或涉及的疾病药物的开发。。
Description
技术领域
本发明属于衍生物及其合成领域，具体是一种芳氧氨基苯甲酸类衍生物及其制备方法和应用。
背景技术
法尼醇X受体(Farnesoid X receptor，FXR)也称为胆汁酸受体，属于核受体超家族的一员，主要分布于肝脏、肠道等器官。FXR在多种代谢途径中起到调节作用，在胆汁酸、胆固醇、脂质以及葡萄糖代谢中发挥着重要的作用，此外，FXR与胆汁淤积、非酒精性脂肪肝病、非酒精性脂肪性肝炎、胆结石、糖尿病、动脉粥样硬化和癌症等多种疾病有紧密的联系。
非酒精性脂肪性肝病(NAFLD)发病机制复杂，是目前全球最常见的慢性肝脏疾病。非酒精性脂肪性肝炎(NASH)是NAFLD的一个进展阶段，是一种代谢综合征的肝脏表现。FXR作为关键的代谢调节因子，已成为治疗NAFLD、NASH等慢性肝脏疾病的一个非常有前景的药物靶点(Zhou S，et al.Biomed Pharmaco,2022,154:113577；Panzitt K,et al.Mol CellEndocrinol,2022:111678)。
FXR调节剂包括FXR激动剂和拮抗剂(抑制剂)。目前众多医药公司和研究院所对FXR激动剂的研发投入了大量的人力物力，发现并报道了许多不同结构类型的FXR激动剂。FXR激动剂总体上可分为两类：一类为甾体类，以Intercept公司的奥贝胆酸(Obeticholicacid，OCA)为代表；另一类是非甾体类，以GlaxoSmithKline公司的GW4064为代表。胆酸衍生的FXR激动剂OCA作为原发性胆汁性胆管炎治疗药物，已经于2016年5月被美国FDA批准上市。OCA针对NASH适应症的临床三期研究已经结束，结果显示，OCA在治疗NASH合并肝纤维化是有效的，但是在结果中也提示，对血脂有负面影响，包括升高低密度脂蛋白(LDL)和降低高密度脂蛋白(HDL)水平，在心血管疾病风险较高的患者群体中，这些负面影响可能会带来大的副作用，并且部分患者出现皮肤瘙痒，且发生率不低于5％等安全性问题。这些不良反应将使OCA在NASH临床使用上受到限制。GW4064是葛兰素史克公司通过高通量筛选得到的第一个非甾体类FXR激动剂，具有高选择性且体外活性强。但是该化合物生物利用度很低，在大鼠体内不足10％，因此并没有进入临床开发阶段。而其他研究开发的一些非甾体活性化合物拥有良好的FXR靶点选择性，但大都存在溶解性和药代动力学性质差的问题。
文献报道氨基苯甲酸类化合物是一类的FXR激动剂，例如Bioorganic&MedicinalChemistry,2015,23:499–514；Bioorganic&Medicinal Chemistry,2014,22(8):2447-2460；Journal of medicinal chemistry,2014,57(19):8035–8055；ChemMedChem,2018,13(23):2530-2545。
尽管氨基苯甲酸类化合物的结构改造获得人们的广泛关注，数目众多的氨基苯甲酸类衍生物已被合成出来，但在生物活性、水溶性及口服生物利用度等成药性方面依然存在不足，到目前为止还未有一款氨基苯甲酸类衍生物进入临床试验研究。
发明内容
为了开拓临床药物的资源，本发明的目的是提供芳氧氨基苯甲酸类衍生物的制备方法及其应用。制备时选择不同的取代酚类或萘酚类衍生物为原料，经多步化学合成反应制备得到芳氧氨基苯甲酸类衍生物。
本发明的第一个方面，提供了如下式(I)所示的芳氧氨基苯甲酸类衍生物，
其中：Ar为取代苯基或萘基，优先选自4-乙基苯基、4-叔丁基苯基、2，4-二叔丁基苯基、4-乙酰基苯基、4-苄氧基苯基、4-丙酰基苯基、联苯基、萘基；
n独立选自2、3；
R1、R2各自独立选自氢、甲基、乙基；
R1、R2及—COOH基团位于苯环的任意位置。
在本发明的第一方面中，式(I)所示衍生物，选自以下化合物：
本发明中，如式(I)所示衍生物的药学上可接受的盐较佳的为本发明的羧基和碱性化合物反应产生的盐。所述的碱性化合物较佳的选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾等。上述药学上可接受的盐容易分离，式(I)所示的化合物可经柱层析纯化，式(I)所示衍生物与碱性化合物成盐可经重结晶纯化。
本发明的第二方面，提供结构如通式(I)所示的衍生物的制备方法，制备路线如下：
制备方法包括如下步骤：
步骤a.硝基苯甲酸及其不同的衍生物II和氨基苯甲酸乙酯及其不同的衍生物III，在适当溶剂和缩合试剂下进行酰胺化反应，制备得到中间体化合物IV；
步骤b.式IV所示化合物在有机溶剂和还原试剂下，经过还原反应制备得到化合物5a-f；
步骤c.化合物5a-f分别与芳氧羧酸类衍生物6a-p进行酰胺化反应，生成式VI所示的芳氧氨基苯甲酸酯类衍生物；
步骤d.式VI所示化合物在有机溶剂以及碱性条件下水解，然后酸化反应制备得到式(I)所示的衍生物。
其中式(II)、式(III)、式(IV)、化合物5a-f和式(VI)所示化合物及式(I)所示化合物中R1、R2定义一致。化合物6a-p所示化合物、式(VI)所示化合物及式(I)所示化合物中Ar、n定义一致。
进一步地，制备方法，步骤a所述的硝基苯甲酸及其不同的衍生物II与氨基苯甲酸乙酯及其不同的衍生物III的摩尔比为1:1.1，反应温度为30～45℃；
步骤a所述适当溶剂，选自N,N-二甲基甲酰胺(DMF)、四氢呋喃(THF)、二氯甲烷、三氯甲烷、二甲基亚砜(DMSO)中一种；
步骤a所述的缩合试剂，缩合条件可适当有所差别，优先选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(简称：HATU)、N,N-二异丙基乙胺(简称：DIPEA)、DMF、反应温度为30～45℃；1-乙基-3(3-二甲基丙胺)碳二亚胺盐酸盐(简称：EDCI·HCl)、1-羟基苯并三唑(简称：HOBT)，DMF、反应温度为30～45℃；二环己基碳二亚胺作为缩合剂，四氢呋喃，反应温度为30～45℃。
进一步地，制备方法，步骤b所述的式(IV)所示化合物与还原试剂的摩尔比为1:5，反应温度为室温～45℃；
步骤b所述的有机溶剂，选自乙醇、甲醇、四氢呋喃、二氯甲烷中的一种；
步骤b所述的还原试剂，选自锌粉或铁粉；
步骤b中，本领域技术人员可以对反应条件做适当选择，例如，一种优选的操作实施方式可以是：式IV所示化合物在乙醇中，加锌粉还原得到衍生物5a-f；或者将式IV所示化合物在氢气氛围下，以5％ Pd/C为催化剂进行氢化还原制备得到化合物5a-f。
进一步地，制备方法，步骤c所述的化合物5a-f与化合物6a-p的摩尔比为1:1.3；
化合物6a-p可通过购买或者制备得到；
步骤c与步骤a方法相同，本领域技术人员可以对反应条件做适当选择。
进一步地，制备方法，步骤d所述的式(VI)所示化合物与碱的摩尔比为1:1.1；
步骤d所述的有机溶剂，选自乙醇、甲醇、四氢呋喃中的一种；
步骤d所述的碱，选自氢氧化钠或氢氧化钾；
步骤d所述的酸化反应条件，本领域技术人员可以对反应条件做适当选择，优先选用1mol/L盐酸溶液，调节pH＝1～2，在0～5℃下反应。
本发明的第三方面，将制备得到的衍生物或其药学上可接受的盐、或其药物组合物作为FXR调节剂，用于FXR相关的疾病，如非酒精性脂肪性肝病、非酒精性脂肪性肝炎、胆汁淤积性肝病、高脂血症、代谢性疾病如糖尿病及并发症等。本发明首先通过双荧光素酶报告基因检测法对所合成的芳氧氨基苯甲酸类衍生物进行FXR激动活性筛选，以及细胞毒活性测试，筛选出的优选化合物，并在体外进行了对游离脂肪酸诱导HepG-2细胞脂肪变性的改善作用研究，在体内进行了抗高脂饮食诱导的NASH小鼠的药效学研究，以及体内药代动力学和急性毒性研究。研究证明本发明芳氧氨基苯甲酸类衍生物可作为非甾体FXR调节剂，这类化合物可以有效地激动FXR受体，有效改善高脂饮食诱导的NASH小鼠血脂异常，与本领域已报道的化合物相比具有改进的药理活性、物理化学性质和药代动力学性质。
附图说明
图1为实施例化合物Z4、Z5对脂肪变性HepG-2的改善作用示意图；
其中(A)不同浓度Z4、Z5对HepG-2细胞的细胞毒性影响示意图；
(B)不同浓度Z4、Z5对HepG-2细胞的脂质毒性影响示意图；
(C)Z4、Z5对FFA诱导HepG-2细胞TG含量的示意图；
(D)Z4、Z5对FFA诱导HepG-2细胞脂肪变性的影响图(油红O染色，光镜20倍，比例尺，50μm)；(E)Z4、Z5对FFA诱导HepG-2细胞脂质累积中脂滴吸光度的示意图；
图2为实施例化合物Z4对高脂肪饮食和CCl4诱导的NASH小鼠肥胖的影响示意图；
其中(A)建模和治疗方法示意图；(B)体重和体重改变量(n＝6-8)；(C)脂肪/体重率(n＝8)；(D)脂肪细胞横截面积(n＝8)；(E)从上到下，分别是肾周白色脂肪组织宏观图像，附睾白色脂肪组织宏观图像，肾周白色脂肪组织切片的H&E染色，附睾白色脂肪组织切片的H&E染色；
图3为实施例化合物Z4对NASH小鼠肝脏脂肪变性和脂肪毒性的影响示意图；
其中(A)从上到下，NCD、NASH、Z4和OCA组小鼠肝脏的宏观图像，肝脏切片的H&E代表性图像；(B)肝脏重量(n＝8)；(C)肝脏/体重比(％)(n＝8)；(D)肝脏TG含量(n＝8)；(E)血清AST水平(n＝8)；(F)血清ALT水平(n＝8)；(G)肝脏CAT含量(n＝8)；(H)血清GSH-Px含量(n＝8)；(I)肝脏MDA含量(n＝8)；(J)血清MDA含量(n＝8)；
图4为实施例化合物Z4对NASH小鼠血脂代谢紊乱的影响示意图；
其中(A)血清TG含量(n＝8)；(B)血清TC含量(n＝8)；(C)血清HDL-C含量(n＝8)；(D)血清LDL-C含量(n＝8)；
图5为实施例化合物Z4在C57BL6J小鼠体内的药动学示意图；
其中(A)Z4的药动学参数；
(B)单次口服给药(10mg/kg)后，C57BL6J小鼠血浆、肝脏和肠道中Z4的组织分布(n＝3)。
具体实施方式
以下通过实施例结合附图对本发明内容作进一步说明，但并不用于限制本发明的保护范围。
实施例1：化合物5a-f的制备
1.3-(2-氨基苯甲酰氨基)苯甲酸乙酯(5a)的制备
将化合物2-硝基苯甲酸(30mmol)加入反应烧瓶中，加入THF(40mL)，HATU(36mmol)，DIPEA(36mmol)，然后加入化合物3-氨基苯甲酸乙酯(33mmol)。将反应液加热至30～45℃，反应6～8h，TLC监控(石油醚:乙酸乙酯＝6:1～2:1，v/v)。反应完全后，减压蒸除溶剂，加入300mL水，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和NaCl(100mL)洗涤，加入无水MgSO4干燥，抽滤，减压蒸除溶剂，35℃干燥4h，得到中间体IV。化合物IV不需纯化，可直接用于下一步反应。
将锌粉(150mmol)加入反应烧瓶中，加入无水乙醇(100mL)，搅拌，缓慢滴加浓HCl(0.2eq)，搅拌活化5min。加入化合物IV(30mmol)，先置于室温下反应1h，升温到45℃，TLC监控反应(石油醚:乙酸乙酯＝5:1～1:1，v/v)。反应结束后，减压浓缩溶剂，加入水(300mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和NaCl(50mL×2)洗涤，加入无水MgSO4干燥，抽滤，减压浓缩，35℃下干燥4h，得到化合物5a。
化合物5a的理化及波谱数据如下：
黄色固体，产率68％，1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),8.34(t,J＝4.7Hz,1H),8.17(d,J＝8.2Hz,1H),7.96–7.85(m,2H),7.85–7.68(m,3H),7.52(t,J＝7.9Hz,1H),4.33(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H)。
2.化合物5b～5f的制备方法、理化及波谱数据如下：
4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b)
按照化合物5a的制备方法，将3-氨基苯甲酸乙酯替换为4-氨基苯甲酸乙酯，其余条件相同。化合物5b：白色固体，产率65％，1H NMR(600MHz,DMSO-d6)δ11.00(s,1H),8.18(d,J＝8.2Hz,1H),7.97(d,J＝8.6Hz,2H),7.89(d,J＝7.5Hz,1H),7.84–7.74(m,4H),4.31(q,J＝7.1Hz,2H),1.32(t,J＝7.1Hz,3H)。
2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c)
按照化合物5a的制备方法，将3-氨基苯甲酸乙酯替换为2-氨基苯甲酸乙酯，其余条件相同。化合物5c：黄色固体，产率73％，1H NMR(600MHz,DMSO-d6)δ11.39(s,1H),8.50(d,J＝8.3Hz,1H),8.00(d,J＝7.9Hz,1H),7.63(dd,J＝18.2,7.8Hz,2H),7.26-7.19(m,1H),6.80(d,J＝8.2Hz,1H),6.64(t,J＝7.5Hz,1H),6.57(s,1H),4.33(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H)。
2-(2-氨基-5-甲基苯甲酰胺)苯甲酸乙酯(5d)
按照化合物5a的制备方法，将2-硝基苯甲酸替换为5-甲基-2-硝基苯甲酸，3-氨基苯甲酸乙酯替换为2-氨基苯甲酸乙酯，其余条件相同。化合物5d：1H NMR(600MHz,DMSO-d6)δ11.25(s,1H),8.43(d,J＝8.4Hz,1H),7.99(dd,J＝7.9,1.4Hz,1H),7.72–7.56(m,1H),7.42(s,1H),7.28–7.16(m,1H),7.08(dd,J＝8.3,1.5Hz,1H),6.72(d,J＝8.4Hz,1H),6.33(s,2H),4.34(d,J＝7.1Hz,2H),2.22(s,3H),1.31(t,J＝7.1Hz,3H)。
2-(2-氨基-4-甲基苯甲酰氨基)苯甲酸乙酯(5e)
按照化合物5a的制备方法，将2-硝基苯甲酸替换为4-甲基-2-硝基苯甲酸，3-氨基苯甲酸乙酯替换为2-氨基-5-甲基苯甲酸乙酯，其余条件相同。化合物5e：黄色固体，产率78％，1HNMR(600MHz,DMSO-d6)δ11.25(s,1H),8.39(d,J＝8.5Hz,1H),7.80(s,1H),7.49(d,J＝8.1Hz,1H),7.47–7.40(m,1H),6.59(s,1H),6.54(s,2H),6.46(d,J＝7.8Hz,1H),4.33(q,J＝7.1Hz,2H),2.32(s,3H),2.21(s,3H),1.31(t,J＝7.1Hz,3H)。
3-(2-氨基苯甲酰氨基)-4-乙基苯甲酸乙酯(5f)
按照化合物5a的制备方法，将3-氨基苯甲酸乙酯替换为3-氨基-4-乙基苯甲酸乙酯，其余条件相同。化合物5f：黄色固体，产率77％，1H NMR(600MHz,DMSO-d6)δ9.76(s,1H),7.88(d,J＝1.4Hz,1H),7.80(dd,J＝8.0,1.6Hz,1H),7.72(d,J＝7.9Hz,1H),7.44(d,J＝8.0Hz,1H),7.21(t,J＝7.7Hz,1H),6.76(d,J＝8.3Hz,1H),6.60(t,J＝7.5Hz,1H),6.42(s,1H),4.32(q,J＝7.1Hz,1H),2.69(q,J＝7.5Hz,1H),1.32(t,J＝7.1Hz,1H),1.15(t,J＝7.5Hz,1H)。
实施例2：目标化合物Z1-Z53的制备
1.3-(2-(4-(4-乙基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z1)的制备
将化合物4-(4-乙基苯氧基)丁酸(6a,13mmol)加入反应烧瓶中，加入THF(16mL)，HATU(15mmol)，DIPEA(15mmol)，然后加入化合物3-(2-氨基苯甲酰氨基)苯甲酸乙酯(5a，10mmol)。升温到45～50℃，反应6～12h，TLC监控(石油醚:乙酸乙酯＝5:1～2:1,v/v)。反应结束后，减压蒸除溶剂，往残留物中加入120mL水，用乙酸乙酯(40mL×3)萃取，合并有机相，用饱和NaCl(40mL)洗涤，加入无水MgSO4干燥，抽滤，减压蒸除溶剂，35℃下干燥4h，得到化合物VI。化合物VI不需纯化，可直接用于下一步反应。
将上步所得化合物VI加入反应烧瓶中，加入无水乙醇(30mL)，逐滴加入1.0mol/LNaOH/EtOH(11mL)，滴加完毕后，升温45～50℃，反应6～12h，TLC监控反应(石油醚:乙酸乙酯＝5:1～2:1，v/v)。反应结束后，减压蒸除溶剂，得到黄色或白色固物残留物。加入水(10mL)，冰水浴下用缓慢滴加1mol/LHCl调pH＝1～2。加入120mL水，用乙酸乙酯(40mL×3)萃取，合并有机相，用饱和NaCl(40mL)洗涤，加入无水MgSO4干燥，抽滤，减压蒸除溶剂，甲醇/二氯甲烷作为洗脱剂，柱层析得到化合物Z1。
化合物Z1的理化及波谱数据如下：
白色固体,产率64％，mp 218.5-220.7℃；1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),10.15(s,1H),8.24(s,1H),8.11–7.38(m,6H),7.28–7.01(m,3H),6.84(d,J＝8.6Hz,2H),3.98(t,J＝6.3Hz,2H),2.60–2.46(m,4H),2.01(dd,J＝13.7,6.9Hz,2H),1.13(t,J＝7.5Hz,3H)；13CNMR(151MHz,DMSO-d6)δ171.15,167.65,167.47,157.02,139.66,138.04,136.07,132.09,131.68,129.29,129.23,129.02,126.49,125.11,123.73,122.56,121.76,114.76,114.36,67.08,31.82,27.74,25.13,16.36；ESI-MS m/z:445.33[M-H]-。
2.化合物Z2～Z53的制备方法、理化及波谱数据如下：
3-(2-(4-(4-乙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z2)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-乙酰基苯氧基)丁酸(6c)，其余条件相同。化合物Z2：白色固体,产率66％，mp 192.9-193.9℃；1H NMR(600MHz,DMSO-d6)δ13.00(s,1H),10.56(s,1H),10.43(s,1H),8.40(s,1H),8.07(d,J＝8.1Hz,1H),7.93(d,J＝7.8Hz,1H),7.87(d,J＝8.7Hz,2H),7.77(d,J＝7.7Hz,1H),7.69(d,J＝7.7Hz,1H),7.53(t,J＝7.7Hz,1H),7.46(t,J＝7.9Hz,1H),7.24(t,J＝7.5Hz,1H),6.98(d,J＝8.7Hz,2H),4.08(t,J＝6.4Hz,2H),2.58–2.50(m,2H),2.49(s,3H),2.05–2.02(m,2H)；13C NMR(151MHz,DMSO-d6)δ196.69,171.04,167.66,167.46,162.85,139.66,137.98,132.08,131.70,130.89,130.26,129.29,129.23,125.46,125.11,125.05,123.79,122.63,121.73,114.68,67.55,33.50,26.83,24.91；ESI-MS m/z:461.15[M+H]+。
3-(2-(5-(4-乙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z3)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙酰基苯氧基)戊酸(6d)，其余条件相同。化合物Z3：白色固体,产率74％，mp 176.6-179.4℃；1H NMR(600MHz,DMSO-d6)δ10.57(s,1H),10.39(s,1H),8.41(s,1H),8.09(d,J＝8.2Hz,1H),7.97–7.86(m,3H),7.79–7.75(m,1H),7.70(d,J＝7.8Hz,1H),7.55–7.45(m,2H),7.27–7.22(m,1H),7.05–6.96(m,2H),4.03(t,J＝6.0Hz,2H),2.50(s,3H),2.41(t,J＝7.0Hz,2H),1.79–1.71(m,4H)；13C NMR(151MHz,DMSO-d6)δ196.73,171.46,167.66,167.51,162.96,139.63,138.05,132.10,131.68,130.90,130.20,129.31,129.20,125.31,125.15,125.12,123.74,122.57,121.78,114.67,67.96,36.71,28.33,26.84,22.05；ESI-MS m/z:473.26[M-H]-。
3-(2-(4-(叔丁基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z4)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(叔丁基)苯氧基)丁酸(6e)，其余条件相同。化合物Z4：白色固体,产率78％，mp 122.1-123.5℃；1H NMR(600MHz,DMSO-d6)δ10.56(s,1H),10.42(s,1H),8.40(s,1H),8.08(d,J＝8.2Hz,1H),7.95(d,J＝8.0Hz,1H),7.77(d,J＝6.9Hz,1H),7.70(d,J＝7.7Hz,1H),7.56–7.50(m,1H),7.46(t,J＝7.9Hz,1H),7.29–7.19(m,3H),6.86–6.77(m,2H),3.94(t,J＝6.4Hz,2H),2.53–2.47(m,2H),2.06–1.96(m,2H),1.22(s,9H)；13C NMR(151MHz,DMSO-d6)δ196.72,171.44,167.66,162.96,139.65,138.04,134.51,132.09,131.66,130.94,130.91,130.18,129.31,125.13,123.73,121.75,120.25,114.71,114.66,67.95,37.44,36.69,36.39,28.33,26.86,22.04；ESI-MSm/z:475.14[M+H]+。
3-(2-(5-(4-(叔丁基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z5)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(叔丁基)苯氧基)戊酸(6f)，其余条件相同。化合物Z5：白色固体,产率77％，mp 188.4-191.1℃；1H NMR(600MHz,DMSO-d6)δ10.57(s,1H),10.39(s,1H),8.41(s,1H),8.11(d,J＝8.2Hz,1H),7.99–7.91(m,1H),7.80–7.67(m,2H),7.56–7.49(m,1H),7.47(t,J＝7.9Hz,1H),7.26–7.21(m,3H),6.82–6.76(m,2H),3.89(s,2H),2.40(s,2H),1.72(s,4H),1.23(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.51,167.65,167.52,156.80,142.94,139.62,138.10,132.11,131.69,129.31,129.21,126.44,125.14,123.70,122.52,121.80,114.31,67.40,36.79,34.17,31.82,28.53,22.19；ESI-MS m/z:489.41[M+H]+。
3-(2-(5-(4-乙基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z6)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙基苯氧基)戊酸(6b)，其余条件相同。化合物Z6：白色固体,产率57％，mp 205-206.5℃；1H NMR(600MHz,DMSO-d6)δ12.97(s,1H),10.11(s,1H),8.48–8.04(m,2H),7.99–7.75(m,2H),7.66(dd,J＝9.5,7.7Hz,2H),7.55–7.30(m,2H),7.08(t,J＝9.0Hz,3H),6.81(dd,J＝9.5,8.4Hz,3H),3.95-3.90(m,2H),2.52-2.31(m,4H),1.72-1.68(m,4H),1.13(t,J＝7.6Hz,3H)；13C NMR(151MHz,DMSO)δ171.81,171.49,167.67,157.14,139.96,139.64,138.12,136.04,132.11,131.72,129.39,129.22,129.06,125.15,124.26,123.59,121.79,120.27,114.74,67.49,36.47,28.74,27.76,22.22,16.41；ESI-MS m/z:461.38[M+H]。
3-(2-(4-(4-丙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z7)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-丙酰基苯氧基)丁酸(6g)，其余条件相同。化合物Z7：白色固体,产率72％，mp 172.3-175.8℃；1H NMR(600MHz,DMSO-d6)δ13.03(s,1H),10.57(s,1H),10.44(s,1H),8.41(s,1H),8.14–8.00(m,1H),7.99–7.67(m,5H),7.65–7.39(m,2H),7.38–7.12(m,1H),7.05–6.82(m,2H),4.16–4.00(m,2H),3.00–2.91(m,2H),2.59–2.49(m,2H),2.15–2.00(m,2H),1.11–1.01(m,3H)；13C NMR(151MHz,DMSO-d6)δ196.72,171.44,167.66,167.50,162.96,139.65,138.04,134.51,132.09,131.66,130.94,130.91,130.18,129.31,125.13,123.73,121.75,120.25,114.71,114.66,67.95,36.69,28.33,26.86,22.04；ESI-MS m/z:473.25[M-H]-。
3-(2-(5-(4-丙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z8)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-丙酰基苯氧基)戊酸(6h)，其余条件相同。化合物Z8：白色固体,产率75％，mp 253.6-255.5℃；1H NMR(600MHz,DMSO-d6)δ12.98(s,1H),10.57(s,1H),10.10(s,1H),8.41(s,1H),8.24(s,1H),8.10(d,J＝8.2Hz,1H),8.00–7.85(m,3H),7.85–7.07(m,4H),7.03(dd,J＝9.1,2.3Hz,1H),6.98(d,J＝8.9Hz,1H),4.06(m,2H),3.00–2.81(m,2H),2.41(dd,J＝9.0,6.9Hz,2H),1.85–1.61(m,4H),1.07(t,J＝7.2Hz,3H)；13C NMR(151MHz,DMSO-d6)δ199.25,171.76,171.44,167.65,162.81,139.95,139.63,138.09,132.10,131.69,130.54,130.50,129.92,129.39,125.14,123.60,121.78,120.28,114.73,114.68,67.99,36.40,31.23,28.53,22.10,8.78；ESI-MS m/z:489.36[M+H]+。
3-(2-(4-(4-(苄氧基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z9)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(苄氧基)苯氧基)丁酸(6i)，其余条件相同。化合物Z9：白色固体,产率62％，mp 196.3-199.5℃；1H NMR(600MHz,DMSO-d6)δ12.99(s,1H),10.54(s,1H),10.39(s,1H),8.38(s,1H),8.06(d,J＝8.2Hz,1H),7.92(d,J＝7.9Hz,1H),7.74(d,J＝7.3Hz,1H),7.67(d,J＝7.7Hz,1H),7.52–7.25(m,7H),7.21(t,J＝7.4Hz,1H),6.85–6.75(m,4H),4.97(s,2H),3.88(t,J＝6.4Hz,2H),2.53–2.35(m,2H),2.03–1.64(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.16,167.67,167.49,153.16,152.79,139.67,138.05,137.83,132.10,131.70,129.31,129.24,128.84,128.17,128.07,125.32,125.13,125.08,123.73,122.56,121.75,116.08,115.77,70.09,67.57,33.69,25.17；ESI-MS m/z:525.32[M+H]+。
3-(2-(5-(4-(苄氧基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z10)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(苄氧基)苯氧基)戊烷酸(6J)，其余条件相同。化合物Z10：白色固体,产率66％，mp 163.5-165.2℃；1H NMR(600MHz,DMSO-d6)δ12.99(s,1H),10.55(s,1H),10.36(s,1H),8.38(s,1H),8.08(d,J＝8.1Hz,1H),7.92(d,J＝7.7Hz,1H),7.83–7.55(m,2H),7.52–7.18(m,7H),6.90–6.70(m,4H),4.98(d,J＝6.1Hz,2H),3.91–3.72(m,2H),2.36(s,2H),1.79–1.54(m,4H)；13C NMR(151MHz,DMSO-d6)δ171.50,167.68,167.52,153.26,152.72,139.64,138.12,137.85,132.11,131.73,129.31,129.22,128.85,128.17,128.07,125.15,125.11,123.68,122.52,121.79,116.15,116.11,115.70,70.10,67.91,36.81,28.60,22.18；ESI-MS m/z:539.40[M+H]+。
3-(2-(4-([1,1'-联苯基]-2-氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z11)
按照化合物Z1的制备方法，将化合物6a替换为4-([1,1'-联苯]-2-氧基)丁酸(6k)，其余条件相同。化合物Z11:白色固体,产率61％，mp 208.1-210.2℃；1H NMR(600MHz,DMSO-d6)δ12.98(s,1H),10.59(s,1H),10.12(s,1H),8.43(s,1H),8.24–8.07(m,1H),8.02–7.90(m,1H),7.84–7.59(m,2H),7.56–7.36(m,5H),7.34–7.19(m,3H),7.15–6.94(m,2H),4.08–3.98(m,2H),2.45(dd,J＝12.7,7.2Hz,2H),1.99–1.91(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.04,167.66,167.56,155.78,139.62,138.60,138.18,132.19,131.71,130.87,130.42,129.69,129.30,129.25,128.38,127.22,126.49,125.18,125.13,124.90,123.67,122.37,121.83,121.29,113.20,67.46,33.62,25.05；ESI-MS m/z:493.16[M-H]-。
3-(2-(5-([1,1'-联苯基]-2-氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z12)
按照化合物Z1的制备方法，将化合物6a替换为5-([1,1'-联苯]-2-氧基)戊烷酸(6l)，其余条件相同。化合物Z11:白色固体,产率76％，mp 137.2-139.3℃；1H NMR(600MHz,DMSO-d6)δ13.02(s,1H),10.57(s,1H),10.36(s,1H),8.41(s,1H),8.25–8.05(m,1H),7.99–7.76(m,2H),7.71–7.59(m,1H),7.56–7.46(m,4H),7.37-7.28(m,2H)7.29-7.22(m,4H),7.13–6.98(m,2H),4.03–3.88(m,2H),2.38–2.30(m,2H),1.77–1.57(m,4H)；13C NMR(151MHz,DMSO-d6)δ171.46,167.65,167.51,155.90,139.63,138.62,138.14,132.11,131.70,130.85,130.38,129.69,129.29,129.24,129.21,128.32,127.21,127.17,125.14,123.67,122.51,121.80,121.25,121.21,113.19,67.81,36.63,28.46,22.05；ESI-MS m/z:509.19[M+H]+。
3-(2-(4-(2,4-二叔丁基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z13)
按照化合物Z1的制备方法，将化合物6a替换为4-(2,4-二叔丁基苯氧基)丁酸(6m)，其余条件相同。化合物Z13:白色固体,产率52％，mp 125.5-127.2℃；1H NMR(600MHz,DMSO-d6)δ12.97(s,1H),10.56(s,1H),10.16(s,1H),8.40(s,1H),8.24(s,1H),8.09(d,J＝8.2Hz,1H),7.95(d,J＝8.1Hz,1H),7.78(dd,J＝7.8,1.1Hz,1H),7.72–7.67(m,1H),7.47–7.41(m,1H),7.20(d,J＝2.5Hz,1H),7.08(dd,J＝8.5,2.4Hz,1H),6.87(d,J＝8.6Hz,1H),6.78(d,J＝8.6Hz,1H),3.97(t,J＝6.4Hz,2H),2.58–2.54(m,2H),2.11–2.05(m,2H),1.32(s,9H),1.23(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.05,167.64,167.48,155.42,142.18,139.93,139.64,138.02,136.60,132.11,131.70,129.26,125.12,125.06,123.91,123.85,123.38,123.32,121.76,120.33,112.25,67.15,35.06,35.00,34.32,33.96,33.53,31.90,30.25,25.45,25.33；ESI-MS m/z:529.64[M-H]-。
3-(2-(5-(2,4-二叔丁基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z14)
按照化合物Z1的制备方法，将化合物6a替换为5-(2,4-二叔丁基苯氧基)戊烷酸(6n)，其余条件相同。化合物Z14:白色固体,产率55％，mp 98.3-101.2℃；1H NMR(600MHz,DMSO-d6)δ13.06(s,1H),8.41–8.38(m,1H),8.13–7.93(m,2H),7.88–7.64(m,3H),7.55–7.43(m,1H),7.25–7.09(m,3H),6.80–6.58(m,1H),4.06–3.85(m,2H),2.43–2.35(m,2H),1.88–1.70(m,4H),1.32-1.30(m,9H),1.24(s,9H)；13C NMR(151MHz,DMSO-d6)δ168.45,167.01,161.99,156.67,155.52,150.38,147.69,142.10,138.11,136.57,130.39,129.21,127.41,126.98,125.12,124.62,123.84,123.31,116.90,115.13,112.18,67.65,36.75,35.27,35.02,34.99,34.33,31.91,30.23,30.19,28.85,23.31,22.47；ESI-MS m/z:543.56[M-H]-。
3-(2-(4-(萘-2-氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z15)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)丁酸(6o)，其余条件相同。化合物Z15:白色固体,产率66％，mp 163.2-165.7℃；1H NMR(600MHz,DMSO-d6)δ12.98(s,1H),10.17(s,1H),8.52–8.40(m,1H),8.27(s,1H),8.14–7.93(m,1H),7.87–7.67(m,5H),7.65–7.52(m,1H),7.49–7.39(m,2H),7.36–7.22(m,3H),7.18–7.12(m,1H),4.18–4.11(m,2H),2.66–2.55(m,2H),2.17–2.08(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.47,170.02,167.67,156.93,141.29,139.96,134.78,134.36,131.72,131.54,129.73,129.40,128.92,127.96,127.13,126.82,125.13,124.30,123.99,123.63,123.01,120.31,119.17,107.20,67.45,33.35,25.05；ESI-MS m/z:469.29[M+H]+。
3-(2-(5-(萘-2-氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z16)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)戊酸(6p)，其余条件相同。化合物Z16:白色固体,产率65％，mp 165.5-167.5℃；1H NMR(600MHz,DMSO-d6)δ13.01(s,1H),10.09(s,1H),8.22(s,1H),8.11–7.96(m,1H),7.93–7.55(m,6H),7.51–7.24(m,4H),7.23–6.97(m,2H),4.11–3.98(m,2H),2.39(t,J＝6.6Hz,2H),1.83–1.71(m,4H)；13CNMR(151MHz,DMSO-d6)δ171.82,167.68,157.01,139.98,134.78,131.73,129.71,129.67,129.40,128.89,128.86,127.96,127.11,126.80,125.14,124.28,123.94,123.61,121.81,120.29,119.23,119.17,107.10,107.05,67.66,36.47,28.66,22.25；ESI-MS m/z:481.41[M-H]-。
4-(2-(5-(4-乙基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z17)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-乙酰基苯氧基)丁酸(6b)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z17:白色固体,产率77％，mp 171.9-172.5℃；1H NMR(600MHz,DMSO-d6)δ12.73(s,1H),10.23(s,1H),8.05–7.85(m,4H),7.75–7.56(m,2H),7.55–7.22(m,1H),7.16–6.76(m,5H),3.95(s,2H),2.57–2.50(m,2H),2.46–2.36(m,2H),1.75(s,4H),1.18–1.11(m,3H)；13C NMR(151MHz,DMSO-d6)δ172.11,171.50,167.41,157.13,143.80,137.81,136.04,132.07,130.84,130.66,129.26,129.07,129.03,126.06,125.32,123.84,122.99,120.04,118.71,114.73,114.69,67.47,36.56,28.73,27.76,22.15,16.43；ESI-MS m/z:461.18[M+H]+。
4-(2-(4-(4-乙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z18)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-乙酰基苯氧基)丁酸(6c)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z18:白色固体,产率70％，mp 152.3-154.5℃；1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),8.49(d,J＝8.2Hz,1H),8.03–7.84(m,5H),7.71(d,J＝8.7Hz,1H),7.64–7.54(m,1H),7.20–6.98(m,4H),4.14(t,J＝6.4Hz,2H),2.61–2.55(m,2H),2.51(s,3H),2.16–2.03(m,2H)；13C NMR(151MHz,DMSO-d6)δ196.73,171.65,171.15,169.99,167.40,162.84,143.75,141.23,134.39,131.52,130.93,130.84,130.33,125.39,123.04,120.49,118.75,117.22,114.73,67.56,34.21,26.85,24.79；ESI-MS m/z:461.30[M+H]+。
4-(2-(5-(4-乙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z19)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙酰基苯氧基)戊酸(6d)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z19:白色固体,产率79％，mp 180.3-182.6℃；1H NMR(600MHz,DMSO-d6)δ12.76(s,1H),10.24(s,1H),8.05–7.96(m,1H),7.96–7.82(m,5H),7.73(t,J＝9.9Hz,2H),7.63–7.48(m,1H),7.29–6.92(m,3H),4.10(t,J＝5.8Hz,2H),2.51(s,3H),2.47–2.38(m,2H),1.82–1.71(m,4H)；13C NMR(151MHz,DMSO-d6)δ196.72,172.06,167.58,167.42,162.96,143.79,137.76,132.06,131.54,130.94,130.85,130.66,130.23,129.25,126.06,125.33,123.88,120.02,118.72,114.70,114.65,68.00,36.49,28.52,26.85,22.03；ESI-MS m/z:475.11[M+H]+。
4-(2-(4-(叔丁基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z20)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(叔丁基)苯氧基)丁酸(6e)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z20:白色固体,产率73％，mp 209.6-210.15℃；1H NMR(600MHz,DMSO-d6)δ12.73(s,1H),10.64(s,1H),10.28(s,1H),8.00–7.80(m,4H),7.70(s,1H),7.50(s,1H),7.19(s,3H),6.76(s,2H),3.91(s,2H),2.47(s,2H),1.96(s,2H),1.20(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.16,167.55,167.43,156.70,143.69,143.04,137.71,132.04,130.84,130.67,129.27,126.51,126.44,126.24,126.04,123.93,122.95,119.98,118.74,114.35,67.04,34.17,33.54,31.80,25.14；ESI-MS m/z:475.43[M+H]+；473.47[M-H]-。
4-(2-(5-(4-(叔丁基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z21)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(叔丁基)苯氧基)戊酸(6f)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z21:白色固体,产率75％，mp 137.7-139.3℃；1H NMR(600MHz,DMSO-d6)δ12.72(s,1H),10.23(s,1H),8.06–7.85(m,4H),7.76–7.20(m,5H),6.86–6.56(m,3H),3.96(s,2H),2.48–2.38(m,2H),1.78–1.70(m,4H),1.31–1.20(m,9H)；13C NMR(151MHz,DMSO-d6)δ172.11,168.59,167.42,156.81,150.42,143.81,142.99,132.92,130.85,130.67,130.60,129.35,126.49,125.32,120.05,119.98,118.71,116.90,115.14,114.34,67.42,36.55,34.19,31.82,28.72,22.16；ESI-MS m/z:489.13[M+H]+。
4-(2-(4-(4-乙基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z22)
按照化合物Z1的制备方法，将化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z22:白色固体,产率70％，mp 184.4-186.7℃；1H NMR(600MHz,DMSO-d6)δ12.73(s,1H),10.65(s,1H),10.26(s,1H),8.13–7.98(m,1H),7.94–7.68(m,5H),7.66–7.51(m,1H),7.29–7.21(m,1H),7.10(d,J＝8.6Hz,1H),7.05(d,J＝8.6Hz,1H),6.85–6.76(m,2H),3.98(t,J＝6.3Hz,1H),3.94(t,J＝6.5Hz,1H),2.54–2.47(m,4H),2.04–1.97(m,2H),1.13(q,J＝7.6Hz,3H)；13C NMR(151MHz,DMSO-d6)δ171.78,171.16,167.42,157.02,143.67,137.73,136.07,132.05,130.83,130.65,129.09,129.01,126.05,125.36,123.91,120.00,118.74,114.78,114.75,67.09,33.45,27.74,25.14,16.34；ESI-MS m/z:447.37[M+H]+，445.48[M-H]-。
4-(2-(4-(4-丙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z23)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-丙酰基苯氧基)丁酸(6g)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z23:白色固体,产率66％，mp 139.1-140.5℃；1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),10.67(s,1H),10.33(s,1H),8.02–7.70(m,7H),7.68–7.52(m,1H),7.30–7.12(m,1H),7.07–6.75(m,3H),4.09–4.03(m,2H),3.00–2.93(m,2H),2.62–2.54(m,1H),2.40(t,J＝7.3Hz,1H),2.07–1.95(m,2H),1.09–1.04(m,3H)；13C NMR(151MHz,DMSO-d6)δ199.25,174.52,171.05,167.53,167.43,162.69,143.69,137.65,132.04,130.65,130.55,130.47,129.97,129.91,129.27,126.00,123.96,122.99,119.94,114.71,114.65,67.50,31.24,30.47,24.56,8.76；ESI-MSm/z:473.20[M-H]-。
4-(2-(5-(4-丙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z24)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-丙酰基苯氧基)戊酸(6h)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z24:白色固体,产率70％，mp 187.6-190.4℃；1H NMR(600MHz,DMSO-d6)δ12.71(s,1H),10.66(s,1H),10.22(s,1H),8.02(d,J＝8.2Hz,1H),7.96–7.84(m,5H),7.76–7.69(m,2H),7.56–7.50(m,1H),7.27–7.21(m,1H),7.03(d,J＝8.9Hz,1H),6.98(d,J＝8.9Hz,1H),4.09(t,J＝5.9Hz,1H),4.02(t,J＝6.0Hz,1H),2.98–2.94(m,2H),2.43–2.40(m,2H),1.81–1.72(m,4H),1.07(t,J＝7.2Hz,3H)；13C NMR(151MHz,DMSO-d6)δ199.26,172.06,171.46,167.58,167.40,162.82,143.78,137.80,132.07,130.83,130.65,130.54,130.49,129.92,129.24,126.09,125.35,123.87,120.06,118.73,114.73,114.67,67.98,36.49,31.24,28.52,22.03,8.78；ESI-MS m/z:489.37[M+H]+。
4-(2-(4-(苄氧基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z25)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(苄氧基)苯氧基)丁酸(6i)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z25:白色固体,产率78％，mp 191.5-192.5℃；1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),10.32(d,J＝4.8Hz,1H),8.07–7.87(m,4H),7.81–7.55(m,2H),7.51–7.12(m,6H),6.99–6.79(m,5H),6.68–6.57(m,1H),5.07(s,2H),4.03–3.90(m,2H),2.65–2.49(m,2H),2.14–1.88(m,2H)；13CNMR(151MHz,DMSO-d6)δ171.79,171.17,167.44,153.17,152.80,143.79,143.67,137.83,137.76,132.07,130.84,130.67,129.27,128.84,128.17,128.07,126.06,125.36,123.89,120.02,118.75,116.18,116.09,115.80,115.78,70.11,67.59,33.46,25.18；ESI-MS m/z:525.39[M+H]+。
4-(2-(5-(4-(苄氧基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z26)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(苄氧基)苯氧基)戊烷酸(6j)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z26:白色固体,产率75％，mp 178.3-180.1℃；1H NMR(600MHz,DMSO-d6)δ12.69(s,1H),10.23(s,1H),7.80(dd,J＝10.2,7.9Hz,5H),7.52–7.09(m,7H),6.89(dd,J＝8.8,7.8Hz,5H),5.03(s,2H),3.92(s,2H),3.37(s,2H),2.46–2.30(m,2H),1.74–1.63(m,4H)；13C NMR(151MHz,DMSO-d6)δ172.12,171.58,170.06,167.42,153.27,152.76,143.81,141.34,137.85,134.36,131.55,130.84,128.84,128.17,128.07,125.34,122.94,120.38,120.07,118.73,116.15,115.75,70.10,67.97,36.57,28.77,22.15；ESI-MS m/z:539.18[M+H]+。
4-(2-(4-([1,1'-联苯]-2-氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z27)
按照化合物Z1的制备方法，将化合物6a替换为4-([1,1'-联苯]-2-氧基)丁酸(6k)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z27:白色固体,产率70％，mp 182.2-184.2℃；1H NMR(600MHz,DMSO-d6)δ12.71(s,1H),10.23(s,1H),8.04–7.86(m,4H),7.76–7.69(m,2H),7.55–7.36(m,5H),7.34–7.18(m,4H),7.13–6.98(m,2H),4.08–3.98(m,2H),2.49–2.41(m,2H),2.00–1.89(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.68,171.07,167.41,155.83,143.75,143.62,138.63,137.85,132.14,130.96,130.83,130.64,130.38,129.71,129.31,129.24,128.43,128.38,127.27,126.11,125.37,123.86,121.37,121.29,120.06,118.76,113.31,67.76,33.29,24.93；ESI-MS m/z:495.03[M+H]+。
4-(2-(5-([1,1'-联苯基]-2-氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z28)
按照化合物Z1的制备方法，将化合物6a替换为5-([1,1'-联苯]-2-氧基)戊烷酸(6l)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z28:白色固体,产率66％，mp 135.4-137.2℃；1H NMR(600MHz,DMSO-d6)δ12.76(s,1H),10.25(s,1H),8.07–7.90(m,2H),7.81–7.67(m,2H),7.63–7.49(m,3H),7.45–7.25(m,6H),7.19–7.03(m,3H),4.05(s,2H),2.42(s,2H),1.75(s,4H)；13C NMR(151MHz,DMSO-d6)δ172.09,171.54,170.10,167.43,155.91,143.81,141.38,138.64,134.25,131.56,130.90,130.85,130.60,130.39,129.71,129.27,128.34,127.22,125.34,122.88,121.25,120.29,120.06,118.72,113.20,67.79,36.40,28.63,22.08；ESI-MS m/z:509.20[M+H]+。
4-(2-(4-(2,4-二叔丁基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z29)
按照化合物Z1的制备方法，将化合物6a替换为4-(2,4-二叔丁基苯氧基)丁酸(6m)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z29:白色固体,产率62％，mp 194.5-196.7℃；1H NMR(600MHz,DMSO-d6)δ12.77(s,1H),10.66(s,1H),10.32(s,1H),8.01–7.84(m,3H),7.76–7.70(m,1H),7.61–7.50(m,1H),7.28–7.05(m,3H),6.89–6.74(m,1H),4.06–3.90(m,2H),2.66–2.52(m,2H),2.16–1.96(m,2H),1.34(s,9H),1.24(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.07,167.54,167.41,155.43,143.66,142.18,137.66,136.56,132.04,130.83,130.63,129.24,126.05,123.99,123.85,123.33,119.98,118.78,112.28,67.18,35.00,34.33,33.79,33.63,31.90,30.31,30.25,25.48；ESI-MS m/z:531.37[M+H]+。
4-(2-(5-(2,4-二叔丁基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z30)
按照化合物Z1的制备方法，将化合物6a替换为5-(2,4-二叔丁基苯氧基)戊烷酸(6n)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z30:白色固体,产率65％，mp 193.7-195.5℃；1H NMR(600MHz,DMSO-d6)δ12.76(s,1H),10.68(s,1H),10.27(d,J＝14.3Hz,1H),8.10–7.79(m,3H),7.72(d,J＝7.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.38–7.03(m,3H),6.82(dd,J＝9.7,7.6Hz,1H),3.94(d,J＝8.9Hz,2H),2.45-2.42(m,2H),1.81(d,J＝9.9Hz,4H),1.33(s,9H),1.24(s,9H)；13C NMR(151MHz,DMSO-d6)δ172.05,171.45,167.42,155.52,143.63,142.08,137.83,136.54,132.06,130.83,130.64,129.24,126.12,125.37,123.84,123.35,123.30,120.06,118.73,112.14,67.36,36.59,36.45,35.05,35.00,34.32,31.91,30.24,30.20,29.00,28.81,22.45,22.41；ESI-MS m/z:543.62[M-H]-。
4-(2-(4-(萘-2-氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z31)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)丁酸(6o)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z31：白色固体,产率61％，mp 218.7-221.3℃；1H NMR(600MHz,DMSO-d6)δ12.75(s,1H),10.31(s,1H),8.02–7.87(m,3H),7.85–7.71(m,6H),7.66–7.41(m,2H),7.37–7.28(m,3H),7.15(dd,J＝8.9,2.3Hz,1H),4.15(t,J＝6.2Hz,2H),2.65–2.56(m,2H),2.18–2.10(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.77,171.24,170.04,167.42,156.92,143.80,141.30,134.77,134.35,131.55,130.86,129.73,128.92,127.96,127.13,126.83,125.37,123.99,123.00,120.43,119.17,118.75,107.16,67.42,34.40,33.47,24.96；ESI-MS m/z:491.11[M+Na]+。
4-(2-(5-(萘-2-氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z32)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)戊酸(6p)，化合物5a替换为4-(2-氨基苯甲酰氨基)苯甲酸乙酯(5b),其余条件相同。化合物Z32：白色固体,产率60％，mp 159.3-160.8℃；1H NMR(600MHz,DMSO-d6)δ12.73(s,1H),10.26(s,1H),8.11–7.66(m,9H),7.57(s,1H),7.45(t,J＝7.2Hz,1H),7.38–7.22(m,3H),7.19–7.09(m,1H),4.12(t,J＝5.6Hz,2H),2.46(t,J＝6.7Hz,2H),1.84(d,J＝5.7Hz,4H)；13C NMR(151MHz,DMSO-d6)δ172.12,167.42,156.99,143.81,134.78,130.86,130.68,129.72,128.88,127.96,127.11,126.81,125.33,123.95,122.96,120.40,120.05,119.23,118.73,107.08,67.64,60.23,36.56,28.65,22.18；ESI-MS m/z:481.17[M-H]-。
2-(2-(5-(4-乙基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z33)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙基苯氧基)戊酸(6b)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z33：白色固体，产率82％，mp 171.8-174.6℃；1H NMR(600MHz,DMSO-d6)δ13.72(s,1H),11.88(s,1H),10.54(s,1H),8.61(d,J＝8.3Hz,1H),8.09(d,J＝8.2Hz,1H),8.04(d,J＝7.4Hz,1H),7.79(d,J＝7.6Hz,1H),7.65(t,J＝7.6Hz,1H),7.56(t,J＝7.7Hz,1H),7.27(t,J＝7.5Hz,1H),7.22(t,J＝7.6Hz,1H),7.07(d,J＝8.3Hz,2H),6.80(d,J＝8.4Hz,2H),3.89(t,2H),2.54–2.51(m,2H),2.39(t,2H),1.75-1.67(m,4H),1.13(t,J＝7.6Hz,3H)；13C NMR(151MHz,DMSO-d6)δ171.53,170.15,166.93,157.13,141.11,138.17,136.00,134.54,132.54,131.63,129.02,128.40,125.31,124.19,123.71,122.91,120.98,117.74,114.72,67.46,36.81,28.59,27.75,22.09,16.39；ESI-MS m/z:459.30[M-H]-。
2-(2-(4-(4-乙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z34)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-乙酰基苯氧基)丁酸(6c)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z34：白色固体，产率55％，mp 83.7-86.9℃；1H NMR(600MHz,DMSO-d6)δ13.27(s,1H),10.90(s,1H),8.58(d,J＝8.1Hz,1H),8.19(s,1H),8.04(d,J＝7.5Hz,1H),7.87-7.84(m,3H),7.61–7.44(m,2H),7.24(t,J＝7.5Hz,1H),7.14(s,1H),6.99(s,2H),4.09(t,J＝6.1Hz,2H),2.57–2.51(m,2H),2.50(s,3H),2.13–1.93(m,2H)；13C NMR(151MHz,DMSO-d6)δ195.66,170.03,165.90,161.82,140.07,137.63,131.45,130.66,129.87,129.25,127.39,122.98,122.23,121.44,119.19,113.68,66.56,32.72,25.83,23.84；ESI-MS m/z:461.16[M+H]+。
2-(2-(5-(4-乙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z35)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙酰基苯氧基)戊酸(6d)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z35：白色固体，产率52％，mp 103.2-106.4℃；1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),10.82(s,1H),8.61(d,J＝8.0Hz,1H),8.19(d,J＝8.2Hz,1H),8.06(dd,J＝7.8,1.3Hz,1H),7.89(d,J＝8.8Hz,2H),7.84(d,J＝6.9Hz,1H),7.60-7.50(m,2H),7.24(t,J＝7.2Hz,1H),7.20–7.12(m,1H),7.00(d,J＝8.9Hz,2H),4.05(t,J＝5.7Hz,2H),2.50(s,3H),2.43(t,J＝6.7Hz,2H),1.82-1.68(m,4H)；13CNMR(101MHz,DMSO-d6)δ196.71,171.45,170.31,166.96,162.96,141.07,138.65,133.35,132.51,131.70,130.90,130.20,128.41,124.55,123.98,123.36,122.46,120.38,116.05,114.69,67.99,36.91,28.37,26.85,21.98；ESI-MS m/z:497.1658[M+Na]+。
2-(2-(4-(4-(叔丁基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z36)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(叔丁基)苯氧基)丁酸(6e)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z36：白色固体，产率76％，mp 87.3-89.5℃；1H NMR(600MHz,DMSO-d6)δ13.79(s,1H),12.02(s,1H),10.59(s,1H),8.61(d,J＝8.3Hz,1H),8.09(d,J＝8.2Hz,1H),8.04(dd,J＝7.9,1.4Hz,1H),7.79(d,J＝6.9Hz,1H),7.65–7.59(m,1H),7.60–7.51(m,1H),7.27(t,J＝7.4Hz,1H),7.23-7.20(m,3H),6.80(d,J＝8.8Hz,1H),6.80(d,J＝8.8Hz,1H),3.94(t,J＝6.4Hz,2H),2.60–2.43(m,2H),2.12–1.88(m,2H),1.22(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.20,170.18,166.90,156.71,143.05,141.16,138.15,134.43,132.52,131.65,129.13,128.38,126.44,124.24,123.63,122.96,120.84,117.91,114.37,67.06,34.17,33.71,31.80,25.06；ESI-MS m/z:473.22[M-H]-。
2-(2-(5-(4-(叔丁基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z37)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(叔丁基)苯氧基)戊酸(6f)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z37：白色固体，产率59％，mp 176.9-180.5℃；1H NMR(600MHz,DMSO-d6)δ14.00(s,1H),11.05(s,1H),8.62(d,J＝8.2Hz,1H),8.29(d,J＝8.2Hz,1H),8.06(d,J＝7.4Hz,1H),7.89(d,J＝7.6Hz,1H),7.53(t,J＝7.8Hz,1H),7.48(t,J＝7.7Hz,1H),7.23(dd,J＝16.5,8.1Hz,1H),7.12(t,J＝7.3Hz,3H),6.82(d,J＝8.7Hz,1H),6.82(d,J＝8.7Hz,1H),3.93(t,J＝5.5Hz,2H),2.43(t,J＝6.6Hz,2H),1.77-1.71(m,4H),1.23(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.46,170.32,167.03,156.83,142.97,141.07,139.19,132.48,132.37,131.68,128.42,126.44,123.71,123.08,121.99,119.99,114.36,67.48,37.18,34.18,31.82,28.59,22.13；ESI-MSm/z:487.22[M-H]-。
2-(2-(4-(4-乙基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z38)
按照化合物Z1的制备方法，将化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z38：白色固体，产率52％，mp 137.0-140.4℃；1H NMR(600MHz,DMSO-d6)δ12.15(s,1H),10.63(s,1H),8.61(dd,J＝8.3,0.7Hz,1H),8.10(d,J＝8.2Hz,1H),8.04(dd,J＝7.9,1.5Hz,1H),7.80(dd,J＝7.8,1.3Hz,1H),7.64–7.59(m,1H),7.58–7.53(m,1H),7.26(m,J＝7.7,1.0Hz,1H),7.23–7.19(m,1H),7.05(d,J＝8.6Hz,1H),7.05(d,J＝8.6Hz,1H),6.79(d,J＝8.6Hz,1H),6.79(d,J＝8.6Hz,1H),3.94(t,J＝6.4Hz,2H),2.51(t,J＝5.1Hz,2H),2.49(q,J＝7.2Hz,2H),2.01-1.97(m,2H),1.12(t,J＝7.6Hz,3H)；13C NMR(151MHz,DMSO-d6)δ171.21,170.19,166.91,157.02,141.14,138.22,136.08,134.27,132.52,131.65,129.01,128.39,125.27,124.20,123.60,122.88,120.78,118.24,114.75,67.10,33.74,27.74,25.07,16.35；ESI-MS m/z:445.34[M-H]-。
2-(2-(4-(4-丙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z39)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-丙酰基苯氧基)丁酸(6g)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z39：白色固体，产率42％，mp 146.0-148.9℃；1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),10.69(s,1H),8.59(d,J＝8.3Hz,2H),8.11(d,J＝8.2Hz,1H),8.04(d,J＝7.7Hz,1H),7.88(d,J＝8.7Hz,2H),7.81(d,J＝7.6Hz,1H),7.64-7.52(m,2H),7.26(t,J＝7.5Hz,1H),7.19(t,J＝7.5Hz,1H),6.98(d,J＝8.7Hz,1H),4.08(t,J＝6.3Hz,2H),2.94(q,J＝7.2Hz,2H),2.55–2.51(m,2H),2.11–1.95(m,2H),1.06(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ199.21,171.10,170.24,166.89,162.68,141.12,138.22,134.03,132.50,131.65,130.48,129.92,128.40,125.24,124.21,123.51,122.85,120.62,118.65,114.67,67.53,33.60,31.21,24.85,8.76；ESI-MS m/z:497.16[M+Na]+。
2-(2-(5-(4-丙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z40)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-丙酰基苯氧基)戊酸(6h)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z40：白色固体，产率51％，mp 137.0-139.1℃；1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.56(s,1H),8.60(d,J＝8.2Hz,1H),8.09(d,J＝8.2Hz,1H),8.03(dd,J＝7.9,1.3Hz,1H),7.90(d,J＝8.8Hz,2H),7.79(d,J＝7.8Hz,1H),7.72–7.59(m,1H),7.55(dd,J＝11.4,4.2Hz,1H),7.18-7.30(m,2H),6.99(d,J＝8.8Hz,2H),4.03(t,J＝5.6Hz,2H),2.96(q,J＝7.2Hz,2H),2.41(t,J＝6.7Hz,2H),1.82-1.65(m,4H),1.07(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ199.24,171.49,170.15,166.92,162.80,141.10,138.13,134.47,132.53,131.63,130.50,129.87,128.42,125.37,124.22,123.69,122.92,120.92,117.85,114.68,67.94,36.72,31.23,28.37,21.97,8.78；ESI-MS m/z:511.18[M+Na]+。
2-(2-(4-(4-(苄氧基)苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z41)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-(苄氧基)苯氧基)丁酸(6i)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z41：白色固体，产率为47％，mp 158.1-160.6℃；1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),10.76(s,1H),8.61(d,J＝8.3Hz,1H),8.15(d,J＝8.2Hz,1H),8.06(d,J＝7.7Hz,1H),7.83(d,J＝7.6Hz,1H),7.62-7.50(m,2H),7.45-7.28(m,5H),7.28-7.15(m,2H),6.89-6.81(m,4H),5.00(s,2H),3.91(t,J＝6.3Hz,2H),2.49(t,J＝7.5Hz,2H),2.05–1.89(m,2H)；13C NMR(101MHz,DMSO-d6)δ196.71,171.45,170.31,166.96,162.96,141.07,138.65,134.59,133.34,132.51,131.70,130.90,130.21,128.41,124.55,123.97,123.63,123.36,123.18,122.45,120.37,116.05,114.69,67.99,28.37,26.85,21.98；ESI-MS m/z:547.18[M+Na]+。
2-(2-(5-(4-(苄氧基)苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z42)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-(苄氧基)苯氧基)戊烷酸(6j)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z42：白色固体，产率58％，mp 128.6-131.4℃；1H NMR(600MHz,DMSO-d6)δ12.27(s,1H),10.63(s,1H),8.61(d,J＝8.1Hz,1H),8.13(d,J＝7.7Hz,1H),8.04(d,J＝7.4Hz,1H),7.81(d,J＝7.4Hz,1H),7.65-7.50(m,2H),7.41(dd,J＝23.8,6.8Hz,4H),7.35-7.15(m,3H),6.90(d,J＝8.3Hz,2H),6.82(d,J＝8.3Hz,2H),5.02(s,2H),3.86(s,2H),2.40(s,2H),1.70(s,4H)；13C NMR(151MHz,DMSO-d6)δ171.53,170.18,166.95,153.28,152.75,141.09,138.35,137.87,134.12,132.53,131.65,128.84,128.41,128.17,128.05,125.04,124.11,123.59,122.75,120.79,116.14,115.74,70.13,67.96,36.88,28.64,22.10；ESI-MS m/z:539.40[M+H]+。
2-(2-(4-([1,1'-联苯]-2-基氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z43)
按照化合物Z1的制备方法，将化合物6a替换为4-([1,1'-联苯]-2-氧基)丁酸(6k)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z43：白色固体，产率58％，mp 167.8-169.5℃；1H NMR(600MHz,DMSO-d6)δ14.18(s,1H),11.13(s,1H),8.63(d,J＝8.2Hz,1H),8.31(d,J＝8.2Hz,1H),8.07(s,1H),7.91(d,J＝5.6Hz,1H),7.57-7.45(m,4H),7.42(t,J＝7.6Hz,2H),7.33–7.25(m,3H),7.22(t,J＝7.0Hz,1H),7.13(t,J＝6.5Hz,1H),7.08(d,J＝8.3Hz,1H),7.01(t,J＝7.4Hz,1H),4.03(t,J＝6.2Hz,2H),2.50(t,J＝1.6Hz,2H),2.01–1.94(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.03,167.06,155.79,141.04,139.26,138.63,132.53,132.22,130.88,130.43,129.72,129.27,128.39,127.23,123.72,123.49,123.10,121.88,121.31,119.89,113.21,67.47,34.00,25.04；ESI-MS m/z:493.31[M-H]-。
2-(2-(5-([1,1'-联苯基]-2-氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z44)
按照化合物Z1的制备方法，将化合物6a替换为5-([1,1'-联苯]-2-氧基)戊烷酸(6l)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z44：白色固体，产率41％，mp 147.7-150.3℃；1H NMR(600MHz,DMSO-d6)δ13.74(s,1H),11.99(s,1H),10.54(s,1H),8.59(d,J＝8.3Hz,1H),8.11(d,J＝8.2Hz,1H),8.03(dd,J＝7.9,1.4Hz,1H),7.85–7.76(m,1H),7.65–7.58(m,1H),7.55(dd,J＝11.4,4.2Hz,1H),7.48(d,J＝7.3Hz,1H),7.48(d,J＝7.3Hz,1H),7.35(t,J＝7.7Hz,1H),7.35(t,J＝7.7Hz,1H),7.33–7.23(m,4H),7.21(t,J＝7.5Hz,1H),7.06(d,J＝8.2Hz,1H),7.01(t,J＝7.4Hz,1H),3.95(d,J＝5.5Hz,2H),2.34(t,J＝6.7Hz,2H),1.70-1.64(m,4H)；13C NMR(151MHz,DMSO-d6)δ171.49,170.14,166.95,155.91,141.09,138.62,138.30,134.39,132.56,131.62,130.86,130.41,129.69,129.24,128.36,128.31,127.17,125.10,124.14,123.69,122.82,121.24,120.93,118.02,113.23,67.84,36.67,28.50,21.98；ESI-MS m/z:507.18[M-H]-。
2-(2-(4-(2,4-二叔丁基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z45)
按照化合物Z1的制备方法，将化合物6a替换为4-(2,4-二叔丁基苯氧基)丁酸(6m)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z45：白色固体，产率68％，mp 160.9-162.9℃；1H NMR(600MHz,DMSO-d6)δ14.14(s,1H),11.16(s,1H),8.62(d,J＝8.2Hz,1H),8.30(d,J＝8.2Hz,1H),8.06(d,J＝6.0Hz,1H),7.90(d,J＝6.8Hz,1H),7.54(t,J＝7.7Hz,1H),7.46(t,J＝7.7Hz,1H),7.22(dd,J＝12.2,4.8Hz,2H),7.15–7.06(m,2H),6.82(d,J＝8.5Hz,1H),4.00(t,J＝6.4Hz,2H),2.59(t,J＝7.4Hz,2H),2.17–2.03(m,2H),1.35(s,9H),1.24(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.03,167.01,155.43,142.19,141.08,139.15,136.60,132.49,132.23,131.72,128.39,123.88,123.79,123.34,123.04,122.03,119.87,112.28,67.19,35.02,34.33,31.90,30.28,25.45；ESI-MSm/z:529.40[M-H]-。
2-(2-(5-(2,4-二叔丁基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z46)
按照化合物Z1的制备方法，将化合物6a替换为5-(2,4-二叔丁基苯氧基)戊酸(6n)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z46：白色固体，产率60％，mp 167.6-168.7℃；1H NMR(600MHz,DMSO-d6)δ13.77(s,1H),11.01(s,1H),8.62(d,J＝8.2Hz,1H),8.29(d,J＝8.2Hz,1H),8.06(d,J＝6.3Hz,1H),7.89(d,J＝6.7Hz,1H),7.53(t,J＝7.7Hz,1H),7.48(t,J＝7.7Hz,1H),7.27–7.17(m,2H),7.17–7.05(m,2H),6.83(d,J＝8.6Hz,1H),3.95(s,2H),2.45(s,2H),1.81(s,4H),1.32(s,9H),1.24(s,9H)；13C NMR(151MHz,DMSO-d6)δ171.43,167.01,155.54,142.08,141.09,139.08,136.59,132.62,132.50,131.71,128.40,123.84,123.79,123.31,123.15,122.12,120.09,112.18,67.43,37.11,35.01,34.33,31.91,30.21,28.91,22.40；ESI-MS m/z:543.21[M-H]-。
2-(2-(4-(萘-2-基氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z47)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)丁酸(6o)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z47：白色固体，产率56％，mp 162.1-163.9℃；1H NMR(600MHz,DMSO-d6)δ13.74(s,1H),11.99(s,1H),10.62(s,1H),8.59(d,J＝8.3Hz,1H),8.11(d,J＝8.2Hz,1H),8.02(dd,J＝7.9,1.2Hz,1H),7.82-7.74(m,4H),7.63–7.52(m,2H),7.43(t,J＝7.4Hz,1H),7.33(t,J＝7.3Hz,1H),7.29–7.24(m,2H),7.19(t,J＝7.6Hz,1H),7.13(dd,J＝8.9,2.4Hz,1H),4.11(t,J＝6.4Hz,2H),2.56(t,J＝7.3Hz,2H),2.12-2.05(m,2H)；13C NMR(151MHz,DMSO-d6)δ171.21,170.16,166.91,156.88,141.13,138.16,134.74,134.41,132.53,131.63,129.67,128.90,128.41,127.94,127.10,126.78,125.40,124.25,123.95,123.64,122.97,120.86,119.15,117.90,107.17,67.25,33.73,25.00；ESI-MS m/z:467.22[M-H]-。
2-(2-(5-(萘-2-基氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z48)
按照化合物Z1的制备方法，将化合物6a替换为4-(萘-2-氧基)戊酸(6p)，化合物5a替换为2-(2-氨基苯甲酰胺)苯甲酸乙酯(5c),其余条件相同。化合物Z48：白色固体，产率62％，mp 162.3-164.1℃；1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),10.58(s,1H),8.61(d,J＝8.3Hz,1H),8.10(d,J＝8.2Hz,1H),8.04(d,J＝7.2Hz,1H),7.86–7.73(m,4H),7.50-7.68(m,2H),7.44(t,J＝7.4Hz,1H),7.33(t,J＝7.4Hz,1H),7.27(dd,J＝8.9,5.1Hz,2H),7.20(t,J＝7.5Hz,1H),7.13(dd,J＝8.9,2.2Hz,1H),4.06(t,J＝5.5Hz,2H),2.44(t,J＝6.6Hz,2H),1.70-1.90(m,4H)；13C NMR(101MHz,DMSO-d6)δ171.54,170.16,166.93,156.99,141.11,138.16,134.77,134.41,132.52,131.63,129.67,128.87,128.44,127.95,127.10,126.79,125.37,124.21,123.92,123.66,122.92,120.91,119.22,117.99,107.06,67.62,36.80,28.52,22.12；ESI-MS m/z:505.17[M+Na]+。
2-(2-(5-(4-乙酰苯氧基)戊酰氨基)-5-甲基苯甲酰氨基)苯甲酸(Z49)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙酰基苯氧基)戊酸(6d)，化合物5a替换为2-(2-氨基-5-甲基苯甲酰胺)苯甲酸乙酯(5d),其余条件相同。化合物Z49：白色固体，产率58％，mp 175.9-178.7℃；1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),11.87(s,1H),10.43(s,1H),8.59(d,J＝8.1Hz,1H),8.02(dd,J＝7.9,1.5Hz,1H),7.94(d,J＝8.3Hz,1H),7.89(d,J＝8.8Hz,2H),7.68–7.57(m,2H),7.37(d,J＝8.4Hz,1H),7.21(t,J＝7.6Hz,1H),6.99(d,J＝8.8Hz,2H),4.02(t,J＝5.8Hz,2H),2.50(s,3H),2.38(t,J＝6.8Hz,2H),2.34(s,3H),1.80–1.65(m,4H)；13C NMR(101MHz,DMSO-d6)δ196.71,171.34,170.22,166.93,162.96,141.13,135.66,134.52,133.40,132.99,131.61,130.90,130.22,128.66,125.42,123.65,123.06,120.88,117.70,114.68,67.97,36.66,28.37,26.85,21.99,20.86；ESI-MS m/z:511.18[M+Na]+。
2-(5-甲基-2-(4-(4-丙酰基苯氧基)丁酰氨基)苯甲酰氨基)苯甲酸(Z50)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-丙酰基苯氧基)丁酸(6g)，化合物5a替换为2-(2-氨基-5-甲基苯甲酰胺)苯甲酸乙酯(5d),其余条件相同。化合物Z50：白色固体，产率59％，mp 189.2-191.1℃；1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),11.93(s,1H),10.48(s,1H),8.58(d,J＝8.3Hz,1H),8.02(d,J＝7.4Hz,1H),7.94(d,J＝8.3Hz,1H),7.87(d,J＝8.7Hz,2H),7.66–7.57(m,2H),7.37(d,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),6.97(d,J＝8.7Hz,2H),4.06(t,J＝6.3Hz,2H),2.94(q,J＝7.2Hz,2H),2.47(t,J＝6.3Hz,2H),2.34(s,3H),2.06-1.98(m,2H),1.06(t,J＝7.2Hz,3H)；13C NMR(101MHz,DMSO-d6)δ199.22,170.96,170.23,166.89,162.69,141.17,135.60,134.44,133.47,132.97,131.62,130.49,129.92,128.65,125.54,123.58,123.13,120.75,117.79,114.68,67.55,33.47,31.22,24.88,20.87,8.77；ESI-MS m/z:511.18[M+Na]+。
5-甲基-2-(4-甲基-2-(5-(4-丙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z51)
按照化合物Z1的制备方法，将化合物6a替换为4-(4-丙酰基苯氧基)丁酸(6g)，化合物5a替换为2-(2-氨基-4-甲基苯甲酰氨基)苯甲酸乙酯(5e),其余条件相同。化合物Z51：白色固体，产率48％，mp 161.9-163.7℃；1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),11.89(s,1H),10.74(s,1H),8.46(d,J＝8.7Hz,1H),8.04(s,1H),7.90(d,J＝8.7Hz,2H),7.83(s,1H),7.69(d,J＝8.2Hz,1H),7.43(d,J＝8.1Hz,1H),7.07(d,J＝7.7Hz,1H),6.99(d,J＝8.5Hz,2H),4.04(t,2H),2.96(q,J＝6.9Hz,2H),2.44-2.37(m,2H),2.35(s,3H),2.31(s,3H),1.82-1.65(m,4H),1.06(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)δ199.24,171.42,170.19,166.88,162.81,142.86,138.67,134.86,132.78,131.70,130.50,129.87,128.25,124.67,122.74,121.41,120.95,114.70,67.96,36.96,31.23,28.36,22.00,21.75,20.73,8.79；ESI-MS m/z:539.21[M+Na]+。
3-(2-(5-(4-乙酰苯氧基)戊酰氨基)苯甲酰氨基)-4-乙基苯甲酸(Z52)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-乙酰基苯氧基)戊酸(6d)，化合物5a替换为3-(2-氨基苯甲酰氨基)-4-乙基苯甲酸乙酯(5f),其余条件相同。化合物Z52：白色固体，产率38％，mp 137.3-139.8℃；1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),8.13(d,J＝7.8Hz,1H),8.04(d,J＝8.1Hz,1H),7.96(s,1H),7.88(dd,J＝15.4,8.5Hz,3H),7.71(d,J＝8.1Hz,1H),7.62(d,J＝8.1Hz,1H),7.54(t,J＝7.5Hz,1H),6.93(d,J＝8.7Hz,2H),4.00–3.98(m,2H),2.51(s,3H),2.46-2.35(m,2H),2.35–2.19(m,2H),1.83(dd,J＝14.7,7.4Hz,2H),1.77–1.62(m,2H),1.08(t,J＝7.5Hz,3H)；13C NMR(101MHz,DMSO-d6)δ196.71,166.99,162.82,161.72,156.65,147.68,146.26,136.34,135.23,130.90,130.75,130.60,130.38,130.22,130.05,127.53,127.16,126.85,120.78,114.61,68.15,34.95,28.16,26.85,23.81,22.95,13.76；ESI-MS m/z:503.14[M+H]+。
4-乙基-3-(2-(5-(4-丙酰基苯氧基)戊酰氨基)苯甲酰氨基)苯甲酸(Z53)
按照化合物Z1的制备方法，将化合物6a替换为5-(4-丙酰基苯氧基)戊酸(6h)，化合物5a替换为3-(2-氨基苯甲酰氨基)-4-乙基苯甲酸乙酯(5f),其余条件相同。化合物Z53：白色固体，产率40％，mp 91.5-93.8℃；1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),8.13(dd,J＝7.9,1.2Hz,1H),8.04(dd,J＝8.0,1.7Hz,1H),7.96(d,J＝1.6Hz,1H),7.94–7.83(m,3H),7.71(d,J＝8.0Hz,1H),7.62(d,J＝8.1Hz,1H),7.58–7.50(m,1H),6.93(d,J＝8.9Hz,2H),4.05–3.91(m,2H),2.97(q,J＝7.2Hz,2H),2.46-2.36(m,5.2Hz,2H),2.35–2.20(m,2H),1.90–1.77(m,2H),1.76–1.61(m,2H),1.10-1.06(m,6H)；13C NMR(101MHz,DMSO-d6)δ199.24,166.99,162.67,161.72,156.65,147.68,146.26,136.34,135.23,130.75,130.60,130.51,130.38,130.05,129.88,127.53,127.15,126.85,120.78,114.62,68.12,34.95,31.23,28.17,23.81,22.96,13.76,8.78；ESI-MS m/z:517.13[M+H]+。
实施例3：双荧光素酶报告基因检测法分析及细胞毒性测试
一、双荧光素酶报告基因检测分析
HEK293T细胞常规培养于37℃，5％ CO2饱和湿度的条件下。转染前1d，细胞按5000个/孔接种于96孔板上，培养基为含10％ FBS和1％的青链霉素的DMEM培养基；转染当天，待细胞汇合度为50％～60％，吸去旧的培养基，然后每孔加入100μL DMEM培养基，置于5％CO2，37℃培养箱中；用DMEM培养基稀释Polyethylenimine Linear 0.15μL，并分别加入pRL-TK，pGL3-BASIC-FXR，Pcdna3.1-NR1H4各50ng，终体积为30μL，得到转染复合物，室温下静置15min，每孔加入30μL转染复合液，晃动96孔板稍加混匀；在5％ CO2，37℃培养箱中孵育6h，用新鲜的完全培养基(含FBS)替换含有转染复合物的培养基；培养24h后，吸去旧的培养基，加入含药物的完全培养基继续在5％ CO2，37℃培养箱继续培养24h，结束后，弃原培养基，每孔加入30μL的裂解液(Passive lysis Buffer)，室温轻微振摇15min，收集细胞裂解液。用UElandy公司的Dual luciferase reporter assay system(F6075L)检测样品的萤火虫荧光素信号(Firefly luciferase，Fluc)和海肾荧光素酶信号(Renilla luciferase，Rluc)。酶标仪Envision读数。数据用Prism 8.0进行曲线拟合，计算出EC50值，结果见表1。
二、细胞增殖抑制活性测试
通过MTT法检测所合成的化合物的细胞增殖抑制活性。取对数生长期的HepG-2、L0-2细胞均匀接种于96孔板中,待细胞贴壁后，分别给予浓度为400μM、300μM、250μM、150μM、100μM、50μM、25μM、12.5μM的药物于细胞培养箱中培养24h，对照组加入等量的DMSO。然后每孔加入20μL MTT溶液反应,避光孵育4h。结束孵育后吸出孔内培养液,每孔加入150μLDMSO,低速震荡,使结晶充分溶解，空白组为不加入细胞的孔。在490nm处测量各孔吸光度值。细胞活力的计算公式为：细胞活力(％)＝(OD待测-OD空白)/(OD对照-OD空白)×100。
FXR激动活性测试结果与讨论：A:0.1μM<EC50<10μM；B:10μM<EC50<30μM；
C:EC50>30μM。
表1化合物Z1-Z53对FXR激动活性以及对HepG-2和L0-2细胞的毒性
/>
/>
数据以至少三个独立运行的几何平均值来表示；OCA(奥贝胆酸)，CDCA为阳性对照化合物。其中OCA为已上市的FXR激动剂，CDCA也为FXR激动剂。
表1结果表明，部分化合物对FXR表现出较强的激动活性，其对FXR的激动活性与阳性对照化合物OCA相当，且优于阳性对照化合物CDCA。对HepG-2、L0-2细胞基本无毒性，而阳性对照药OCA对HepG-2和L0-2细胞的细胞毒性IC50分别为257.50±1.63μM和168.10±1.25μM，其细胞毒性都比本发明所合成的多数化合物的细胞毒性大。其中化合物Z4、Z5表现出强效的FXR激动活性，对FXR的EC50值分别为1.35μM和2.23μM，同时对HepG-2、L0-2细胞无细胞毒性(IC50>100μM)。
实施例4：油红O染色分析、TG含量测定，参照图1。
本发明采用0.5mM FFA直接刺激HepG-2细胞24h，构建细胞脂肪变性模型，通过油红O染色及细胞TG含量测定化合物Z4、Z5对脂质蓄积的影响。
从图1A可以看出，当浓度≤300μM，经Z4、Z5处理的HepG-2的存活率达70.0％以上，化合物Z4和Z5的细胞毒性较小，而在300μM下，OCA处理的HepG-2的存活率只有1.2％，表明在一定浓度下，化合物Z4、Z5的细胞毒性比OCA小。
本发明考察了Z4、Z5对高脂HepG-2细胞脂质毒性的保护作用。当化合物浓度在0～100μg/mL时，经Z4、Z5及OCA处理的脂肪变性HepG-2的存活率基本达100％以上，存活率的波动幅度较小，无脂质毒性(图1B)。为了避免其他因素干扰，综合考虑细胞存活率及稳定性，本研究选用25、50、75μM三个浓度分别作为Z4、Z5的低、中、高剂量组用于后续研究。脂溶性染料油红O在脂肪中较易溶解，能与组织和细胞中的TG等中性脂肪特异着色。经Z4、Z5干预24h后，细胞内TG含量显著降低，红色脂滴得到改善，490nm处的吸光度值也显著减少(图1C、D、E)。
实施例5：化合物Z4的体内抗非酒精性脂肪性肝炎活性评价
1.化合物Z4改善NASH小鼠肥胖的效果，参照图2。
本发明选择高脂饮食和化学诱导的方式，高脂饮食伴随每周腹腔注射CCl4会加重小鼠肝损伤从而加速纤维化的发展，有效缩短模型周期，建立伴随有轻中度纤维化的NASH小鼠模型。选择奥贝胆酸(OCA)作为阳性对照药物。5至6周龄的C57BL/6J雄性小鼠，分为正常组(NCD组)，模型组(NASH组)，Z4低剂量组(10mg/kg)，Z4的中剂量组(20mg/kg)，Z4高剂量组(40mg/kg)，和OCA组(10mg/kg)，每组8只小鼠。实验小鼠高脂喂养18周，最后五周模型组及给药组每周腹腔注射两次50μL浓度为3.5％ CCl4溶液，NCD组每周腹腔注射两次50μL橄榄油且持续每日分别灌胃给药OCA(10mg/kg)，Z4(40mg/kg，20mg/kg，10mg/kg)。每周记录每只小鼠体重和精神状态。
为了确定化合物Z4对NASH的治疗效果，本发明首先研究了化合物Z4给药是否影响全身代谢状态。高脂饮食和CCl4诱导18周构建NASH模型并在最后5周持续每日灌胃给药(图2A)。药物干预期间，NCD组小鼠精神状况较好、警惕高，NASH组小鼠精神状况相对恍惚，警惕较低、反应较迟钝，Z4和OCA治疗后，小鼠的精神状况有所改善，活动明显增多，体态明显变少。与NCD组相比，NASH组的小鼠体重显著增加；腹腔注射CCl4后，小鼠体重开始下降，而Z4和OCA处理的小鼠体重减少大于NASH小鼠，化合物Z4和OCA的治疗限制了NASH小鼠的体重增加(图2B)。脂肪的形态学分析显示，与NCD组小鼠的脂肪细胞相比，NASH组小鼠脂肪组织肥大。H&E染色表明，同一视野下，脂肪细胞个数较少，形状极不规则，排列错乱，细胞横截面积显著变大，同时脂肪/体重率也显著增大，Z4、OCA治疗后，脂肪组织明显变小，脂肪细胞较NASH组相比的个数变多，形状逐渐变规则，排列变整齐，细胞横截面积显著变小，脂肪/体重率也显著减少(图2C、D、E)。数据以平均值±SEM表示，与NASH相比，*P≤0.05，**P≤0.01和***P≤0.001，总之，这些数据表明，Z4可以有效改善NASH小鼠的肥胖情况。
2.化合物Z4改善NASH小鼠肝脂肪变性及肝损伤，参照图3。
肝脏的形态学和H&E染色表明，NCD组小鼠肝脏颜色和质地上均表现为新鲜，滑润和致密，肝细胞形态完整，大小均等，轮廓清晰，细胞核排列整齐，NASH组小鼠肝脏表面出现许多微小的乳白色颗粒且肝脏外观粗糙，呈灰色，肝细胞肿大，出现较多脂肪空泡，累积大量的脂滴，细胞核排列紊乱。Z4和OCA干预后，肝脏外观明显改善，肝细胞空泡缩小，轮廓变清晰，细胞核慢慢排列整齐(图3A)。脏器指数可以间接反映脏器的受损程度。与NCD组相比，NASH组小鼠肝重及肝脏指数显著增大，Z4和OCA干预五周后，小鼠的肝重和肝脏指数显著下降(图3B、C)，此外也显著抑制了肝脏TG的上调(图3D)。
临床上，血清中ALT、AST含量是检测肝损伤的敏感指标。相比于NCD组，NASH组小鼠血清中的AST、ALT含量显著升高，Z4干预后显著减低小鼠血清AST、ALT，而OCA干预后只显著减低小鼠血清AST，对ALT水平只呈下降趋势，无显著差异(图3E，F)。血脂水平长期偏高会使肝脏脂肪蓄积，长期处于脂毒性状态，激活机体的氧化途径，产生大量的活性氧簇(ROS)，引起体内的氧化应激。过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)是体内重要的抗氧化酶，对机体的氧化还原平衡具有重要作用。丙二醛(MDA)是机体脂质过氧化的产物，是检测机体自由基损伤的敏感指标，化合物Z4治疗显著升高肝脏CAT，血清GSH-Px，显著降低了肝脏MDA(图3G，H，I，J)。数据以平均值±SEM表示，与NASH组相比，*P≤0.05，**P≤0.01和***P≤0.001，总之，这些数据表明Z4治疗能减轻NASH小鼠肝脂肪变性及肝损伤，提高体内抗氧化酶活性，增强机体的抗氧化能力。
3.化合物Z4改善NASH小鼠血脂代谢紊乱的效果，参照图4。
从图4可以看出，与NCD组相比，NASH组小鼠血清的TC、TG和LDL-C水平显著升高，HDL-C水平呈降低的趋势，但无显著差异降低。Z4干预后，小鼠的TC、TG、LDL-C水平均有不同程度的改善，其中TC、TG含量显著降低，LDL-C含量降低，HDL-C含量呈升高趋势，但无显著差异(图4A，B，C，D)，数据以平均值±SEM表示，与NASH相比，*P≤0.05，**P≤0.01和***P≤0.001。这些结果表明Z4可以很好的调控NASH小鼠体内的血脂水平，改善血脂紊乱，其改善血脂异常的效果与阳性对照化合物OCA相当。
4.实施例6：化合物Z4的药代动力学分析，参照图5。
选取雄性C57BL/6J小鼠，对化合物Z4进行药代动力学及组织分布研究。结果发现化合物Z4的口服生物利用度为61.2％，T1/2为2.5h，Tmax为0.25h。口服和静脉给药的AUC0-last分别是2593.4和848.0ng/mL*h(图5A)。化合物Z4在口服给药0.5h，在肝脏中的浓度6230ng/mL，显著高于在血浆和小肠，给药2h，小肠中药物浓度略高于肝脏中，给药8h后，药物在肝脏和小肠中浓度都低于1500ng/mL(图5B)，数据以平均值±SEM表示。总之，化合物Z4表现出良好的药代动力学性质。
总之，本发明的优选化合物Z4对FXR具有很强的激动活性，且体内生物活性高，药代动力学性质良好，具有良好的应用前景。
实施例7：化合物Z4在C57BL/6J小鼠体内的急性毒性
实验过程中，发现化合物Z4单次灌胃给药后(3000mg/kg、1500mg/kg、750mg/kg、375mg/kg、187.5mg/kg、93.75mg/kg、40mg/kg)常规饲养，观察14天小鼠均未出现任何毒副作用，小鼠全部存活，灌胃给药后无法测出化合物Z4的致死区间。14天后解剖，各个给药剂量组小鼠体重均无明显差异，与0mg/kg组相比，375mg/kg给药剂量组小鼠的肝脏指数、心脏指数显著增大、但对其他脏器指数无显著影响，血清中的AST和ALT活力显著增大，187.5mg/kg给药剂量组小鼠的肝脏指数显著增大，其他剂量组对脏器指数、血清中的AST和ALT活力均无显著影响。阳性化合物OCA在灌胃给药1500mg/kg、750mg/kg、70mg/kg、40mg/kg、20mg/kg、0mg/kg后，常规饲养，灌胃给药1500mg/kg、750mg/kg给药组的小鼠在灌胃给药一天后全部死亡，灌胃给药70mg/kg、40mg/kg给药组的小鼠肾脏指数，血清中的AST和ALT活力显著增大，表现出毒性反应；灌胃给药20mg/kg给药组的小鼠血清中的AST和ALT活力显著增大，结果见表2。总之，与阳性化合物OCA相比，化合物Z4的毒性更小，在体内安全性更高。
表2化合物Z4和OCA在C57BL/6J小鼠体内的急性毒性
注：数据以平均值±SEM表示，与0mg/kg组相比，*差异显著(P＜0.05)；**差异极显著(P＜0.01)；***差异极显著(P＜0.001)。
Claims (9)
1.一种芳氧氨基苯甲酸类衍生物，其特征在于：其结构式如式(I)所示，
其中：
Ar为取代苯基或萘基，选自4-乙基苯基、4-叔丁基苯基、2，4-二叔丁基苯基、4-乙酰基苯基、4-丙酰基苯基、4-苄氧基苯基、联苯基、萘基；
n独立选自2、3；
R1、R2各自独立选自氢、甲基、乙基；
R1、R2及—COOH基团位于苯环的任意位置。
2.如权利要求1所述芳氧氨基苯甲酸类衍生物，其特征在于：式(I)所示衍生物，选自以下化合物：
3.如权利要求1所述芳氧氨基苯甲酸类衍生物的制备方法，其特征在于，式(I)所示衍生物的制备路线如下：
其中，式(II)、式(III)、式(IV)、化合物5a-f和式(VI)所示化合物及式(I)所示化合物中R1、R2定义一致；
化合物6a-p所示化合物、式(VI)所示化合物及式(I)所示化合物中Ar、n定义一致；
制备方法包括如下步骤：
步骤a.硝基苯甲酸及其不同的衍生物II和氨基苯甲酸乙酯及其不同的衍生物III，在适当溶剂和缩合试剂下进行酰胺化反应，制备得到中间体化合物IV；
步骤b.式IV所示化合物在有机溶剂和还原试剂下，经过还原反应制备得到化合物5a-f；
步骤c.化合物5a-f分别与芳氧羧酸类衍生物6a-p进行酰胺化反应，生成式VI所示的芳氧氨基苯甲酸酯类衍生物；
步骤d.式VI所示化合物在有机溶剂以及碱性条件下水解，然后酸化反应制备得到式(I)所示的衍生物。
4.如权利要求3所述芳氧氨基苯甲酸类衍生物的制备方法，其特征在于：
步骤a所述的硝基苯甲酸及其不同的衍生物II与氨基苯甲酸乙酯及其不同的衍生物III的摩尔比为1:1.1，反应温度为30～45℃；
步骤a所述适当溶剂，选自N,N-二甲基甲酰胺、四氢呋喃、二氯甲烷、三氯甲烷、二甲基亚砜中一种；
步骤a所述的缩合试剂，选自2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N-二异丙基乙胺、1-乙基-3-(3-二甲基丙胺)碳二亚胺盐酸盐、1-羟基苯并三唑、二环己基碳二亚胺中的一种。
5.如权利要求3所述芳氧氨基苯甲酸类衍生物的制备方法，其特征在于：
步骤b所述的式(IV)所示化合物与还原试剂的摩尔比为1:5，反应温度为室温～45℃；
步骤b所述的有机溶剂，选自乙醇、甲醇、四氢呋喃、二氯甲烷中一种；
步骤b所述的还原试剂，选自锌粉或铁粉；
步骤b的方法，或者是将式IV所示化合物在乙醇中，加锌粉还原得到衍生物5a-f；
或者将式IV所示化合物在氢气氛围下，以5％Pd/C为催化剂进行氢化还原制备得到化合物5a-f。
6.如权利要求3所述芳氧氨基苯甲酸类衍生物的制备方法，其特征在于：
步骤c所述的化合物5a-f与化合物6a-p的摩尔比为1:1.3。
7.如权利要求3所述芳氧氨基苯甲酸类衍生物的制备方法，其特征在于：
步骤d所述的式(VI)所示化合物与碱的摩尔比为1:1.1；
步骤d所述的有机溶剂，选自乙醇、甲醇、四氢呋喃中的一种；
步骤d所述的碱，选自氢氧化钠或氢氧化钾；
步骤d所述的酸化反应条件，用1mol/L盐酸溶液调pH＝1～2，在0～5℃下反应。
8.如权利要求1所述的式(I)所示衍生物或其药学上可接受的盐、或其药物组合物作为法尼醇X受体调节剂，在制备治疗法尼醇X受体相关疾病的药物中的应用。
9.如权利要求1所述的式(I)所示衍生物或其药学上可接受的盐、或其药物组合物在制备治疗胆汁淤积性肝病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、高脂血症、糖尿病、肥胖症及动脉粥样硬化中至少一种疾病的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310661008.1A CN116693416A (zh) | 2023-06-06 | 2023-06-06 | 一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310661008.1A CN116693416A (zh) | 2023-06-06 | 2023-06-06 | 一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116693416A true CN116693416A (zh) | 2023-09-05 |
Family
ID=87836788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310661008.1A Pending CN116693416A (zh) | 2023-06-06 | 2023-06-06 | 一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116693416A (zh) |
-
2023
- 2023-06-06 CN CN202310661008.1A patent/CN116693416A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6387938B1 (en) | Benzimidazole derivatives | |
| CN109415363B (zh) | 用于治疗代谢疾病和癌症的新的线粒体解偶联剂 | |
| WO2021114864A1 (zh) | 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途 | |
| CN102140064A (zh) | 用于治疗代谢失调的化合物 | |
| CN108349911B (zh) | 可释放一氧化氮的前药分子 | |
| CN105189452B (zh) | 苯基亚甲基胍衍生物以及其用于蛋白质错误折叠疾病的治疗用途 | |
| CN102083799A (zh) | 用作fxr激动剂的苯并咪唑衍生物 | |
| CN101945848A (zh) | 四取代的苯 | |
| KR100682276B1 (ko) | 안트라닐산 유도체 | |
| WO2017041732A1 (zh) | 一类用于治疗或预防高尿酸血症或痛风的化合物 | |
| WO2021238328A1 (zh) | 一种含有异羟肟酸的化合物及其制备方法、应用 | |
| CN102964322A (zh) | 异黄酮或类黄酮脂肪醚类衍生物、其制备方法和医药用途 | |
| TW202039439A (zh) | ４（１ｈ）－奎諾酮衍生物及其用途 | |
| KR20210097100A (ko) | 2-(1-아실옥시-n-펜틸)벤조산 및 염기성 아미노산 또는 아미노구아니딘이 형성하는 염, 이의 제조 방법 및 용도 | |
| JP2022500395A (ja) | ファルネソイドｘ受容体アゴニストの結晶形態 | |
| WO2001060354A1 (fr) | Medicament anticancereux comprenant un derive d'acide anthranilique en tant qu'ingredient actif | |
| MX2009001104A (es) | Derivados de 4-trimetilamonio-3-aminobutirato y 4-trimetilfosfonio-3-aminobutirato como inhibidores de carnitina palmitoil transferasa. | |
| TW558554B (en) | Crystals of oxyiminoalkanoic acid derivative | |
| CN101193853B (zh) | 邻氨基苯甲酸衍生物 | |
| CN116693416A (zh) | 一种芳氧氨基苯甲酸类衍生物及其制备方法和应用 | |
| WO2016197463A1 (zh) | 刺芒柄花素脂肪醚类衍生物、其制备方法和医药用途 | |
| CN105198786B (zh) | 芳基取代的酰胺类化合物及其制备方法、包含其的药物组合物及其应用 | |
| US8846752B2 (en) | Isoflavone fatty acid ester derivatives, preparation method and pharmaceutical uses thereof | |
| JP2004175778A (ja) | 新規桂皮酸類 | |
| CN111393421B (zh) | 丁烯酸内酯类衍生物及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |