CN106279023B - 3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 - Google Patents
3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 Download PDFInfo
- Publication number
- CN106279023B CN106279023B CN201510239918.6A CN201510239918A CN106279023B CN 106279023 B CN106279023 B CN 106279023B CN 201510239918 A CN201510239918 A CN 201510239918A CN 106279023 B CN106279023 B CN 106279023B
- Authority
- CN
- China
- Prior art keywords
- preparation
- dichlorophenyl
- acid
- methyl
- ethyl
- 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.)
- Expired - Fee Related
Links
- -1 3,4, 5-trisubstituted pyrazole compound Chemical class 0.000 title claims abstract description 203
- 238000002360 preparation method Methods 0.000 title claims abstract description 199
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 108010063919 Glucagon Receptors Proteins 0.000 claims description 21
- 102100040890 Glucagon receptor Human genes 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 229940122904 Glucagon receptor antagonist Drugs 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000003914 insulin secretion Effects 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 150000003217 pyrazoles Chemical class 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000002503 metabolic effect Effects 0.000 claims description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 54
- 229940079593 drug Drugs 0.000 abstract description 11
- 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 abstract description 10
- 102000004877 Insulin Human genes 0.000 abstract description 5
- 108090001061 Insulin Proteins 0.000 abstract description 5
- 229940125396 insulin Drugs 0.000 abstract description 5
- 230000001737 promoting effect Effects 0.000 abstract description 4
- 230000028327 secretion Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 273
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 143
- 238000005160 1H NMR spectroscopy Methods 0.000 description 91
- 239000000047 product Substances 0.000 description 91
- 239000003153 chemical reaction reagent Substances 0.000 description 90
- 239000002994 raw material Substances 0.000 description 82
- 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 81
- 239000005711 Benzoic acid Substances 0.000 description 72
- 235000010233 benzoic acid Nutrition 0.000 description 72
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 62
- QBHDSQZASIBAAI-UHFFFAOYSA-N 4-acetylbenzoic acid Chemical compound CC(=O)C1=CC=C(C(O)=O)C=C1 QBHDSQZASIBAAI-UHFFFAOYSA-N 0.000 description 38
- KSYOLEOXPIYUNZ-UHFFFAOYSA-N ethyl 3-(3,5-dichlorophenyl)-2-methyl-3-oxopropanoate Chemical compound ClC=1C=C(C=C(C=1)Cl)C(C(C(=O)OCC)C)=O KSYOLEOXPIYUNZ-UHFFFAOYSA-N 0.000 description 38
- 235000019260 propionic acid Nutrition 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000000623 heterocyclic group Chemical group 0.000 description 26
- ZJXHVYSDMUKUCA-UHFFFAOYSA-N tert-butyl 3-aminopropanoate Chemical compound CC(C)(C)OC(=O)CCN ZJXHVYSDMUKUCA-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 206010012601 diabetes mellitus Diseases 0.000 description 21
- GZFAVYWCPSMLCM-UHFFFAOYSA-N (6-methoxynaphthalen-2-yl)boronic acid Chemical compound C1=C(B(O)O)C=CC2=CC(OC)=CC=C21 GZFAVYWCPSMLCM-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 12
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000027455 binding Effects 0.000 description 11
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 230000009471 action Effects 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- KLAAXTKTDRQPOF-UHFFFAOYSA-N 4-fluoro-2-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1C=O KLAAXTKTDRQPOF-UHFFFAOYSA-N 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WLTZCRCZDLLXQP-UHFFFAOYSA-N 4-(2,2,2-trifluoroacetyl)benzoic acid Chemical compound OC(=O)C1=CC=C(C(=O)C(F)(F)F)C=C1 WLTZCRCZDLLXQP-UHFFFAOYSA-N 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- RQIFXTOWUNAUJC-UHFFFAOYSA-M ethanesulfinate Chemical compound CCS([O-])=O RQIFXTOWUNAUJC-UHFFFAOYSA-M 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- DIMJDZRCNOLERT-FQEVSTJZSA-N ClC=1C=C(C=C(C=1)Cl)C1=NN(C(=C1C)C1=CC2=CC=C(C=C2C=C1)OC)[C@@H](C)C1=CC=C(C(=O)NCCC(=O)O)C=C1 Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NN(C(=C1C)C1=CC2=CC=C(C=C2C=C1)OC)[C@@H](C)C1=CC=C(C(=O)NCCC(=O)O)C=C1 DIMJDZRCNOLERT-FQEVSTJZSA-N 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 208000030159 metabolic disease Diseases 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
- 108060003199 Glucagon Proteins 0.000 description 4
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 4
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 4
- 102100033266 Insulin-like peptide INSL5 Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 102000030621 adenylate cyclase Human genes 0.000 description 4
- 108060000200 adenylate cyclase Proteins 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- KPTRDYONBVUWPD-UHFFFAOYSA-N naphthalen-2-ylboronic acid Chemical compound C1=CC=CC2=CC(B(O)O)=CC=C21 KPTRDYONBVUWPD-UHFFFAOYSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000001603 reducing effect Effects 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
- IFQUPKAISSPFTE-UHFFFAOYSA-N 4-benzoylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(=O)C1=CC=CC=C1 IFQUPKAISSPFTE-UHFFFAOYSA-N 0.000 description 3
- ZLJKWECEUFJPIZ-UHFFFAOYSA-N 4-carboniodidoylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(I)=O)C=C1 ZLJKWECEUFJPIZ-UHFFFAOYSA-N 0.000 description 3
- WZADVYBKUABRSB-UHFFFAOYSA-N 4-carbonobromidoylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(Br)=O)C=C1 WZADVYBKUABRSB-UHFFFAOYSA-N 0.000 description 3
- OYEQKMASMPBQMP-UHFFFAOYSA-N 4-carbonochloridoylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(Cl)=O)C=C1 OYEQKMASMPBQMP-UHFFFAOYSA-N 0.000 description 3
- CGCJFPSCSVLKRF-UHFFFAOYSA-N 4-carbonocyanidoylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(=O)C#N)C=C1 CGCJFPSCSVLKRF-UHFFFAOYSA-N 0.000 description 3
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 3
- MQZBJHMHKZVYHB-UHFFFAOYSA-N 4-propanoylbenzoic acid Chemical compound CCC(=O)C1=CC=C(C(O)=O)C=C1 MQZBJHMHKZVYHB-UHFFFAOYSA-N 0.000 description 3
- 102000040350 B family Human genes 0.000 description 3
- 108091072128 B family Proteins 0.000 description 3
- DIMJDZRCNOLERT-HXUWFJFHSA-N ClC=1C=C(C=C(C=1)Cl)C1=NN(C(=C1C)C1=CC2=CC=C(C=C2C=C1)OC)[C@H](C)C1=CC=C(C(=O)NCCC(=O)O)C=C1 Chemical compound ClC=1C=C(C=C(C=1)Cl)C1=NN(C(=C1C)C1=CC2=CC=C(C=C2C=C1)OC)[C@H](C)C1=CC=C(C(=O)NCCC(=O)O)C=C1 DIMJDZRCNOLERT-HXUWFJFHSA-N 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 3
- 108091006065 Gs proteins Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000005518 carboxamido group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 3
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 description 2
- BJQCPCFFYBKRLM-UHFFFAOYSA-N (3-methylphenyl)boronic acid Chemical compound CC1=CC=CC(B(O)O)=C1 BJQCPCFFYBKRLM-UHFFFAOYSA-N 0.000 description 2
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- BIWQNIMLAISTBV-UHFFFAOYSA-N (4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C=C1 BIWQNIMLAISTBV-UHFFFAOYSA-N 0.000 description 2
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 2
- YDHOAQXHVQTASS-UHFFFAOYSA-N 3-amino-n-hydroxypropanamide Chemical compound NCCC(=O)NO YDHOAQXHVQTASS-UHFFFAOYSA-N 0.000 description 2
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108091006101 Gi proteins Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 2
- 101000998774 Homo sapiens Insulin-like peptide INSL5 Proteins 0.000 description 2
- 101710125723 Insulin-like peptide INSL5 Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 2
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- UZDPQDBLCJDUAX-UHFFFAOYSA-N (4-chloro-3-methylphenyl)boronic acid Chemical compound CC1=CC(B(O)O)=CC=C1Cl UZDPQDBLCJDUAX-UHFFFAOYSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- MNJYZNVROSZZQC-UHFFFAOYSA-N (4-tert-butylphenyl)boronic acid Chemical compound CC(C)(C)C1=CC=C(B(O)O)C=C1 MNJYZNVROSZZQC-UHFFFAOYSA-N 0.000 description 1
- FMBVAOHFMSQDGT-UHFFFAOYSA-N (5-chloro-2-methoxyphenyl)boronic acid Chemical group COC1=CC=C(Cl)C=C1B(O)O FMBVAOHFMSQDGT-UHFFFAOYSA-N 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- VLXSIHLNPYRFFN-UHFFFAOYSA-N 1,4-dioxane;methanol Chemical compound OC.C1COCCO1 VLXSIHLNPYRFFN-UHFFFAOYSA-N 0.000 description 1
- IMDTYQHPAJZVOB-UHFFFAOYSA-N 2-amino-n-methylethanesulfonamide;hydrochloride Chemical group Cl.CNS(=O)(=O)CCN IMDTYQHPAJZVOB-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- ULRPISSMEBPJLN-UHFFFAOYSA-N 2h-tetrazol-5-amine Chemical compound NC1=NN=NN1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 description 1
- ZHCLIFKUVIFYBY-UHFFFAOYSA-N 2h-tetrazol-5-ylmethanamine Chemical compound NCC1=NN=NN1 ZHCLIFKUVIFYBY-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- 125000000981 3-amino-3-oxopropyl group Chemical group [H]C([*])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- BFJOJIJWHRDGQO-UHFFFAOYSA-N 3-amino-n-methylpropanamide Chemical compound CNC(=O)CCN BFJOJIJWHRDGQO-UHFFFAOYSA-N 0.000 description 1
- JNWVYFVCBJPQTO-UHFFFAOYSA-N 3-amino-n-phenylpropanamide Chemical compound NCCC(=O)NC1=CC=CC=C1 JNWVYFVCBJPQTO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- MQPOZFUWRMPYIN-UHFFFAOYSA-N 4-carbonofluoridoylbenzoic acid Chemical compound OC(=O)C1=CC=C(C(F)=O)C=C1 MQPOZFUWRMPYIN-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 1
- 102100039997 Gastric inhibitory polypeptide receptor Human genes 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101000886866 Homo sapiens Gastric inhibitory polypeptide receptor Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- RSDOASZYYCOXIB-UHFFFAOYSA-N beta-alaninamide Chemical compound NCCC(N)=O RSDOASZYYCOXIB-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- NHHRBRPLVQZVSE-UHFFFAOYSA-N boric acid;trifluoromethoxybenzene Chemical compound OB(O)O.FC(F)(F)OC1=CC=CC=C1 NHHRBRPLVQZVSE-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000013262 cAMP assay Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- SYFFHRPDTQNMQB-UHFFFAOYSA-N ethyl 3-oxopropanoate Chemical compound CCOC(=O)CC=O SYFFHRPDTQNMQB-UHFFFAOYSA-N 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000003316 glycosidase inhibitor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- VVIUBCNYACGLLV-UHFFFAOYSA-N hypotaurine Chemical compound [NH3+]CCS([O-])=O VVIUBCNYACGLLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- UZCXPYDBYUEZCV-UHFFFAOYSA-N methyl 3-aminopropanoate Chemical compound COC(=O)CCN UZCXPYDBYUEZCV-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940037201 oris Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- GZFAXMFQTNLJDG-UHFFFAOYSA-N phenyl 3-aminopropanoate Chemical compound NCCC(=O)OC1=CC=CC=C1 GZFAXMFQTNLJDG-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical class *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- DOMTZTVJNZKUNX-UHFFFAOYSA-N tert-butyl 3-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CCN DOMTZTVJNZKUNX-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及3,4,5‑三取代吡唑类化合物、制备方法、药物组合物及用途。3,4,5‑三取代吡唑类化合物结构如式I所示，各取代基的定义如说明书和权利要求书所述。本发明的3,4,5‑三取代吡唑类化合物及含此类化合物的药物组合物可促进胰岛素的分泌，用于制备促进胰岛素分泌的药物。
Description
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及一类3,4,5-三取代的吡唑类化合物、其制备方法、含此类化合物的药物组合物及作为胰高血糖素受体拮抗剂，特别是制备用于治疗糖尿病、动脉粥样硬化和肥胖症的药物用途。
背景技术
糖尿病是一种遗传因素和环境因素长期共同作用所导致的慢性、全身性、代谢性疾病，以血浆葡萄糖水平增高为特征，主要是因体内胰岛素分泌不足或作用障碍(胰岛素抵抗)引起的糖、脂肪、蛋白质代谢紊乱而影响正常生理活动的一种疾病，表现为多种急性并发症和慢性并发症。可分为1型糖尿病、2型糖尿病、以及其他特殊类型糖尿病(如，妊娠糖尿病等)，全世界糖尿病患者中约90％为2型糖尿病。糖尿病已经成为继心血管、肿瘤威胁人类健康的第三大疾病。因此研究治疗糖尿病的药物成为目前新药研究的热点之一。
2013年，国际糖尿病联合会(IDF)统计，全球3.82亿人群患有糖尿病，中国糖尿病患者人数9840万，位居全球第一。预计，到2035年，全球糖尿病患者人数将增至5.92亿，中国糖尿病患者人数将达到1.43亿。糖尿病全球医疗花费达5480亿美元，占全球医疗支出的11％。预计到2035年，与糖尿病相关的全球医疗花费将达到6273亿美元。由此可见，抗糖尿病药物市场潜力巨大。
目前II型糖尿病的治疗药物主要包括胰岛素、磺酰脲类、二甲双胍类、阿卡波糖类糖苷酶抑制剂、噻唑烷二酮类、PPARα/γ双重激动剂、DPP IV抑制剂、SGLT2抑制剂、GLP-1类似物等。虽然现有药物能控制血糖水平，减少并发症的发生几率，但大多数具有比较严重的副作用，例如胃肠道毒性、体重增加、水肿、低血糖等，不能从根本上控制、治愈II型糖尿病。由于传统的糖尿病治疗药物效果有限且耐受性不佳，同时还有明显的副作用，因此，从人类健康和经济利益的角度来考虑，研究开发安全、高效的糖尿病治疗药物具有良好的开发前景以及重要的研究意义。
胰高血糖素受体(Glucagon Receptor,GR)是近年来糖尿病药物研究的重要治疗靶标，GR拮抗剂对糖尿病均具有良好的治疗效果，且副作用小，是最具前景的糖尿病治疗药物。GR拮抗剂通过抑制胰高血糖素介导的腺苷酸环化酶活性，从而减少正常人的肝糖输出，达到降低体内血糖的效果。由于GR受体拮抗剂独特的作用机制，使其成为糖尿病药物的研发热点。
GR受体拮抗剂的研究已经取得了较大的突破，多个化合物处于临床II期研究阶段，但是如何提高该类化合物的选择性，在拮抗胰高血糖素受体的同时促进胰岛素的分泌仍然是目前亟待解决的问题，因此，对GR受体拮抗剂的研究仍然是一项很大的挑战。
发明内容
本发明的一个目的在于提供一种3,4,5-三取代的吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物。
本发明的另一个目的在于提供一种上述吡唑类化合物的制备方法。
本发明的再一个目的在于提供一种药物组合物，其包含治疗有效量的选自上述吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供一种胰高血糖素受体拮抗剂，其包含选自上述吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供一种胰高血糖素受体拮抗剂，在具有胰高血糖素受体的拮抗活性同时，还具有促进人体胰岛素分泌的作用效果，能够通过两种作用机制达到治疗II型糖尿病的作用效果。
本发明的又一个目的在于提供上述吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物在制备用于治疗与胰高血糖素受体相关的代谢性疾病，例如：糖尿病、动脉粥样硬化、肥胖症等疾病中的药物用途。
本发明的又一个目的在于提供一种治疗与与胰高血糖素受体相关的代谢性疾病，例如：糖尿病、动脉粥样硬化、肥胖症等疾病的方法，其包括向需要该治疗的患者给药选自上述吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
基于上述目的，本发明提供了一种具有如下通式I所示结构的3,4,5-三取代的吡唑类化合物，及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物：
其中：
n为0、1、2或3；
X为(CH2)p、CO或SO2，其中p为0、1、2或3；
R1为取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代3-12元杂环基、取代或未取代的C6-C12芳基；所述取代是指具有选自下组的1、2、3、4或5个相同或不同的取代基：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基和3-12元杂环基；或者在所述C6-C12芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基；各个杂环基各自独立地含有1～4个选自氧、硫和氮的杂原子；
R2选自：C1-C6烷基、卤素取代的C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、-O[(CH2)qO]rY、C6-C12芳基和3-12元杂环基；其中，所述杂环基含有1～3个选自氧、硫和氮的杂原子；Y选自：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C2-C6烯基、C2-C6炔基和羟甲基；q为1、2、3或4；r为1、2、3或4；
R3为取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烯基、取代或未取代3-12元杂环基、取代或未取代的C6-C12芳基；所述取代是指具有选自下组的1、2、3、4或5个相同或不同的取代基：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基和3-12元杂环基；或者在所述C6-C12芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基；各个杂环基各自独立地含有1～4个选自氧、硫和氮的杂原子；
R4选自：氢、C1-C6烷基、卤素取代的C1-C6烷基、卤素、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、-O[(CH2)qO]rY、C6-C12芳基和3-12元杂环基；其中，所述杂环基含有1～3个选自氧、硫和氮的杂原子；Y选自氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C2-C6烯基、C2-C6炔基和羟甲基中；q为1、2、3或4；r为1、2、3或4；
R5为选自氢或C1-C6烷基、卤素取代的C1-C6烷基、卤素、三氟甲基和三氟甲氧基；
R6为选自COOR7、SO2R7、CONHR7、SO2NHR7、5-四氮唑或
R7选自：H、羟基、C1-C6烷基、卤素取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、苯基和3-12元杂环基；其中，所述杂环基含有1～3个选自氧、硫和氮中的杂原子。
在另一优选例中，X为(CH2)p或CO，p为1或者2。较佳地，X为CO。
在另一优选例中，R1为取代或未取代的C3-C10环烷基、取代或未取代3-12元杂环基、取代或未取代的C6-C12芳基；所述取代是指具有选自下组的1、2、3、4或5个相同或不同的取代基：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C6-C10芳基和3-12元杂环基；或者在所述C6-C12芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基；各个杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子。
在另一优选例中，R1为取代或未取代的C6-C10芳基和3-12元杂环基；或者在所述C6-C10芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基；各个杂环基各自独立地含有1～4个选自氧、硫和氮的杂原子；所述取代基选自卤素、甲基、甲氧基、乙基、氨基、羟基、氰基、硝基、酯基、酰胺基、乙酰基、甲酰氨基、氨甲酰基、甲酰氧基、甲氧羰基、三氟甲基和三氟甲氧基。
在另一优选例中，R1为取代或未取代的C6-C12芳基。在另一优选例中，R1为取代的苯基。所述取代是指具有选自下组的1、2、3、4或5个相同或不同的取代基：卤素、C1-C6烷基、卤素取代的C1-C6烷氧基。
在另一优选例中，R1为取代或未取代的苯基，所述取代基选自卤素、甲基、甲氧基、乙基、氨基、羟基、氰基、硝基、乙酰基、甲酰氨基、氨甲酰基、甲酰氧基、甲氧羰基、三氟甲基和三氟甲氧基。
在另一优选例中，R2为C1-C6烷基、卤素取代的C1-C6烷基、卤素、氰基、苯基。
在另一优选例中，所述卤素取代的C1-C6烷基优选为三氟甲基。
在另一优选例中，R3为取代或未取代的C6-C10芳基、或取代或未取代的3-12元杂环基；所述取代是指具有选自下组的1、2、3、4或5个相同或不同的取代基：卤素、C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷基取代的磺酰基；或者在所述C6-C10芳基上两个相邻的取代基与其相邻的芳环上的碳原子共同构成C3-C7环烷基、C3-C7环烯基或者3-7元杂环基；各个杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子。
在另一优选例中，R3为取代或未取代的选自下组的基团：苯基、萘基、噻吩基、呋喃基，所述取代是指具有选自下组的1、2、3或4个相同或不同的取代基：卤素、C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基。所述卤素取代的C1-C4烷氧基优选为三氟甲氧基。
在另一优选例中，R3为取代或未取代的11-12元双环芳香杂环，苯基取代的C1-C6芳基或杂芳基、萘基、吲哚基、苯并二杂原子取代C5-C6芳基、C5-C6稠环芳基，所述取代基选自卤素、甲基、甲氧基、乙基、氨基、酯基、酰胺基、羟基、氰基、硝基、乙酰基、甲酰氨基、氨甲酰基、甲酰氧基、甲氧羰基、三氟甲基和三氟甲氧基。
在另一优选例中，R4为选自氢、C1-C6烷基、卤素取代的C1-C6烷基、卤素、氰基、苯基、萘基。
在另一优选例中，卤素取代的C1-C6烷基为三氟甲基。
在另一优选例中，R5为氢或C1-C6烷基。
在另一优选例中，R7为H、羟基、苯基或C1-6烷基。
在另一优选例中，所述通式I所示结构的3,4,5-三取代的吡唑类化合物中任一手性碳原子的构型为S型或R型。
在本发明更优选的实施方案中，本发明的通式I的化合物优选为编号为A1-A92的具体化合物之一。
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明提供了通式I化合物的可药用的盐，具体地为通式I化合物与无机酸或有机酸反应形成常规的药学上可接受的盐。例如，常规的药学上可接受的盐可通过通式I化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
本发明另一方面提供了一种通式I表示的化合物的制备方法，包括中间体10与化合物11反应得到通式I所示结构的3,4,5-三取代的吡唑类化合物的步骤，
其中，R1、R2、R3、R4、R5、R6、X和n的定义与前相同。
在另一优选例中，制备方法按照如下方案1进行。
方案1：
其中，R1、R2、R3、R4、R5、R6、X和n的定义与前相同。
步骤a：将化合物溶于甲苯溶液中，搅拌加入肼基甲酸叔丁酯，滴加催化量的冰醋酸，搅拌加热，得中间体3；加热温度范围为60～100℃。
步骤b：将中间体3溶入有机溶剂中，加入氰基硼氢化钠，室温搅拌，加入对甲苯磺酸，继续反应至原料消失，分离纯化得中间体4；所述有机溶剂可为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物。
步骤c：将中间体4溶入有机溶剂中，加入三氟醋酸(TFA)或者盐酸(HCl)的有机溶剂，脱去Boc保护基，得中间体5；所述有机溶剂可为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物。
步骤d：将中间体5溶入乙酸中，加入化合物6，加热搅拌，分离纯化得中间体7；加热温度范围为60～100℃。
步骤e：将中间体7溶入有机溶剂中，降温，加入一定碱，搅拌至温度恒定，加入三幅甲磺酸酐，搅拌，分离纯化得中间体8加入钯碳，通入氢气还原，得中间体7；所述碱可为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙胺；所述有机溶剂可为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；温度范围为-80～-40℃。
步骤f：将中间体8溶入有机溶剂中，加入化合物9，加入一定碱和一定催化剂，加热搅拌，分离纯化得中间体10；所述碱可为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙胺；所述有机溶剂可为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述催化剂可为四三苯基膦钯、氯化钯、醋酸钯。
步骤g：将中间体10溶入有机溶剂中，加入一定量的碱，加热搅拌，加入化合物11，搅拌至原料消失，得终产物；所述有机溶剂可为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；加热温度范围为60～100℃。
本发明的另一方面提供了一种药物组合物，包含：(a)通式I所示结构的3,4,5-三取代的吡唑类化合物，及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物；和(b)药学上可接受的载体。
在另一优选例中，所述药物组合物含有治疗有效量的选自上述通式(Ⅰ)的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及任选地，一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99％的活性成份，其优选的比例是，通式I化合物作为活性成分占总重量的65wt％～99wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含0.05-200mg通式I化合物，优选地，制剂配方的单位计量中包含0.1mg-100mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-200mg/kg体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明的又一方面，提供第一方面所述的吡唑类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物，或者上述药物组合物的应用，用于制备(i)胰岛素分泌促进剂；(ii)胰高血糖素受体拮抗剂；或(iii)治疗和/或预防与胰高血糖素受体相关的代谢系统疾病的药物。
在另一优选例中，所述代谢系统疾病包括，但不限于糖尿病、动脉粥样硬化、肥胖症等疾病。
本发明的又一方面提供了一种胰高血糖素受体拮抗剂，其包含选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的又一个方面提供了一种治疗与胰高血糖素受体相关的代谢系统疾病，例如：糖尿病、动脉粥样硬化、肥胖症等疾病的方法，其包括向需要该治疗的患者给药选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种；或者给予上述药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一赘述。
附图说明
图1为化合物和类胰岛素肽5(INSL5)对人体胰岛素的促分泌作用结果图。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种结构新颖的3,4,5-三取代的吡唑类化合物，及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物，吡唑类化合物的结构如通式I所示。本发明的化合物，可以用作胰高血糖素受体拮抗剂。在此基础上，完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中，术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中，术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。本发明中用到的起始原料未经特别说明，均为商业购买。
实施例1 3-(4-((3-(3,5-二氯苯基-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A1)
合成路线：
1.1 4-甲酰基苯甲酸乙酯1-2的制备方法
将5g对甲酰基苯甲酸溶于50mL无水乙醇，冰浴，搅拌，并向溶液中缓慢滴加5mL浓硫酸，滴加完毕，80℃回流3h，反应液冷却至室温，倒入冰水中，抽滤，水洗，干燥，得1-2(5.4g)，收率91％。MS(ESI,m/z):179[M+H]+.
1.2(E)-2-(4-(乙氧羰基)苯亚甲基)肼基甲酸叔丁酯1-3的制备方法
将化合物1-2(5g)溶于40mL甲苯，室温搅拌，加入5.56g肼基甲酸叔丁酯，滴加催化量的冰醋酸，80℃加热过夜，冷却，抽滤，干燥，得1-3(5.8g)，收率70％。MS(ESI,m/z):293[M+H]+.
1.3 2-(4-(乙氧羰基)苄基)肼基甲酸叔丁酯1-4的制备方法
将化合物1-3(5.8g)，氰基硼氢化钠1.37g溶于30mL四氢呋喃，氮气保护，缓慢滴加4g对甲苯磺酸的四氢呋喃溶液，3h后加入乙酸乙酯淬灭并萃取，干燥，旋蒸。将固体溶于二氯甲烷，加入1N氢氧化钠溶液，有机层分别用1N HCl和饱和食盐水洗两遍，干燥，过滤，旋蒸。经柱层析得1-4(5.35g)，收率92％。MS(ESI,m/z):295[M+H]+.
1.4 4-(1-肼基甲基)苯酸乙酯1-5的制备方法
将化合物1-4(2.8g)溶于10mL二氯甲烷，缓慢滴加10mL三氟醋酸，室温反应1h，减压蒸除溶剂。得1-5(1.39g)，收率75％。MS(ESI,m/z):195[M+H]+.
1.5 4-((3-(3,5-二氯苯基)-4-甲基-5-氧-4,5-二氢-1H-吡唑-1-基)甲基)苯甲酸乙酯1-6的制备方法
将化合物1-5(2g)，3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯3.12g溶于30mL乙酸，80℃回流4h，减压蒸除溶剂。萃取，干燥，减压蒸除溶剂，经柱层析得1-6(2.1g)，收率50％。MS(ESI,m/z):406[M+H]+.
1.6 4-((3-(3,5-二氯苯基)-4-甲基-5-(((三氟甲基)磺酰基)氧)-1H-吡唑-1-基)甲基)苯甲酸乙酯1-7的制备方法
将化合物1-6(2g)溶于35mL四氢呋喃，置于-78℃，滴加三乙胺2.1mL，缓慢滴加三氟甲磺酸酐1.24mL，移入室温反应1h，加入乙酸乙酯和水淬灭，分别用0.5N HCl溶液和饱和食盐水洗两遍，干燥，过滤，减压蒸除溶剂，经柱层析得1-7(1.77g)，收率70％。MS(ESI,m/z):635[M+H]+.
1.7 4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酸乙酯1-8的制备方法
将化合物1-7(1g)，6-甲氧基-2-萘硼酸477mg，三乙胺1.41mL溶于25mL乙二醇二甲醚，氮气保护，加入214.9mg四三苯基膦钯(10％)，100℃微波反应反应0.5h，乙酸乙酯和饱和氯化铵溶液淬灭反应，萃取，干燥，过滤，减压蒸除溶剂，经柱层析得1-8(0.91g)，收率90％。MS(ESI,m/z):546[M+H]+.
1.8 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸叔丁酯1-9的制备方法
将化合物1-8(1g)溶于甲醇-二氧六环(1:1,16mL)混合溶液，滴加氢氧化钠溶液(0.7g/15mL)5.6mL，60℃加热1h，加入2N HCl溶液，减压蒸除溶剂。将固体溶于15mLDMF溶液中，顺序加入1.6ml二异丙基乙胺，1gβ-丙氨酸叔丁酯盐酸盐。将六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBOP)1.14g溶于5mL DMF，缓慢滴加到上述反应液中。室温搅拌3h，补加332mg PyBOP，反应过夜，滴加5mL水，60℃加热0.5h后冷却至室温，乙酸乙酯萃取，分别用0.5N盐酸溶液、5％碳酸钾溶液和饱和食盐水溶液洗两遍，干燥，过滤，减压蒸除溶剂。经柱层析得1-9(1.08g)，收率91％。MS(ESI,m/z):645[M+H]+.
1.9 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸A1制备方法
将化合物1-9(645mg)溶于14mL二氯甲烷，滴加7mL三氟乙酸，反应半小时后减压蒸除溶剂，经柱层析得A1(0.5g)，收率85％。MS(ESI,m/z):589[M+H]+.
实施例2 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(萘基-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A2)
将6-甲氧基-2-萘硼酸替换成2-萘硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A2，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(t,J＝1.4Hz,1H),8.06(d,J＝7.2Hz,2H),8.04–7.99(m,1H),7.83(dd,J＝7.5,1.5Hz,1H),7.72(d,J＝2.0Hz,2H),7.70–7.66(m,2H),7.65–7.60(m,3H),7.42(d,J＝7.5Hz,2H),5.46(s,2H),3.67(t,J＝8.0Hz,2H),2.53(t,J＝8.0Hz,2H),2.19(s,3H)；MS(ESI,m/z):559[M+H]+.
实施例3 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(萘基-1-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A3)
将6-甲氧基-2-萘硼酸替换成2-萘硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A3，收率82％。1H NMR(500MHz,DMSO)δ8.69(d,J＝7.1Hz,1H),8.50(s,1H),8.06(d,J＝7.5Hz,2H),7.81–7.72(m,6H),7.69(td,J＝7.5,1.1Hz,1H),7.62(t,J＝1.9Hz,1H),7.52(td,J＝7.7,1.3Hz,1H),7.33(d,J＝7.4Hz,2H),5.46(s,2H),3.67(t,J＝4.8Hz,2H),2.53(t,J＝4.7Hz,2H),2.20(s,3H)；MS(ESI,m/z):559[M+H]+.
实施例4 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-苯基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A4)
将6-甲氧基-2-萘硼酸替换成苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A4，收率84％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.77(d,J＝7.5Hz,2H),7.70(d,J＝1.9Hz,2H),7.61(t,J＝1.9Hz,1H),7.58(dd,J＝8.6,6.4Hz,2H),7.49–7.46(m,3H),7.45(s,2H),5.46(s,2H),3.67(t,J＝8.0Hz,2H),2.53(t,J＝8.0Hz,2H),2.16(s,3H)；MS(ESI,m/z):509[M+H]+.
实施例5 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(对甲苯基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A5)
将6-甲氧基-2-萘硼酸替换成对甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A5，收率86％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.74(d,J＝7.5Hz,2H),7.70(d,J＝1.9Hz,2H),7.61(t,J＝1.9Hz,1H),7.46(d,J＝7.4Hz,2H),7.35(d,J＝7.5Hz,2H),7.20(d,J＝6.7Hz,2H),5.46(s,2H),3.67(t,J＝4.9Hz,2H),2.53(t,J＝5.0Hz,2H),2.33(s,3H),2.16(s,3H)；MS(ESI,m/z):523[M+H]+.
实施例6 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(间甲苯基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A6)
将6-甲氧基-2-萘硼酸替换成间甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A6，收率86％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.81(d,J＝7.5Hz,2H),7.71(d,J＝1.9Hz,2H),7.66–7.63(m,1H),7.63–7.58(m,2H),7.51(d,J＝7.4Hz,2H),7.38(dt,J＝7.5,1.9Hz,1H),7.30–7.26(m,1H),5.46(s,2H),3.67(s,2H),2.53(t,J＝4.9Hz,2H),2.47(s,3H),2.17(s,3H)；MS(ESI,m/z):523[M+H]+.
实施例7 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(邻甲苯基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A7)
将6-甲氧基-2-萘硼酸替换成邻甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A7，收率86％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.84–7.78(m,3H),7.70(d,J＝1.9Hz,2H),7.61(t,J＝1.9Hz,1H),7.46(d,J＝7.5Hz,2H),7.43(dd,J＝7.4,1.9Hz,1H),7.36–7.29(m,2H),5.46(s,2H),3.67(t,J＝4.9Hz,2H),2.53(t,J＝5.0Hz,2H),2.35(s,3H),2.18(s,3H)；MS(ESI,m/z):523[M+H]+.
实施例8 3-(4-((3-(3,5-二氯苯基)-5-(4-氟苯基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A8)
将6-甲氧基-2-萘硼酸替换成4-氟苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A8，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,J＝7.5Hz,2H),7.70(dd,J＝5.3,1.8Hz,4H),7.61(t,J＝1.9Hz,1H),7.53(d,J＝7.4Hz,2H),7.31(dd,J＝8.8,7.6Hz,2H),5.46(s,2H),3.67(t,J＝5.3Hz,2H),2.53(t,J＝5.3Hz,2H),2.17(s,3H)；MS(ESI,m/z):527[M+H]+.
实施例9 3-(4-((5-(4-氯苯基)-3-(3,5-二氯苯基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A9)
将6-甲氧基-2-萘硼酸替换成4-氯苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A9，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.82(d,J＝7.5Hz,2H),7.71(d,J＝1.8Hz,2H),7.66–7.60(m,3H),7.56(d,J＝7.4Hz,2H),7.48(d,J＝7.5Hz,2H),5.46(s,2H),3.67(t,J＝8.0Hz,2H),2.53(t,J＝8.0Hz,2H),2.17(s,3H)；MS(ESI,m/z):543[M+H]+.
实施例10 3-(4-((3-(3,5-二氯苯基)-5-(4-甲氧基苯基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A10)
将6-甲氧基-2-萘硼酸替换成4-甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A10，收率85％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.80(d,J＝7.5Hz,2H),7.71(d,J＝1.8Hz,2H),7.61(t,J＝1.8Hz,1H),7.51(d,J＝7.5Hz,2H),7.47(d,J＝7.5Hz,2H),7.05(d,J＝7.5Hz,2H),5.46(s,2H),3.79(s,3H),3.67(t,J＝8.0Hz,2H),2.53(t,J＝8.0Hz,2H),2.16(s,3H)；MS(ESI,m/z):539[M+H]+.
实施例11 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(4-(三氟甲氧基)苯基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A11)
将6-甲氧基-2-萘硼酸替换成4-三氟甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A11，收率75％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.81–7.76(m,2H),7.76(t,J＝2.1Hz,1H),7.65(t,J＝1.9Hz,1H),7.61(t,J＝1.9Hz,1H),7.53–7.45(m,4H),7.32(d,J＝7.5Hz,2H),5.46(s,2H),3.67(t,J＝8.0Hz,2H),2.53(t,J＝8.0Hz,2H),2.16(s,3H)；MS(ESI,m/z):593[M+H]+.
实施例12 3-(4-((3-(3,5-二氯苯基)-4-甲基-5-(噻吩-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A12)
将6-甲氧基-2-萘硼酸替换成2-噻吩硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A12，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.83(d,J＝7.5Hz,2H),7.70(d,J＝1.9Hz,2H),7.61(t,J＝1.9Hz,1H),7.58(dd,J＝7.4,1.4Hz,1H),7.55(d,J＝7.5Hz,2H),7.27(d,J＝8.8Hz,1H),7.15(t,J＝7.5Hz,1H),5.46(s,2H),3.67(t,J＝4.9Hz,2H),2.53(t,J＝5.0Hz,2H),2.22(s,3H)；MS(ESI,m/z):515[M+H]+.
实施例13 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A13)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成2-萘硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A13，收率83％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.35(s,1H),8.06(d,J＝7.1Hz,2H),8.02(d,J＝4.1Hz,1H),7.76(d,J＝7.4Hz,2H),7.72(d,J＝1.9Hz,2H),7.71–7.66(m,1H),7.66–7.56(m,3H),7.40(d,J＝6.7Hz,2H),5.47(q,J＝6.8Hz,1H),3.71(td,J＝12.0,1.5Hz,1H),3.59(ddd,J＝12.4,3.2,2.2Hz,1H),2.70(ddd,J＝12.5,3.2,1.5Hz,1H),2.19(s,3H),2.13(td,J＝12.1,2.1Hz,1H),1.57(d,J＝6.8Hz,3H)；MS(ESI,m/z):573[M+H]+.
实施例14 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(萘基-1-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A14)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成1-萘硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A14，收率82％。1H NMR(500MHz,DMSO)δ8.67(d,J＝7.2Hz,1H),8.50(s,1H),8.11(d,J＝7.4Hz,1H),8.06(d,J＝7.5Hz,1H),7.87–7.75(m,5H),7.70–7.65(m,2H),7.62(t,J＝1.8Hz,1H),7.52(t,J＝7.5Hz,1H),7.43(d,J＝6.7Hz,2H),5.46(q,J＝6.9Hz,1H),3.76(td,J＝12.4,3.7Hz,1H),3.64(td,J＝12.3,3.1Hz,1H),2.82(td,J＝12.4,3.6Hz,1H),2.19(s,3H),2.05(td,J＝12.4,3.3Hz,1H),1.56(d,J＝6.8Hz,3H)；MS(ESI,m/z):573[M+H]+.
实施例15 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-苯基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A15)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A15，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.84(d,J＝7.5Hz,2H),7.71(d,J＝1.9Hz,2H),7.61(t,J＝1.8Hz,1H),7.60–7.54(m,4H),7.51–7.43(m,3H),5.45(q,J＝6.8Hz,1H),3.81(td,J＝12.3,3.6Hz,1H),3.70(td,J＝12.3,3.1Hz,1H),2.76(td,J＝12.4,3.7Hz,1H),2.16(s,3H),2.02(td,J＝12.3,3.3Hz,1H),1.54(d,J＝6.8Hz,3H)；MS(ESI,m/z):523[M+H]+.
实施例16 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(对甲苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A16)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成对甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A16，收率82％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.86(d,J＝7.5Hz,2H),7.72(d,J＝1.9Hz,2H),7.61(t,J＝1.9Hz,1H),7.59(d,J＝6.7Hz,2H),7.38(d,J＝7.5Hz,2H),7.20(d,J＝6.7Hz,2H),5.41(q,J＝6.9Hz,1H),3.76(td,J＝12.2,3.7Hz,1H),3.67(td,J＝12.4,3.3Hz,1H),2.87(td,J＝12.3,3.6Hz,1H),2.33(s,3H),2.16(s,3H),2.05(td,J＝12.3,3.3Hz,1H),1.54(d,J＝6.8Hz,3H)；MS(ESI,m/z):537[M+H]+.
实施例17 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(间甲苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A17)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成间甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A17，收率83％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.84(d,J＝7.5Hz,2H),7.70(d,J＝1.9Hz,2H),7.66(t,J＝7.5Hz,1H),7.61(t,J＝1.8Hz,1H),7.57–7.55(m,1H),7.54(d,J＝6.7Hz,2H),7.44(dt,J＝7.5,1.9Hz,1H),7.32–7.27(m,1H),5.44(q,J＝6.8Hz,1H),3.78(td,J＝12.4,3.7Hz,1H),3.67(td,J＝12.3,3.2Hz,1H),2.71(td,J＝12.4,3.7Hz,1H),2.47(s,3H),2.16(s,3H),2.04(td,J＝12.3,3.2Hz,1H),1.55(d,J＝6.8Hz,3H)；MS(ESI,m/z):537[M+H]+.
实施例18 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(邻甲苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A18)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成邻甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A18，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.85(d,J＝7.5Hz,2H),7.71(d,J＝2.0Hz,2H),7.61(t,J＝1.9Hz,1H),7.57(ddd,J＝8.6,7.4,1.5Hz,3H),7.41(qd,J＝6.8,6.3,3.3Hz,2H),7.32(td,J＝6.9,2.9Hz,1H),5.46(q,J＝6.8Hz,1H),3.76(td,J＝12.3,3.8Hz,1H),3.66(td,J＝12.4,3.4Hz,1H),2.87(td,J＝12.4,3.8Hz,1H),2.35(s,3H),2.17(s,3H),2.04(td,J＝12.3,3.3Hz,1H),1.55(d,J＝6.8Hz,3H)；MS(ESI,m/z):537[M+H]+.
实施例19 3-(4-(1-(3-(3,5-二氯苯基)-5-(4-氟苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A19)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成4-氟苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A19，收率79％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.79(d,J＝7.5Hz,2H),7.69(d,J＝1.8Hz,2H),7.66–7.58(m,3H),7.49(d,J＝6.7Hz,2H),7.31(dd,J＝8.8,7.6Hz,2H),5.56(q,J＝6.8Hz,1H),3.73(td,J＝12.4,2.4Hz,1H),3.62(ddd,J＝12.5,3.5,2.0Hz,1H),2.54(td,J＝12.4,3.3Hz,1H),2.14(s,3H),2.11(dt,J＝12.5,2.2Hz,1H),1.56(d,J＝6.8Hz,3H)；MS(ESI,m/z):541[M+H]+.
实施例20 3-(4-(1-(5-(5-氯-2-甲氧基苯基)-3-(3,5-二氯苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A20)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成5-氯-2-甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A20，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.86–7.78(m,2H),7.71(d,J＝2.0Hz,2H),7.61(d,J＝2.0Hz,2H),7.58–7.52(m,2H),7.47(dd,J＝7.5,2.0Hz,1H),7.05(d,J＝7.5Hz,1H),5.50(q,J＝6.8Hz,1H),3.88(dd,J＝12.3,3.3Hz,1H),3.85(s,3H),3.55(td,J＝12.5,3.4Hz,1H),2.56(td,J＝12.4,3.2Hz,1H),2.26(td,J＝12.4,3.4Hz,1H),2.16(s,3H),1.56(d,J＝6.8Hz,3H)；MS(ESI,m/z):587[M+H]+.
实施例21 3-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(噻吩-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A21)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成2-噻吩硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A21，收率73％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.86(d,J＝7.5Hz,2H),7.70(d,J＝2.0Hz,2H),7.61(t,J＝1.9Hz,1H),7.58(ddd,J＝7.3,3.3,1.3Hz,3H),7.27(dd,J＝7.5,1.5Hz,1H),7.15(t,J＝7.5Hz,1H),5.61(q,J＝6.8Hz,1H),3.76(td,J＝12.4,3.3Hz,1H),3.66(td,J＝12.2,3.6Hz,1H),2.85(td,J＝12.3,3.3Hz,1H),2.22(s,3H),2.03(td,J＝12.4,3.7Hz,1H),1.58(d,J＝6.8Hz,3H)；MS(ESI,m/z):529[M+H]+.
实施例22 3-(4-(1-(3-(3,5-二氯苯基)-5-(呋喃-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A22)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将6-甲氧基-2-萘硼酸替换成2-呋喃硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A22，收率72％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.07(dd,J＝7.5,1.7Hz,1H),7.85(d,J＝7.5Hz,2H),7.70(d,J＝1.9Hz,2H),7.63–7.59(m,3H),7.03(dd,J＝7.3,1.7Hz,1H),6.98(t,J＝7.4Hz,1H),5.70(q,J＝6.8Hz,1H),3.91(td,J＝12.3,3.8Hz,1H),3.73(td,J＝12.3,2.8Hz,1H),2.73(td,J＝12.4,3.8Hz,1H),2.24(s,3H),2.07(td,J＝12.2,2.7Hz,1H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):513[M+H]+.
实施例23 3-(4-(1-(5-(6-甲氧萘基-2-基)-4-甲基-3-(对甲苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A23)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-甲基-3-氧代-3-(对甲苯基)丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A23，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.14(s,1H),7.89(dd,J＝7.4,1.5Hz,1H),7.80(ddd,J＝12.7,7.5,1.5Hz,2H),7.70(d,J＝7.5Hz,2H),7.48(dd,J＝9.6,7.2Hz,4H),7.31(t,J＝1.4Hz,1H),7.22–7.17(m,2H),7.14(dd,J＝7.5,1.5Hz,1H),5.51(q,J＝6.8Hz,1H),3.80(s,3H),3.50(dt,J＝12.2,3.9Hz,1H),3.21(ddd,J＝12.5,9.7,2.9Hz,1H),2.44(ddd,J＝12.5,4.0,2.9Hz,1H),2.33(s,3H),2.20(s,3H),2.14(ddd,J＝12.5,9.8,4.0Hz,1H),1.58(d,J＝6.8Hz,3H)；MS(ESI,m/z):548[M+H]+.
实施例24 3-(4-(1-(5-(6-甲氧萘基-2-基)-4-甲基-3-(4-(三氟甲氧基)苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A24)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-甲基-3-氧代-3-(4-(三氟甲氧基)苯基)丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A24，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.01(s,1H),7.94(dd,J＝7.4,1.4Hz,1H),7.86(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.66(d,J＝7.5Hz,2H),7.60(d,J＝7.5Hz,2H),7.42(d,J＝6.7Hz,2H),7.32(dd,J＝8.0,2.1Hz,3H),7.14(dd,J＝7.4,1.5Hz,1H),5.57(q,J＝6.8Hz,1H),3.80(s,3H),3.72(td,J＝12.3,3.1Hz,1H),3.61(td,J＝12.3,3.7Hz,1H),2.86(td,J＝12.4,3.3Hz,1H),2.18(s,3H),1.98(td,J＝12.3,3.7Hz,1H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):618[M+H]+.
实施例25(S)-3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A25)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A25，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.01–7.95(m,2H),7.88(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝1.9Hz,1H),7.67(t,J＝1.9Hz,1H),7.64(d,J＝7.5Hz,2H),7.61(t,J＝1.9Hz,1H),7.37(d,J＝6.9Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.46(q,J＝6.8Hz,1H),3.80(s,3H),3.63(ddd,J＝12.5,3.3,2.3Hz,1H),3.55(td,J＝12.3,2.3Hz,1H),2.51(dt,J＝12.2,2.2Hz,1H),2.18(s,3H),2.12(td,J＝12.3,3.3Hz,1H),1.57(d,J＝6.8Hz,3H)；MS(ESI,m/z):602[M+H]+.
实施例26(R)-3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A26)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A26，收率77％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.09(s,1H),7.90(dd,J＝7.4,1.5Hz,1H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝1.8Hz,1H),7.67(d,J＝7.3Hz,3H),7.61(t,J＝1.8Hz,1H),7.46(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.55(q,J＝6.8Hz,1H),3.80(s,3H),3.78(t,J＝2.6Hz,1H),3.47(td,J＝12.2,1.8Hz,1H),2.55(ddd,J＝12.4,2.8,1.8Hz,1H),2.19(s,3H),2.07(td,J＝12.1,2.4Hz,1H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):603[M+H]+.
实施例27 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸甲酯的制备(A27)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成β-丙氨酸甲酯，其余所需原料、试剂及制备方法同实施例1，得产物A27，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.24(s,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.78–7.75(m,2H),7.73(dd,J＝7.4,1.5Hz,1H),7.67(t,J＝1.8Hz,1H),7.60(d,J＝7.5Hz,3H),7.44(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.57(q,J＝6.8Hz,1H),3.83(dd,J＝12.4,4.0Hz,1H),3.80(s,3H),3.60(s,3H),3.46(td,J＝12.4,2.6Hz,1H),2.87(td,J＝12.4,4.0Hz,1H),2.19(s,3H),2.11(td,J＝12.3,2.7Hz,1H),1.63(d,J＝6.8Hz,3H)；MS(ESI,m/z):617[M+H]+.
实施例28 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸苯酯的制备(A28)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成β-丙氨酸苯酯，其余所需原料、试剂及制备方法同实施例1，得产物A28，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.02(s,1H),7.97(dd,J＝7.4,1.5Hz,1H),7.88(dd,J＝7.5,1.5Hz,1H),7.86–7.81(m,2H),7.81–7.77(m,1H),7.76(t,J＝2.0Hz,1H),7.67(t,J＝2.0Hz,1H),7.61(t,J＝2.0Hz,1H),7.49(d,J＝6.7Hz,2H),7.46–7.41(m,1H),7.37(t,J＝7.3Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),7.08(dd,J＝7.5,1.8Hz,2H),5.44(q,J＝6.8Hz,1H),3.80(s,3H),3.76(td,J＝12.2,1.7Hz,1H),3.56(dt,J＝12.3,2.6Hz,1H),2.67(ddd,J＝12.5,3.0,1.7Hz,1H),2.40(td,J＝12.2,2.4Hz,1H),2.20(s,3H),1.56(d,J＝6.8Hz,3H)；MS(ESI,m/z):679[M+H]+.
实施例29 2-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙烷亚磺酸的制备(A29)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成亚牛磺酸，其余所需原料、试剂及制备方法同实施例1，得产物A29，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.16(s,1H),7.88(dd,J＝7.5,1.4Hz,1H),7.82(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝1.9Hz,1H),7.67(d,J＝8.1Hz,4H),7.62(t,J＝1.9Hz,1H),7.46(d,J＝6.7Hz,2H),7.31(t,J＝1.4Hz,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.55(q,J＝6.8Hz,1H),3.80(s,3H),3.70–3.63(m,1H),3.41(td,J＝9.4,2.7Hz,2H),3.10–3.02(m,1H),2.20(s,3H),1.63(d,J＝6.8Hz,3H)；MS(ESI,m/z):623[M+H]+.
实施例30 2-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙烷亚磺酸甲酯的制备(A30)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成亚牛磺酸甲酯，其余所需原料、试剂及制备方法同实施例1，得产物A30，收率82％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.25(s,1H),7.86(dd,J＝7.5,1.5Hz,1H),7.81–7.77(m,2H),7.76(d,J＝7.5Hz,2H),7.71(dd,J＝7.5,1.6Hz,1H),7.66(t,J＝1.9Hz,1H),7.61(t,J＝2.0Hz,1H),7.48(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.48(q,J＝6.9Hz,1H),3.80(s,3H),3.77(dd,J＝12.3,2.7Hz,1H),3.64–3.47(m,2H),3.39(s,3H),2.92(td,J＝11.8,11.4,3.0Hz,1H),2.19(s,3H),1.56(d,J＝6.9Hz,3H)；MS(ESI,m/z):637[M+H]+.
实施例31 2-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙烷亚磺酸苯酯的制备(A31)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成亚牛磺酸苯酯，其余所需原料、试剂及制备方法同实施例1，得产物A31，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.16(s,1H),7.98(dd,J＝7.4,1.5Hz,1H),7.87(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.77(t,J＝2.0Hz,1H),7.70–7.65(m,3H),7.61(t,J＝2.0Hz,1H),7.44(d,J＝6.7Hz,2H),7.34–7.27(m,3H),7.14(dd,J＝7.5,1.5Hz,1H),7.05(dd,J＝7.6,1.8Hz,2H),7.01(dt,J＝7.5,2.1Hz,1H),5.54(q,J＝6.9Hz,1H),4.18(td,J＝12.1,5.0Hz,1H),3.87(td,J＝12.0,4.9Hz,1H),3.80(s,3H),3.07(dtd,J＝33.7,12.1,2.4Hz,2H),2.25(s,3H),1.54(d,J＝6.8Hz,3H)；MS(ESI,m/z):699[M+H]+.
实施例32 N-(3-氨基-3-氧代丙基)-4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基苯基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰胺的制备(A32)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A32，收率73％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.08(s,1H),7.92(dd,J＝7.5,1.4Hz,1H),7.85(dd,J＝7.5,1.6Hz,1H),7.81–7.75(m,4H),7.68(t,J＝1.9Hz,1H),7.62(t,J＝1.9Hz,1H),7.56(s,2H),7.47(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.48(q,J＝6.9Hz,1H),3.80(s,3H),3.43(ddd,J＝12.3,9.8,3.4Hz,1H),3.24(dt,J＝12.4,4.0Hz,1H),2.66(ddd,J＝12.3,9.8,4.3Hz,1H),2.20(s,3H),2.12(dt,J＝12.3,3.5Hz,1H),1.59(d,J＝6.8Hz,3H)；MS(ESI,m/z):602[M+H]+.
实施例33 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(3-(甲基氨基)-3-氧代丙基)苯甲酰胺的制备(A33)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基-N-甲基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A33，收率73％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.23(s,1H),7.84–7.77(m,2H),7.76(t,J＝1.9Hz,1H),7.71(dd,J＝7.5,1.6Hz,1H),7.67(t,J＝1.9Hz,1H),7.63(d,J＝7.6Hz,2H),7.61(t,J＝2.0Hz,1H),7.42(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.20(s,1H),5.56(q,J＝6.7Hz,1H),3.80(s,3H),3.50(dt,J＝12.4,4.0Hz,1H),3.17(ddd,J＝12.5,9.8,2.9Hz,1H),2.67(s,3H),2.34(ddd,J＝12.5,4.1,2.8Hz,1H),2.19(s,3H),2.11(ddd,J＝12.5,9.8,3.9Hz,1H),1.62(d,J＝6.8Hz,3H)；MS(ESI,m/z):616[M+H]+.
实施例34 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(3-氧代-3-(苯基氨基)丙基)苯甲酰胺的制备(A34)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基-N-苯基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A34，收率74％。1H NMR(500MHz,DMSO)δ9.82(s,1H),8.50(s,1H),7.99–7.91(m,2H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝1.9Hz,1H),7.71(d,J＝7.5Hz,2H),7.67(t,J＝2.0Hz,1H),7.62(t,J＝2.0Hz,1H),7.56(dd,J＝7.5,2.0Hz,2H),7.40(d,J＝6.7Hz,2H),7.33–7.26(m,3H),7.14(dd,J＝7.5,1.5Hz,1H),7.07(tt,J＝7.4,2.0Hz,1H),5.57(q,J＝6.8Hz,1H),3.80(s,3H),3.34(ddd,J＝12.5,5.1,3.1Hz,1H),3.22(ddd,J＝12.2,9.9,3.9Hz,1H),2.44(ddd,J＝12.5,4.0,3.1Hz,1H),2.31(ddd,J＝12.3,9.8,5.0Hz,1H),2.19(s,3H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):678[M+H]+.
实施例35 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(2-磺酰乙基)苯甲酰胺的制备(A35)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基乙烷磺酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A35，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.06(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝2.0Hz,1H),7.66(t,J＝2.0Hz,1H),7.61(t,J＝2.0Hz,1H),7.60–7.56(m,2H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.56(q,J＝6.9Hz,1H),4.35(s,2H),3.80(s,3H),3.63(ddd,J＝12.5,11.2,1.6Hz,1H),3.50–3.35(m,2H),2.64(ddd,J＝12.5,3.0,1.7Hz,1H),2.18(s,3H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):638[M+H]+.
实施例36 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(2-(N-甲基磺酰基)乙基)苯甲酰胺的制备(A36)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成2-氨基-N-甲基乙烷磺酰胺盐酸盐，其余所需原料、试剂及制备方法同实施例1，得产物A36，收率71％。1HNMR(500MHz,DMSO)δ8.50(s,1H),8.02(t,J＝1.4Hz,1H),7.98(dd,J＝7.5,1.4Hz,1H),7.90(d,J＝1.5Hz,1H),7.88(dd,J＝7.8,1.9Hz,2H),7.82–7.74(m,2H),7.68(t,J＝2.0Hz,1H),7.62(t,J＝2.0Hz,1H),7.54(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.46(q,J＝6.8Hz,1H),4.83(s,1H),3.80(s,3H),3.69–3.59(m,1H),3.56–3.42(m,2H),2.60–2.54(m,1H),2.53(s,3H),2.20(s,3H),1.55(d,J＝6.8Hz,3H)；MS(ESI,m/z):652[M+H]+.
实施例37 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(2-(N-苯基磺酰基)乙基)苯甲酰胺的制备(A37)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成2-氨基-N-苯基乙烷磺酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A37，收率71％。1H NMR(500MHz,DMSO)δ9.80(s,1H),8.50(s,1H),8.26(s,1H),7.82–7.75(m,5H),7.67(t,J＝2.0Hz,1H),7.61(t,J＝2.0Hz,1H),7.55(dd,J＝7.4,1.6Hz,1H),7.37(d,J＝6.7Hz,2H),7.29(dd,J＝14.8,7.3Hz,3H),7.18(d,J＝2.0Hz,1H),7.16(d,J＝2.0Hz,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.85–6.79(m,1H),5.56(q,J＝6.8Hz,1H),4.24(ddd,J＝12.5,11.0,1.5Hz,1H),3.80(s,3H),3.66(ddd,J＝12.5,3.2,1.6Hz,1H),2.97(ddd,J＝12.5,11.0,1.5Hz,1H),2.73(ddd,J＝12.5,3.2,1.4Hz,1H),2.17(s,3H),1.58(d,J＝6.8Hz,3H)；MS(ESI,m/z):714[M+H]+.
实施例38 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(3-(羟胺基-3-氧代丙基)苯甲酰胺的制备(A38)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基-N-羟基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A38，收率79％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.18(s,1H),7.89(dd,J＝7.5,1.4Hz,1H),7.83–7.75(m,5H),7.68(t,J＝1.9Hz,1H),7.62(t,J＝1.8Hz,1H),7.51(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),7.06(s,1H),5.50(q,J＝6.8Hz,1H),3.80(s,3H),3.71(dd,J＝12.3,3.7Hz,1H),3.37(td,J＝12.4,2.8Hz,1H),3.08(td,J＝12.4,3.6Hz,1H),2.20(s,3H),1.98(td,J＝12.3,2.9Hz,1H),1.58(d,J＝6.8Hz,3H)；MS(ESI,m/z):618[M+H]+.
实施例39 N-((2H-四氮唑-5-基)甲基)-4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰胺的制备(A39)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成5-氨基甲基-1H-四氮唑，其余所需原料、试剂及制备方法同实施例1，得产物A39，收率76％。1H NMR(500MHz,DMSO)δ8.97(s,1H),8.23(s,1H),7.79(ddd,J＝7.5,4.3,1.4Hz,2H),7.76(t,J＝1.9Hz,1H),7.74(dd,J＝7.5,1.5Hz,1H),7.71(d,J＝7.5Hz,2H),7.66(t,J＝1.9Hz,1H),7.61(t,J＝1.8Hz,1H),7.47(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.57(q,J＝6.8Hz,1H),4.74–4.41(m,2H),3.80(s,3H),2.18(s,3H),1.62(d,J＝6.8Hz,3H)；MS(ESI,m/z):613[M+H]+.
实施例40 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)-N-(2H-四氮唑-5-基)苯甲酰胺的制备(A40)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成5-氨基四氮唑，其余所需原料、试剂及制备方法同实施例1，得产物A40，收率80％。1H NMR(500MHz,DMSO)δ9.35(s,1H),8.13(s,1H),7.89(dd,J＝7.5,1.4Hz,1H),7.83–7.78(m,2H),7.76(t,J＝1.9Hz,1H),7.68–7.63(m,3H),7.61(t,J＝1.9Hz,1H),7.41(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.52(q,J＝6.8Hz,1H),3.80(s,3H),2.19(s,3H),1.59(d,J＝6.8Hz,3H)；MS(ESI,m/z):599[M+H]+.
实施例41 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基乙基)-N-(2-(5-氧代-1,2,4-恶二唑-3-基)乙基)苯甲酰胺的制备(A41)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-(2-氨基乙基)-1,2,4-恶二烷基-5-酮，其余所需原料、试剂及制备方法同实施例1，得产物A41，收率77％。1H NMR(500MHz,DMSO)δ9.86(s,1H),8.23(s,1H),8.19(s,1H),7.82–7.73(m,4H),7.67(t,J＝1.9Hz,1H),7.61(t,J＝2.0Hz,1H),7.60(d,J＝7.5Hz,2H),7.45(d,J＝6.7Hz,2H),7.31(s,1H),7.14(d,J＝7.5Hz,1H),5.56(q,J＝6.8Hz,1H),4.63(t,J＝7.0Hz,1H),3.80(s,3H),3.58(ddd,J＝12.5,3.9,2.5Hz,1H),3.33(t,J＝13.6Hz,1H),3.02(s,1H),2.19(s,3H),1.94(ddt,J＝11.9,7.0,2.4Hz,1H),1.83–1.74(m,1H),1.63(d,J＝6.8Hz,3H)；MS(ESI,m/z):645[M+H]+.
实施例42 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)-2,2,2-三氟乙基)-N-(3-(羟胺基)-3-氧代丙基)苯甲酰胺的制备(A42)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基-N-羟基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A42，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.98(d,J＝7.0Hz,1H),7.93(d,J＝7.1Hz,2H),7.79(d,J＝7.5Hz,1H),7.76(d,J＝7.5Hz,2H),7.73(t,J＝2.0Hz,1H),7.71(t,J＝2.0Hz,1H),7.62(t,J＝1.9Hz,1H),7.54(d,J＝6.7Hz,2H),7.31(s,1H),7.17(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.60(q,J＝9.1Hz,1H),3.80(s,3H),3.61(td,J＝12.4,2.6Hz,1H),3.38(td,J＝12.2,3.8Hz,1H),3.14(td,J＝12.4,3.9Hz,1H),2.19(s,3H),2.05(td,J＝12.3,2.7Hz,1H)；MS(ESI,m/z):672[M+H]+.
实施例43 4-((3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-甲基-1H-吡唑-1-基)氟代甲基)-N-(3-(羟胺基)-3-氧代丙基)苯甲酰胺的制备(A43)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将β-丙氨酸叔丁酯替换成3-氨基-N-羟基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A43，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.21(s,1H),7.93(dd,J＝7.5,1.5Hz,1H),7.86(dd,J＝7.5,1.4Hz,1H),7.79(dd,J＝7.6,1.5Hz,1H),7.76(t,J＝2.0Hz,1H),7.72(dt,J＝6.0,2.0Hz,3H),7.69–7.65(m,3H),7.62(t,J＝2.0Hz,1H),7.31(s,1H),7.14(d,J＝6.5Hz,1H),7.01(s,1H),3.80(s,3H),3.21(ddd,J＝12.8,9.7,3.1Hz,1H),3.09(dt,J＝12.3,4.0Hz,1H),2.38(dt,J＝12.4,3.5Hz,1H),2.24(s,3H),2.23–2.17(m,1H)；MS(ESI,m/z):622[M+H]+.
实施例44 4-(1-(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧萘基-2-基)-1H-吡唑-1-基)乙基)-N-(3-(羟胺基)-3-氧代丙基)苯甲酰胺的制备(A44)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，将β-丙氨酸叔丁酯替换成3-氨基-N-羟基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A44，收率70％。1HNMR(500MHz,DMSO)δ8.79(s,1H),8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.4Hz,1H),7.89–7.86(m,2H),7.84(dd,J＝7.5,1.5Hz,1H),7.81–7.75(m,3H),7.62(t,J＝1.9Hz,1H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.08(q,J＝6.8Hz,1H),3.80(s,3H),3.68(t,J＝7.1Hz,2H),2.72(t,J＝7.1Hz,2H),1.64(d,J＝6.8Hz,3H)；MS(ESI,m/z):622[M+H]+.
实施例45 4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)乙基)-N-(3-(羟胺基)-3-氧代丙基)苯甲酰胺的制备(A45)
将对醛基苯甲酸替换成4-乙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，将β-丙氨酸叔丁酯替换成3-氨基-N-羟基丙酰胺，其余所需原料、试剂及制备方法同实施例1，得产物A45，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.25(s,1H),7.84–7.72(m,5H),7.66–7.59(m,3H),7.46(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),7.10(s,1H),5.57(q,J＝6.9Hz,1H),3.80(s,3H),3.72(td,J＝12.4,3.4Hz,1H),3.32(td,J＝12.4,3.1Hz,1H),3.06(td,J＝12.3,3.3Hz,1H),1.95(td,J＝12.3,3.1Hz,1H),1.64(d,J＝6.8Hz,3H)；MS(ESI,m/z):672[M+H]+.
实施例46 3-(4-(氯代(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰胺基)丙酸的制备(A46)
将对醛基苯甲酸替换成4-氯代甲酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A46，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.99(d,J＝9.8Hz,3H),7.79(d,J＝8.2Hz,1H),7.77(t,J＝1.9Hz,1H),7.68(d,J＝7.5Hz,2H),7.67–7.66(m,1H),7.63–7.58(m,3H),7.51(s,1H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.84(td,J＝12.3,2.8Hz,1H),3.80(s,3H),3.71(td,J＝12.3,3.8Hz,1H),2.67(td,J＝12.4,2.9Hz,1H),2.26(td,J＝12.4,3.7Hz,1H),2.19(s,3H)；MS(ESI,m/z):623[M+H]+.
实施例47 3-(4-(溴代(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A47)
将对醛基苯甲酸替换成4-溴代甲酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A47，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.29(s,1H),8.04(s,2H),7.79(dd,J＝7.6,1.5Hz,1H),7.77–7.74(m,3H),7.67(t,J＝1.9Hz,1H),7.64(s,1H),7.62(t,J＝1.9Hz,1H),7.36(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),3.80(s,3H),3.72(td,J＝12.4,3.3Hz,1H),3.62(td,J＝12.3,3.6Hz,1H),2.73(td,J＝12.2,3.2Hz,1H),2.22(s,3H),1.95(td,J＝12.3,3.5Hz,1H)；MS(ESI,m/z):668[M+H]+.
实施例48 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)碘代甲基)苯甲酰氨基)丙酸的制备(A48)
将对醛基苯甲酸替换成4-碘代甲酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A48，收率70％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.39(s,1H),7.98(dd,J＝7.5,1.7Hz,1H),7.91–7.84(m,3H),7.81–7.76(m,2H),7.71–7.65(m,3H),7.63(t,J＝1.9Hz,1H),7.31(s,1H),7.17(s,1H),7.14(d,J＝7.5Hz,1H),3.97(td,J＝12.2,3.9Hz,1H),3.80(s,3H),3.61–3.49(m,1H),2.37–2.25(m,2H),2.22(s,3H)；MS(ESI,m/z):715[M+H]+.
实施例49 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)丙基)苯甲酰氨基)丙酸的制备(A49)
将对醛基苯甲酸替换成4-丙酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A49，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.98(d,J＝5.7Hz,2H),7.89(dd,J＝7.5,1.4Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝2.0Hz,1H),7.69–7.64(m,3H),7.61(t,J＝2.0Hz,1H),7.41(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.29(d,J＝11.4Hz,1H),3.80(s,3H),3.38–3.24(m,2H),2.43(ddd,J＝12.4,7.7,5.9Hz,1H),2.28(ddd,J＝12.3,8.0,1.4Hz,1H),2.18(s,3H),2.12(dt,J＝12.5,3.5Hz,1H),1.94–1.82(m,1H),0.95(t,J＝8.0Hz,3H)；MS(ESI,m/z):617[M+H]+.
实施例50 3-(4-(氰基(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A50)
将对醛基苯甲酸替换成4-(氰基甲酰基)苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A50，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.39(s,1H),7.81–7.75(m,3H),7.69–7.66(m,2H),7.64(d,J＝7.5Hz,2H),7.62(t,J＝1.9Hz,1H),7.51(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.46(s,1H),3.80(s,3H),3.76(ddd,J＝12.4,11.4,2.3Hz,1H),3.62(dt,J＝12.4,2.5Hz,1H),2.34–2.23(m,2H),2.20(s,3H)；MS(ESI,m/z):614[M+H]+.
实施例51 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)(苯基)甲基)苯甲酰氨基)丙酸的制备(A51)
将对醛基苯甲酸替换成4-苯甲酰苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A51，收率79％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.90(dd,J＝7.5,1.4Hz,1H),7.86(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝7.6,1.4Hz,1H),7.75(td,J＝5.5,4.9,1.9Hz,3H),7.69(t,J＝2.0Hz,1H),7.64(d,J＝6.7Hz,2H),7.62–7.57(m,3H),7.43(t,J＝7.5Hz,2H),7.31(s,1H),7.21(tt,J＝7.5,2.0Hz,1H),7.14(d,J＝8.5Hz,1H),6.54(s,1H),3.84–3.76(m,4H),3.67(td,J＝12.3,3.6Hz,1H),2.82(td,J＝12.4,3.3Hz,1H),2.21(s,3H),1.99(td,J＝12.4,3.6Hz,1H)；MS(ESI,m/z):665[M+H]+.
实施例52 3-(4-(1-(4-氯-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A52)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氯-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A52，收率76％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.01–7.96(m,2H),7.91(dd,J＝7.5,1.5Hz,1H),7.82(t,J＝1.9Hz,1H),7.79(d,J＝7.6Hz,1H),7.77(t,J＝1.9Hz,1H),7.67(d,J＝7.5Hz,2H),7.61(t,J＝1.8Hz,1H),7.40(d,J＝6.8Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.59(q,J＝6.8Hz,1H),3.92(td,J＝12.5,2.9Hz,1H),3.80(s,3H),3.59(td,J＝12.4,3.7Hz,1H),2.61(td,J＝12.4,2.9Hz,1H),2.16(td,J＝12.5,3.6Hz,1H),1.59(d,J＝6.8Hz,3H)；MS(ESI,m/z):623[M+H]+.
实施例53 3-(4-(1-(4-溴-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A53)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-溴-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A53，收率73％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.08(s,1H),7.94(dd,J＝7.5,1.6Hz,1H),7.86(dd,J＝7.4,1.5Hz,1H),7.82–7.77(m,2H),7.75(t,J＝2.0Hz,1H),7.74–7.71(m,2H),7.62(t,J＝1.8Hz,1H),7.45(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.55(q,J＝6.7Hz,1H),3.80(s,3H),3.50(ddd,J＝12.6,9.9,3.1Hz,1H),3.23(dt,J＝12.2,4.0Hz,1H),2.46(ddd,J＝12.4,9.7,3.9Hz,1H),2.15(ddd,J＝12.4,4.0,2.9Hz,1H),1.60(d,J＝6.8Hz,3H)；MS(ESI,m/z):668[M+H]+.
实施例54 3-(4-(1-(3-(3,5-二氯苯基)-4-碘-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A54)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-碘-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A54，收率75％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.87(d,J＝7.5Hz,2H),7.84(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝1.9Hz,1H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.08(q,J＝6.8Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H),1.64(d,J＝6.8Hz,3H)；MS(ESI,m/z):715[M+H]+.
实施例55 3-(4-(1-(3-(3,5-二氯苯基)-4-乙基-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A55)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A55，收率77％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.07(s,1H),7.93(dd,J＝7.5,1.5Hz,1H),7.85(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.74(t,J＝2.0Hz,1H),7.73–7.69(m,2H),7.66(t,J＝2.0Hz,1H),7.62(t,J＝1.9Hz,1H),7.46(d,J＝6.7Hz,2H),7.31(s,1H),7.14(d,J＝8.5Hz,1H),5.54(q,J＝6.8Hz,1H),3.80(s,3H),3.52(dt,J＝12.4,4.0Hz,1H),3.26(ddd,J＝12.6,9.8,2.9Hz,1H),2.71(qd,J＝8.0,2.5Hz,2H),2.45(ddd,J＝12.3,4.1,2.9Hz,1H),2.15(ddd,J＝12.2,9.7,3.8Hz,1H),1.60(d,J＝6.8Hz,3H),1.18(t,J＝8.0Hz,3H)；MS(ESI,m/z):617[M+H]+.
实施例56 3-(4-(1-(4-氰基-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A56)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氰基-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A56，收率74％。1HNMR(500MHz,DMSO)δ8.50(s,1H),8.21(s,1H),7.88(dd,J＝7.5,1.4Hz,1H),7.83(dd,J＝7.5,1.6Hz,1H),7.81–7.77(m,2H),7.75(t,J＝1.9Hz,1H),7.67–7.64(m,2H),7.63(t,J＝2.0Hz,1H),7.46(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.57(q,J＝6.8Hz,1H),3.80(s,3H),3.74–3.58(m,2H),2.65(td,J＝12.0,3.7Hz,1H),2.09(td,J＝12.1,3.7Hz,1H),1.64(d,J＝6.8Hz,3H)；MS(ESI,m/z):614[M+H]+.
实施例57 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-苯基-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A57)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-3-氧代-2-苯基丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A57，收率78％。1HNMR(500MHz,DMSO)δ8.50(s,1H),7.98(s,2H),7.95(s,1H),7.82(t,J＝2.0Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.69–7.61(m,4H),7.59(t,J＝1.9Hz,1H),7.56(t,J＝2.0Hz,1H),7.47–7.35(m,5H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),5.61(q,J＝6.8Hz,1H),3.94(td,J＝12.4,2.9Hz,1H),3.80(s,3H),3.52(td,J＝12.4,3.7Hz,1H),2.58(td,J＝12.3,2.9Hz,1H),2.13(td,J＝12.4,3.7Hz,1H),1.62(d,J＝6.8Hz,3H)；MS(ESI,m/z):665[M+H]+.
实施例58 3-(4-(氯(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A58)
将对醛基苯甲酸替换成4-氯代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A58，收率76％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.43(s,1H),7.83(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝7.6,1.4Hz,1H),7.77(d,J＝1.9Hz,2H),7.74(d,J＝7.6Hz,2H),7.69(dd,J＝7.5,1.5Hz,1H),7.62(t,J＝1.9Hz,1H),7.57(d,J＝7.0Hz,2H),7.52(s,1H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),3.84(dd,J＝12.3,3.5Hz,1H),3.80(s,3H),3.64(td,J＝12.3,3.1Hz,1H),2.64(td,J＝12.4,3.5Hz,1H),1.93(td,J＝12.4,3.1Hz,1H)；MS(ESI,m/z):677[M+H]+.
实施例59 3-(4-(溴(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A59)
将对醛基苯甲酸替换成4-溴代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A59，收率73％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.45(s,1H),8.02(dd,J＝7.5,1.4Hz,1H),7.96(dd,J＝7.4,1.5Hz,1H),7.82–7.76(m,3H),7.74(d,J＝7.5Hz,2H),7.65(s,1H),7.62(t,J＝1.8Hz,1H),7.35(d,J＝7.0Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.86(td,J＝12.4,2.8Hz,1H),3.80(s,3H),3.71(td,J＝12.3,3.8Hz,1H),2.69(td,J＝12.4,2.8Hz,1H),1.98(td,J＝12.4,3.8Hz,1H)；MS(ESI,m/z):722[M+H]+.
实施例60 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)碘甲基)苯甲酰氨基)丙酸的制备(A60)
将对醛基苯甲酸替换成4-碘代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A60，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.31(s,1H),8.06(s,2H),7.79–7.75(m,4H),7.62(t,J＝1.9Hz,1H),7.35(d,J＝7.3Hz,2H),7.32–7.28(m,2H),7.14(dd,J＝7.5,1.4Hz,1H),3.84(td,J＝12.4,2.8Hz,1H),3.80(s,3H),3.61(td,J＝12.3,3.7Hz,1H),2.50(td,J＝12.4,2.8Hz,1H),2.03(td,J＝12.4,3.8Hz,1H)；MS(ESI,m/z):769[M+H]+.
实施例61 3-(4-(氰基(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A61)
对醛基苯甲酸替换成4-(氰基甲酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A61，收率75％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.41(s,1H),7.82(dd,J＝7.5,1.4Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(dd,J＝7.2,1.7Hz,2H),7.71(t,J＝1.9Hz,1H),7.65–7.61(m,3H),7.54(d,J＝6.8Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),6.46(s,1H),3.80(s,3H),3.69(td,J＝12.4,2.4Hz,1H),3.61(ddd,J＝12.4,3.5,2.2Hz,1H),2.50(dt,J＝12.4,2.3Hz,1H),2.12(td,J＝12.4,3.4Hz,1H)；MS(ESI,m/z):668[M+H]+.
实施例62 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)(苯基)甲基)苯甲酰氨基)丙酸的制备(A62)
对醛基苯甲酸替换成4-苯甲酰苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A62，收率81％。1H NMR(500MHz,DMSO)δ8.97(s,1H),8.11(t,J＝1.4Hz,1H),7.95–7.80(m,3H),7.67–7.57(m,4H),7.45(dd,J＝5.9,4.3Hz,3H),7.40(dd,J＝7.5,1.4Hz,1H),7.30–7.22(m,4H),7.18(dd,J＝5.1,3.7Hz,1H),7.05(t,J＝1.5Hz,1H),6.84(s,1H),3.80(s,3H),3.51(t,J＝4.9Hz,1H),3.46(t,J＝4.9Hz,1H),2.51(t,J＝5.0Hz,2H)；MS(ESI,m/z):719[M+H]+.
实施例63 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-(三氟甲基)-1H-吡唑-1-基)丙基)苯甲酰氨基)丙酸的制备(A63)
将对醛基苯甲酸替换成4-丙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A63，收率83％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.27(s,1H),7.83–7.71(m,5H),7.62(d,J＝6.8Hz,3H),7.45(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.29(d,J＝12.4Hz,1H),3.80(s,3H),3.78–3.66(m,2H),2.88–2.71(m,1H),2.40(dqd,J＝12.5,8.0,1.4Hz,1H),2.06–1.89(m,2H),0.98(t,J＝8.0Hz,3H)；MS(ESI,m/z):671[M+H]+.
实施例64 3-(4-(氯(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A64)
将对醛基苯甲酸替换成4-氯代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A64，收率76％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.94–7.86(m,3H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝1.9Hz,1H),7.45(d,J＝6.9Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.96(s,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):627[M+H]+.
实施例65 3-(4-(溴(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A65)
将对醛基苯甲酸替换成4-溴代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A65，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.91(tt,J＝8.5,2.0Hz,3H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.45(d,J＝6.9Hz,2H),7.30(d,J＝14.9Hz,2H),7.14(dd,J＝7.4,1.5Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):672[M+H]+.
实施例66 3-(4-((3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)碘甲基)苯甲酰氨基)丙酸的制备(A66)
将对醛基苯甲酸替换成4-碘代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A66，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.91(tt,J＝8.5,2.0Hz,3H),7.84(dd,J＝7.5,1.6Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.54(s,1H),7.45(d,J＝6.8Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):719[M+H]+.
实施例67 3-(4-(1-(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)丙基)苯甲酰氨基)丙酸的制备(A67)
将对醛基苯甲酸替换成4-丙酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A67，收率77％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.87(d,J＝7.5Hz,2H),7.84(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),4.88(t,J＝6.9Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H),2.35(qd,J＝8.0,6.8Hz,1H),1.85(qd,J＝7.9,6.8Hz,1H),0.93(t,J＝8.0Hz,3H)；MS(ESI,m/z):621[M+H]+.
实施例68 3-(4-(氰基(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A68)
将对醛基苯甲酸替换成4-(氰基甲酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A68，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.96–7.91(m,1H),7.86–7.80(m,3H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.37–7.29(m,3H),7.14(dd,J＝7.4,1.5Hz,1H),5.98(s,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):618[M+H]+.
实施例69 3-(4-((3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)(苯基)甲基)苯甲酰氨基)丙酸的制备(A69)
将对醛基苯甲酸替换成4-苯甲酰苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A69，收率82％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.90–7.82(m,3H),7.81–7.76(m,3H),7.62(t,J＝2.0Hz,1H),7.35(d,J＝6.8Hz,2H),7.31(s,1H),7.29–7.11(m,6H),6.26(s,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):669[M+H]+.
实施例70 3-(4-((4-氯-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A70)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氯-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A70，收率83％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.30(s,1H),7.93(dd,J＝7.4,1.5Hz,1H),7.86–7.81(m,2H),7.79(dd,J＝7.5,1.4Hz,1H),7.75(dd,J＝3.7,1.6Hz,1H),7.66(s,4H),7.62(t,J＝1.9Hz,1H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.83–3.75(m,4H),3.43(td,J＝12.1,5.0Hz,1H),2.63(td,J＝12.1,2.0Hz,1H),2.17(td,J＝12.3,5.0Hz,1H)；MS(ESI,m/z):627[M+H]+.
实施例71 3-(4-((4-溴-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A71)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-溴-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A71，收率71％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.08(s,1H),7.99–7.93(m,2H),7.82–7.76(m,2H),7.75–7.70(m,3H),7.65–7.61(m,3H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),3.80(s,3H),3.70–3.59(m,2H),2.63(ddd,J＝12.4,10.3,4.6Hz,1H),2.25–2.11(m,1H)；MS(ESI,m/z):672[M+H]+.
实施例72 3-(4-((3-(3,5-二氯苯基)-4-碘-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A72)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-碘-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A72，收率77％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.91(tt,J＝8.5,2.0Hz,3H),7.84(dd,J＝7.4,1.6Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝1.9Hz,1H),7.50(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.81(d,J＝46.5Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):719[M+H]+.
实施例73 3-(4-((3-(3,5-二氯苯基)-4-乙基-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A73)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A73，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.21(s,1H),7.94(dd,J＝7.4,1.5Hz,1H),7.88(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76–7.58(m,8H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.80(s,3H),3.72(td,J＝12.2,4.1Hz,1H),3.57(td,J＝12.4,2.7Hz,1H),2.79(ddt,J＝11.4,7.9,3.6Hz,2H),2.54(td,J＝12.4,4.2Hz,1H),2.14(td,J＝12.3,2.7Hz,1H),1.22(t,J＝8.0Hz,3H)；MS(ESI,m/z):621[M+H]+.
实施例74 3-(4-((4-氰基-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰胺基)丙酸的制备(A74)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氰基-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A74，收率77％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.24(s,1H),7.97(dd,J＝7.5,1.5Hz,1H),7.89(dd,J＝7.4,1.5Hz,1H),7.82–7.77(m,2H),7.74(dd,J＝7.8,5.6Hz,3H),7.68–7.62(m,3H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),3.80(s,3H),3.60(ddd,J＝12.6,9.8,3.1Hz,1H),3.23(dt,J＝12.2,4.0Hz,1H),2.35(ddd,J＝12.5,9.9,4.1Hz,1H),2.14–1.99(m,1H)；MS(ESI,m/z):618[M+H]+.
实施例75 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-苯基-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A75)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-3-氧代-2-苯基丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A75，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.06(dd,J＝7.5,1.5Hz,1H),8.00(dd,J＝7.5,1.4Hz,1H),7.96(s,1H),7.81(t,J＝2.0Hz,1H),7.80–7.76(m,1H),7.73–7.68(m,2H),7.68–7.61(m,4H),7.60(t,J＝2.0Hz,1H),7.57(t,J＝2.0Hz,1H),7.46–7.36(m,3H),7.31(s,1H),7.14(dd,J＝7.4,1.4Hz,1H),3.91(td,J＝12.4,2.9Hz,1H),3.80(s,3H),3.54(d,J＝3.6Hz,1H),2.61(td,J＝12.3,2.9Hz,1H),2.15(td,J＝12.4,3.6Hz,1H)；MS(ESI,m/z):669[M+H]+.
实施例76 3-(4-(1-(4-氯-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)-2,2,2-t三氟乙基)苯甲酰氨基)丙酸的制备(A76)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氯-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A76，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.22(s,1H),7.96(dd,J＝7.4,1.5Hz,1H),7.90(dd,J＝7.5,1.4Hz,1H),7.82(t,J＝1.9Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝2.0Hz,1H),7.67–7.63(m,2H),7.63–7.58(m,3H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.61(q,J＝9.0Hz,1H),3.80(s,3H),3.75(dd,J＝12.4,2.0Hz,1H),3.46(td,J＝12.0,4.8Hz,1H),2.61(td,J＝12.0,2.0Hz,1H),2.11(td,J＝12.4,4.9Hz,1H)；MS(ESI,m/z):677[M+H]+.
实施例77 3-(4-(1-(4-溴-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)-2,2,2-三氟乙基)苯甲酰氨基)丙酸的制备(A77)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-溴-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A77，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.21(s,1H),7.95(dd,J＝7.5,1.5Hz,1H),7.91(dd,J＝7.5,1.4Hz,1H),7.82–7.77(m,2H),7.74(t,J＝2.0Hz,1H),7.69–7.55(m,5H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.59(q,J＝9.0Hz,1H),3.80(s,3H),3.76(dd,J＝12.4,2.1Hz,1H),3.47(td,J＝12.2,4.9Hz,1H),2.60(td,J＝12.1,2.0Hz,1H),2.11(td,J＝12.3,4.7Hz,1H)；MS(ESI,m/z):722[M+H]+.
实施例78 3-(4-(1-(3-(3,5-二氯苯基)-4-碘-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)-2,2,2-三氟乙基)苯甲酰氨基)丙酸的制备(A78)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-碘-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A78，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.89–7.86(m,2H),7.84(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),7.08(q,J＝9.0Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):769[M+H]+.
实施例79 3-(4-(1-(3-(3,5-二氯苯基)-4-乙基-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)-2,2,2-三氟乙基)苯甲酰氨基)丙酸的制备(A79)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A79，收率83％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.99(dd,J＝7.6,1.4Hz,1H),7.95(s,1H),7.90(dd,J＝7.4,1.4Hz,1H),7.79(dd,J＝7.5,1.4Hz,1H),7.76(t,J＝1.9Hz,1H),7.75–7.70(m,2H),7.68(t,J＝2.0Hz,1H),7.62(t,J＝2.0Hz,1H),7.47(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.48(q,J＝9.0Hz,1H),3.91–3.81(m,1H),3.80(s,3H),3.73(td,J＝12.3,3.2Hz,1H),2.85–2.75(m,2H),2.75–2.65(m,1H),2.02(td,J＝12.4,3.4Hz,1H),1.23(t,J＝8.0Hz,3H)；MS(ESI,m/z):671[M+H]+.
实施例80 3-(4-(1-(4-氰基-3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)-2,2,2-三氟乙基)苯甲酰氨基)丙酸的制备(A80)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-氰基-3-(3,5-二氯苯基)-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A80，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.07–7.95(m,3H),7.82–7.76(m,2H),7.74(t,J＝2.0Hz,1H),7.72–7.67(m,2H),7.63(t,J＝1.9Hz,1H),7.51(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.63(q,J＝9.0Hz,1H),3.80(s,3H),3.78–3.70(m,2H),2.79(ddd,J＝12.5,10.5,5.4Hz,1H),1.97(ddd,J＝12.2,10.3,5.0Hz,1H)；MS(ESI,m/z):678[M+H]+.
实施例81 3-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-苯基-1H-吡唑-1-基)-2,2,2-三氟乙基)苯甲酰氨基)丙酸的制备(A81)
将对醛基苯甲酸替换成4-(2,2,2-三氟乙酰基)苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-3-氧代-2-苯基丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A81，收率81％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.31(s,1H),7.83(t,J＝2.0Hz,1H),7.79(dd,J＝7.5,1.5Hz,1H),7.77–7.75(m,3H),7.70–7.64(m,2H),7.59(t,J＝2.0Hz,1H),7.57(t,J＝1.9Hz,1H),7.54–7.50(m,2H),7.45–7.36(m,3H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.64(q,J＝8.9Hz,1H),3.80(s,3H),3.56(ddd,J＝12.6,9.8,3.0Hz,1H),3.31(dt,J＝12.4,4.0Hz,1H),2.46(ddd,J＝12.4,9.7,4.0Hz,1H),2.15(ddd,J＝12.4,3.9,3.0Hz,1H)；MS(ESI,m/z):719[M+H]+.
实施例82 3-(4-((3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A82)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，其余所需原料、试剂及制备方法同实施例1，得产物A82，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.34(s,1H),7.83(dd,J＝7.5,1.4Hz,1H),7.78(ddd,J＝7.4,5.9,1.5Hz,2H),7.75(t,J＝1.9Hz,1H),7.68–7.61(m,7H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),3.80(s,3H),3.75(dd,J＝12.3,3.8Hz,1H),3.58(td,J＝12.3,2.9Hz,1H),2.59(td,J＝12.5,3.8Hz,1H),2.23(s,3H),2.19(dd,J＝12.3,3.0Hz,1H)；MS(ESI,m/z):607[M+H]+.
实施例83 2-(4-(1-(3-(3,5-二氯苯基)-5-(4-甲氧基苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A83)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成4-甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A83，收率85％。1H NMR(500MHz,DMSO)δ9.75(s,1H),8.50(s,1H),7.75(d,J＝7.5Hz,2H),7.71(t,J＝2.0Hz,1H),7.60(t,J＝2.0Hz,1H),7.55(t,J＝2.0Hz,1H),7.44(d,J＝6.7Hz,2H),7.36(d,J＝7.5Hz,2H),7.05(d,J＝7.5Hz,2H),5.43(q,J＝6.8Hz,1H),4.03(ddd,J＝11.9,10.5,1.2Hz,1H),3.79(s,3H),3.50(ddd,J＝12.3,3.7,1.2Hz,1H),2.89(ddd,J＝12.5,3.7,1.3Hz,1H),2.63(ddd,J＝12.2,10.5,1.3Hz,1H),2.15(s,3H),1.55(d,J＝6.9Hz,3H)；MS(ESI,m/z):589[M+H]+.
实施例84 3-(4-(1-(3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)丙酸的制备(A84)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成2-(3,5-二氯苯基)-3,3,3-三氟丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A84，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.5Hz,1H),7.89–7.85(m,2H),7.84(dd,J＝7.5,1.5Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝1.9Hz,1H),7.37(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.5,1.5Hz,1H),5.08(q,J＝6.8Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H),1.64(d,J＝6.8Hz,3H)；MS(ESI,m/z):607[M+H]+.
实施例85 3-(4-((3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)氟甲基)苯甲酰氨基)丙酸的制备(A85)
将对醛基苯甲酸替换成4-氟代甲酰基苯甲酸，将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A85，收率74％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.94–7.88(m,3H),7.84(dd,J＝7.4,1.6Hz,1H),7.79(dd,J＝8.8,1.7Hz,3H),7.62(t,J＝2.0Hz,1H),7.50(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),6.81(d,J＝46.5Hz,1H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):611[M+H]+.
实施例86 2-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(4-(三氟甲氧基)苯基)-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A86)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成4-三氟甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A86，收率78％。1H NMR(500MHz,DMSO)δ8.50(s,1H),7.78(d,J＝7.5Hz,2H),7.70(t,J＝2.0Hz,1H),7.60(t,J＝2.0Hz,1H),7.56(t,J＝2.0Hz,1H),7.52(d,J＝6.7Hz,2H),7.45(d,J＝7.5Hz,2H),7.32(d,J＝7.5Hz,2H),5.44(q,J＝6.8Hz,1H),3.71(ddd,J＝12.7,9.3,3.5Hz,1H),3.64(dt,J＝12.3,3.8Hz,1H),3.22(dt,J＝12.5,3.4Hz,1H),2.49(ddd,J＝12.3,9.4,4.0Hz,1H),2.16(s,3H),1.56(d,J＝6.8Hz,3H)；MS(ESI,m/z):643[M+H]+.
实施例87 2-(4-(1-(3-(3,5-二氯苯基)-4-甲基-5-(萘基-2-基)-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A87)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成2-萘硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A87，收率78％。1H NMR(500MHz,DMSO)δ9.75(s,1H),8.50(s,1H),8.26(s,1H),8.09–8.04(m,2H),8.03–8.00(m,1H),7.77(dd,J＝7.5,1.7Hz,1H),7.70(t,J＝2.0Hz,1H),7.62(dq,J＝3.4,1.7Hz,3H),7.59–7.53(m,3H),7.39(d,J＝6.8Hz,2H),5.56(q,J＝6.8Hz,1H),3.69(td,J＝12.1,4.1Hz,1H),3.53(td,J＝12.0,3.0Hz,1H),3.43(td,J＝12.1,4.0Hz,1H),2.42(td,J＝11.9,2.8Hz,1H),2.18(s,3H),1.63(d,J＝6.8Hz,3H)；MS(ESI,m/z):609[M+H]+.
实施例88 3-(4-((3-(3,5-二氯苯基)-4-氟-5-(6-甲氧基萘基-2-基)-1H-吡唑-1-基)甲基)苯甲酰氨基)丙酸的制备(A88)
将3-(3,5-二氯苯基)-2-甲基-3-氧代丙酸乙酯替换成3-(3,5-二氯苯基)-2-氟-3-氧代丙酸乙酯，其余所需原料、试剂及制备方法同实施例1，得产物A88，收率80％。1H NMR(500MHz,DMSO)δ8.50(s,1H),8.32(s,1H),7.92(dd,J＝7.5,1.4Hz,1H),7.87–7.80(m,3H),7.78(d,J＝2.0Hz,3H),7.62(t,J＝2.0Hz,1H),7.44(d,J＝7.5Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.46(s,2H),3.80(s,3H),3.67(t,J＝7.1Hz,2H),2.53(t,J＝7.1Hz,2H)；MS(ESI,m/z):593[M+H]+.
实施例89 2-(4-(1-(3-(3,5-二氯苯基)-5-(4-氟苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A89)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成4-氟苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A89，收率81％。1H NMR(500MHz,DMSO)δ9.75(s,1H),8.50(s,1H),7.82(d,J＝7.5Hz,2H),7.70–7.63(m,4H),7.60–7.54(m,3H),7.34–7.28(m,2H),5.41(q,J＝6.8Hz,1H),3.76(td,J＝12.2,4.2Hz,1H),3.55(td,J＝12.0,2.9Hz,1H),3.42(td,J＝12.2,4.2Hz,1H),2.46(td,J＝12.1,2.9Hz,1H),2.16(s,3H),1.53(d,J＝6.9Hz,3H)；MS(ESI,m/z):577[M+H]+.
实施例90 2-(4-(1-(3-(3,5-二氯苯基)-5-(6-甲氧基萘基-2-基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A90)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，其余所需原料、试剂及制备方法同实施例1，得产物A90，收率83％。1H NMR(500MHz,DMSO)δ9.78(s,1H),8.50(s,1H),8.05(s,1H),7.88(dd,J＝7.5,1.4Hz,1H),7.80(ddd,J＝9.0,7.4,1.5Hz,2H),7.76–7.72(m,2H),7.71(t,J＝1.9Hz,1H),7.62(t,J＝2.0Hz,1H),7.56(t,J＝2.0Hz,1H),7.44(d,J＝6.7Hz,2H),7.31(s,1H),7.14(dd,J＝7.4,1.5Hz,1H),5.48(q,J＝6.8Hz,1H),3.84(dd,J＝12.2,3.1Hz,1H),3.80(s,3H),3.49(td,J＝12.2,4.2Hz,1H),3.29(td,J＝12.3,3.1Hz,1H),2.49(dd,J＝12.1,4.2Hz,1H),2.20(s,3H),1.58(d,J＝6.8Hz,3H)；MS(ESI,m/z):639[M+H]+.
实施例91 2-(4-(1-(5-(4-(叔丁基)苯基)-3-(3,5-二氯苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A91)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成4-叔丁基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A91，收率83％。1H NMR(500MHz,DMSO)δ9.76(s,1H),8.50(s,1H),7.79(d,J＝7.5Hz,2H),7.70(t,J＝2.0Hz,1H),7.61(t,J＝2.0Hz,1H),7.56(t,J＝2.0Hz,1H),7.53(d,J＝7.0Hz,2H),7.45(d,J＝7.5Hz,2H),7.33(d,J＝7.5Hz,2H),5.44(q,J＝6.8Hz,1H),3.70(td,J＝11.8,11.4,2.7Hz,1H),3.63–3.43(m,2H),2.48(td,J＝12.3,11.8,3.5Hz,1H),2.16(s,3H),1.54(d,J＝6.8Hz,3H),1.31(s,9H)；MS(ESI,m/z):615[M+H]+.
实施例92 2-(4-(1-(5-(4-氯-3-甲基苯基)-3-(3,5-二氯苯基)-4-甲基-1H-吡唑-1-基)乙基)苯甲酰氨基)乙磺酸的制备(A92)
对醛基苯甲酸替换成4-乙酰基苯甲酸，将β-丙氨酸叔丁酯替换成氨基乙磺酸，将6-甲氧基-2-萘硼酸替换成4-氯-3-甲基苯硼酸，其余所需原料、试剂及制备方法同实施例1，得产物A92，收率80％。1H NMR(500MHz,DMSO)δ9.74(s,1H),8.50(s,1H),7.81(d,J＝7.5Hz,2H),7.66(d,J＝1.8Hz,2H),7.61–7.50(m,5H),7.30(s,1H),5.41(q,J＝6.8Hz,1H),3.71(td,J＝12.2,4.2Hz,1H),3.55(td,J＝12.1,3.1Hz,1H),3.48(td,J＝12.2,3.1Hz,1H),2.48(td,J＝12.2,4.3Hz,1H),2.22(d,J＝1.1Hz,3H),2.16(s,3H),1.54(d,J＝6.7Hz,3H)；MS(ESI,m/z):607[M+H]+.
理化性质实施例
采用ChemOffice软件包计算化合物的物理化学属性(LogP、CLogP和tPSA的值为ChemOffice软件包中的Chemdraw软件预测数值。“-”代表没有)
LogP，疏水常数，指化合物的所有分子均以中性形式存在的pH条件下，其中一种有机相(例如正辛醇)和一种水相(例如缓冲溶液)中分配系数的对数，反映了物质在油水两相中的分配情况。LogP值越大，说明该物质越亲油；反之，LogP值越小，则说明该物质越亲水。
包括有机化合物脂水分配系数ClogP(Calculated LogP)，是基于片段加合法LogP计算方法。
tPSA，拓扑极性表面积，假设分子中每种相同原子或者基团类型对极性表面积的贡献都是相似的，整个分子的tPSA就是所有原子或者基团贡献的加和。
表1化合物的物理化学性质
结论：该类化合物的物理化学属性(LogP、CLogP和tPSA等)与阳性药(MK-0893)相当，也具有良好成药性。
药理活性试验实施例
实验实施例1
通过实验测定通式I化合物对胰高血糖素受体的结合作用，实验操作按如下参考文献进行。
Siu FY,He M,de Graaf C,Han GW,Yang D,Zhang Z,Zhou C,Xu Q,Wacker D,Joseph JS,Liu W,Lau J,Cherezov V,Katritch V,Wang MW,Stevens RC.Structure ofthe human glucagon class B G-protein-coupled receptor.Nature.2013Jul 25；499(7459):444-9。
实验数据如表2所示。
表2化合物对胰高血糖素受体结合的IC50值a
a取实验结果的平均值三次
结论：本发明部分化合物与MK-0893阳性对照相比，对胰高血糖素受体结合活性相当，或者优于MK-0893。
实验实施例2
通过实验测定通式I化合物c-AMP的抑制活性。cAMP assays针对的是与Gi和Gs蛋白结合的GPCR，该方法测定的对象是细胞内cAMP的浓度。Gi蛋白在与GPCR结合后，会抑制腺苷酸环化酶(AC)的活性，从而造成细胞内cAMP浓度的下降。Gs蛋白则相反，它在与GPCR结合后，通过第二信使通道能激活AC的活性，导致细胞内cAMP浓度的上升。胰高血糖素受体属于Gs蛋白结合的GPCR，所以通过测定一定条件下的细胞内cAMP降低的浓度便能推断出GPCR是否已经与G蛋白结合。
293T细胞铺板转染24小时后，无酶消化液消化后，以3000cells/well加入384白板中(Corning,Corning,NY,USA)，10μL/well,室温放置5分钟后加入不同浓度梯度的待测化合物(5μL)与EC80浓度的激动剂Glucagon(5μL)，反应半小时后，加入20μL D2(CISbiointernational)与anti-cAMP(CISbio international)底物，作用40分钟后，于EnSpire上检测其650/620。
实验数据如表3所示。
表3化合物对cAMP的IC50值a
a取实验结果的平均值三次
结论：本发明部分化合物对cAMP的抑制活性与阳性对照药MK-0893相当，或者优于MK-0893。
实验实施例3
测定部分通式I所示化合物和MK-0893(阳性对照，购自Med Chem Express公司)对B家族GPCR的选择性。
G蛋白偶联受体是人类基因组中最大的膜蛋白家族，约包含800～1000个成员，在视觉、嗅觉、味觉以及神经传递等人类各项生理代谢活动过程中发挥着重要的作用。肠促胰肽(GIP)和胰高血糖素样肽(GLP-1)作为小肠分泌的促进胰岛素分泌的多肽，在降低血糖方面起到重要作用，两者的受体都属于B家族GPCR受体，若拮抗剂与其结合，会扼制其降血糖的作用。如上所述，胰高血糖素受体也属于B家族GPCR受体，因此，我们在设计胰高血糖素拮抗剂时要尽量避免与GIP受体和GLP-1受体结合，提高化合物的选择性。
为了考察化合物对GPCR家族其他酶的选择性，挑选化合物A27进行GPCR家族其他两种受体(GIPR、GLP-1R)的测试，针对GLP-1R同样采取全细胞受体配体结合分析的方法，实验操作步骤按照上述GLR的受体配体结合检测方法进行，将hGLP-1R表达质粒顺势转染入CHO细胞后进行结合活力检测。实验结果如表4。
表4化合物A25对B家族GPCR的选择性a
a取实验结果的平均值三次；bND.:Not Determined.
结论：化合物A25具有较强的胰高血糖素受体结合活性以及cAMP抑制活性，作用效果优于MK-0893，同时该化合物对GLP-1R的结合活性较弱，显示出良好的选择性。
实验实施例4
测定部分通式I所示化合物和类胰岛素肽5(INSL5)对人体胰岛素的促分泌作用。人胰岛取自美国加州的Integrated Islet Distribution Program(IIDP)，标准活力为80-90％，纯度大于80％。原代胰岛细胞以1.5×104/well接入96孔板并培养过夜，将待测化合物加入后继续培养72小时，以新鲜准备的含2.8mM葡萄糖的KRBH buffer洗两次，培养2小时后换为含20mM葡萄糖的KRBH buffer继续培养1小时，收集上清进行胰岛素水平的检测，胰岛素检测采用Life Technology公司的胰岛素ELISA试剂盒，按试剂盒说明书进行操作。
结果如图1所示，表明本发明中的化合物不仅具备GR受体拮抗活性，同时具有促进人体胰岛素分泌的潜力，通过两种作用方式达到治疗II型糖尿病的效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种通式I所示结构的3,4,5-三取代的吡唑类化合物，及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物：
其中：
n为1、2或3；
X为CO；
R1为取代的苯基；所述取代是指具有选自下组的1、2或3个相同的取代基：F、Cl、Br、I；
R2为C1-C6烷基；
R3为取代或未取代的C6-C12芳基；所述取代是指具有选自下组的1或2个相同或不同的取代基：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基；
R4选自：氢、C1-C6烷基；
R5为氢；
R6为COOH。
2.如权利要求1所述的吡唑类化合物，其特征在于，R1为取代的苯基；所述取代是指具有2个相同的取代基：F、Cl、Br。
3.如权利要求1所述的吡唑类化合物，其特征在于，R2为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
4.如权利要求1所述的吡唑类化合物，其特征在于，R3为取代或未取代的选自下组的基团：苯基、萘基，所述取代是指具有选自下组的1、2或3个相同或不同的取代基：卤素、C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基。。
5.如权利要求1所述的吡唑类化合物，其特征在于，R4为甲基、乙基、正丙基或异丙基。
6.如权利要求1所述的吡唑类化合物，其特征在于，所述吡唑类化合物选自下组：
7.如权利要求1所述的吡唑类化合物的制备方法，其特征在于，所述制备方法包括以下步骤：中间体10与化合物11反应得到通式I所示结构的3,4,5-三取代的吡唑类化合物，
其中，R1、R2、R3、R4、R5、R6、X和n的定义与权利要求1中的定义相同。
8.一种药物组合物，其特征在于，所述药物组合物包含：(a)权利要求1所述的通式I所示结构的3,4,5-三取代的吡唑类化合物，及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物；和(b)药学上可接受的载体。
9.如权利要求1所述的吡唑类化合物或权利要求8所述的药物组合物的应用，其特征在于，用于制备(i)胰岛素分泌促进剂；(ii)胰高血糖素受体拮抗剂；或(iii)治疗和/或预防与胰高血糖素受体相关的代谢系统疾病的药物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239918.6A CN106279023B (zh) | 2015-05-12 | 2015-05-12 | 3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239918.6A CN106279023B (zh) | 2015-05-12 | 2015-05-12 | 3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106279023A CN106279023A (zh) | 2017-01-04 |
| CN106279023B true CN106279023B (zh) | 2021-06-22 |
Family
ID=57631034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510239918.6A Expired - Fee Related CN106279023B (zh) | 2015-05-12 | 2015-05-12 | 3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106279023B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3886854A4 (en) | 2018-11-30 | 2022-07-06 | Nuvation Bio Inc. | PYRROLE AND PYRAZOLE COMPOUNDS AND METHODS OF USE THERE |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015999A2 (en) * | 2005-07-26 | 2007-02-08 | Merck & Co., Inc. | Process for synthesizing a substituted pyrazole |
| WO2014047111A1 (en) * | 2012-09-18 | 2014-03-27 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
-
2015
- 2015-05-12 CN CN201510239918.6A patent/CN106279023B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015999A2 (en) * | 2005-07-26 | 2007-02-08 | Merck & Co., Inc. | Process for synthesizing a substituted pyrazole |
| WO2014047111A1 (en) * | 2012-09-18 | 2014-03-27 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
Non-Patent Citations (2)
| Title |
|---|
| A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design, synthesis and evaluation of biological activities;Shuangjie Shu等;《Bioorganic & Medicinal Chemistry》;20180222;第26卷;1896–1908 * |
| Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes;Yusheng Xiong等;《J. Med. Chem.》;20120618;第55卷;第6137-6148页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106279023A (zh) | 2017-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI652269B (zh) | 氮雜吡啶酮化合物及其用途 | |
| CA2449999C (en) | Compounds and methods for the treatment or prevention of flavivirus infections | |
| US8524726B2 (en) | Amido derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors | |
| EP3081553B1 (en) | Sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof | |
| JP5294419B2 (ja) | 縮合二環式ヘテロアリール誘導体 | |
| WO2017048962A1 (en) | Hepatitis b core protein modulators | |
| JP5623289B2 (ja) | ウイルスポリメラーゼインヒビター | |
| CA2848561C (en) | Guanidinobenzoic acid compound | |
| EP3414227B1 (en) | Piperidinone formyl peptide 2 receptor and formyl peptide 1 receptor agonists | |
| WO2014020350A1 (en) | Par2 receptor antagonists | |
| WO2017157322A1 (zh) | 一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途 | |
| KR20070041762A (ko) | 위장관 장애의 치료에 유용한 피페라진 유도체 | |
| US20120115869A1 (en) | Tetrazole derivatives | |
| US20120101091A1 (en) | Viral polymerase inhibitors | |
| CN105130888A (zh) | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 | |
| WO2009018656A1 (en) | Viral polymerase inhibitors | |
| WO2019117148A1 (ja) | スルホンアミド誘導体またはその薬学的に許容される酸付加塩 | |
| Yang et al. | Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3, 5-dimethylisoxazole | |
| US20200115357A1 (en) | Liver x receptors (lxr) modulators | |
| WO2018219204A1 (zh) | 一类新型苯氧乙酸衍生物、其制备方法及其作为药物的用途 | |
| US7135472B2 (en) | 3-Heterocyclic benzylamide derivatives as potassium channel openers | |
| CN106279023B (zh) | 3,4,5-三取代吡唑类化合物、制备方法、药物组合物及用途 | |
| TWI762634B (zh) | 胺基-芳基-苯甲醯胺化合物及其使用方法 | |
| CN102170882A (zh) | 治疗淀粉状蛋白疾病的组合物和方法 | |
| CN112204018B (zh) | 一类丙烯酸类化合物及其制备方法、药物组合物和用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210622 |