WO2023000834A1 - 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 - Google Patents
苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 Download PDFInfo
- Publication number
- WO2023000834A1 WO2023000834A1 PCT/CN2022/096230 CN2022096230W WO2023000834A1 WO 2023000834 A1 WO2023000834 A1 WO 2023000834A1 CN 2022096230 W CN2022096230 W CN 2022096230W WO 2023000834 A1 WO2023000834 A1 WO 2023000834A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mmol
- methyl
- carboxylic acid
- mixture
- ethyl acetate
- Prior art date
Links
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 30
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims abstract description 14
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 claims abstract description 14
- 230000001737 promoting effect Effects 0.000 claims abstract description 6
- 230000003914 insulin secretion Effects 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 200
- 150000001875 compounds Chemical class 0.000 claims description 195
- 229910052757 nitrogen Inorganic materials 0.000 claims description 93
- 150000003839 salts Chemical class 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 24
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 230000007783 downstream signaling Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 206010022489 Insulin Resistance Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 208000010444 Acidosis Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000002177 Cataract Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 3
- 208000007976 Ketosis Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
- 206010027417 Metabolic acidosis Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 208000004104 gestational diabetes Diseases 0.000 claims description 3
- 208000019622 heart disease Diseases 0.000 claims description 3
- 201000001421 hyperglycemia Diseases 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 230000004140 ketosis Effects 0.000 claims description 3
- 208000001921 latent autoimmune diabetes in adults Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 230000001071 malnutrition Effects 0.000 claims description 3
- 235000000824 malnutrition Nutrition 0.000 claims description 3
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003472 antidiabetic agent Substances 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- GNZCSGYHILBXLL-UHFFFAOYSA-N n-tert-butyl-6,7-dichloro-3-methylsulfonylquinoxalin-2-amine Chemical compound ClC1=C(Cl)C=C2N=C(S(C)(=O)=O)C(NC(C)(C)C)=NC2=C1 GNZCSGYHILBXLL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 230000019491 signal transduction Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 891
- -1 dihydroazetidinyl Chemical group 0.000 description 376
- 239000000203 mixture Substances 0.000 description 349
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 247
- 230000002829 reductive effect Effects 0.000 description 231
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 231
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 230
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 194
- 239000007787 solid Substances 0.000 description 192
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 183
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 174
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 165
- 239000012074 organic phase Substances 0.000 description 151
- 239000000243 solution Substances 0.000 description 142
- 239000003480 eluent Substances 0.000 description 132
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 126
- 239000003208 petroleum Substances 0.000 description 115
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 114
- 238000006243 chemical reaction Methods 0.000 description 114
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 108
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 91
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 88
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
- 238000001816 cooling Methods 0.000 description 82
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 80
- 238000010898 silica gel chromatography Methods 0.000 description 77
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 72
- 239000000741 silica gel Substances 0.000 description 51
- 229910002027 silica gel Inorganic materials 0.000 description 51
- 239000000706 filtrate Substances 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 41
- 229910000027 potassium carbonate Inorganic materials 0.000 description 40
- 239000012043 crude product Substances 0.000 description 37
- SLQIJFSQRNXACV-JTQLQIEISA-N methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate Chemical compound ClCC1=NC2=C(N1C[C@H]1OCC1)C=C(C=C2)C(=O)OC SLQIJFSQRNXACV-JTQLQIEISA-N 0.000 description 36
- 238000004587 chromatography analysis Methods 0.000 description 35
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 35
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 35
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 35
- 238000000746 purification Methods 0.000 description 35
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 34
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- RMHQDKYZXJVCME-UHFFFAOYSA-N 2-pyridin-4-ylpyridine Chemical group N1=CC=CC=C1C1=CC=NC=C1 RMHQDKYZXJVCME-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 30
- YAWLZFBIZMMVLI-UHFFFAOYSA-N tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate Chemical compound ClC1=CC=CC(=N1)C1CCN(CC1)C(=O)OC(C)(C)C YAWLZFBIZMMVLI-UHFFFAOYSA-N 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 239000002244 precipitate Substances 0.000 description 28
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 238000000605 extraction Methods 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- 238000012746 preparative thin layer chromatography Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000008280 blood Substances 0.000 description 18
- 210000004369 blood Anatomy 0.000 description 18
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 18
- 229910000024 caesium carbonate Inorganic materials 0.000 description 18
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 18
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- QOSPLGZPFBYJPK-UHFFFAOYSA-N O1C(CC1)CN1C=NC2=C1C=C(C=C2)C(=O)O Chemical compound O1C(CC1)CN1C=NC2=C1C=C(C=C2)C(=O)O QOSPLGZPFBYJPK-UHFFFAOYSA-N 0.000 description 13
- NDEKLIORQJEGQC-UHFFFAOYSA-N COC(C(C=C1)=CC2=C1N=CN2CC1OCC1)=O Chemical compound COC(C(C=C1)=CC2=C1N=CN2CC1OCC1)=O NDEKLIORQJEGQC-UHFFFAOYSA-N 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 12
- 239000012046 mixed solvent Substances 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 11
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 10
- HYBAKUMPISVZQP-DEOSSOPVSA-N 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound C(#N)C1=CC(=C(COC2=CC=CC(=N2)C2CCN(CC2)CC2=NC3=C(N2C[C@H]2OCC2)C=C(C=C3)C(=O)O)C=C1)F HYBAKUMPISVZQP-DEOSSOPVSA-N 0.000 description 10
- 229940125817 PF-06882961 Drugs 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 241000009298 Trigla lyra Species 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 229940126142 compound 16 Drugs 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- YSLWOAWEVXQWPB-QMMMGPOBSA-N methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate Chemical compound ClCC1=NC=2C(=NC(=CC=2)C(=O)OC)N1C[C@H]1OCC1 YSLWOAWEVXQWPB-QMMMGPOBSA-N 0.000 description 9
- 229920000137 polyphosphoric acid Polymers 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 8
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 8
- DJKJORLPPXZVOF-UHFFFAOYSA-N 7-(hydroxymethyl)-1-benzofuran-4-carbonitrile Chemical compound N#CC1=C(C=CO2)C2=C(CO)C=C1 DJKJORLPPXZVOF-UHFFFAOYSA-N 0.000 description 8
- 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 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- HMOZVPDMLSWNGN-UHFFFAOYSA-N (4-chloro-1-benzofuran-7-yl)methanol Chemical compound OCC(C1=C2C=CO1)=CC=C2Cl HMOZVPDMLSWNGN-UHFFFAOYSA-N 0.000 description 7
- VFHUZGRTHRHHKO-UHFFFAOYSA-N 4-chloro-7-ethynyl-1-benzofuran Chemical compound C#CC(C1=C2C=CO1)=CC=C2Cl VFHUZGRTHRHHKO-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- QDEFNAHLCTUWAH-BYPYZUCNSA-N [(2s)-oxetan-2-yl]methanamine Chemical compound NC[C@@H]1CCO1 QDEFNAHLCTUWAH-BYPYZUCNSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- KUEWODBWICKFEC-UHFFFAOYSA-N tert-butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C(C=CC=C1O)=C1O)=O KUEWODBWICKFEC-UHFFFAOYSA-N 0.000 description 7
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 6
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 6
- WMPMXUCWDZXMEW-UHFFFAOYSA-N 6-chloro-5-nitropicolinic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C(Cl)=N1 WMPMXUCWDZXMEW-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 6
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 229940125797 compound 12 Drugs 0.000 description 6
- 229940095074 cyclic amp Drugs 0.000 description 6
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 6
- 238000007446 glucose tolerance test Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 229950011186 semaglutide Drugs 0.000 description 6
- 108010060325 semaglutide Proteins 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 6
- OXTBBSFVFHKJOI-UHFFFAOYSA-N (4-chloro-2-methyl-1-benzofuran-7-yl)methanol Chemical compound CC1=CC(C(Cl)=CC=C2CO)=C2O1 OXTBBSFVFHKJOI-UHFFFAOYSA-N 0.000 description 5
- UKUIAWYNZOXWAM-UHFFFAOYSA-N (4-methyl-1-benzofuran-7-yl)methanol Chemical compound CC1=CC=C(CO)C2=C1C=CO2 UKUIAWYNZOXWAM-UHFFFAOYSA-N 0.000 description 5
- VOXPKEAYSUSRDW-UHFFFAOYSA-N (7-fluoro-1-benzofuran-6-yl)methanol Chemical compound OCC(C=CC1=C2OC=C1)=C2F VOXPKEAYSUSRDW-UHFFFAOYSA-N 0.000 description 5
- VCQONKRSTAUGEP-UHFFFAOYSA-N 1-benzofuran-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1C=CO2 VCQONKRSTAUGEP-UHFFFAOYSA-N 0.000 description 5
- NEGDYVLJFGSRKZ-UHFFFAOYSA-N 2-bromo-6-[(4-chloro-1-benzofuran-7-yl)methoxy]pyridine Chemical compound ClC1=CC=C(COC2=CC=CC(Br)=N2)C2=C1C=CO2 NEGDYVLJFGSRKZ-UHFFFAOYSA-N 0.000 description 5
- ZIDIKYIZXMYHAW-UHFFFAOYSA-N 2-bromo-6-fluoropyridine Chemical compound FC1=CC=CC(Br)=N1 ZIDIKYIZXMYHAW-UHFFFAOYSA-N 0.000 description 5
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 5
- PZKDOSHWQBLVJW-UHFFFAOYSA-N 4-(hydroxymethyl)naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(CO)=CC=C(C#N)C2=C1 PZKDOSHWQBLVJW-UHFFFAOYSA-N 0.000 description 5
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 5
- DQMZKGPSCVHHPB-UHFFFAOYSA-N 6-fluoro-7-(hydroxymethyl)-1-benzofuran-4-carbonitrile Chemical compound N#CC1=C(C=CO2)C2=C(CO)C(F)=C1 DQMZKGPSCVHHPB-UHFFFAOYSA-N 0.000 description 5
- UYLDXSZCMYWHDO-UHFFFAOYSA-N 7-(hydroxymethyl)-1-benzothiophene-4-carbonitrile Chemical compound N#CC1=CC=C(CO)C2=C1C=CS2 UYLDXSZCMYWHDO-UHFFFAOYSA-N 0.000 description 5
- ISXXFZMIWBBHBP-UHFFFAOYSA-N 7-(hydroxymethyl)-2-methyl-1-benzofuran-4-carbonitrile Chemical compound CC(OC1=C(CO)C=C2)=CC1=C2C#N ISXXFZMIWBBHBP-UHFFFAOYSA-N 0.000 description 5
- JWOJUSUDVYNUGT-UHFFFAOYSA-N 7-ethynyl-1-benzofuran-4-carbonitrile Chemical compound C#CC(C=C1)=C2OC=CC2=C1C#N JWOJUSUDVYNUGT-UHFFFAOYSA-N 0.000 description 5
- GPCOUSIIXPBMKD-NSHDSACASA-N ClCC1=NC2=C(N1C[C@H]1OCCC1)C=C(C=C2)C(=O)OC Chemical compound ClCC1=NC2=C(N1C[C@H]1OCCC1)C=C(C=C2)C(=O)OC GPCOUSIIXPBMKD-NSHDSACASA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical class CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 5
- PBCRUVPJWNSSCK-JTQLQIEISA-N NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCCC1 Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCCC1 PBCRUVPJWNSSCK-JTQLQIEISA-N 0.000 description 5
- MFPDUBXPRDZWBM-UHFFFAOYSA-N OCc1cc2ccoc2cc1F Chemical compound OCc1cc2ccoc2cc1F MFPDUBXPRDZWBM-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- CVWJXSHPQBZGAZ-UHFFFAOYSA-N [2-methyl-4-(trifluoromethyl)-1-benzofuran-7-yl]methanol Chemical compound CC1=CC(C(C(F)(F)F)=CC=C2CO)=C2O1 CVWJXSHPQBZGAZ-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 5
- 230000002218 hypoglycaemic effect Effects 0.000 description 5
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- VYDXRLUAPZZPEZ-UHFFFAOYSA-N methyl 2-(chloromethyl)-3-(2-methoxyethyl)benzimidazole-5-carboxylate Chemical compound COCCN1C(CCl)=NC2=C1C=C(C=C2)C(=O)OC VYDXRLUAPZZPEZ-UHFFFAOYSA-N 0.000 description 5
- YELUKQRRBLOBKP-UHFFFAOYSA-N methyl 4-amino-3-(2-methoxyethylamino)benzoate Chemical compound COCCNC1=CC(C(=O)OC)=CC=C1N YELUKQRRBLOBKP-UHFFFAOYSA-N 0.000 description 5
- CEYHKCZODRRMMV-VIFPVBQESA-N methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1 CEYHKCZODRRMMV-VIFPVBQESA-N 0.000 description 5
- ILKIHCYHKYHCLM-ZETCQYMHSA-N methyl 5-nitro-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate Chemical compound [N+](=O)([O-])C=1C=CC(=NC=1NC[C@H]1OCC1)C(=O)OC ILKIHCYHKYHCLM-ZETCQYMHSA-N 0.000 description 5
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 5
- IKCBFDMOZPJZQJ-UHFFFAOYSA-N tert-butyl 4-[6-[(4-cyanonaphthalen-1-yl)methoxy]pyridin-2-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C1=NC(OCC(C2=CC=CC=C22)=CC=C2C#N)=CC=C1)=O IKCBFDMOZPJZQJ-UHFFFAOYSA-N 0.000 description 5
- WPLWZAGYHQVUTC-UHFFFAOYSA-N (5-fluoro-1-benzofuran-6-yl)methanol Chemical compound OCC1=CC(OC=C2)=C2C=C1F WPLWZAGYHQVUTC-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- OZTNRXBMJSJJAZ-UHFFFAOYSA-N 2-(4-chloro-1-benzofuran-7-yl)ethanol Chemical compound OCCC(C1=C2C=CO1)=CC=C2Cl OZTNRXBMJSJJAZ-UHFFFAOYSA-N 0.000 description 4
- ADSJLJRLWNJVTD-NRFANRHFSA-N 2-[[4-[6-[(4-chloro-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid Chemical compound OC(C1=CC=C2N=C(CN(CC3)CCC3C3=NC(OCC(C4=C5C=CO4)=CC=C5Cl)=CC=C3)N(C[C@H]3OCC3)C2=N1)=O ADSJLJRLWNJVTD-NRFANRHFSA-N 0.000 description 4
- JWTZSVLLPKTZJP-UHFFFAOYSA-N 2-bromo-6-chloropyridine Chemical compound ClC1=CC=CC(Br)=N1 JWTZSVLLPKTZJP-UHFFFAOYSA-N 0.000 description 4
- SBCYMHNJXRVZGY-UHFFFAOYSA-N 4-(6-chloropyridin-2-yl)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)(C(=O)O)C1=NC(=CC=C1)Cl SBCYMHNJXRVZGY-UHFFFAOYSA-N 0.000 description 4
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 description 4
- KLFFBCNYLYDJJU-UHFFFAOYSA-N 7-(hydroxymethyl)-3-methyl-1-benzofuran-4-carbonitrile Chemical compound CC1=COC2=C(CO)C=CC(C#N)=C12 KLFFBCNYLYDJJU-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- NALKUTSPQGNISH-YFKPBYRVSA-N [(2S)-oxetan-2-yl]methyl methanesulfonate Chemical compound CS(=O)(=O)OC[C@H]1OCC1 NALKUTSPQGNISH-YFKPBYRVSA-N 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- FXELLBQNJIKREQ-UHFFFAOYSA-N methyl 4-amino-3-[(3-ethylimidazol-4-yl)methylamino]benzoate Chemical compound NC1=C(C=C(C(=O)OC)C=C1)NCC1=CN=CN1CC FXELLBQNJIKREQ-UHFFFAOYSA-N 0.000 description 4
- HTYWVEUBCLGQES-VIFPVBQESA-N methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate Chemical compound [N+](=O)([O-])C1=C(C=C(C(=O)OC)C=C1)NC[C@H]1OCC1 HTYWVEUBCLGQES-VIFPVBQESA-N 0.000 description 4
- RVRSGGHPMXSDSD-ZETCQYMHSA-N methyl 5-amino-6-[[(2S)-oxetan-2-yl]methylamino]pyridine-2-carboxylate Chemical compound NC=1C=CC(=NC=1NC[C@H]1OCC1)C(=O)OC RVRSGGHPMXSDSD-ZETCQYMHSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 4
- VZKSYFOYHCOXRJ-UHFFFAOYSA-N tert-butyl 4-[6-[(7-cyano-1-benzofuran-4-yl)methoxy]pyridin-2-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C1=NC(OCC(C2=C3OC=C2)=CC=C3C#N)=CC=C1)=O VZKSYFOYHCOXRJ-UHFFFAOYSA-N 0.000 description 4
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 208000016261 weight loss Diseases 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 3
- LMLDXXXZBRCPIP-NSHDSACASA-N (2s)-2-(phenylmethoxymethyl)oxetane Chemical compound C([C@H]1OCC1)OCC1=CC=CC=C1 LMLDXXXZBRCPIP-NSHDSACASA-N 0.000 description 3
- SNHZKRHWKTVKBR-UHFFFAOYSA-N (3-methylbenzimidazol-5-yl)methanol Chemical compound C1=C(CO)C=C2N(C)C=NC2=C1 SNHZKRHWKTVKBR-UHFFFAOYSA-N 0.000 description 3
- PNZULXLKCVSAQI-UHFFFAOYSA-N (4-fluoro-1-benzofuran-7-yl)methanol Chemical compound OCC(C1=C2C=CO1)=CC=C2F PNZULXLKCVSAQI-UHFFFAOYSA-N 0.000 description 3
- VRLNOXRCNGNLDC-UHFFFAOYSA-N 1-O-tert-butyl 4-O-methyl 4-(6-chloropyridin-2-yl)piperidine-1,4-dicarboxylate Chemical compound ClC1=CC=CC(=N1)C1(CCN(CC1)C(=O)OC(C)(C)C)C(=O)OC VRLNOXRCNGNLDC-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- UMIYSIDPIVQNTO-QHCPKHFHSA-N 2-[[4-[6-[(4-cyano-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid Chemical compound N#CC1=CC=C(COC2=CC=CC(C3CCN(CC4=NC5=CC=C(C(O)=O)N=C5N4C[C@H]4OCC4)CC3)=N2)C2=C1C=CO2 UMIYSIDPIVQNTO-QHCPKHFHSA-N 0.000 description 3
- NPEIUNVTLXEOLT-UHFFFAOYSA-N 2-chloro-1,1,1-trimethoxyethane Chemical compound COC(CCl)(OC)OC NPEIUNVTLXEOLT-UHFFFAOYSA-N 0.000 description 3
- COYPLDIXZODDDL-UHFFFAOYSA-N 3h-benzimidazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CNC2=C1 COYPLDIXZODDDL-UHFFFAOYSA-N 0.000 description 3
- KMOGYESRAGTCET-UHFFFAOYSA-N 4-(hydroxymethyl)-1-benzofuran-7-carbonitrile Chemical compound N#CC1=CC=C(CO)C2=C1OC=C2 KMOGYESRAGTCET-UHFFFAOYSA-N 0.000 description 3
- FUNLMDCWGXAUHO-UHFFFAOYSA-N 7-(bromomethyl)-4-chloro-1-benzofuran Chemical compound ClC1=CC=C(CBr)C2=C1C=CO2 FUNLMDCWGXAUHO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 3
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 3
- 108010019598 Liraglutide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- 229940123464 Thiazolidinedione Drugs 0.000 description 3
- PQZJTHGEFIQMCO-BYPYZUCNSA-N [(2s)-oxetan-2-yl]methanol Chemical compound OC[C@@H]1CCO1 PQZJTHGEFIQMCO-BYPYZUCNSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 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
- 229940125904 compound 1 Drugs 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 3
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229960002701 liraglutide Drugs 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 229960003105 metformin Drugs 0.000 description 3
- XKFQLRWVHUTKMC-DEOSSOPVSA-N methyl 2-[[4-[6-[(4-cyano-1-benzofuran-7-yl)methoxy]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate Chemical compound COC(C1=CC=C2N=C(CN(CC3)CC=C3C3=NC(OCC(C4=C5C=CO4)=CC=C5C#N)=CC=C3)N(C[C@H]3OCC3)C2=N1)=O XKFQLRWVHUTKMC-DEOSSOPVSA-N 0.000 description 3
- HCIREWNLXZXGFU-UHFFFAOYSA-N methyl 3-(2-methoxyethylamino)-4-nitrobenzoate Chemical compound COCCNC=1C=C(C(=O)OC)C=CC=1[N+](=O)[O-] HCIREWNLXZXGFU-UHFFFAOYSA-N 0.000 description 3
- FKMZNQQOPCCUTD-UHFFFAOYSA-N methyl 3-fluoro-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(F)=C1 FKMZNQQOPCCUTD-UHFFFAOYSA-N 0.000 description 3
- WHAROXSRJJMTIK-UHFFFAOYSA-N methyl 4-chloro-2-methyl-1-benzofuran-7-carboxylate Chemical compound CC1=CC(C(Cl)=CC=C2C(OC)=O)=C2O1 WHAROXSRJJMTIK-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- UBTMMEQNMLEPFA-UHFFFAOYSA-N tert-butyl 4-[6-[(4-chloro-2-methyl-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C1=NC(OCC(C2=C3C=C(C)O2)=CC=C3Cl)=CC=C1)=O UBTMMEQNMLEPFA-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000001467 thiazolidinediones Chemical class 0.000 description 3
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- QNYBOILAKBSWFG-SNVBAGLBSA-N (2s)-2-(phenylmethoxymethyl)oxirane Chemical compound C([C@H]1OC1)OCC1=CC=CC=C1 QNYBOILAKBSWFG-SNVBAGLBSA-N 0.000 description 2
- YFYOKKZYXAKMDP-UHFFFAOYSA-N (4-bromo-6-fluoro-1-benzofuran-7-yl)methanol Chemical compound OCC(C(OC=C1)=C1C(Br)=C1)=C1F YFYOKKZYXAKMDP-UHFFFAOYSA-N 0.000 description 2
- AUYXIPHRBVMBDW-UHFFFAOYSA-N (4-cyanonaphthalen-1-yl)methyl acetate Chemical compound C(#N)C1=CC=C(C2=CC=CC=C12)COC(C)=O AUYXIPHRBVMBDW-UHFFFAOYSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- HAKSOKWVNPZVNM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine;hydrochloride Chemical compound Cl.C1CNC=CC1 HAKSOKWVNPZVNM-UHFFFAOYSA-N 0.000 description 2
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 2
- FPVIWMAMFOENDJ-UHFFFAOYSA-N 1-(2,2-diethoxyethoxy)-2-fluoro-3-methylbenzene Chemical compound CCOC(COc1cccc(C)c1F)OCC FPVIWMAMFOENDJ-UHFFFAOYSA-N 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- HAICRZPDDBKXPQ-UHFFFAOYSA-N 1-benzofuran-7-carbonitrile Chemical compound N#CC1=CC=CC2=C1OC=C2 HAICRZPDDBKXPQ-UHFFFAOYSA-N 0.000 description 2
- OQBBRWKSGPQHLA-UHFFFAOYSA-N 1-bromo-2-prop-2-ynoxy-4-(trifluoromethyl)benzene Chemical compound C#CCOC(C=C(C(F)(F)F)C=C1)=C1Br OQBBRWKSGPQHLA-UHFFFAOYSA-N 0.000 description 2
- ZVAVEQLDILCGOK-UHFFFAOYSA-N 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene Chemical compound CCOC(OCC)COC1=CC(Cl)=CC=C1Br ZVAVEQLDILCGOK-UHFFFAOYSA-N 0.000 description 2
- FAUNLIZLVCOYRO-UHFFFAOYSA-N 2-(2,2-diethoxyethoxy)-4-fluoro-1-methylbenzene Chemical compound CCOC(OCC)COC1=CC(F)=CC=C1C FAUNLIZLVCOYRO-UHFFFAOYSA-N 0.000 description 2
- KJYBKBOWPFHDTR-UHFFFAOYSA-N 2-(4-chloro-1-benzofuran-7-yl)acetic acid Chemical compound OC(CC(C1=C2C=CO1)=CC=C2Cl)=O KJYBKBOWPFHDTR-UHFFFAOYSA-N 0.000 description 2
- DINGQDHTOQEHQW-UHFFFAOYSA-N 2-(4-chloro-1-benzofuran-7-yl)acetonitrile Chemical compound N#CCC(C1=C2C=CO1)=CC=C2Cl DINGQDHTOQEHQW-UHFFFAOYSA-N 0.000 description 2
- WGSKVAFGNVVQCF-UHFFFAOYSA-N 2-[4-[6-[(4-chloro-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidin-1-yl]acetic acid Chemical compound OC(CN(CC1)CCC1C1=NC(OCC(C2=C3C=CO2)=CC=C3Cl)=CC=C1)=O WGSKVAFGNVVQCF-UHFFFAOYSA-N 0.000 description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 2
- YKCLILNXSJDDOF-QHCPKHFHSA-N 2-[[4-[6-(1,3-benzodioxol-5-ylmethoxy)pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound O1COC2=C1C=CC(=C2)COC1=CC=CC(=N1)C=1CCN(CC=1)CC1=NC2=C(N1C[C@H]1OCC1)C=C(C=C2)C(=O)O YKCLILNXSJDDOF-QHCPKHFHSA-N 0.000 description 2
- RZIWHAHWHXKFRG-DEOSSOPVSA-N 2-[[4-[6-[(3-methylbenzimidazol-5-yl)methoxy]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound CN1C=NC2=C1C=C(C=C2)COC1=CC=CC(=N1)C=1CCN(CC=1)CC1=NC2=C(N1C[C@H]1OCC1)C=C(C=C2)C(=O)O RZIWHAHWHXKFRG-DEOSSOPVSA-N 0.000 description 2
- QEVWOFWFLRAXQP-QHCPKHFHSA-N 2-[[4-[6-[(4-cyano-1-benzofuran-7-yl)methoxy]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid Chemical compound N#CC1=CC=C(COC2=CC=CC(C3=CCN(CC4=NC5=CC=C(C(O)=O)N=C5N4C[C@H]4OCC4)CC3)=N2)C2=C1C=CO2 QEVWOFWFLRAXQP-QHCPKHFHSA-N 0.000 description 2
- NBHWFMLCMCZHLN-MHZLTWQESA-N 2-[[4-[6-[(4-cyanonaphthalen-1-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound N#CC1=CC=C(COC2=CC=CC(C3CCN(CC4=NC(C=CC(C(O)=O)=C5)=C5N4C[C@H]4OCC4)CC3)=N2)C2=C1C=CC=C2 NBHWFMLCMCZHLN-MHZLTWQESA-N 0.000 description 2
- MTVBBLNLYSYKCQ-UHFFFAOYSA-N 2-[[cyclohexyl(methyl)amino]methyl]aniline Chemical compound C1CCCCC1N(C)CC1=CC=CC=C1N MTVBBLNLYSYKCQ-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- RZWIQCYYXYYFPH-UHFFFAOYSA-N 2-bromo-6-[2-(4-chloro-1-benzofuran-7-yl)ethoxy]pyridine Chemical compound ClC1=CC=C(CCOC2=CC=CC(Br)=N2)C2=C1C=CO2 RZWIQCYYXYYFPH-UHFFFAOYSA-N 0.000 description 2
- UIEVSGOVFXWCIK-UHFFFAOYSA-N 2-chloro-6-methyl-3-nitropyridine Chemical compound CC1=CC=C([N+]([O-])=O)C(Cl)=N1 UIEVSGOVFXWCIK-UHFFFAOYSA-N 0.000 description 2
- PQAMFDRRWURCFQ-UHFFFAOYSA-N 2-ethyl-1h-imidazole Chemical group CCC1=NC=CN1 PQAMFDRRWURCFQ-UHFFFAOYSA-N 0.000 description 2
- LMOKSIOFBYFTNZ-UHFFFAOYSA-N 2-fluoro-4-hydroxy-5-iodobenzaldehyde Chemical compound FC1=C(C=O)C=C(C(=C1)O)I LMOKSIOFBYFTNZ-UHFFFAOYSA-N 0.000 description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- JPBDMIWPTFDFEU-UHFFFAOYSA-N 3-bromobenzene-1,2-diol Chemical compound OC1=CC=CC(Br)=C1O JPBDMIWPTFDFEU-UHFFFAOYSA-N 0.000 description 2
- KRANMNZBPQVOQR-UHFFFAOYSA-N 3-ethylimidazole-4-carboxamide Chemical compound CCN1C=NC=C1C(N)=O KRANMNZBPQVOQR-UHFFFAOYSA-N 0.000 description 2
- MJRGQSOSWLZODB-UHFFFAOYSA-N 4-(bromomethyl)-1-benzofuran-7-carbonitrile Chemical compound N#CC1=CC=C(CBr)C2=C1OC=C2 MJRGQSOSWLZODB-UHFFFAOYSA-N 0.000 description 2
- MFUZJLPIGYIBSM-UHFFFAOYSA-N 4-(bromomethyl)naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(CBr)=CC=C(C#N)C2=C1 MFUZJLPIGYIBSM-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- NHLXEHFPQHXBLJ-UHFFFAOYSA-N 4-bromo-2-(2,2-diethoxyethoxy)-1-methylbenzene Chemical compound CCOC(COC1=CC(Br)=CC=C1C)OCC NHLXEHFPQHXBLJ-UHFFFAOYSA-N 0.000 description 2
- MECGYZSGNVPTER-UHFFFAOYSA-N 4-bromo-7-methyl-1-benzofuran Chemical compound CC1=CC=C(Br)C2=C1OC=C2 MECGYZSGNVPTER-UHFFFAOYSA-N 0.000 description 2
- YYUDAJFHHKIIJT-UHFFFAOYSA-N 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene Chemical compound CCOC(OCC)COC1=CC(Cl)=CC=C1C YYUDAJFHHKIIJT-UHFFFAOYSA-N 0.000 description 2
- RSFCKBFYZZOVPQ-UHFFFAOYSA-N 4-chloro-2-methyl-1-benzofuran-7-carboxylic acid Chemical compound Cc1cc2c(Cl)ccc(C(O)=O)c2o1 RSFCKBFYZZOVPQ-UHFFFAOYSA-N 0.000 description 2
- JNBRYZQPDMSSRU-UHFFFAOYSA-N 4-chloro-7-methyl-1-benzofuran Chemical compound CC1=CC=C(Cl)C2=C1OC=C2 JNBRYZQPDMSSRU-UHFFFAOYSA-N 0.000 description 2
- HFEGEZCMIAQSHF-UHFFFAOYSA-N 4-fluoro-7-methyl-1-benzofuran Chemical compound CC1=CC=C(F)C2=C1OC=C2 HFEGEZCMIAQSHF-UHFFFAOYSA-N 0.000 description 2
- XDIWTJZAYBYKHM-UHFFFAOYSA-N 4-methylnaphthalene-1-carbonitrile Chemical compound C1=CC=C2C(C)=CC=C(C#N)C2=C1 XDIWTJZAYBYKHM-UHFFFAOYSA-N 0.000 description 2
- QIMLOOJXQWHBKU-UHFFFAOYSA-N 6-(bromomethyl)-7-fluoro-1-benzofuran Chemical compound FC1=C(CBr)C=CC2=C1OC=C2 QIMLOOJXQWHBKU-UHFFFAOYSA-N 0.000 description 2
- ILEYDNZCKAFZPF-UHFFFAOYSA-N 6-fluoro-1-benzofuran-5-carbaldehyde Chemical compound C1=C(C=O)C(F)=CC2=C1C=CO2 ILEYDNZCKAFZPF-UHFFFAOYSA-N 0.000 description 2
- URNKCAVBIVIRPX-UHFFFAOYSA-N 7-(bromomethyl)-1-benzofuran-4-carbonitrile Chemical compound N#CC1=C(C=CO2)C2=C(CBr)C=C1 URNKCAVBIVIRPX-UHFFFAOYSA-N 0.000 description 2
- VDVSSQRRSCXZPD-UHFFFAOYSA-N 7-(bromomethyl)-4-fluoro-1-benzofuran Chemical compound FC1=CC=C(CBr)C2=C1C=CO2 VDVSSQRRSCXZPD-UHFFFAOYSA-N 0.000 description 2
- HSIWDQXZIICTKJ-UHFFFAOYSA-N 7-bromo-2-methyl-4-(trifluoromethyl)-1-benzofuran Chemical compound CC1=CC(C(C(F)(F)F)=CC=C2Br)=C2O1 HSIWDQXZIICTKJ-UHFFFAOYSA-N 0.000 description 2
- FRFKOGIDFNTSBY-UHFFFAOYSA-N 7-bromo-4-chloro-1-benzofuran Chemical compound ClC1=CC=C(Br)C2=C1C=CO2 FRFKOGIDFNTSBY-UHFFFAOYSA-N 0.000 description 2
- RLFNFZUSLJLHPU-UHFFFAOYSA-N 7-fluoro-6-methyl-1-benzofuran Chemical compound CC1=C(F)C2=C(C=CO2)C=C1 RLFNFZUSLJLHPU-UHFFFAOYSA-N 0.000 description 2
- ODUGGKQAQLPPAD-UHFFFAOYSA-N 7-formyl-1-benzofuran-4-carbonitrile Chemical compound N#CC1=C(C=CO2)C2=C(C=O)C=C1 ODUGGKQAQLPPAD-UHFFFAOYSA-N 0.000 description 2
- CVRUJIMUIOVAOP-UHFFFAOYSA-N 7-methyl-1-benzofuran-4-carbonitrile Chemical compound CC1=CC=C(C#N)C2=C1OC=C2 CVRUJIMUIOVAOP-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- RTAOTYGRJRQLBR-UHFFFAOYSA-N COC(=O)C1=C2C(=C(C=C1F)Br)C=CO2 Chemical compound COC(=O)C1=C2C(=C(C=C1F)Br)C=CO2 RTAOTYGRJRQLBR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-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
- 102100039997 Gastric inhibitory polypeptide receptor Human genes 0.000 description 2
- 101000886866 Homo sapiens Gastric inhibitory polypeptide receptor Proteins 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 241000713666 Lentivirus Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 150000001204 N-oxides Chemical group 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 2
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- NQZFAUXPNWSLBI-UHFFFAOYSA-N carbon monoxide;ruthenium Chemical group [Ru].[Ru].[Ru].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] NQZFAUXPNWSLBI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229940126545 compound 53 Drugs 0.000 description 2
- 229940127113 compound 57 Drugs 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 229960003345 empagliflozin Drugs 0.000 description 2
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- 229960001381 glipizide Drugs 0.000 description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 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
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- USAXBIAOTWEZOR-UHFFFAOYSA-N methyl 2-(2,2-diethoxyethoxy)-4-methylbenzoate Chemical compound CCOC(COC(C=C(C)C=C1)=C1C(OC)=O)OCC USAXBIAOTWEZOR-UHFFFAOYSA-N 0.000 description 2
- ONHJFZCVJRYPKH-UHFFFAOYSA-N methyl 2-fluoro-5-hydroxy-4-iodobenzoate Chemical compound COC(=O)C1=CC(O)=C(I)C=C1F ONHJFZCVJRYPKH-UHFFFAOYSA-N 0.000 description 2
- WJHHIVYNOVTVGY-UHFFFAOYSA-N methyl 3h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=C2N=CNC2=C1 WJHHIVYNOVTVGY-UHFFFAOYSA-N 0.000 description 2
- YIHVRHPEECGGFK-UHFFFAOYSA-N methyl 4-bromo-1-benzothiophene-7-carboxylate Chemical compound COC(C(C1=C2C=CS1)=CC=C2Br)=O YIHVRHPEECGGFK-UHFFFAOYSA-N 0.000 description 2
- QXWLOFCMJIYTHD-UHFFFAOYSA-N methyl 4-bromo-2-fluoro-6-hydroxybenzoate Chemical compound COC(=O)C1=C(O)C=C(Br)C=C1F QXWLOFCMJIYTHD-UHFFFAOYSA-N 0.000 description 2
- HYJFLZRBRFDQBT-UHFFFAOYSA-N methyl 4-bromo-2-fluoro-6-methoxybenzoate Chemical compound COC(=O)C1=C(F)C=C(Br)C=C1OC HYJFLZRBRFDQBT-UHFFFAOYSA-N 0.000 description 2
- JEMVEVUWSJXZMX-UHFFFAOYSA-N methyl 4-bromo-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1O JEMVEVUWSJXZMX-UHFFFAOYSA-N 0.000 description 2
- ZCHSBBNPCUFNLR-UHFFFAOYSA-N methyl 4-bromo-2-methyl-1-benzofuran-7-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C2=C1OC(C)=C2 ZCHSBBNPCUFNLR-UHFFFAOYSA-N 0.000 description 2
- OCYYNJBCBCZDLK-UHFFFAOYSA-N methyl 4-bromo-2-sulfanylbenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1S OCYYNJBCBCZDLK-UHFFFAOYSA-N 0.000 description 2
- MAQCYZUSBOOPOM-UHFFFAOYSA-N methyl 4-bromo-3-methyl-1-benzofuran-7-carboxylate Chemical compound CC1=COC2=C1C(Br)=CC=C2C(OC)=O MAQCYZUSBOOPOM-UHFFFAOYSA-N 0.000 description 2
- SWFGBRNDPCZJNA-UHFFFAOYSA-N methyl 4-methyl-1-benzofuran-7-carboxylate Chemical compound COC(=O)c1ccc(C)c2ccoc12 SWFGBRNDPCZJNA-UHFFFAOYSA-N 0.000 description 2
- CWOQJENBLKUBHW-UHFFFAOYSA-N methyl 5-fluoro-1-benzofuran-6-carboxylate Chemical compound COC(=O)c1cc2occc2cc1F CWOQJENBLKUBHW-UHFFFAOYSA-N 0.000 description 2
- GLAHCGFYRJZAGY-UHFFFAOYSA-N methyl 6-chloro-5-nitropyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(Cl)=N1 GLAHCGFYRJZAGY-UHFFFAOYSA-N 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 2
- 229960003086 naltrexone Drugs 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XJEYWNFHYAKOIS-UHFFFAOYSA-N tert-butyl 4-(6-aminopyridin-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2N=C(N)C=CC=2)=C1 XJEYWNFHYAKOIS-UHFFFAOYSA-N 0.000 description 2
- QWUBZAZOZWCENL-UHFFFAOYSA-N tert-butyl 4-(6-aminopyridin-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC=CC(N)=N1 QWUBZAZOZWCENL-UHFFFAOYSA-N 0.000 description 2
- AXSJUHYVBIMIBU-UHFFFAOYSA-N tert-butyl 4-(6-chloropyridin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=CC1)c1cccc(Cl)n1 AXSJUHYVBIMIBU-UHFFFAOYSA-N 0.000 description 2
- CAIOLUQAKCTBAY-UHFFFAOYSA-N tert-butyl 4-[2,3-bis(2-trimethylsilylethoxymethoxy)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C[Si](CCOCOC1=C(C=CC=C1OCOCC[Si](C)(C)C)C=1CCN(CC=1)C(=O)OC(C)(C)C)(C)C CAIOLUQAKCTBAY-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 2
- PJPDSEYHEHGLOH-UHFFFAOYSA-N (2,2-difluoro-1,3-benzodioxol-5-yl)methanol Chemical compound OCC1=CC=C2OC(F)(F)OC2=C1 PJPDSEYHEHGLOH-UHFFFAOYSA-N 0.000 description 1
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 1
- FRNCAMZAPFINSG-UHFFFAOYSA-N (3-ethylimidazol-4-yl)methanol Chemical compound CCN1C=NC=C1CO FRNCAMZAPFINSG-UHFFFAOYSA-N 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
- SQHSJJGGWYIFCD-UHFFFAOYSA-N (e)-1-diazonio-1-dimethoxyphosphorylprop-1-en-2-olate Chemical compound COP(=O)(OC)C(\[N+]#N)=C(\C)[O-] SQHSJJGGWYIFCD-UHFFFAOYSA-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
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- IDRVLLRKAAHOBP-UHFFFAOYSA-N 1-bromo-4-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=C(Br)C2=C1 IDRVLLRKAAHOBP-UHFFFAOYSA-N 0.000 description 1
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 1
- PTZNCCIULVXFIJ-UHFFFAOYSA-N 1-o-tert-butyl 4-o-methyl piperidine-1,4-dicarboxylate Chemical compound COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 PTZNCCIULVXFIJ-UHFFFAOYSA-N 0.000 description 1
- FYFVQMZBJZOXGR-UHFFFAOYSA-N 1-phenyl-2-propan-2-yloxybenzene Chemical group CC(C)OC1=CC=CC=C1C1=CC=CC=C1 FYFVQMZBJZOXGR-UHFFFAOYSA-N 0.000 description 1
- FFLHNBGNAWYMRH-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-6-ylmethanol Chemical compound O1CCOC2=CC(CO)=CC=C21 FFLHNBGNAWYMRH-UHFFFAOYSA-N 0.000 description 1
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- MRVICCVJYSSPBR-VIFPVBQESA-N 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound OC(=O)c1ccc2nc(CCl)n(C[C@@H]3CCO3)c2c1 MRVICCVJYSSPBR-VIFPVBQESA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JYMVHLRPLYTHHU-QFIPXVFZSA-N 2-[[4-[6-[(2,2-difluoro-1,3-benzodioxol-5-yl)methoxy]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid Chemical compound FC1(OC2=C(O1)C=CC(=C2)COC1=CC=CC(=N1)C=1CCN(CC=1)CC1=NC2=C(N1C[C@H]1OCC1)C=C(C=C2)C(=O)O)F JYMVHLRPLYTHHU-QFIPXVFZSA-N 0.000 description 1
- KNRHLDHQLDLOCS-QFIPXVFZSA-N 2-[[4-[6-[(6-fluoro-1-benzofuran-5-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylic acid Chemical compound OC(C1=CC=C2N=C(CN(CC3)CCC3C3=NC(OCC(C(F)=C4)=CC5=C4OC=C5)=CC=C3)N(C[C@H]3OCC3)C2=N1)=O KNRHLDHQLDLOCS-QFIPXVFZSA-N 0.000 description 1
- INHVNZLKNPJCJD-UHFFFAOYSA-N 2-bromo-5-(trifluoromethyl)phenol Chemical compound OC1=CC(C(F)(F)F)=CC=C1Br INHVNZLKNPJCJD-UHFFFAOYSA-N 0.000 description 1
- FMRKYXVZQWHGDA-UHFFFAOYSA-N 2-bromo-5-chlorophenol Chemical compound OC1=CC(Cl)=CC=C1Br FMRKYXVZQWHGDA-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- QTCQBPOWSWCJLQ-UHFFFAOYSA-N 2-fluoro-3-methylphenol Chemical compound CC1=CC=CC(O)=C1F QTCQBPOWSWCJLQ-UHFFFAOYSA-N 0.000 description 1
- ONRPXRPUBXXCCM-UHFFFAOYSA-N 2-fluoro-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(F)=C1 ONRPXRPUBXXCCM-UHFFFAOYSA-N 0.000 description 1
- PAXQXJDYVORMOO-UHFFFAOYSA-N 2-methyl-4-(trifluoromethyl)aniline Chemical group CC1=CC(C(F)(F)F)=CC=C1N PAXQXJDYVORMOO-UHFFFAOYSA-N 0.000 description 1
- NWPNXBQSRGKSJB-UHFFFAOYSA-N 2-methylbenzonitrile Chemical compound CC1=CC=CC=C1C#N NWPNXBQSRGKSJB-UHFFFAOYSA-N 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
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 description 1
- QXDVIFCTZBKLMY-UHFFFAOYSA-N 3-ethylimidazole-4-carboxylic acid Chemical compound CCN1C=NC=C1C(O)=O QXDVIFCTZBKLMY-UHFFFAOYSA-N 0.000 description 1
- GKPKZMOUMKZJSM-UHFFFAOYSA-N 3-methylbenzimidazole-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2N(C)C=NC2=C1 GKPKZMOUMKZJSM-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- ZNLNVFDERRMQPF-UHFFFAOYSA-N 4-methyl-1-benzofuran-7-carbonitrile Chemical compound CC1=CC=C(C#N)C2=C1C=CO2 ZNLNVFDERRMQPF-UHFFFAOYSA-N 0.000 description 1
- VIKSJRLPRPRFIV-QMMMGPOBSA-N 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoic acid Chemical compound OC(=O)c1ccc(c(NC[C@@H]2CCO2)c1)[N+]([O-])=O VIKSJRLPRPRFIV-QMMMGPOBSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 1
- OONJCAWRVJDVBB-UHFFFAOYSA-N 5-bromo-2-methylphenol Chemical compound CC1=CC=C(Br)C=C1O OONJCAWRVJDVBB-UHFFFAOYSA-N 0.000 description 1
- KKFPXGXMSBBNJI-UHFFFAOYSA-N 5-chloro-2-methylphenol Chemical compound CC1=CC=C(Cl)C=C1O KKFPXGXMSBBNJI-UHFFFAOYSA-N 0.000 description 1
- CKJOSIHYVLHIER-UHFFFAOYSA-N 5-fluoro-2-methylphenol Chemical compound CC1=CC=C(F)C=C1O CKJOSIHYVLHIER-UHFFFAOYSA-N 0.000 description 1
- BKLJUYPLUWUEOQ-UHFFFAOYSA-N 6-bromopyridin-2-amine Chemical compound NC1=CC=CC(Br)=N1 BKLJUYPLUWUEOQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000040350 B family Human genes 0.000 description 1
- 108091072128 B family Proteins 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 1
- VHIBOFWCGOAFJE-UHFFFAOYSA-N C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] Chemical compound C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] VHIBOFWCGOAFJE-UHFFFAOYSA-N 0.000 description 1
- WIELBGXNEWWUFP-UHFFFAOYSA-N CCOC(COC1=C(C(O)=O)C(F)=CC(Br)=C1)OCC Chemical compound CCOC(COC1=C(C(O)=O)C(F)=CC(Br)=C1)OCC WIELBGXNEWWUFP-UHFFFAOYSA-N 0.000 description 1
- USUWIEBBBWHKNI-KHIFEHGGSA-N C[C@H]1C[C@]1(c1noc(=O)[nH]1)n1c(cc2cc(ccc12)[C@H]1CCOC(C)(C)C1)C(=O)N1CCc2nn(c(c2[C@@H]1C)-n1ccn(-c2ccc3n(C)ncc3c2F)c1=O)-c1cc(C)c(F)c(C)c1 Chemical compound C[C@H]1C[C@]1(c1noc(=O)[nH]1)n1c(cc2cc(ccc12)[C@H]1CCOC(C)(C)C1)C(=O)N1CCc2nn(c(c2[C@@H]1C)-n1ccn(-c2ccc3n(C)ncc3c2F)c1=O)-c1cc(C)c(F)c(C)c1 USUWIEBBBWHKNI-KHIFEHGGSA-N 0.000 description 1
- RWJUGQVGOGXJCK-UHFFFAOYSA-N C[Si](CCOCOC1=C(C=CC=C1OCOCC[Si](C)(C)C)C1CCN(CC1)C(=O)OC(C)(C)C)(C)C Chemical compound C[Si](CCOCOC1=C(C=CC=C1OCOCC[Si](C)(C)C)C1CCN(CC1)C(=O)OC(C)(C)C)(C)C RWJUGQVGOGXJCK-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-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
- 229910052693 Europium Inorganic materials 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=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](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 1
- 101710153349 Fibroblast growth factor 19 Proteins 0.000 description 1
- 102100031356 Fibroblast growth factor 21 Human genes 0.000 description 1
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 229940125827 GPR40 agonist Drugs 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 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
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 1
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 102100038991 Neuropeptide Y receptor type 2 Human genes 0.000 description 1
- 101710197945 Neuropeptide Y receptor type 2 Proteins 0.000 description 1
- 229940123959 Neuropeptide Y5 receptor antagonist Drugs 0.000 description 1
- 208000031662 Noncommunicable disease Diseases 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100029909 Peptide YY Human genes 0.000 description 1
- 108010088847 Peptide YY Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- BHUIUXNAPJIDOG-UHFFFAOYSA-N Piperonol Chemical compound OCC1=CC=C2OCOC2=C1 BHUIUXNAPJIDOG-UHFFFAOYSA-N 0.000 description 1
- 239000004697 Polyetherimide Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 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
- 102100033451 Thyroid hormone receptor beta Human genes 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 1
- YNOGYQAEJGADFJ-YFKPBYRVSA-N [(2s)-oxolan-2-yl]methanamine Chemical compound NC[C@@H]1CCCO1 YNOGYQAEJGADFJ-YFKPBYRVSA-N 0.000 description 1
- PWDLDBWXTVILPC-QGGVPXFVSA-N [(3as,5ar,8ar)-2,2,7,7-tetramethyl-5,5a,8a,8b-tetrahydrodi[1,3]dioxolo[4,5-a:5',3'-d]pyran-3a-yl]methyl sulfamate;2-methyl-1-phenylpropan-2-amine Chemical compound CC(C)(N)CC1=CC=CC=C1.C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)OC2[C@@H]2OC(C)(C)O[C@@H]21 PWDLDBWXTVILPC-QGGVPXFVSA-N 0.000 description 1
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 description 1
- 229960005164 acesulfame Drugs 0.000 description 1
- FKYDFGYBTUVVHL-UHFFFAOYSA-N acetic acid hexylurea Chemical compound C(C)(=O)O.C(CCCCC)NC(=O)N FKYDFGYBTUVVHL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229940121373 acetyl-coa carboxylase inhibitor Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229960001667 alogliptin Drugs 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
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000003295 arcuate nucleus Anatomy 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
- 238000003149 assay kit Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- ANTGQBPGYZDWAW-UHFFFAOYSA-N azane;1,4-dioxane Chemical compound N.C1COCCO1 ANTGQBPGYZDWAW-UHFFFAOYSA-N 0.000 description 1
- VJBCNMFKFZIXHC-UHFFFAOYSA-N azanium;2-(4-methyl-5-oxo-4-propan-2-yl-1h-imidazol-2-yl)quinoline-3-carboxylate Chemical compound N.N1C(=O)C(C(C)C)(C)N=C1C1=NC2=CC=CC=C2C=C1C(O)=O VJBCNMFKFZIXHC-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 230000001593 cAMP accumulation Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000010036 cardiovascular benefit Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 238000002967 competitive immunoassay Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960003834 dapagliflozin Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005048 dihydroisoxazolyl group Chemical group O1N(CC=C1)* 0.000 description 1
- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005051 dihydropyrazinyl group Chemical group N1(CC=NC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005053 dihydropyrimidinyl group Chemical group N1(CN=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005058 dihydrotriazolyl group Chemical group N1(NNC=C1)* 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229960005175 dulaglutide Drugs 0.000 description 1
- 108010005794 dulaglutide Proteins 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- GWQVMPWSEVRGPY-UHFFFAOYSA-N europium cryptate Chemical compound [Eu+3].N=1C2=CC=CC=1CN(CC=1N=C(C=CC=1)C=1N=C(C3)C=CC=1)CC(N=1)=CC(C(=O)NCCN)=CC=1C(N=1)=CC(C(=O)NCCN)=CC=1CN3CC1=CC=CC2=N1 GWQVMPWSEVRGPY-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960003468 gliquidone Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 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
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229960001103 hydroxocobalamin Drugs 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960002397 linagliptin Drugs 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- 229940125411 ly3502970 Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance Methods 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
- 150000002696 manganese Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- BXDBHKQIZHIMRX-SFHVURJKSA-N methyl 2-[[4-(6-chloropyridin-2-yl)piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate Chemical compound COC(C(C=C1)=CC2=C1N=C(CN(CC1)CCC1C1=NC(Cl)=CC=C1)N2C[C@H]1OCC1)=O BXDBHKQIZHIMRX-SFHVURJKSA-N 0.000 description 1
- OCTNKWVCWQDVCT-QFIPXVFZSA-N methyl 2-[[4-[6-[(4-chloro-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate Chemical compound COC(C1=CC=C2N=C(CN(CC3)CCC3C3=NC(OCC(C4=C5C=CO4)=CC=C5Cl)=CC=C3)N(C[C@H]3OCC3)C2=N1)=O OCTNKWVCWQDVCT-QFIPXVFZSA-N 0.000 description 1
- DSLZPUTVLFTPST-QHCPKHFHSA-N methyl 2-[[4-[6-[(6-fluoro-1-benzofuran-5-yl)methoxy]pyridin-2-yl]piperidin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate Chemical compound COC(C1=CC=C2N=C(CN(CC3)CCC3C3=NC(OCC(C(F)=C4)=CC5=C4OC=C5)=CC=C3)N(C[C@H]3OCC3)C2=N1)=O DSLZPUTVLFTPST-QHCPKHFHSA-N 0.000 description 1
- MMSODGJNFCCKAZ-UHFFFAOYSA-N methyl 2-amino-4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1N MMSODGJNFCCKAZ-UHFFFAOYSA-N 0.000 description 1
- YAEWITNKCKZHNO-UHFFFAOYSA-N methyl 2-fluoro-5-hydroxybenzoate Chemical compound COC(=O)C1=CC(O)=CC=C1F YAEWITNKCKZHNO-UHFFFAOYSA-N 0.000 description 1
- UITFCFWKYAOJEJ-UHFFFAOYSA-N methyl 2-hydroxy-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C=C1O UITFCFWKYAOJEJ-UHFFFAOYSA-N 0.000 description 1
- XNILAPCHEAOFQR-UHFFFAOYSA-N methyl 3-[(3-ethylimidazol-4-yl)methylamino]-4-nitrobenzoate Chemical compound C(C)N1C=NC=C1CNC=1C=C(C(=O)OC)C=CC=1[N+](=O)[O-] XNILAPCHEAOFQR-UHFFFAOYSA-N 0.000 description 1
- JBXJLZRTTCGLNR-UHFFFAOYSA-N methyl 4-bromo-2,6-difluorobenzoate Chemical compound COC(=O)C1=C(F)C=C(Br)C=C1F JBXJLZRTTCGLNR-UHFFFAOYSA-N 0.000 description 1
- QXDWMJQRXWLSDP-UHFFFAOYSA-N methyl 4-chloro-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1O QXDWMJQRXWLSDP-UHFFFAOYSA-N 0.000 description 1
- KGYHVRMFHIGLFB-UHFFFAOYSA-N methyl 4-cyano-2-methyl-1-benzofuran-7-carboxylate Chemical compound CC1=CC(C(C#N)=CC=C2C(OC)=O)=C2O1 KGYHVRMFHIGLFB-UHFFFAOYSA-N 0.000 description 1
- ZGPXOQDWIBQEDL-UHFFFAOYSA-N methyl 4-cyano-3-methyl-1-benzofuran-7-carboxylate Chemical compound CC1=COC2=C1C(C#N)=CC=C2C(OC)=O ZGPXOQDWIBQEDL-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 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
- 230000004053 pancreatic β cell dysfunction Effects 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
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940000306 phentermine / topiramate Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920001601 polyetherimide Polymers 0.000 description 1
- 108010074658 polyethylene glycol loxenatide Proteins 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IBPVHDOKVSXPCA-UHFFFAOYSA-N tert-butyl 4-[6-[(4-chloro-1-benzofuran-7-yl)methoxy]pyridin-2-yl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(N(CC1)CCC1C1=NC(OCC(C2=C3C=CO2)=CC=C3Cl)=CC=C1)=O IBPVHDOKVSXPCA-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 108091008762 thyroid hormone receptors ß Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D405/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the invention relates to the technical field of chemistry and medicine, in particular to a benzimidazole or azabenzimidazole-6-carboxylic acid compound and an application thereof.
- T2DM Type 2 diabetes mellitus
- pancreatic ⁇ -cell dysfunction and insulin resistance are important pathogenesis of T2DM (N Engl J Med, 2007.356:213-215).
- Current diabetes treatment drugs mainly include insulin and its analogs, dipeptidyl peptidase-4 inhibitor (DPP-4i), glucagon-like peptide-1 receptor agonist (GLP-1RA), sodium-glucose co-transporter Protein-2 inhibitors (SGLT-2i), metformin, ⁇ -glucosidase inhibitors, sulfonylureas (SU), thiazolidinediones (TZDs), glinides, etc. (Biomed Pharmacother, 2020.131: 110708).
- DPP-4i dipeptidyl peptidase-4 inhibitor
- GLP-1RA glucagon-like peptide-1 receptor agonist
- SGLT-2i sodium-glucose co-transporter Protein-2 inhibitors
- metformin ⁇ -glucosidase inhibitors
- SU sulfonylureas
- TZDs thiazolidinediones
- glinides etc.
- GLP-1RA has the advantages of blood sugar-dependent strong hypoglycemia, no increase in hypoglycemia risk, weight loss, mild blood pressure reduction, etc., and most drugs have also been proven to have cardiovascular benefits, and the market share has grown significantly in recent years ( Cell Metab, 2018.27:740-756).
- N Engl J Med, 2021.384:e42 has a significant effect.
- Glucagon-like peptide-1 receptor (GLP-1R) is mainly expressed in tissues such as small intestine, pancreas, cardiovascular, brain and salivary glands (Endocrinology, 2014.155:1280-1290), and belongs to the G protein couple with 7 transmembrane GPCR B family member, which is activated by glucagon-like peptide-1 (GLP-1) secreted by intestinal L cells by increasing intracellular cyclic adenosine monophosphate (cAMP) levels Induce the opening of voltage-gated Ca 2+ channels, thereby promoting the proliferation and differentiation of islet ⁇ cells to regulate blood sugar (J Mol Biol, 2020.432:1347-1366).
- GLP-1R glucagon-like peptide-1 receptor
- GLP-1RA injectable peptides GLP-1RA approved for the treatment of T2DM, such as liraglutide, exenatide, dulaglutide, semaglutide, polyethylene glycol loxenatide, etc.
- Liraglutide is also approved for the treatment of obesity due to its role in reducing body weight (Mol Metab, 2021.46:101102; ACS Pharmacol Transl Sci, 2019.2:468-484).
- the US FDA officially approved the marketing of the world's first oral GLP-1 hypoglycemic drug semaglutide, which is used to improve blood sugar control in patients with type 2 diabetes in combination with diet and exercise.
- semaglutide is a polypeptide drug
- an oral formulation is formed by combining semaglutide with a small molecule absorption enhancer, SNAC.
- the combination with SNAC enables semaglutide to be absorbed in the stomach, and the partial dissolution of SNAC can A relatively high pH environment is formed locally in the stomach, thereby increasing the solubility of semaglutide and reducing the degradation of peptidase in the stomach.
- the main disadvantage is that its oral bioavailability is extremely low (only 0.4%-1%), and the cost is significantly increased.
- the incidence of gastrointestinal reactions and nausea is about 15-20% (Ann Pharmacotherapy, 2019, 54:478 -485).
- Small-molecule GLP-1R agonists can overcome the oral absorption barrier of peptide drugs, and at the same time, they can more easily pass through the blood-brain barrier, and act on GLP-1R in the arcuate nucleus of the hypothalamus to reduce appetite, and finally reduce blood sugar. At the same time, it may have a better weight loss effect (J Clin Invest, 2014.124:4223-4226).
- small molecule oral GLP-1R agonists mainly include OWL833 (Proc Natl Acad Sci U SA, 2020.117:29959-29967), PF-06882961 (Proc Natl Acad Sci U S A, 2020.117:29959-29967) and TTP273 (Nature, 2020.577:432-436).
- OWL833 Proc Natl Acad Sci U SA, 2020.117:29959-29967
- PF-06882961 Proc Natl Acad Sci U S A, 2020.117:29959-29967
- TTP273 Triure, 2020.577:432-436.
- the Phase I clinical results of PF-06882961 show that it has a significant effect on hypoglycemic and weight loss in patients with type 2 diabetes.
- PF-06882961 was administered twice a day in combination with metformin. After 28 days of treatment, the 120 mg dose reduced HBA1c by 1.2% and weight loss by 7.9 kg
- the present invention provides a new class of benzimidazole or azabenzimidazole-6-carboxylic acid compounds, It can effectively activate the GLP-1R downstream signaling pathway, increase the expression of cAMP, thereby achieve the effects of promoting insulin secretion and treating diabetes and its complications, and has great application value.
- the present invention provides benzimidazole or azabenzimidazole-6-carboxylic acid compounds represented by formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:
- R 1 and R 2 are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
- R 3 and R 4 are independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy; or R 3 and R 4 are connected to form a 3-8-membered carbocycle or a 3-8-membered heterocycle;
- R is selected from: C1 - C4 alkyl substituted by 3-8 membered heterocyclic group, C1-C4 alkyl substituted by 5-10 membered heteroaryl, C1-C4 alkyl substituted by C1-C6 alkoxy; wherein , the 3-8-membered heterocyclic group and the 5-10-membered heteroaryl group in R 5 can be independently and optionally substituted by one or more R 10 ;
- Each R and R are independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen Substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamino substituted C1 -C6 alkyl, aryl, heteroaryl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , - C(O)R, -S(O)R, -S(O)2R, -S(O ) 2N(R )2 , -N(R)C(O
- R is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl, hydroxyl Substituted C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkylamine substituted C1-C6 alkyl;
- n is selected from: 0, 1 or 2;
- p is selected from: 1 or 2;
- n is selected from: 1, 2 or 3;
- W is selected from: O, S, NR 10 ;
- W 1 is selected from: O, S;
- Q is selected from: C, CH, N;
- X is selected from: N, CR 10 ;
- Y is selected from: N, CR 11 ;
- R 10 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy;
- R 11 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy; or R 11 and R 6 are connected to form a 5-8 membered heterocyclic ring;
- the dotted line between Q and adjacent C indicates that the chemical bond between Q and adjacent C can be a single bond or a double bond.
- the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (II) or formula (III):
- the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (IV) or formula (V):
- the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (VI) or formula (VII):
- W is O
- R 6 and R 7 are independently selected from: H, C1-C6 alkyl.
- W 1 is O.
- Q is selected from: C, CH.
- X is selected from: N, CH.
- R 1 and R 2 are independently selected from: H, halogen, C1-C3 alkyl, C1-C3 alkoxy.
- R 3 and R 4 are independently selected from: H, C1-C3 alkyl, C1-C3 alkoxy.
- R is selected from: C1 - C4 alkyl substituted by 3-4 membered heterocyclic group, C1-C4 alkyl substituted by 5-6 membered heteroaryl, C1-C3 alkoxy substituted C1-C4 alkyl; wherein, the 3-4-membered heterocyclic group and the 5-6-membered heteroaryl group in R 5 can be independently and optionally substituted by one or more R 10 .
- R is selected from: 3-4 membered heterocyclyl substituted methyl, 3-4 membered heterocyclyl substituted ethyl, 5-6 membered heteroaryl substituted methyl, 5- 6-membered heteroaryl-substituted ethyl; wherein, the 3-4-membered heterocyclic group and the 5-6-membered heteroaryl group in R 5 can be independently and optionally replaced by one or more R 10 , and R 10 is selected from From: H, C1-C3 alkyl.
- R is selected from: methyl substituted by oxetane, ethyl substituted by oxetane, methyl substituted by ethylimidazole, ethyl substituted by ethylimidazole.
- R 6 and R 7 are independently selected from: H, C1-C3 alkyl.
- each R 8 and R 9 are independently selected from: H, halogen, cyano, C1-C3 alkyl, and C1-C3 alkyl substituted by halogen.
- each R 8 is independently selected from: H, halogen, C1-C3 alkyl; each R 9 is independently selected from: H, halogen, cyano, C1-C3 alkyl, trifluoromethyl .
- each R 8 is independently selected from: H, Cl, F, methyl; each R 9 is independently selected from: cyano, Cl, methyl.
- the benzimidazole or azabenzimidazole-6-carboxylic acid compound is selected from the following compounds:
- the present invention also provides the application of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer.
- benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer is used for preventing and/or treating GLP-1R downstream signaling pathway related Drug application for diseases and/or symptoms.
- the diseases and/or symptoms related to GLP-1R downstream signaling pathway are selected from but not limited to: diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, diabetic nephropathy, High blood pressure, cataract, osteoporosis, hyperuricemia and infection caused by diabetes, obesity, metabolic syndrome, dyslipidemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, fibrosis, heart disease, stroke , liver cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular discomfort, epilepsy, atherosclerosis, Parkinson's disease and Alzheimer's disease, etc.
- the diabetes is selected from but not limited to: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes and other special types of diabetes (idiopathic T1D, early-onset T2DM, maturity onset diabetes in young people, adolescent Onset of atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults, etc.
- T1DM type 1 diabetes
- T2DM type 2 diabetes
- gestational diabetes idiopathic T1D, early-onset T2DM, maturity onset diabetes in young people, adolescent Onset of atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults, etc.
- the invention also provides a pharmaceutical composition for preventing and/or treating diabetes and its complications.
- a pharmaceutical composition for preventing and/or treating diabetes and its complications comprising an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, the active ingredient includes the above-mentioned benzimidazole or azabenzimidazole- 6-carboxylic acid compounds or pharmaceutically acceptable salts or stereoisomers thereof.
- the new imidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer provided by the present invention can effectively activate GLP-1R downstream signaling pathway and increase the expression of cAMP , so as to achieve the effect of promoting insulin secretion and treating diabetes and its complications, which has great application value.
- Fig. 1 is the average drug-time curve of compound 1, 2, 3, 4 and compound 6 administered to rats by gavage (20 mg/kg).
- Fig. 2 is a graph showing the average drug duration of compounds PF-06882961, 12, 16, 46 and compound 58 administered by intragastric administration (20 mg/kg) to rats.
- Fig. 3 is the blood glucose curves of compound 12 and compound 16 in mouse glucose tolerance test.
- Figure 4 shows the AUC (0-2h) of compound 12 and compound 16 in the mouse glucose tolerance test.
- Figure 5 is the blood glucose curves of compound 6 and compound 16 in mouse glucose tolerance test.
- Fig. 7 Blood glucose curves of compound 3, compound 16 and compound 58 in mouse glucose tolerance test.
- Fig. 8 AUC (0-2h) of compound 3, compound 16 and compound 58 in mouse glucose tolerance test.
- any variable eg, R, etc.
- its definition for each occurrence is independent of the definition for each other occurrence.
- combinations of substituents and variables are permissible only if such combinations render the compounds stable.
- a line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
- alkyl as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- C1-C6 in “C1-C6 alkyl” includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
- C1-C6 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
- alkoxy refers to a group in which an alkyl group is directly connected to oxygen, that is, a group with an -O-alkyl structure, such as -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -O -CH 2 CH(CH 3 ) 2 , -OCH 2 CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 and the like.
- cycloalkyl or “carbocycle” refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
- cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
- heterocyclyl or “heterocycle” is a saturated or partially unsaturated monocyclic or polycyclic ring substituent in which one or more ring atoms are selected from N, O or S(O)m (where m is 0-2 integer) heteroatoms, and the remaining ring atoms are carbon, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroiso Thiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, two Thiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroaze
- heteroaryl refers to an aromatic ring containing one or more heteroatoms selected from O, N or S.
- the heteroaryl groups within the scope of the present invention include but are not limited to: quinolinyl, pyrazolyl, pyrrolyl , thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuryl, benzothienyl, benzo Oxazole, indolyl, etc.; "heteroaryl” is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
- substituted refers to the replacement of a hydrogen group in a specified structure with a group of the designated substituent.
- halo or halo means chlorine, fluorine, bromine and iodine, as understood by those skilled in the art.
- alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents can be unsubstituted or substituted.
- C1-C6 alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like.
- the present invention includes the free form of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII), and also includes its pharmaceutically acceptable Salts and Stereoisomers.
- the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.
- pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
- conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as organic acids such as acetic, propionic, succinic, glycolic, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid,
- salts derived from inorganic bases include aluminum salts, ammonium salts, Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt, etc. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine ,Piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
- the present invention provides a kind of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII)
- the compound of the structure and pharmaceutically acceptable salts or stereoisomers thereof treat diseases and/or symptoms related to GLP-1R downstream signaling pathways in humans or other mammals.
- the diseases and/or symptoms related to GLP-1R downstream signaling pathway can be selected from but not limited to: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes and other special types of diabetes (idiopathic T1D, early-onset T2DM, adult-onset diabetes in young adults, atypical diabetes in adolescents, malnutrition-related diabetes, latent autoimmune diabetes in adults, etc.), diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy , insulin resistance, hyperglycemia, diabetic nephropathy, hypertension, cataract, osteoporosis, hyperuricemia and various infections caused by diabetes, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease ( NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis, heart disease, stroke, cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular disorders, epilepsy and atherosclerosis, Parkinson's disease and Diseases such as Alzheimer's.
- T1DM type
- Combination medicine the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) can be combined with other known drugs for treating or improving similar symptoms drug combination.
- the administration mode & dosage of the original drug remain unchanged, while simultaneously or subsequently taking formula (I), formula (II), formula (III), formula (IV), formula (V), formula ( VI) or a compound of formula (VII).
- Drug combinations also include administration of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) and another or several known drugs.
- Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to The following drugs for the treatment of diabetes: biguanides (such as metformin), sulfonylureas (acetate hexylurea, chlorpropamide, tolbutamide, tolazamide, acesulfame, glibenclamide, glibenclamide Glipizide, glipizide, gliquidone, gliboride, glipipide, and glimepiride), thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, cyclamate Glitazone), meglitaides (such as nateglinide, repaglinide, mitaglinide), dipeptidyl peptidase 4 inhibitors (sitagliptin, vildagli
- Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to Drugs for the treatment of obesity in the following: peptide YY or its analogues, neuropeptide Y receptor type 2 agonists, melanocortin receptor 4 agonists, amylin, GIPR agonists, phosphodiesterase, AMP activation protein kinase, neuropeptide Y5 receptor antagonist, GPR40 agonist, GIP/GLP-1 dual receptor agonist, naltrexone (naltrexone)/bupropion, lorcaserin , phentermine/topiramate, orlistat, liraglutide.
- Drugs for the treatment of obesity in the following: peptide YY or its analogues, neuropeptide Y receptor type 2 agonists, melanocortin receptor 4 agonists, amylin, GI
- Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to Drugs for the treatment of NASH in the following: farnesoid X receptor agonists, PPAR ⁇ / ⁇ agonists, fibroblast growth factor 19/21 analogs, thyroid hormone receptor ⁇ agonists, sodium-glucose cotransporter (SGLT) -1/2 inhibitors, acetyl-CoA carboxylase inhibitors, chemokine receptor-2/5 inhibitors, antiapoptotic signal-regulated kinase 1 inhibitors, ATP-binding transporter 1 agonists, 5-fat oxidation Enzyme inhibitors, vascular adhesion protein 1 inhibitors.
- Drugs for the treatment of NASH in the following: farnesoid X receptor agonists, PPAR ⁇ / ⁇ agonists, fibroblast growth factor 19/21 analogs, thyroid hormone receptor ⁇ agonists, sodium-
- Step 1a Preparation of 1-(tert-butyl)4-methyl 4-(6-chloropyridin-2-yl)piperidine-1,4-dicarboxylate (compound 0102-1): under nitrogen protection , To a solution of methyl N-tert-butoxycarbonyl-4-piperidinecarboxylate (3.00 g, 12.33 mmol, 1.0 eq) in THF (40 mL) was added dropwise a solution of lithium bis(trimethylsilyl)amide in THF (1.0 mol/L, 25 mL, 24.66 mmol, 2.0 equiv).
- Step 1b Preparation of 1-(tert-butoxycarbonyl)-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid (Compound 0103-1): At 43°C, the crude product 1- (tert-butyl) 4-methyl 4-(6-chloropyridin-2-yl)piperidine-1,4-dicarboxylate (0102-1) (4.49g) was dissolved in methanol (12ml) , 4 mol/L aqueous sodium hydroxide solution (9 mL) was added dropwise over 20 minutes. The mixture was warmed to 50°C and stirred for 35 minutes.
- Step 1c Preparation of tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (compound 0104-1): Under nitrogen protection, 1-(tert-butoxycarbonyl)-4 -(6-Chloropyridine-2-yl)piperidine-4-carboxylic acid (0103-1) (3.85 g, 11.32 mmol) in 1,2-dichloroethane (30 ml) was heated to 82°C and stir overnight. After cooling to room temperature, the solvent was removed under reduced pressure.
- Step 2a Preparation of 6-chloro-5-nitropyridine-2-carboxylic acid (compound 0106-1): at room temperature, to 2-chloro-6-methyl-3-nitropyridine (0105-1) ( To a solution of 5.0 g, 29.1 mmol, 1.0 eq) in concentrated sulfuric acid (20 mL) was added chromium trioxide (8.6 g, 87.3 mmol, 3.0 eq) in portions. The mixture was stirred overnight at 60°C. After cooling to room temperature, the mixture was poured into ice water, then the solid was filtered and dried in vacuo to give 6-chloro-5-nitropyridine-2-carboxylic acid (4.15 g, yield: 71%) as gray solid.
- LCMS(ESI): m/z 201(MH) - .
- Step 2b Preparation of 6-chloro-5-nitropyridine-2-carboxylic acid methyl ester (compound 0107-1): nitrogen protection, at 0°C, to 6-chloro-5-nitropyridine-2-carboxylic acid (0106-1) (4.0 g, 19.8 mmol, 1.0 equiv) and N,N-dimethylformamide (2 drops) in dichloromethane (60 ml) were added oxalyl chloride (5.0 g, 39.6 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. Methanol (4 ml) was added, and the mixture was stirred at room temperature for 10 minutes. Water was added and the mixture was separated.
- Step 2c Preparation of (S)-2-((benzyloxy)methyl)oxetane (compound 0109): nitrogen protection, room temperature, to potassium tert-butoxide (13.6 g, 122.0 mmol, 2.0 eq) in tert-butanol (180 mL) was added trimethylsulfoxide iodide (26.8 g, 122.0 mmol, 2.0 eq). The mixture was stirred at 60°C for 30 minutes.
- (S)-2-((Benzyloxy)methyl)oxirane (0108) (10.0 g, 61.0 mmol, 1.0 equiv) was added, and the mixture was stirred at 80° C. for 2 hours.
- Step 2d Preparation of (S)-2-hydroxymethyloxetane (compound 0110): under hydrogen, (S)-2-((benzyloxy)methyl)oxetane (0109 ) (9.2 g, 51.7 mmol, 1.0 eq) and Pd/C (1.8 g, 10% by mass) in methanol (100 mL) was stirred overnight at room temperature. The mixture was filtered, and the filtrate was concentrated in vacuo to give (S)-2-hydroxymethyloxetane (5.0 g, yield: 111%) as a colorless liquid.
- Step 2c Preparation of (S)-oxetan-2-ylmethyl methanesulfonate (compound 0111): Nitrogen protection, at 0°C, to (S)-2-hydroxymethyloxetane Methanesulfonyl chloride (9.1 g, 79.5 mmol, 1.4 equivalents). The mixture was stirred at room temperature for 3 hours. The mixture was washed with water and concentrated in vacuo.
- Step 2d Preparation of (S)-oxetan-2-ylmethylamine (compound 0113): (S)-oxetan-2-ylmethyl methanesulfonate (0111) (5.8 g , 35 mmol, 1.0 eq), sodium azide (2.7 g, 42 mmol, 1.2 eq) and potassium iodide (1.2 g, 7.0 mmol, 0.2 eq) in N,N-dimethylformamide (80 ml ) solution was stirred overnight at 60 °C. After cooling to room temperature, methyl tert-butyl ether was added, and the mixture was washed with water.
- Step 2e Preparation of (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylate (compound 0114-1): 6-chloro - Methyl 5-nitropyridine-2-carboxylate (0107-1) (1.2 g, 5.6 mmol, 1.0 equiv), N,N-diisopropylethylamine (2.2 g, 16.8 mmol, 3.0 equiv ) and (S)-oxetan-2-ylmethylamine (0113) (1.0 g, 11.2 mmol, 2.0 equiv) in N,N-dimethylformamide (30 ml) was stirred at room temperature overnight.
- Step 2f Preparation of (S)-methyl 5-amino-6-((oxetane-2-ylmethyl)amino)pyridine-2-carboxylate (compound 0115-1): under hydrogen, (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylate (0114-1) (1.0 g, 3.7 mmol, 1.0 equiv ) and Pd/C (100 mg, 10% by mass) in methanol (30 mL) was stirred overnight at room temperature.
- Step 2g (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (Compound 0116-1) Preparation: Under nitrogen protection conditions, (S)-5-amino-6-((oxetane-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (0115 A mixture of -1) (800mg, 3.4mmol, 1.0eq) and 2-chloroacetic anhydride (872mg, 5.1mmol, 1.5eq) in tetrahydrofuran (50ml) was stirred at 70°C overnight.
- Step 3a Preparation of (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (compound 0114-3): under nitrogen protection conditions, 3- Methyl fluoro-4-nitrobenzoate (0107-3) (6.23 g, 31.30 mmol, 1.0 equiv), (S)-oxetan-2-ylmethylamine (0113) (3.00 g, 34.44 A mixture of N,N-dimethylformamide (60 mL) and potassium carbonate (8.97 g, 64.87 mmol, 2.0 eq) was stirred at room temperature for 3 hours.
- Step 3b Preparation of (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (compound 0115-3): under hydrogen, (S)- Methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (0114-3) (6.61 g, 24.84 mmol, 1.0 equiv) and palladium on carbon (661 mg, 10% by mass) in tetrahydrofuran (80 mL) was stirred at room temperature for 4 hours.
- Step 3c (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 0116- 3)
- (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (0115-3) (5.88 g, 24.89 mmol, 1.0 equiv)
- 2-chloro-1,1,1-trimethoxyethane (4.62 g, 29.86 mmol, 1.2 equiv)
- p-toluenesulfonic acid monohydrate 514 mg, 2.99 mmol, 0.12 eq) in THF (60 mL) was heated to 45°C and stirred overnight.
- Step 4a Preparation of 7-(hydroxymethyl)benzofuran-4-carbonitrile (Compound 0201-1):
- Step 4b Preparation of tert-butyl 4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202-1) : Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (125 mg, 0.44 mmol, 1.0 equivalents), 7-(hydroxy Methyl)benzofuran-4-carbonitrile (0201-1) (106 mg, 0.61 mmol, 1.4 equiv), cesium carbonate (400 mg, 1.22 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2' , 6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.12 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (57 mg, 0.06
- Step 4c 7-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzofuran-4-carbonitrile p-toluenesulfonate (Compound 0203-1)
- Step 4d (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -3-(Oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (compound 0204-1): 7-(( (6-(Piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzofuran-4-carbonitrile p-toluenesulfonate (0203-1) (150 mg, 0.29 mmol, 1.2 equivalent), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester A solution of (0116-1) (72 mg, 0.24 mmol, 1.0 eq) and potassium carbonate (115 mg, 0.83 mmol, 4.0 e
- Step 5b 6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H) -
- tert-butyl carboxylate compound 0303-2
- 6-chloro-3', 6'-dihydro-[2,4'-bipyridine]-1'(2'H )-tert-butylcarboxylate (0302-2) (491 mg, 1.67 mmol, 1.2 equiv), 7-(hydroxymethyl) benzofuran-4-carbonitrile (0201-1) (241 mg, 1.39 mmol , 1.0 equiv), cesium carbonate (906 mg, 2.78 mmol, 2.0 equiv), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (130 mg, 0.28 A mixture of mmol, 0.2 equi
- reaction solution was filtered through celite, and the solid was washed with ethyl acetate (15 mL).
- the filtrate was diluted with water (20 mL), and extracted with ethyl acetate (20 mL).
- the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 5c 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl)oxy)methyl)benzofuran-4-
- nitrile hydrochloride compound 0304-2
- 6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Bipyridine]-1'(2'H)-tert-butyl carboxylate (0303-2) (462 mg, 1.07 mmol, 1.0 equiv) dissolved in dioxane hydrochloride solution (4 mol/L, 5 mL) , the reaction was stirred overnight at room temperature.
- Step 5d (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (Compound 0305-2) Preparation: 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl)oxy)methyl ) Benzofuran-4-carbonitrile hydrochloride (0304-2) (200 mg, 0.54 mmol, 1.0 equivalent), (S)-2-(chloromethyl)-3-(oxetane-2 -ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116-1) (160mg,
- Step 5e (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 2)
- Acetate methyl ester (0305-2) (70 mg, 0.12 mmol, 1.0 equivalent) and lithium hydroxide monohydrate (25 mg, 0.48 mmol, 4.0 equivalent) in aceton
- Step 6a (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)
- the preparation of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-3): 7-(((6-( Piperidin-4-yl)pyridinyl-2-yl)oxy)methyl)benzofuran-4-carbonitrile p-toluenesulfonate (0203-1) (105 mg, 0.24 mmol, 1.2 equivalents), ( S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (60mg , 0.20 mmol, 1.0 equiv) and potassium carbonate (111 mg, 0.
- Step 7b (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] Preparation of -1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) :(S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0305-4)( A mixture of 97 mg, 0.16 mmol, 1.0 eq) and lithium hydroxide monohydrate (25 mg, 0.48 mmol, 3.0
- Step 8a Preparation of 7-(hydroxymethyl)-2-methylbenzofuran-4-carbonitrile (compound 0201-5):
- Step 8d (S)-2-((4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1- Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-5): 2-methyl -7-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-carbonitrile hydrochloride (0203-5) (98 mg, 0.255 mg moles, 1.5 equivalents), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 0116-3) (50 mg, 0.17 mmol, 1.0 eq) and potassium carbonate (140 mg, 1.01 mmol, 4.0 eq) in acetonit
- Step 9a tert-butyl 4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202- 6)
- Step 9c (S)-2-((4-(6-((2-Chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl ) methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-6): the 2-chloro- 7-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-carbonitrile 4-methylbenzenesulfonate (0203-6) (93mg , 0.173 mmol, 1.5 equivalents), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of methyl ester (0116-3) (34 mg, 0.115 mmol, 1.0 equiv) and potassium carbonate
- Methyl 2-amino-4-bromobenzoate (2.3 g, 10.0 mmol, 1.0 equiv) was added to dilute hydrochloric acid (2 mL conc. HCl and 8 mL water). The mixture was stirred at 80°C for 15 minutes, then cooled to 0°C. Sodium nitrite (828 mg, 12 mmol, 1.2 eq) dissolved in 8 ml of water was added dropwise to the above mixture, and the mixture was stirred at 0°C for 2 hours. Potassium ethyl xanthate (2.72 g, 17 mmol, 1.7 eq) was added to 8 ml of water and stirred at 65°C.
- the diazonium salt mixture obtained above was added to the mixture over 20 minutes, and the mixture was stirred at 65°C for 2 hours. Add dichloromethane for extraction, wash with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was added to a solution of potassium hydroxide (5.6 g, 100 mmol, 10.0 eq) in 10 mL of ethanol, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and water was added. The pH of the aqueous phase was adjusted to 1 by adding concentrated hydrochloric acid. Ethyl acetate was added for extraction, and washed with saturated brine.
- Step 10d (S)-2-((4-(6-((4-cyanobenzo[b]thiophen-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-8): 7-((( 6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzo[b]thiophene-4-carbonitrile hydrochloride (0203-8) (240 mg, 0.43 mmol, 2.5 equivalent) was added to 5 ml of N-methylpyrrolidone, and N,N-diisopropylethylamine (175 mg, 1.36 mmol, 8.0 equivalents) was added.
- Step 11c Preparation of 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine hydrochloride (compound 0203-12): to 4-( tert-butyl 6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (0202-12) (235 mg, 0.53 mmol, 1.0 equiv ) and hydrogen chloride in dioxane (4M, 1 ml) was added dioxane (2 ml), and the mixture was stirred overnight at room temperature. The mixture was filtered. The residue was washed with dioxane.
- Step 11d (S)-2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-12): 2-((4-chlorobenzofuran -7-yl)methoxy)-6-(piperidin-4-yl)pyridine hydrochloride (0203-12) (142 mg, 0.374 mmol, 1.5 equiv), (S)-2-(chloroform yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (73mg, 0.249mmol, 1.0eq) A solution of N,N-diisopropylethylamine (161 mg
- Step 12b (S)-2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
- Step 13a tert-butyl 4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202-15) Preparation: under nitrogen protection and -70 ° C, to 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl To a solution of ester (0202-12) (200 mg, 0.452 mmol, 1 eq) in 10 mL of THF was added lithium diisopropylamide (0.45 mL, 2 mol/L THF, 0.905 mmol, 2 eq).
- Step 13c (S)-2-((4-(6-((2,4-Dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methoxy Base)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-15): 2-((2,4 -Dichlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0203-15) (206 mg, 0.377 mmol, 1.2 equiv ), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (92 mg, 0.314 mmol, 1.0 eq) and potassium carbonate (173 mg, 1.256 m
- Step 14b 2-((4-Chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0203- 16)
- tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (0202 -16) (200 mg, 0.43 mmol, 1.0 eq) and p-toluenesulfonic acid (224 mg, 1.3 mmol, 3.0 eq) in ethyl acetate (15 ml) were stirred at 60°C overnight.
- Step 14c (S)-2-((4-(6-((4-Chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Preparation of methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-16): 2-((4- Chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0203-16) (104 mg, 0.203 mmol, 1.2 equivalents), (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116- 3) A solution of (50 mg, 0.169 mmol, 1.0 eq) and potassium carbonate (93 mg, 0.676
- Step 15a Preparation of (4-chloro-2-methylbenzofuran-7-yl)methanol (compound 0201-17):
- Step 15b tert-butyl 4-(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202- 17) Preparation: Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (137 mg, 0.46 mol, 1.0 equivalents), (4 -Chloro-2-methylbenzofuran-7-yl)methanol (0201-17) (100 mg, 0.51 mmol, 1.1 equiv), cesium carbonate (333 mg, 1.02 mmol, 2.0 equiv), 4,5 - bisdiphenylphosphine-9,9-dimethylxanthene (59 mg, 0.05 mmol, 0.1 equiv) and tris(dibenzylideneacetone) dipalladium(0) (47 mg, 0.148 mmol, 0.2
- Step 15d (S)-2-((4-(6-((4-Chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl ) methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-17): 2-(( 4-Chloro-2-methylbenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0203-17) (90 mg, 0.24 Millimoles, 1.2 equivalents), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester A solution of (0116-3) (60 mg, 0.20 mmol, 1.0 eq) and potassium carbonate (110 mg, 0.80 mmol
- Step 16a Preparation of tert-butyl 4-(6-(4-chloro-2-methylbenzofuran-7-carboxamido)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202-20) preparation:
- 6-bromopyridin-2-amine (519 mg, 3 mmol, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopent-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1113 mg, 3.6 mmol, 1.2 equiv), sodium carbonate (636 mg, 6 mmol, 2.0 eq) and bistriphenylphosphinepalladium dichloride (210 mg, 0.3 mmol, 0.1 eq) in toluene/ethanol/water (10/5/5 mL) were stirred at 110°C for 16 hours.
- tert-butyl 6-amino-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate 600 mg, 2.18 mmol, 1.0 equiv
- LCMS (ESI): m/z 278 (M+ H) + .
- Step 16b 4-Chloro-2-methyl-N-(6-(piperidin-4-yl)pyridin-2-yl)benzofuran-7-carboxamide 4-methylbenzenesulfonate (compound 0203 -20)
- Step 16c (S)-2-((4-(6-(4-Chloro-2-methylbenzofuran-7-carboxamido)pyridin-2-yl)piperidin-1-yl)methyl )-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-20): 4-chloro-2-methyl -N-(6-(piperidin-4-yl)pyridin-2-yl)benzofuran-7-carboxamide 4-methylbenzenesulfonate (0203-20) (106 mg, 0.203 mmol, 1.2 equivalent), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.169 mmol, 1.0 equiv) and potassium carbonate (93 mg, 0.676 mmol,
- Step 17a Preparation of methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (compound 0118-23): To methyl 3-fluoro-4-nitrobenzoate (0107 -23) (1.0 g, 5.02 mmol, 1.0 eq) and N,N-diisopropylethylamine (1.34 mL, 7.53 mmol, 1.5 eq) in THF (15 mL) Ethylamine (0.45 g, 6.03 mmol, 1.2 equiv). The mixture was heated to 55°C overnight. The solvent was removed under reduced pressure. The residue was diluted with water (30 mL).
- Step 17b Preparation of methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (compound 0119-23): to 3-((2-methoxyethyl)amino)- Methyl 4-nitrobenzoate (0118-23) (1.17g, 4.61mmol, 1.0eq) was added to a mixture of methanol (30ml) and palladium on carbon (0.22g). The mixture was stirred at room temperature under hydrogen balloon pressure for 3.5 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure to give methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (1.03 g, yield: 100%) as a white solid.
- LCMS (ESI): m/z 225[M+1] + ; TLC: Rf0.3 (petroleum ether: ethyl acetate 5:1).
- Step 17d 2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(2 -Methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-23): to 2-((4-chlorobenzofuran-7-yl)methoxy Base)-6-(piperidin-4-yl)pyridine p-toluenesulfonate (0203-12) (90 mg, 0.18 mmol, 1.1 equivalents) and 2-(chloromethyl)-1-(2-methyl Oxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0120-23) (45 mg, 0.16 mmol, 1.0 equiv) in a mixture of acetonitrile (6 mL) was added potassium carbonate ( 66 mg, 0.48
- the mixture was heated to 40°C overnight.
- the combined organic layers were washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate and concentrated.
- Step 18b Preparation of (S)-methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (Compound 0119-24): (S)-4-Nitrate Base-3-((tetrahydrofuran-2-yl)methyl)amino)benzoic acid methyl ester (0118-24) (1120 mg, 3.996 mmol, 1.0 equivalent) and palladium/carbon (112 mg, 10% mass ratio) A mixture of THF (13 mL) was stirred overnight at room temperature.
- Step 18c ((S)-methyl 2-(chloromethyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 0120-24 )
- (S)-methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (0119-24) (1090 mg, 4.35 mmol, 1.0 equivalent), 2-chloro-1,1,1-trimethoxyethane (807 mg, 5.55 mmol, 1.2 unit amount) and p-toluenesulfonic acid monohydrate (89.889 mg, 0.522 mmol, 0.12 unit amount) THF (10 ml) solution was heated to 45°C and stirred overnight.
- Step 18d (S)-2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-24): 2-((4-chlorobenzo Furan-7-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (compound 0203-12) (96.82 mg, 0.1948 mmol, 1.2 equiv) and potassium carbonate (89.5896 mg, 0.6492 mmol, 4.0 eq) in acetonitrile (5 mL) was stirred at 60°C to pH 7-8, then (S)-2-(chloromethyl)-1-((tetrahydrofuran -2-yl)
- Methyl 3-fluoro-4-nitrobenzoate (367 mg, 1.85 mmol, 1.0 equiv), potassium carbonate (511 g, 3.70 mmol, 2.0 equiv) and (1-ethyl-1H-imidazole-5 -)
- a mixture of methylamine hydrochloride (300 mg, 1.85 mmol, 1.0 eq) in N-methylpyrrolidone (10 mL) was stirred at room temperature overnight. Ethyl acetate and water were added, the mixture was separated, and the organic layer was washed with saturated brine and concentrated.
- Step 19b 2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(( Preparation of 1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-25):
- Step 20a Preparation of (4-fluorobenzofuran-7-yl)methanol (compound 0201-28):
- a methanolic solution of sodium methoxide (5.4 mol/ liter, 0.7 ml, 3.64 mmol, 1.5 equiv). The mixture was stirred at room temperature for 1 hour. The pH of the reaction was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 20b Preparation of tert-butyl 4-(6 - ((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (compound 0202-28): Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (195 mg, 0.66 mmol, 1.0 equivalents), (4-fluorobenzene Furan-7-yl)methanol (0201-28) (132mg, 0.79mmol, 1.2eq), cesium carbonate (430mg, 1.32mmol, 2.0eq), 2-dicyclohexylphosphine-2',6 '-Diisopropoxy-1,1'-biphenyl (61 mg, 0.132 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium(0) (55 mg, 0.06 mmol,
- Step 20d (S)-2-((4-(6 - ((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-28): 2-((4-fluorobenzo Furan-7-yl)methoxy)-6-(piperidin-4-yl)pyridine hydrochloride (0203-28) (84 mg, 0.257 mmol, 1.2 equivalents), (S)-2-(chloro Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0116-3) (60 mg, 0.21 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (0.5 mL
- Step 21a Preparation of (4-methylbenzofuran-7-yl)methanol (compound 0201-30):
- Methyl 2-(2,2-diethoxyethoxy)-4-methylbenzoate (1.72 g, 5.0 mmol, 1.0 equivalent) obtained above and polyphosphoric acid (300 mg, 0.88 mmol , 0.18 equivalents) of toluene mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure.
- Step 21b (S)-2-((4-(6-Chloropyridin-2-yl)piperidin 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H -Preparation of benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-20): to 4-(6-chloropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (0104-1 ) (200 mg, 0.67 mmol, 1.0 eq) was added to a mixture of 4 ml of dioxane in 1.5 ml of 4M hydrogen chloride in dioxane. The mixture was stirred overnight at room temperature.
- Step 21c (S)-2-((4-(6-((4-Methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) - Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 30): (S)-2-((4-(6- ((4-Methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl) -1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (0204-30) (68 mg, 0.12 mmol, 1.0 equiv) and lithium hydroxide monohydrate (10 mg, 0.23 mmol, 2.0 equiv) in A mixture in a mixed solvent of 5 ml of acetonitrile and 1
- Step 22a Preparation of (2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methanol (compound 0201-31):
- Step 22b tert-butyl 4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate
- ester compound 0202-31
- tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (150 mg, 0.51 mmol, 1.0 equivalents), (2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methanol (0201-31) (140 mg, 0.61 mmol, 1.2 equivalents), cesium carbonate (416 mg, 1.28 mmol, 2.5 equiv), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (36 mg, 0.077 mmol, 0.15 equiv), and tris(dibenzylideneacetone)dipalladium
- a mixture 1, 2-bicyclo
- Step 22c 2-((2-Methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine hydrochloride (Compound 0203 -31)
- To a mixture of tert-butyl carboxylate (0202-31) (220 mg, 0.45 mmol, 1.0 eq) in 5 mL of dioxane was added 1 mL of 4M hydrogen chloride in dioxane. The mixture was stirred overnight at room temperature.
- Step 22d (S)-2-((4-(6-((2-Methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piper Preparation of pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-31): 2-((2-Methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine hydrochloride (0203-21) (250mg, 0.45mmol, 2.6eq) was added to 10ml of N-methylpyrrolidone, and N,N-diisopropylethylamine (171mg, 1.25mmol, 7.3eq) was added.
- Step 22e (S)-2-((4-(6-((2-Methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piper Preparation of pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 31): (S)- 2-((4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-31) (74mg, 0.11mmol, 1.0eq) and a mixture of lithium hydroxide monohydrate (12 mg, 0.8 mmol, 2.5 equiv) in a mixed solvent
- Step 23a Preparation of (5-fluorobenzofuran-6-yl)methanol (compound 0401-32):
- Step 23b Preparation of tert-butyl 4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (compound 0402-32): Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (297 mg, 1.0 mmol, 1.0 equivalents), (5-fluorobenzo Furan-6-yl)methanol (0401-32 (200mg, 1.2mmol, 1.2eq), cesium carbonate (652mg, 2.0mmol, 2.0eq), 2-dicyclohexylphosphine-2',6'- Diisopropoxy-1,1'-biphenyl (46.7 mg, 0.1 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol, 0.05 equi
- Step 23c Preparation of 2-((5-fluorobenzofuran-6-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (compound 0403-32) : In tert-butyl 4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (0402-32) (250 mg, 0.587 To a solution of p-toluenesulfonic acid monohydrate (303 mg, 1.76 mmol, 3 eq) in ethyl acetate (10 mL) was added. The mixture was stirred overnight at 60°C. The mixture was filtered.
- Step 23d (S)-2-((4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0404-32): 2-((5-fluorobenzo Furan-6-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0403-32) (203 mg, 0.407 mmol, 1.5 equiv), (S) -2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (80 mg, 0.27 A solution of mmol, 1.0 equiv) and potassium carbonate (149 mg, 1.08 mmol,
- Step 24a Preparation of (6-fluorobenzofuran-5-yl)methanol (compound 0501-33):
- Step 24b Preparation of tert-butyl 4-(6 - ((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (compound 0502-33): Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (350 mg, 1.18 mmol, 1.0 equiv), (6-fluorobenzo Furan-5-yl)methanol (0501-33) (235 mg, 1.416 mmol, 1.2 equiv), cesium carbonate (769 mg, 2.36 mmol, 2.0 equiv), 2-dicyclohexylphosphine-2',6' - Diisopropoxy-1,1'-biphenyl (55 mg, 0.118 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.0
- Step 24c Preparation of 2-((6-fluorobenzofuran-5-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (compound 0503-33) : In tert-butyl 4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (0502-33) (450 mg, 1.06 To a solution of p-toluenesulfonic acid monohydrate (546 mg, 3.17 mmol, 3 eq) in ethyl acetate (10 mL) was added. The mixture was stirred overnight at 60 °C. The mixture was filtered.
- Step 24d (S)-2-((4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (compound 0504-33): 2-((6 -Fluorobenzofuran-5-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0503-33) (127 mg, 0.255 mmol, 1.5 equiv) , (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116 A solution of -1) (50 mg, 0.17 mmol, 1.0 eq) and potassium carbonate (94 mg, 0.68 m
- Step 25a Preparation of (7-fluorobenzofuran-6-yl)methanol (compound 0601-44)
- Step 25b Preparation of tert-butyl 4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (compound 0602-44): Under nitrogen protection, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (178.8 mg, 0.602 mmol, 1.0 equivalents), (7-fluorobenzofuran -6-yl)methanol (0601-44) (120mg, 0.722mmol, 1.2eq), cesium carbonate (391mg, 1.2mmol, 2.0eq), 2-dicyclohexylphosphine-2',6'- Diisopropoxy-1,1'-biphenyl (56 mg, 0.12 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol, 0.1
- Step 25d (S)-2-((4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0604-44): 2-((7-fluorobenzofuran -6-yl)methoxy)-6-(piperidin-4-yl)pyridine 4-methylbenzenesulfonate (0603-44) (72mg, 0.22mmol, 1.3eq), (S)- 2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.169 mg mol, 1.0 eq) and potassium carbonate (93.5 mg, 0.678 mmol, 4.0 eq)
- Step 26a Preparation of 7-(hydroxymethyl)-3-methylbenzofuran-4-carbonitrile (compound 0201-46):
- methyl 4-bromo-3-methylbenzofuran-7-carboxylate (320 mg, 1.19 mmol, 1.0 equiv), tetrakistriphenylphosphine palladium (137 mg, 0.12 mmol, 0.1 eq) and zinc cyanide (208 mg, 1.78 mmol, 1.5 eq) in N,N-dimethylformamide (5 mL) were stirred at 90°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure.
- Step 26b 6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'
- (2'H)-tert-butyl carboxylate compound 0303-46): 6-chloro-3',6'-dihydro-[2,4'-bipyridyl]-1' under nitrogen protection (2'H)-tert-butyl carboxylate (0302-2) (174 mg, 0.59 mmol, 1.2 equiv), 7-(hydroxymethyl)-3-methylbenzofuran-4-carbonitrile (0201- 46) (92 mg, 0.492 mmol, 1.0 equiv), cesium carbonate (320 mg, 0.984 mmol, 2.0 equiv), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1
- a mixture of '-biphenyl 92 mg, 0.197 mmol,
- Step 26c 3-Methyl-7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl)oxy)methyl)benzene
- furan-4-carbonitrile hydrochloride compound 0304-46): 6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6 '-Dihydro-[2,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate (0303-46) (123 mg, 0.276 mmol, 1.0 equiv) and dioxane hydrochloride
- a solution of ring solution (4M, 1 mL) in dioxane (4 mL) was stirred overnight at room temperature.
- Step 26d (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-Bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl
- ester compound 0305-46): 3-methyl-7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl) Oxy)methyl)benzofuran-4-carbonitrile hydrochloride (0304-46) (105 mg, 0.276 mmol, 1.5 equivalents), (S)-2-(chloromethyl)-1-(oxy Heterobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116
- Step 26e (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Compound 46) Preparation: (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro- [2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 - methyl carboxylate (0305-46) (80 mg, 0.13 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg, 0.26 mmol
- Step 27a Preparation of 4-(hydroxymethyl)benzofuran-7-carbonitrile (compound 0701-47):
- Step 27b Preparation of tert-butyl 4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0702-47) : Under nitrogen protection conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (178 mg, 0.6 mmol, 1.2 equivalents), 4-(hydroxymethyl base) benzofuran-7-carbonitrile (0701-47 (87mg, 0.5mmol, 1.0eq), cesium carbonate (325mg, 1mmol, 2.0eq), 2-dicyclohexylphosphonium-2',6 '-Diisopropoxy-1,1'-biphenyl (93 mg, 0.2 mmol, 0.4 equiv) and tris(dibenzylideneacetone) dipalladium(0) (91 mg, 0.1 mmol, 0.2
- Step 27c Preparation of 4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-7-carbonitrile hydrochloride (compound 0703-47): tert-butyl 4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (0702-47) (94 mg, 0.217 mmol, 1.0 equiv) and hydrochloric acid in dioxane (4M, 1 mL) in dioxane (4 mL) was stirred overnight at room temperature.
- Step 27d (S)-2-((4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl) -1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester (compound 0704-47): 4-(((6-(piper Pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-7-carbonitrile hydrochloride (0703-47) (80 mg, 0.217 mmol, 1.3 equivalents), (S)- 2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mg mol, 1.0 equiv) and N,N-diisopropylethylamine (88 mg, 0.68
- Step 28a Preparation of 4-(Hydroxymethyl)-1-Naphthonitrile (Compound 0801-49):
- Step 28b Preparation of tert-butyl 4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0802-49): Nitrogen Under protected conditions, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (202 mg, 0.68 mmol, 1 equiv), 4-(hydroxymethyl) -1-Naphthonitrile (0801-49) (150mg, 0.82mmol, 1.2eq), cesium carbonate (443.36mg, 1.36mmol, 2.0eq), 2-dicyclohexylphosphine-2',6'-di Isopropoxy-1,1'-biphenyl (32 mg, 0.068 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.034
- Step 28c Preparation of 4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-1-naphthalonitrile hydrochloride (compound 0803-49): 4 -(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (0802-49) (272 mg, 0.614 mmol, 1.0 equivalent) and hydrochloric acid in dioxane (4M, 5 mL) were stirred overnight at room temperature. The mixture was filtered. The residue was washed with dioxane.
- Step 28d (S)-2-(((4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- Preparation of 1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0804-49): 4 - (((6-(piperidine -4-yl)pyridin-2-yl)oxy)methyl)-1-naphthalonitrile hydrochloride (0803-49) (96 mg, 0.254 mmol, 1.5 equivalents), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mmol, 1.0 Equiv) and potassium carbonate (93.5 mg, 0.678 mmol, 4.0 eq)
- Step 29a Preparation of 6-fluoro-7-(hydroxymethyl)benzofuran-4-carbonitrile (compound 0201-53):
- Step 29b tert-butyl 4-(6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (Compound 0202- 53) Preparation: Under nitrogen protection, tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0104-1) (143 mg, 0.482 mmol, 1.0 equiv), 6- Fluoro-7-(hydroxymethyl)benzofuran-4-carbonitrile (0201-53) (92mg, 0.482mmol, 1.0eq), cesium carbonate (314mg, 0.964mmol, 2.0eq), 2-di Cyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (45 mg, 0.0964 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (44
- Step 29c 6-fluoro-7-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl]benzofuran-4-carbonitrile hydrochloride (Compound 0203- 53)
- LCMS (ESI): m/z 352 (M+H) + .
- Step 29d (S)-2-(((4-(6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridinyl-2-yl)piperidine-1 Preparation of -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-53): 6-fluoro -7-(((6-(piperidin-4-yl)pyridinyl-2-yl)oxy)methyl]benzofuran-4-carbonitrile hydrochloride (0203-53) (77 mg, 0.220 Millimoles, 1.3 equivalents), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.169 mmol, 1.0 eq) and potassium carbonate (93.5 mg,
- Step 30a Preparation of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (compound 0901-54): under nitrogen protection, to (4-chlorobenzofuran-7 -yl)methanol (0201-12) (230mg, 1.26mmol, 1.0eq) in a mixture of tetrahydrofuran at 10-15°C was added potassium hexamethyldisilazide (1mol/L, 3.78mmol, 3.0eq), the mixture was stirred at 15°C for 1 hour. Dissolve 2-bromo-6-fluoropyridine in tetrahydrofuran and add it dropwise into the reaction system. The mixture was stirred at 15°C for 1 hour.
- Step 30b Preparation of tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (Compound 0902-54): Under nitrogen protection, 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (0901-54) (150 mg, 0.44 mmol, 1.0 equiv), 1-tert-butoxy Carbonylpiperazine (92 mg, 0.49 mmol, 1.1 equiv), cesium carbonate (290 mg, 0.89 mmol, 2.0 equiv), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (31 mg, A mixture of 0.05 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol, 0.05 equiv) in toluene (15
- Step 30c Preparation of 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine hydrochloride (compound 0903-54): 4-(6 -((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0902-54) (71 mg, 0.16 mmol, 1.0 equiv) A solution of hydrochloric acid in ethyl acetate (2M, 4 mL) in methanol (4 mL) was stirred at 40°C for 2 hours.
- Step 30d (S)-2-((4-(6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0904-54): 1-(6-((4-chloro Benzofuran-7-yl)methoxy)pyridin-2-yl)piperazine hydrochloride (0903-54) (55 mg, 0.16 mmol, 1.2 equiv), (S)-2-(chloromethyl )-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (40 mg, 0.13 mmol, 1.0 equiv) and A solution of N,N-diisopropylethylamine (1
- the mixture was cooled to room temperature and concentrated under reduced pressure.
- the mixture was washed with water, and the pH of the residue was adjusted to 6 with 1 mol/L hydrochloric acid.
- the residue was extracted with ethyl acetate and concentrated under reduced pressure.
- Step 31a Preparation of 2-(4-chlorobenzofuran-7-yl)ethan-1-ol (compound 0201-55):
- Step 31b 6-((2-(4-Chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2' H)-
- tert-butyl carboxylate compound 0303-55
- 2-(4-chlorobenzofuran-7-yl)ethan-1-ol (0201-55) (338 mg, 1.724 mmol, 1.0 equivalent) in THF (20 mL) was added potassium hexamethyldisilazide (3.5 mL, 1 mol/L THF, 3.448 mmol, 2 equivalent).
- Step 31c 6-((2-(4-Chlorobenzofuran-7-yl)ethoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine 4- Preparation of toluenesulfonate (compound 0304-55): to 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2 ,4'-bipyridyl]-1'(2'H)-tert-butyl carboxylate (0303-55) (100 mg, 0.22 mmol, 1.0 equiv) in ethyl acetate (5 mL) was added in p-toluene Sulfonic acid monohydrate (114 mg, 0.66 mmol, 3 equiv).
- Step 31d (S)-2-((6-(2-(4-Chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine ]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0305 -55)
- Step 31e (S)-2-((6-(2-(4-Chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine ]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 55)
- Example 32 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) Piperidin-1-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 56) Preparation (prepared according to scheme ten lines)
- Step 32a Preparation of tert-butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate (compound 1003-56):
- 3-bromocatechol (1.2 g, 6.35 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (2.82 ml, 15.87 mmol, 2.5 equivalent) were dissolved in dichloromethane (20 mL) was added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 15.87 mmol, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure.
- Step 32b 4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidine-1-
- tert-butyl carboxylate compound 1004-56
- To tert-butyl 4-(2,3-dihydroxyphenyl)piperidine-1-carboxylate (1003-56) (0.25 g, 0.85 mmol, 1.0 eq), triruthenium dodecacarbonyl (27 mg, 0.043 mmol, 0.05 eq) and sodium bicarbonate (72 mg, 0.85 mmol, 1.0 eq) in toluene (10 ml) were added 4-chloro-7 - Ethynylbenzofuran (compound 1101-57) (150 mg, 0.85 mmol, 1.0 equiv).
- Step 32c 4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidine hydrochloride
- (Compound 1005-56) 4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl )
- a mixture of tert-butyl piperidine-1-carboxylate (1004-56) 70 mg, 0.15 mmol, 1.0 equiv) in dioxane hydrogen chloride (4M solution, 1.5 mL) was stirred at room temperature for 1 hour.
- Step 32d 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piper Pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 1006 -56)
- Step 32e 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piper Pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 56) Preparation: To 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piper Pyridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1006- 56) (81 mg, 0.13 mmol, 1.0 equiv) To a mixture of THF (5 mL) and water (2 mL) was added lithium hydro
- the mixture was heated at 40°C overnight.
- the combined organic layers were washed with saturated brine (15 mL ⁇ 1), dried over anhydrous sodium sulfate and concentrated.
- Example 33 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) -3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -
- 6-carboxylic acid compound 57
- Step 33a Preparation of 4-chloro-7-ethynylbenzofuran (compound 1001-57):
- Step 33b Preparation of 4-bromo-2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane (compound 1002-57): Under nitrogen protection, 4-chloro-7-ethynylbenzofuran (1001-57) (1.3 g, 7.4 mmol, 1.0 equiv), 3-bromo-1,2-benzenediol (1.5 g, 8.1 mmol , 1.1 eq), sodium bicarbonate (622 mg, 7.4 mmol, 1.0 eq) and ruthenium dodecacarbonyl (236 mg, 0.37 mmol, 0.05 eq) in toluene (50 mL) was stirred overnight at 120°C.
- Step 33c 4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6- Preparation of dihydropyridine-1(2H)-tert-butyl carboxylate (compound 1004-57): 4-bromo-2-(4-chlorobenzofuran-7-yl)-2-methyl ylbenzo[d][1,3]dioxolane (1002-57) (660 mg, 1.8 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1, tert-butyl 3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (612 g, 1.98 mmol, 1.1 equiv), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (132 mg, 0.18 mmol,
- Step 33d 4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2, Preparation of 3,6-tetrahydropyridine hydrochloride (compound 1005-57): 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3 ]Dioxolan-4-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (1004-57) (100 mg, 0.21 mmol, 1.0 equiv) 4 moles per A solution of dioxane hydrochloride (4 mL) was stirred overnight at room temperature.
- Step 33e 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-
- methyl 6-carboxylate compound 1006-57
- Step 33f 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-
- 6-carboxylic acid compound 57
- Step 34a 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piper Pyridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl
- ester compound 1006-58: to 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4 -yl)piperidine hydrochloride (1005-56) (33mg, 0.08mmol, 1.0eq) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl base)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116-1) (24 mg, 0.08 mmol, 1.0
- Step 34b 2-((4-(2-(4-Chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piper Pyridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ( Compound 58) preparation: to 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4 -yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5 -Methyl carboxylate (1006-58) (29 mg, 0.05 mmol, 1.0 equiv) To a mixture of tetrahydrofuran (4 mL) and water (2 mL
- the mixture was heated at 40°C overnight.
- the combined organic layers were washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate and concentrated.
- Example 35 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 61 ) preparation (prepared according to scheme ten lines)
- Step 35a Preparation of 7-ethynylbenzofuran-4-carbonitrile (compound 1001-61):
- Step 35b 4-(2-(4-Cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl)piperidine-1 -
- tert-butyl carboxylate compound 1004-61: under nitrogen protection, 7-ethynylbenzofuran-4-carbonitrile (1001-61) (228 mg, 1.37 mmol, 1.0 equivalents), 4- (2,3-Dihydroxyphenyl)piperidine-1-carboxylate tert-butyl ester (1003-56) (442 mg, 1.51 mmol, 1.1 equiv), sodium bicarbonate (115 mg, 1.37 mmol, 1.0 equiv ) and triruthenium dodecacarbonyl (44 mg, 0.07 mmol, 0.05 eq) in toluene (6 mL) were refluxed overnight at 120°C.
- Step 35c 7-(2-Methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)benzofuran-4-carbonitrile hydrochloride
- salt compound 1005-61: to 4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane- 4-yl) piperidine-1-carboxylate tert-butyl ester (1004-61) (80 mg, 0.17 mmol, 1.0 eq) in dioxane (2 ml) was added to a solution of hydrogen chloride in dioxane (4.0 mol/L, 4 mL), and the mixture was stirred overnight at room temperature.
- Step 35d 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 1006-61) preparation: 7-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolan-2-yl)benzofuran- 4-Nitrile hydrochloride (1005-61) (80 mg, assumed to be 0.17 mmol, 1.0 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl base)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (52 mg, 0.17 mmol, 1.0 equiv) and potassium
- Step 35e 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) Piperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 61) Preparation: 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 1006-61) (50 mg, 0.08 mmol, 1.0 eq) and lithium hydroxide monohydrate (7 mg, 0.16 mmol, 2.0 eq) in acetonitrile
- Embodiment 36 biological activity test
- the used contrast compound of the present invention is PF-06882961, and structure is as follows:
- Step 1-1 Preparation of 2-(benzo[d][1,3]dioxolan-5-ylmethoxy)-6-bromopyridine:
- Step 1-2 6-(Benzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine] -Preparation of 1'(2'H)-tert-butyl carboxylate:
- Step 1-3 (S)-2-((6-(Benzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-
- methyl carboxylate (S)-2-((6-(Benzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-
- Step 1-4 (S)-2-((6-(Benzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-
- carboxylic acid compound 24067
- Step 2-1 Preparation of 2-bromo-6-(2,2-difluorobenzo[d][1,3]dioxolan-5-ylmethoxy)pyridine:
- Step 2-2 6-(2,2-Difluorobenzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[2, Preparation of 4'-bipyridyl]-1'(2'H)-tert-butyl carboxylate:
- Step 2-3 (S)-2-((6-(2,2-Difluorobenzo[d][1,3]dioxolan-5-ylmethoxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d]
- 6-(2,2-difluorobenzo[d][1,3]dioxolan-5-ylmethoxy)-3',6'-dihydro-[2, 4'-bipyridine]-1'(2'H)-tert-butyl carboxylate 300 mg, 0.67 mmol, 3.3 eq
- 4M hydrogen chloride in dioxane was added ring solution, and the mixture was stirred at room temperature for 60 min.
- the mixture was concentrated to dryness under reduced pressure, and the resulting residue was added to 5 ml of N-methylpyrrolidone.
- Step 2-4 (S)-2-((6-(2,2-Difluorobenzo[d][1,3]dioxolan-5-ylmethoxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d]
- imidazole-6-carboxylic acid compound 24068
- Step 3-1 Preparation of (1-methyl-1H-benzo[d]imidazol-6-yl)methanol:
- Step 3-2 Preparation of 6-(((6-bromopyridin-2-yl)oxy)methyl)-1-methyl-1H-benzo[d]imidazole:
- Step 3-3 6-(1-Methyl-1H-benzo[d]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine]-1
- '(2'H)-tert-butyl carboxylate 6-(1-Methyl-1H-benzo[d]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine]-1
- Step 3-4 (S)-2-((6-(1-methyl-1H-benzo[d]imidazol-5-ylmethoxy)-3',6'-dihydro-[2, 4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid
- 6-(1-methyl-1H-benzo[d]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-tert-butylcarboxylate (187 mg, 0.45 mmol, 2.25 eq) was dissolved in 5 mL of dioxane, 1 mL of 4M hydrogen chloride in dioxane was added, and the mixture was stirred at room temperature 60 minutes. The mixture was concentrated to dryness under reduced pressure, and the resulting residue was added to 5 ml of N-methylpyrrolidone.
- Step 3-5 (S)-2-((6-((1-methyl-1H-benzo[d]imidazol-6-yl)methoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-
- carboxylic acid compound 24069
- Step 4-1 Preparation of tert-butyl 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate:
- 2-bromo-6-chloropyridine 1.0 g, 5.20 mmol, 1.0 equivalent
- 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Borane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 1.6 g, 5.20 mmol, 1.0 equiv
- 1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride and sodium carbonate were added to a mixed solvent (11 ml) of dioxane and water (10:1), and stirred overnight at 90°C.
- Step 4-2 Preparation of 6-chloro-1',2',3',6'-tetrahydro-2,4'-bipyridine p-toluenesulfonate:
- Step 4-3 (S)-2-((6-Chloro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester:
- Step 4-4 (S)-2-((6-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methoxy)-3 ',6'-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-
- benzo[d]imidazole-6-carboxylic acid methyl ester
- Step 4-5 (S)-2-((6-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methoxy)-3 ',6'-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-
- benzo[d]imidazole-6-carboxylic acid compound 24070
- Cisbio's cyclic AMP assay kit is a competitive immunoassay designed to measure intracellular cyclic AMP accumulation.
- the principle is based on technique, cell-produced natural cyclic AMP or unlabeled cyclic AMP (standard curve) competes with d2-labeled cyclic AMP (red receptor) for binding to a monoclonal cyclic AMP Europium Cryptate-labeled antibody (supplied by Europium body).
- the specific signal is inversely proportional to the concentration of cyclic AMP in the standard or sample.
- the calculation of the fluorescence ratio (665nm/620nm) eliminates any possible photophysical interference, which means that the assay is independent of experimental culture medium conditions (e.g. medium, serum, biotin, colored compounds, etc.) influences.
- 3-isobutyl-1-methylxanthine (500 mM) was diluted to 50 mM with DMSO, dispensed into 20 ul tubes, and stored at 4°C. Add 2ml stimulation buffer 1 to 20ul and dilute to 0.5mM for use.
- the compounds of the present invention can activate the cAMP level in hGLP-1R 293Ta cells, and the activity is higher than that of the control compounds PF-06882961, 24067, 24068, 24069 and 24070.
- SBE- ⁇ -CD 30% sulfobutyl- ⁇ -cyclodextrin
- the blood was taken from the tail end, about 0.3ml at each time point, placed in a centrifuge tube containing K2-EDTA, and centrifuged (2000g, 10 minutes, 4°C) to collect plasma and store it in an ultra-low temperature freezer at -70°C to -80°C.
- the benzimidazole or azabenzimidazole-6-carboxylic acid compounds provided by the present invention are well absorbed after oral administration to rats, and the blood exposure is relatively high.
- the results are shown in Figures 1, 2 and Table 2.
- the T max of the benzimidazole or azabenzimidazole-6-carboxylic acid compound of the present invention is 0.5-2.67 hours, the C max is 180-2553.33ng/ml, and the AUC 0-24h is 934.28-9583.02ng/ml* h.
- C max refers to the maximum blood concentration
- T 1/2 refers to the half-life
- AUC 0-24 refers to the area under the 0-24 hour time-concentration curve
- AUC 0-inf refers to the area under the 0-Inf time-concentration curve.
- mice Male, 7 weeks old, were purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd.
- the experimental animals are all kept in horizontal flow independent ventilation cages, the temperature is 20-26 °C, the relative humidity is 40-70% RH, the number of air changes is 15-30 times/hour, the air cleanliness is 7 grades, and the day and night are alternately bright and dark.
- the time was 12h/12h; continuous supply of cobalt 60 radiation sterilized mouse full-price pellet feed (Guangdong Provincial Medical Experimental Animal Center, large and mouse maintenance feed), unlimited free intake; drinking tap water (used after high-pressure steam sterilization), Uninterrupted water supply, free intake.
- the rearing cage is a transparent polyetherimide cage box (Suzhou Aikelin Purification Equipment Co., Ltd., horizontal flow mouse cage box), free of pathogenic microorganisms; the litter is corncobs (Guangdong Provincial Medical Experimental Animal Center, high-pressure steam Use after sterilization), 2-5 animals per cage, the IACUC approval number, experiment number, experiment start time, project leader, experimenter, animal source, group and animal number, etc. are marked on the cage card. The animal use method in this experiment was approved by IACUC of Guangzhou Bebet Medical Technology Co., Ltd.
- Oral glucose tolerance test in hGLP1R mice Animals are fasted overnight, without water, and the vehicle or the corresponding compound is given orally once, and the blood sugar is measured before the vehicle or the compound (equivalent to -60min blood sugar value), and the vehicle or the compound is given orally 60 minutes later.
- Give glucose (2g/kg) measure blood sugar before giving glucose (equivalent to 0min blood sugar value), and measure blood sugar 15min, 30min, 60min, 90min, 120min after giving glucose.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Psychology (AREA)
- Ophthalmology & Optometry (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用,所述苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物具有式(I)所示结构。该苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物可以有效激活GLP-1R下游信号通路,提高cAMP的表达,从而达到促进胰岛素分泌,治疗糖尿病及其并发症的作用,有较大的应用价值。
Description
本发明涉及化学医药技术领域,具体涉及一种苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用。
2型糖尿病(T2DM)及其并发症已成为严重威胁人类健康的慢性非传染性疾病,发病人数呈逐年上升趋势,胰岛β细胞功能障碍和胰岛素抵抗是T2DM的重要发病机制(N Engl J Med,2007.356:213-215)。目前糖尿病治疗药物主要包括胰岛素及其类似物、二肽基肽酶-4抑制剂(DPP-4i)、胰高血糖素样肽-1受体激动剂(GLP-1RA)、钠-葡萄糖协同转运蛋白-2抑制剂(SGLT-2i)、二甲双胍、α-糖苷酶抑制剂、磺脲类药物(SU)、噻唑烷二酮类药物(TZDs)、格列奈类药物等(Biomed Pharmacother,2020.131:110708)。GLP-1RA具有血糖依赖性强效降糖、不增加低血糖风险、降低体重、轻度降压等优点,而且大部分药物还被证实了心血管获益,近几年市场份额增速明显(Cell Metab,2018.27:740-756)。越来越多的临床实验证实GLP-1RA在非酒精性脂肪肝炎(NASH)(Adv Exp Med Biol,2021.1307:417-440)、改善心血管预后(Diabetes Metab Syndr,2021.15:837-843)、阿尔兹海默病(Diabetes,2014.63:2262-72)、保护肾脏及改善糖尿病肾病结局上(N Engl J Med,2021.384:e42)具有显著作用。
胰高血糖素样肽-1受体(GLP-1R)主要表达于小肠、胰腺、心血管、脑和唾液腺等组织中(Endocrinology,2014.155:1280-1290),属于7次跨膜的G蛋白偶联受体(GPCR)B家族成员,其由肠道L细胞分泌的胰高血糖素样肽-1(GLP-1)激活后,通过提高细胞内环磷酸腺苷(cyclic adenosine monophosphate,cAMP)水平诱发电压门控型Ca
2+通道开放,进而促进胰岛β细胞增殖与分化等作用来调控血糖(J Mol Biol,2020.432:1347-1366)。
目前,已有多个注射肽类GLP-1RA批准用于治疗T2DM,如利拉鲁肽、艾赛那肽、度拉糖肽、索马鲁肽、聚二乙醇洛塞那肽等等,其中利拉鲁肽因在降低体重方面的作用,其也被批准用于治疗肥胖症(Mol Metab,2021.46:101102;ACS Pharmacol Transl Sci,2019.2:468-484)。2020年9月,美国FDA正式批准了全球首个口服GLP-1降糖药索马鲁肽上市,用于饮食、运动结合改善II型糖尿病患者的血糖控制。由于索马鲁肽为多肽类药物,通过将索马鲁肽与小分子吸收增强剂SNAC结合形成口服配方,与SNAC的结合使得索马鲁肽能够在胃部完成吸收,并且SNAC的部分溶解能够在胃内局部形成相对高的pH环境,从而提高索马鲁肽的溶解度,减少胃内肽酶的降解作用。主要缺点是其口服生物利用度极低(仅 0.4%-1%),成本明显增加,主要不良反应中胃肠道反应,恶心发生率约为15~20%(Ann Pharmacotherapy,2019,54:478-485)。小分子GLP-1R激动剂由于可以克服肽类药物的口服吸收障碍,同时其更容易透过血脑屏障,并作用于下丘脑弓状核中的GLP-1R而降低食欲,最终在降低血糖的同时,可能会起到更优的减轻体重的效果(J Clin Invest,2014.124:4223-4226)。
目前,小分子口服GLP-1R激动剂主要包括OWL833(Proc NatlAcad Sci U SA,2020.117:29959-29967),PF-06882961(Proc Natl Acad Sci U S A,2020.117:29959-29967)及TTP273(Nature,2020.577:432-436)。PF-06882961的一期临床结果表明,其在2型糖尿病患者降糖和减重效果作用显著。在患有2型糖尿病的患者中,联合二甲双胍,每天2次给药PF-06882961,治疗28天时,120mg剂量降低HBA1c达1.2%,减重达7.9kg(ClinicalTrials.gov Identifier:NCT03538743)。
发明内容
基于整个2型糖尿病发病率很高,且目前没有有效的口服小分子药物获批对其进行治疗,本发明提供一类新的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物,可以有效激活GLP-1R下游信号通路,提高cAMP的表达,从而达到促进胰岛素分泌,治疗糖尿病及其并发症的作用,有较大的应用价值。
具体地,本发明提供了式(I)所示的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体:
其中:
R
1和R
2分别独立选自:H,卤素,C1-C6烷基,C1-C6烷氧基;
R
3和R
4分别独立选自:H,C1-C6烷基,C1-C6烷氧基;或者R
3和R
4相连组成3-8元碳环或3-8元杂环;
R
5选自:3-8元杂环基取代的C1-C4烷基,5-10元杂芳基取代的C1-C4烷基,C1-C6烷氧基取代的C1-C4烷基;其中,所述R
5中的3-8元杂环基和5-10元杂芳基可以独立任选的 被一个或多个R
10取代;
R
6和R
7分别独立选自:H,C1-C6烷基;或者R
6和R
7一起形成G,G选自=O;
各R
8和R
9分别独立选自:H,卤素,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烷基甲基,卤素取代的C1-C6烷基,羟基取代的C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,氨基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基,芳基,杂芳基,硝基,氰基,-OR,-N(R)
2,-SR,-C(O)OR,-C(O)N(R)
2,-C(O)R,-S(O)R,-S(O)
2R,-S(O)
2N(R)
2,-N(R)C(O)R;
R选自:H,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烷基甲基,卤素取代的C1-C6烷基,羟基取代的C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,氨基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基;
n选自:0,1或2;
p选自:1或2;
m选自:1,2或3;
W选自:O,S,NR
10;
W
1选自:O,S;
Q选自:C,CH,N;
X选自:N,CR
10;
Y选自:N,CR
11;
R
10选自:H,C1-C6烷基,C1-C6烷氧基;
R
11选自:H,C1-C6烷基,C1-C6烷氧基;或者R
11和R
6相连组成5-8元杂环;
Q与相邻C之间的虚线表示所述Q与相邻C之间的化学键可选单键或双键。
在其中一些实施例中,所述苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物具有如下式(II)或者式(III)所示结构:
在其中一些实施例中,所述苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物具有如下式(IV)或者式(V)所示结构:
在其中一些实施例中,所述苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物具有如下式(VI)或者式(VII)所示结构:
在其中一些实施例中,W为O,R
6和R
7分别独立选自:H,C1-C6烷基。
在其中一些实施例中,W
1为O。
在其中一些实施例中,Q选自:C,CH。
在其中一些实施例中,X选自:N,CH。
在其中一些实施例中,R
1和R
2分别独立选自:H,卤素,C1-C3烷基,C1-C3烷氧基。
在其中一些实施例中,R
3和R
4分别独立选自:H,C1-C3烷基,C1-C3烷氧基。
在其中一些实施例中,R
5选自:3-4元杂环基取代的C1-C4烷基,5-6元杂芳基取代的C1-C4烷基,C1-C3烷氧基取代的C1-C4烷基;其中,所述R
5中的3-4元杂环基和5-6元杂芳基可以独立任选的被一个或多个R
10取代。
在其中一些实施例中,R
5选自:3-4元杂环基取代的甲基,3-4元杂环基取代的乙基,5-6元杂芳基取代的甲基,5-6元杂芳基取代的乙基;其中,所述R
5中的3-4元杂环基和5-6元杂芳基可以独立任选的被一个或多个R
10取代,R
10选自:H、C1-C3烷基。
在其中一些实施例中,R
5选自:氧杂环丁烷取代的甲基,氧杂环丁烷取代的乙基,乙基咪唑取代的甲基,乙基咪唑取代的乙基。
在其中一些实施例中,R
6和R
7分别独立选自:H,C1-C3烷基。
在其中一些实施例中,各R
8和R
9分别独立选自:H,卤素,氰基,C1-C3烷基,卤素取代的C1-C3烷基。
在其中一些实施例中,各R
8分别独立选自:H,卤素,C1-C3烷基;各R
9分别独立选自:H,卤素,氰基,C1-C3烷基,三氟甲基。
在其中一些实施例中,各R
8分别独立选自:H、Cl、F、甲基;各R
9分别独立选自:氰基、Cl、甲基。
在其中一些实施例中,所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物选自如下化合物:
本发明还提供了上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体的应用。
具体技术方案如下:
上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备GLP-1R激动剂中的应用。
上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备用于预防和/或治疗与GLP-1R下游信号通路相关的疾病和/或症状的药物中的应用。
其中,与GLP-1R下游信号通路相关的疾病和/或症状选自但不限于:糖尿病,糖尿病视网膜病变,糖尿病性脑血管病变,糖尿病性神经病变,胰岛素抵抗,高血糖症,糖尿病性肾病,高血压,白内障,骨质疏松症,高尿酸血症以及糖尿病引起的感染、肥胖症、代谢综合征、血脂异常、非酒精性脂肪肝病、非酒精性脂肪性肝炎、纤维化、心脏病、中风、肝硬化、肝癌、代谢性酸中毒、酮病、心血管不适、癫痫、动脉粥样硬化、帕金森氏病和阿尔兹海默病等。
上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备促进胰岛素分泌的药物中的应用。
上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备降血糖的药物中的应用。
上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗糖尿病的药物中的应用。
其中,所述糖尿病选自但不限于:1型糖尿病(T1DM)、2型糖尿病(T2DM)、妊娠糖尿病及其他特殊类型糖尿病(特发性T1D、早发型T2DM、青年人的成年型糖尿病、青少年发作的非典型糖尿病、营养不良相关性糖尿病、成人隐匿性自身免疫性糖尿病等。
本发明还提供了一种预防和/或治疗糖尿病及其并发症的药物组合物。
具体技术方案如下:
一种预防和/或治疗糖尿病及其并发症的药物组合物,包括活性成分以及药学上可接受的辅料和/或载体,所述活性成分包括有上述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体。
本发明提供的新的并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,可以有效激活GLP-1R下游信号通路,提高cAMP的表达,从而达到促进胰岛素分泌,治疗糖尿病及其并发症的作用,有较大的应用价值。
图1为化合物1、2、3、4和化合物6的大鼠灌胃给药(20mg/kg)的平均药时曲线图。
图2为化合物PF-06882961、12、16、46和化合物58的大鼠灌胃给药(20mg/kg)的平均药时曲线图。
图3为化合物12和化合物16在小鼠葡萄糖耐量试验的血糖曲线。
图4为化合物12和化合物16在小鼠葡萄糖耐量试验的AUC
(0-2h)。
图5为化合物6和化合物16在小鼠葡萄糖耐量试验的血糖曲线。
图6化合物6和化合物16在小鼠葡萄糖耐量试验的AUC
(0-2h)。
图7化合物3、化合物16和化合物58在小鼠葡萄糖耐量试验的血糖曲线。
图8化合物3、化合物16和化合物58在小鼠葡萄糖耐量试验的AUC
(0-2h)。
本发明所述化合物中,当任何变量(例如R等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使 化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
术语“烷氧基”指烷基与氧直接连接的基团,即具有-O-烷基结构的基团,如-OCH
3、-OCH
2CH
3、-OCH
2CH
2CH
3、-O-CH
2CH(CH
3)
2、-OCH
2CH
2CH
2CH
3、-O-CH(CH
3)
2等。
术语“环烷基”或者“碳环”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。
术语“杂环基”或者“杂环”为饱和或部分不饱和的单环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,例如:吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基等,及其N-氧化物,杂环取代基的连接可通过碳原子或通过杂原子实现。
术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环,本发明范围内的杂芳基包括但不限于:喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基、苯并呋喃基、苯并噻吩基、苯并恶唑、吲哚基等;“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。
术语“取代的”是指用指定取代基的基团置换特定结构中的氢基。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
除非另有定义,烷基、环烷基、芳基、杂芳基和杂环烷基取代基可为未被取代的或取代的。例如,C1-C6烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式(Ⅰ)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物的游离形式,也包括其药学上可接受的盐及立体异构体。可通过常规化学方法自含有 碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
在一个实施方案中,本发明提供了一种利用具有式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)所示结构的化合物及其药学可接受的盐或者立体异构体治疗人或其它哺乳动物与GLP-1R下游信号通路相关的疾病和/或症状。
其中,所述与GLP-1R下游信号通路相关的疾病和/或症状可以选自但不限于:1型糖尿病(T1DM),2型糖尿病(T2DM),妊娠糖尿病及其他特殊类型糖尿病(特发性T1D、早发型T2DM、青年人的成年型糖尿病、青少年发作的非典型糖尿病、营养不良相关性糖尿病、成人隐匿性自身免疫性糖尿病等),糖尿病视网膜病变,糖尿病性脑血管病变,糖尿病性神经 病变,胰岛素抵抗,高血糖症,糖尿病性肾病,高血压,白内障,骨质疏松症,高尿酸血症以及糖尿病引起的多种感染、肥胖症、代谢综合征、血脂异常、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、纤维化、心脏病、中风、肝硬化、肝癌、代谢性酸中毒、酮病、心血管不适、癫痫和动脉粥样硬化、帕金森氏病和阿尔兹海默等疾病。
联合用药:式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物。当式(I)、式(II)、式(ⅠII)、式(IV)、式(V)、式(VI)或者式(VII)化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物与其它一种或几种已知药物。当式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物与其它一种或几种药物进行药物联用时,式(I)、式(II)、式(ⅠII)、式(IV)、式(V)、式(VI)或者式(VII)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物进行药物联用的药物或活性成分包括但不局限于以下治疗糖尿病的药物:双胍类(如二甲双胍)、磺酰脲类(醋酸己脲、氯磺丙脲、甲苯磺丁脲、妥拉磺脲、氨磺丁脲、格列本脲、格列齐特、格列吡嗪、格列喹酮、格列波脲、格列派特以及格列美脲)、噻唑烷二酮类(如曲格列酮、罗格列酮、吡格列酮、环格列酮)、美格列脲类(例如那格列奈、瑞格列奈、米格列奈)、二肽基肽酶4抑制剂(西格列汀、维格列汀、沙格列汀、阿格列汀、利格列汀、吉格列汀和替格列汀)、钠-葡萄糖连接转运蛋白2抑制剂(坎格列净、达格列净、恩格列净、依格列净、鲁格列净以及托格列净)、钠-葡萄糖连接转运蛋白1/2抑制剂、GPR40激动剂、GIPR激动剂、GIP/GLP-1双重受体激动剂、α葡萄糖苷酶抑制剂、胰岛素或胰岛素类似物。
可以与式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化合物进行药物联用的药物或活性成分包括但不局限于以下治疗肥胖的药物:肽YY或其类似物、神经肽Y受体2型激动剂、黑素皮质素受体4激动剂、胰岛淀粉样多肽、GIPR激动剂、磷酸二酯酶、AMP激活的蛋白激酶、神经肽Y5受体拮抗剂、GPR40激动剂、GIP/GLP-1双重受体激动剂、环丙甲羟二羟吗啡酮(纳曲酮)/安非他酮、氯卡色林、芬特明/托吡酯、奥利司他、利拉鲁肽。
可以与式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或者式(VII)化 合物进行药物联用的药物或活性成分包括但不局限于以下治疗NASH的药物:法尼酯X受体激动剂、PPARα/δ激动剂、成纤维细胞生长因子19/21类似物、甲状腺激素受体β激动剂、钠-葡萄糖协同转运蛋白(SGLT)-1/2抑制剂、乙酰辅酶A羧化酶抑制剂、趋化因子受体-2/5抑制剂、抗凋亡信号调节激酶1抑制剂、ATP结合转运蛋白1激动剂、5-脂肪氧化酶抑制剂、血管黏附蛋白1抑制剂。
合成方法:除在文献中已知的或在实验程序中例证的标准方法外,可采用如下合成方案(方案1-10)中的方法制备本发明化合物。结合下述的合成方案,能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法,所述的方法仅仅是为说明目的的说明性方案描述,并不构成对本发明所具有的范围的限制。
方案1
方案2
方案3
方案4
方案5
方案6
方案7
方案8
方案9
方案10
以下为具体实施例。
实施例1:4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(中间体0104-1)的制备(按照方案一线路制备)
步骤1a:1-(叔丁基)4-甲基4-(6-氯吡啶-2-基)哌啶-1,4-二羧酸酯(化合物0102-1)的制备:在氮气保护下,向N-叔丁氧羰基-4-哌啶甲酸甲酯(3.00克,12.33毫摩尔,1.0当量)的四氢呋喃(40毫升)溶液中滴加双(三甲基硅基)氨基锂的四氢呋喃溶液(1.0摩尔/升,25毫升,24.66毫摩尔,2.0当量)。将混合物在0℃下搅拌1.5小时,然后滴加2,6-二氯吡啶(2.00克,13.51毫摩尔,1.1当量)的四氢呋喃溶液(5毫升)。将混合物升温至室温,并搅拌2.5小时。用饱和氯化铵水溶液(10毫升)淬灭反应,并用水(70毫升)和乙酸乙酯(160毫升)分液。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩得到粗产品1-(叔丁基)4-甲基4-(6-氯吡啶-2-基)哌啶-1,4-二羧酸酯(4.49克,产率:103%)。该产品不需要进一步纯化直接用于下一步。
步骤1b:1-(叔丁氧羰基)-4-(6-氯吡啶-2-基)哌啶-4-羧酸(化合物0103-1)的制备:在43℃下,将粗产品1-(叔丁基)4-甲基4-将(6-氯吡啶-2-基)哌啶-1,4-二羧酸酯(0102-1)(4.49g)溶解于甲醇(12毫升)中,在20分钟内滴加4摩尔/升的氢氧化钠水溶液(9毫升)。将混合物升温至50℃并搅拌35分钟。将混合物冷却至室温,在冰水浴中用6摩尔/升的盐酸水溶液(6毫升)将pH调节至~2,此后形成固体沉淀。将浆液用水(10毫升)稀释并搅拌40分钟,然后通过过滤收集固体,固体用水洗涤,真空下干燥以得到白色固体1-(叔丁氧羰基)-4-(6-氯吡啶-2-基)哌啶-4-羧酸(3.85克,产率:89.0%)。LCMS(ESI):m/z=341(M+H)
+.
步骤1c:4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0104-1)的制备:氮气保护下,将1-(叔丁氧基羰基)-4-(6-氯吡啶-的2-基)哌啶-4-羧酸(0103-1)(3.85克,11.32毫摩尔)的1,2-二氯乙烷(30毫升)溶液加热至82℃并搅拌过夜。冷却至室温后,减压除去溶剂。用柱色谱法(PE/EA=10/1)纯化粗产物,得到白色固体状的4-(6-氯吡啶-2--2-基)哌啶-1-羧酸叔丁酯(1.61g,收率:48.0%)。LCMS(ESI):m/z=297(M+H)
+.
实施例2:(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(中间体0116-1)的制备(按照方案一线路制备)
步骤2a:6-氯-5-硝基吡啶-2-羧酸(化合物0106-1)的制备:室温下,往2-氯-6-甲基-3-硝基吡啶(0105-1)(5.0克,29.1毫摩尔,1.0当量)的浓硫酸(20毫升)溶液分批加入三氧化铬(8.6克,87.3毫摩尔,3.0当量)。混合物60℃下搅拌过夜。冷却到室温后,混合物倒入冰水中,然后将固体过滤和真空干燥得到灰色固体6-氯-5-硝基吡啶-2-羧酸(4.15克,收率:71%)。LCMS(ESI):m/z=201(M-H)
-.
步骤2b:6-氯-5-硝基吡啶-2-羧酸甲酯(化合物0107-1)的制备:氮气保护,0℃下,往6-氯-5-硝基吡啶-2-羧酸(0106-1)(4.0克,19.8毫摩尔,1.0当量)和N,N-二甲基甲酰胺(2滴)的二氯甲烷(60毫升)混合物加入草酰氯(5.0克,39.6毫摩尔,2.0当量)。混合物室温搅拌1小时。加入甲醇(4毫升),混合物在室温搅拌10分钟。加入水,混合物分液。浓缩有机层,残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=20/1到5/1)得到白色固体6-氯-5-硝基吡啶-2-羧酸甲酯(4.2克,收率:97.7%)。LCMS(ESI):m/z=217(M+H)
+.
步骤2c:(S)-2-((苄氧基)甲基)氧杂环丁烷(化合物0109)的制备:氮气保护,室温下,往叔丁醇钾(13.6克,122.0毫摩尔,2.0当量)的叔丁醇(180毫升)混合物中加入三甲基碘化亚砜(26.8克,122.0毫摩尔,2.0当量)。混合物在60℃下搅拌30分钟。加入(S)-2-((苄氧基)甲基)环氧乙烷(0108)(10.0克,61.0毫摩尔,1.0当量),混合物80℃下搅拌2小时。冷却到室温后,混合物过滤,然后将滤液水洗、浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=20/1到10/1)得到无色油状液体(S)-2-((苄氧基)甲基)氧杂环丁烷(4.1克,收率:38%)。
步骤2d:(S)-2-羟甲基氧杂环丁烷(化合物0110)的制备:氢气条件下,(S)-2-((苄氧基)甲基)氧杂环丁烷(0109)(9.2克,51.7毫摩尔,1.0当量)和Pd/C(1.8克,10%质量比)的甲醇(100毫升)溶液室温下搅拌过夜。混合物过滤,滤液真空浓缩得到无色液体(S)-2-羟甲基氧杂环丁烷(5.0克,收率:111%)。
步骤2c:(S)-氧杂环丁烷-2-基甲基甲磺酸酯(化合物0111)的制备:氮气保护,0℃下,往(S)-2-羟甲基氧杂环丁烷(0110)(5.0克,56.8毫摩尔,1.0当量)和三乙胺(217.2克,170.4毫摩尔,3.0当量)的二氯甲烷(80毫升)混合物中滴加甲磺酰氯(9.1克,79.5毫摩尔,1.4当量)。混合物室温下搅拌3小时。混合物用水洗、真空浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=5/1到1/1)得到无色油状液体(S)-氧杂环丁烷-2-基甲基甲磺酸酯(5.8克,收率:61.7%)。
步骤2d:(S)-氧杂环丁烷-2-基甲胺(化合物0113)的制备:(S)-氧杂环丁烷-2-基甲基甲磺酸酯(0111)(5.8克,35毫摩尔,1.0当量),叠氮化钠(2.7克,42毫摩尔,1.2当量)和碘化钾(1.2克,7.0毫摩尔,0.2当量)的N,N-二甲基甲酰胺(80毫升)溶液在60℃下搅拌过夜。冷却到室温后,加入甲基叔丁基醚,混合物用水洗。有机层浓缩,残留物溶于四氢呋喃,加入Pd/C(600毫克,10%质量比)。氢气条件下,混合物在室温下搅拌过夜。混合物过滤,滤液真空浓缩得到无色油状物(S)-氧杂环丁烷-2-基甲胺,该产品不需要进一步纯化直接用于下一步。
步骤2e:(S)-5-硝基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(化合物0114-1)的制备:6-氯-5-硝基吡啶-2-羧酸甲酯(0107-1)(1.2克,5.6毫摩尔,1.0当量),N,N-二异丙基乙胺(2.2克,16.8毫摩尔,3.0当量)和(S)-氧杂环丁烷-2-基甲胺(0113)(1.0克,11.2毫摩尔,2.0当量)的N,N-二甲基甲酰胺(30毫升)混合物在室温下搅拌过夜。加入乙酸乙酯和水,混合物分液,有机层用饱和食盐水洗、浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=8/1到2/1)得到黄色固体(S)-5-硝基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(1.0克,收率:80.6%)。LCMS(ESI):m/z=268(M+H)
+.
步骤2f:(S)-5-氨基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(化合物0115-1)的制备:氢气条件下,(S)-5-硝基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(0114-1)(1.0克,3.7毫摩尔,1.0当量)和Pd/C(100毫克,10%质量比)的甲醇(30毫升)混合物在室温下搅拌过夜。混合物过滤,滤液真空浓缩,得到黄色固体(S)-5-氨基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(800毫克,收率:90.1%)。LCMS(ESI):m/z=238(M+H)
+.
步骤2g:(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物0116-1)的制备:氮气保护条件下,(S)-5-氨基-6-((氧杂环丁烷-2-基甲基)氨基)吡啶-2-羧酸甲酯(0115-1)(800毫克,3.4毫摩尔,1.0当量)和2-氯乙酸酐(872毫克,5.1毫摩尔,1.5当 量)的四氢呋喃(50毫升)混合物在70℃搅拌过夜。冷却到室温后,加入碳酸钠水溶液和乙酸乙酯,混合物分液。有机层用饱和食盐水洗、真空浓缩。残留物用硅胶柱层析纯化(洗脱剂为:二氯甲烷/甲醇=200/1到100/1)得到黄色固体(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(1.0克,收率:100%)。LCMS(ESI):m/z=296(M+H)
+.
实施例3:(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(中间体0116-3)的制备(按照方案一线路制备)
步骤3a:(S)-4-硝基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(化合物0114-3)的制备:氮气保护条件下,3-氟-4-硝基苯甲酸甲酯(0107-3)(6.23克,31.30毫摩尔,1.0当量)、(S)-氧杂环丁烷-2-基甲胺(0113)(3.00克,34.44毫摩尔,1.1当量)和碳酸钾(8.97克,64.87毫摩尔,2.0当量)的N,N-二甲基甲酰胺混合物(60毫升)在室温下搅拌3小时。反应用水(90毫升)淬灭,加入乙酸乙酯(80毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,滤液减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=5/1)纯化粗产物,得到白色固体(S)-4-硝基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(6.61克,产率:79.4%)。LCMS(ESI):m/z=267(M+H)
+.
步骤3b:(S)-4-氨基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(化合物0115-3)的制备:氢气条件下,(S)-4-硝基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(0114-3)(6.61克,24.84毫摩尔,1.0当量)和钯碳(661毫克,10%质量比)的四氢呋喃(80毫升)混合物在室温搅拌4小时。将反应液过滤,滤液真空浓缩得到苍白色固体(S)-4-氨基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(5.88克,收率:100.2%)。LCMS(ESI):m/z=237(M+H)
+.
步骤3c:(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0116-3)的制备:在干燥条件下,将(S)-4-氨基-3-((氧杂环丁烷-2-基甲基)氨基)苯甲酸甲酯(0115-3)(5.88克,24.89毫摩尔,1.0当量)、2-氯-1,1,1-三甲氧基乙烷(4.62克,29.86毫摩尔,1.2当量)和一水合对甲苯磺酸(514毫克,2.99毫摩尔,0.12当量)的四氢呋喃(60毫升)溶液加热至45℃并搅拌过夜。冷却至室温后,反应液加水(40毫升)稀释并用乙酸乙酯(60毫升)稀释。用柱色谱法(二氯甲烷/甲醇=50/1)纯化粗产物,得到白色固体(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(6.54克,收率:74.5%)。LCMS(ESI):m/z=295(M+H)
+.
实施例4:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物1)的制备(按照方案二线路制备)
步骤4a:7-(羟甲基)苯并呋喃-4-腈(化合物0201-1)的制备:
氮气保护条件下,将5-溴-2-甲基苯酚(2.0克,10.7毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(2.5克,12.8毫摩尔,1.2当量),碳酸钾(3.0克,21.4毫摩尔,2.0当量)和碘化钾(0.2克,10%质量比)的N,N-二甲基甲酰胺的混合物在120℃下搅拌过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到粗产品4-溴-2-(2,2-二乙氧基乙氧基)-1-甲基苯(2.88克,产率:88.9%)。该产品不需要进一步纯化直接用于下一步。
氮气保护条件下,将上述得到的4-溴-2-(2,2-二乙氧基乙氧基)-1-甲基苯(2.9克,9.55毫摩尔,1.0当量)和多聚磷酸(8.0克,23.75毫摩尔,2.5当量)的二氯乙烷混合物回流过夜。冷却到室温后,反应用水(40毫升)淬灭,并用乙酸乙酯(50毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到黄色油状4-溴-7-甲基苯并呋喃(1.61克,产率:80.5%)。LCMS(ESI):m/z=211(M+H)
+.
氮气保护条件下,将上述得到的4-溴-7-甲基苯并呋喃(800毫克,3.8毫摩尔,1.0当量)和氰化亚铜(1.7克,19.0毫摩尔,5.0当量)的N,N-二甲基甲酰胺(15毫升)混合物在120℃搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,并用乙酸乙酯(15毫升)洗涤。将滤液用水(30毫升)稀释,并用乙酸乙酯(30毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,并减压浓缩。粗品用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体状的7-甲基苯并呋喃-4-腈(305毫克,收率:51.3%)。LCMS(ESI):m/z=158(M+H)
+.
氮气保护条件下,将上述得到的7-甲基苯并呋喃-4-腈(305毫克,1.94毫摩尔,1.0当量)、N-溴代琥珀酰亚胺(416毫克,2.33毫摩尔,1.2当量)和偶氮二异丁腈(65毫克,0.39毫摩尔,0.2当量)的二氯乙烷(10毫升)混合物在72℃搅拌过夜。冷却至室温后,减压除去溶剂。残留物用水(20毫升)稀释,并用石油醚/乙酸乙酯=2/1(30毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,并减压浓缩。粗品经柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯 化,得到白色固体7-(溴甲基)苯并呋喃-4-腈(377毫克,收率:82.0%)。LCMS(ESI):m/z=236(M+H)
+.
将上述得到的7-(溴甲基)苯并呋喃-4-腈(326毫克,1.38毫摩尔,1.0当量)和乙酸钾(1.35克,13.76毫摩尔,10.0当量)的N,N-二甲基甲酰胺的混合物(10毫升)在室温下搅拌3小时。反应用水(20毫升)淬灭,并用乙酸乙酯(30毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩得到粗产品乙酸(4-氰基苯并呋喃-7-基)甲基酯(190毫克,产率:64.2%)。该产品不需要进一步纯化直接用于下一步。
在上述得到的乙酸(4-氰基苯并呋喃-7-基)甲基酯(168毫克,0.78毫摩尔,1.0当量)的四氢呋喃(5毫升)溶液中加入甲醇钠的甲醇溶液(5.4摩尔/升,282毫克,1.56毫摩尔,2.0当量)。混合物在室温下搅拌1小时。反应液用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(15毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。残留物用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=4/1)纯化,得到黄色固体7-(羟甲基)苯并呋喃-4-腈(135毫克,收率:100.0%)。LCMS(ESI):m/z=174(M+H)
+.
步骤4b:4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-1)的制备:氮气保护条件下,将4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(125毫克,0.44毫摩尔,1.0当量),7-(羟甲基)苯并呋喃-4-腈(0201-1)(106毫克,0.61毫摩尔,1.4当量)、碳酸铯(400毫克,1.22毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(58毫克,0.12毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(57毫克,0.06毫摩尔,0.1当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯(15毫升)洗涤。将滤液用水(20毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(165毫克,产率:86.8%)。LCMS(ESI):m/z=434(M+H)
+.
步骤4c:7-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并呋喃-4-腈对甲苯磺酸盐(化合物0203-1)的制备:将4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-1)(165毫克,0.38毫摩尔,1.0当量)和一水合对甲苯磺酸(197毫克,1.14毫摩尔,3.0当量)的乙酸乙酯(15毫升)混合物在60℃下搅拌过夜。冷却至室温后,将反应溶液过滤,将滤饼用乙酸乙酯洗涤并真空干燥,得到白色固体7-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并呋喃-4-腈对甲苯磺酸盐(150毫克,收率:90.9%).LCMS(ESI):m/z=343(M+H)
+.
步骤4d:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物0204-1)的制备:将7-(((6-(哌啶 -4-基)吡啶基-2-基)氧基)甲基)苯并呋喃-4-腈对甲苯磺酸盐(0203-1)(150毫克,0.29毫摩尔,1.2当量)、(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0116-1)(72毫克,0.24毫摩尔,1.0当量)和碳酸钾(115毫克,0.83毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃的条件下搅拌4小时。在冷却至室温后,加水,加二氯甲烷萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(132毫克,收率:75.9%)。LCMS(ESI):m/z=593(M+H)
+.
步骤4e:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物1)的制备:将(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0204-1)(132毫克,0.22毫摩尔,1.0当量)和一水合氢氧化锂(11毫克,0.25毫摩尔,1.1当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(12毫升)稀释,搅拌4小时,然后通过过滤收集固体。固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤,将滤液用无水硫酸钠干燥并减压浓缩。将残留物真空干燥得到白色固体(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(97毫克,收率:75.2%)。LCMS(ESI):m/z=579(M+H)
+.
1H NMR(500MHz,DMSO)δ13.04(s,1H),8.33(d,J=2.2Hz,1H),8.14(d,J=8.2Hz,1H),7.99(d,J=8.2Hz,1H),7.77(d,J=7.7Hz,1H),7.68–7.61(m,1H),7.55(d,J=7.8Hz,1H),7.19(d,J=2.2Hz,1H),6.87(d,J=7.3Hz,1H),6.72(d,J=8.1Hz,1H),5.72(s,2H),5.24–5.15(m,1H),4.84(dd,J=14.6,6.4Hz,1H),4.72(dd,J=14.6,4.3Hz,1H),4.53–4.46(m,1H),4.37(dt,J=8.9,6.0Hz,1H),3.94(dd,J=32.0,13.7Hz,2H),2.97–2.87(m,2H),2.73–2.63(m,1H),2.56(ddd,J=16.8,8.5,4.7Hz,1H),2.47(d,J=7.1Hz,1H),2.22(tt,J=16.1,8.1Hz,2H),1.73(d,J=10.1Hz,4H).
实施例5:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物2)的制备(按照方案三线路制备)
步骤5a:6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(化合物0302-2)的制备:氮气保护下,将2-溴-6-氯吡啶(0301-2)(2.00克,10.39毫摩尔,1.0当量),N-叔丁氧羰基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(3.21克,10.39毫摩尔,1.0当量),碳酸钠(2.20克,20.78毫摩尔, 2.0当量)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(II)(761毫克,1.04毫摩尔,0.1当量)的二氧六环/水=10/1(30毫升)的混合物在90℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,并用乙酸乙酯(30毫升)洗涤。将滤液用水(30毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(2.51克,产率:81.9%)。LCMS(ESI):m/z=295(M+H)
+.
步骤5b:6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(化合物0303-2)的制备:氮气保护条件下,将6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(0302-2)(491毫克,1.67毫摩尔,1.2当量),7-(羟甲基)苯并呋喃-4-腈(0201-1)(241毫克,1.39毫摩尔,1.0当量)、碳酸铯(906毫克,2.78毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(130毫克,0.28毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(127毫克,0.14毫摩尔,0.1当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯(15毫升)洗涤。将滤液用水(20毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(462毫克,产率:76.9%)。LCMS(ESI):m/z=432(M+H)
+.
步骤5c:7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-腈盐酸盐(化合物0304-2)的制备:将6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(0303-2)(462毫克,1.07毫摩尔,1.0当量)溶于盐酸二氧六环溶液(4摩尔/升,5毫升)中,反应液在室温下搅拌过夜。然后将反应溶液过滤,将滤饼用乙酸乙酯洗涤并真空干燥,得到白色固体7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-腈盐酸盐(400毫克,收率:100.0%)。LCMS(ESI):m/z=332(M+H)
+.
步骤5d:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物0305-2)的制备:将7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-腈盐酸盐(0304-2)(200毫克,0.54毫摩尔,1.0当量)、(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0116-1)(160毫克,0.54毫摩尔,1.0当量)和碳酸钾(298毫克,2.16毫摩尔,4.0当量)的乙腈(5毫升)的混合物在60℃下搅拌4小时。将反应混合物冷却至室温后加水,加二氯甲烷萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(212毫 克,收率:66.7%)。LCMS(ESI):m/z=590(M+H)
+.
步骤5e:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物2)的制备:将(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0305-2)(70毫克,0.12毫摩尔,1.0当量)和一水合氢氧化锂(25毫克,0.48毫摩尔,4.0当量)的乙腈/水=5/1(3毫升)混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(12毫升)稀释,搅拌4小时。然后通过过滤收集固体,固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤。将滤液用无水硫酸钠干燥并减压浓缩。真空干燥得到白色固体(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(47毫克,收率:69.1%)。LCMS(ESI):m/z=576(M+H)
+.
1H NMR(500MHz,DMSO)δ8.32(s,1H),8.05(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.78(d,J=7.5Hz,1H),7.69(t,J=7.7Hz,1H),7.54(d,J=7.6Hz,1H),7.20(s,1H),7.07(d,J=7.2Hz,1H),6.77(d,J=8.1Hz,1H),6.63(s,1H),5.74(s,2H),4.99(s,1H),4.83(dd,J=14.3,7.4Hz,1H),4.65(d,J=14.0Hz,1H),4.42(d,J=6.9Hz,1H),4.33(d,J=7.2Hz,1H),4.16(d,J=13.5Hz,1H),3.91(d,J=13.4Hz,1H),3.20(s,2H),2.71(s,2H),2.51(s,1H),2.44(s,2H),2.29(s,1H).
实施例6:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物3)的制备(按照方案二线路制备)
步骤6a:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-3)的制备:将7-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基)苯并呋喃-4-腈对甲苯磺酸盐(0203-1)(105毫克,0.24毫摩尔,1.2当量)、(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(60毫克,0.20毫摩尔,1.0当量)和碳酸钾(111毫克,0.81毫摩尔,4.0当量)的乙腈(5毫升)的混合物在60℃下搅拌4小时。将反应混合物冷却至室温后加水,加二氯甲烷萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(78毫克,收率:65.5%)。LCMS(ESI):m/z=592(M+H)
+.
步骤6b:(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物3)的制备:将(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯 (0204-3)(78毫克,0.13毫摩尔,1.0当量)和一水合氢氧化锂(11毫克,0.26毫摩尔,2.0当量)的乙腈/水=5/1(3毫升)的混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(12毫升)稀释,搅拌4小时,然后通过过滤收集固体,固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤。将滤液用无水硫酸钠干燥并减压浓缩。将残留物真空干燥得到白色固体(S)-2-((4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(54毫克,收率:71.1%)。LCMS(ESI):m/z=578(M+H)
+.
1H NMR(500MHz,DMSO)δ12.65(s,1H),8.28(d,J=22.1Hz,2H),7.80(dd,J=28.6,7.5Hz,2H),7.64(d,J=7.0Hz,2H),7.54(d,J=7.4Hz,1H),7.18(s,1H),6.87(d,J=6.9Hz,1H),6.72(d,J=7.9Hz,1H),5.72(s,2H),5.10(s,1H),4.76(s,1H),4.64(d,J=14.4Hz,1H),4.45(d,J=5.8Hz,1H),4.36(s,1H),3.95(d,J=12.5Hz,1H),3.79(d,J=11.9Hz,1H),2.97(d,J=8.7Hz,1H),2.84(s,1H),2.68(s,1H),2.57(s,1H),2.42(s,1H),2.21(d,J=29.3Hz,2H),1.72(d,J=12.1Hz,4H).
实施例7:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物4)的制备(按照方案三线路制备)
步骤7a:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0305-4)的制备:将7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-腈盐酸盐(0304-2)(100毫克,0.27毫摩尔,1.0当量)、(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(80毫克,0.27毫摩尔,1.0当量)和碳酸钾(149毫克,1.08毫摩尔,3.0当量)的乙腈(5毫升)的混合物在60℃下搅拌4小时。将反应混合物冷却至室温后加水,加二氯甲烷萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(97毫克,收率:60.9%)。LCMS(ESI):m/z=590(M+H)
+.
步骤7b:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物4)的制备:(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0305-4)(97毫克,0.16毫摩尔,1.0当量)和一水合氢氧化锂(25毫克,0.48毫摩尔,3.0当量)的乙腈/水=5/1(3毫升)混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。用水(12毫升)稀释浆液, 搅拌4小时,然后通过过滤收集固体,固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤,将滤液用无水硫酸钠干燥并减压浓缩。真空干燥得到白色固体(S)-2-((6-((4-氰基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(68毫克,收率:76.6%)。LCMS(ESI):m/z=576(M+H)
+.
1H NMR(500MHz,DMSO)δ12.67(s,1H),8.32(s,1H),8.25(s,1H),7.79(dd,J=18.0,8.0Hz,2H),7.74–7.61(m,2H),7.55(d,J=7.7Hz,1H),7.21(s,1H),7.08(d,J=7.4Hz,1H),6.78(d,J=8.1Hz,1H),6.62(s,1H),5.74(s,2H),5.05(d,J=5.3Hz,1H),4.79(dd,J=15.2,7.3Hz,1H),4.64(d,J=13.4Hz,1H),4.46(dd,J=13.8,7.3Hz,1H),4.35(dd,J=14.6,5.9Hz,1H),4.05(d,J=13.5Hz,1H),3.91(d,J=13.5Hz,1H),3.22–3.15(m,2H),2.77–2.60(m,3H),2.46–2.31(m,3H).
实施例8:(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物5)的制备(按照方案二线路制备)
步骤8a:7-(羟甲基)-2-甲基苯并呋喃-4-腈(化合物0201-5)的制备:
氮气保护下,4-溴-2-羟基苯甲酸甲酯(1.0克,4.33毫摩尔,1.0当量),3-溴丙炔(618毫克,5.19毫摩尔,1.2当量),和碳酸钾(896毫克,6.49毫摩尔,1.5当量)的N,N-二甲基甲酰胺的混合物在50℃下搅拌5小时。反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。将有机相减压浓缩。残留物用N,N-二乙基苯胺(5毫升)溶解。往混合物中加入氟化铯(855毫克,5.63毫摩尔,1.3当量)。混合物在220℃下搅拌3小时。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)得到黄色固体4-溴-2-甲基苯并呋喃-7-羧酸甲酯(563毫克,产率:48.53%)。LCMS(ESI):m/z=269(M+H)
+.
氮气保护条件下,将上述得到的4-溴-2-甲基苯并呋喃-7-羧酸甲酯(500毫克,1.86毫摩尔,1.0当量),四三苯基膦钯(215毫克,0.186毫摩尔,0.1当量)和氰化锌(326毫克,2.79毫摩尔,1.5当量)的N,N-二甲基甲酰胺(5毫升)溶液在90℃下搅拌过夜。冷却至室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化,得到黄色固 体4-氰基-2-甲基苯并呋喃-7-羧酸甲酯(290毫克,收率:72.68%)。LCMS(ESI):m/z=216(M+H)
+.
在氮气保护和冰浴下,往四氢锂铝(62毫克,1.618毫摩尔,1.2当量)的四氢呋喃混合物中加入上述得到的4-氰基-2-甲基苯并呋喃-7-羧酸甲酯(290毫克,1.348毫摩尔,1.0当量)。混合物在冰浴下搅拌1小时。反应用水淬灭。混合物用无水硫酸钠干燥并过滤。将滤液减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=100/1-2/1)得到黄色固体7-(羟甲基)-2-甲基苯并呋喃-4-腈(248毫克,产率:98.41%)。LCMS(ESI):m/z=188(M+H)
+.
步骤8b:4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-5)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(220毫克,0.74毫摩尔,1.0当量),7-(羟甲基)-2-甲基苯并呋喃-4-腈(0201-5)(166毫克,0.88毫摩尔,1.2当量)、碳酸铯(481毫克,1.48毫摩尔,2.0当量),2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(138毫克,0.296毫摩尔,0.4当量)和三(二亚苄基丙酮)二钯(0)(135毫克,0.148毫摩尔,0.2当量)的甲苯(10毫升)的混合物在125℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化粗产物,得到黄色油状物4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(237毫克,产率:71.60%)。LCMS(ESI):m/z=448(M+H)
+.
步骤8c:2-甲基-7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(化合物0203-5)的制备:将4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-5)(248毫克,0.55毫摩尔,1.0当量)和盐酸的二氧六环溶液(4M,1毫升)的二氧六环(4毫升)溶液在室温下搅拌过夜。混合物减压浓缩,得到2-甲基-7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(105毫克,粗品),该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=348(M+H)
+.
步骤8d:(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-5)的制备:2-甲基-7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(0203-5)(98毫克,0.255毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量)和碳酸钾(140毫克,1.01毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃的条件下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色固体(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(70毫克,收率:68.03%)。 LCMS(ESI):m/z=606(M+H)
+.
步骤8e:(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物5)的制备:(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-5)(27.6毫克,0.045毫摩尔,1.0当量)和一水合氢氧化锂(4毫克,0.09毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,然后形成固体沉淀。混合物过滤。残留物用水洗。残留物用厚制备薄层硅胶色谱法纯化(洗脱剂为:二氯甲烷/甲醇=10/1),得到黄色固体(S)-2-((4-(6-((4-氰基-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(21.6毫克,收率:80.12%)。LCMS(ESI):m/z=592(M+H)
+.
1H NMR(500MHz,DMSO)δ12.69(s,1H),8.26(s,1H),7.81(dd,J=8.4,1.3Hz,1H),7.73–7.59(m,3H),7.44(d,J=7.8Hz,1H),6.87(d,J=7.3Hz,1H),6.83(d,J=1.0Hz,1H),6.72(d,J=8.1Hz,1H),5.68(s,2H),5.10(ddd,J=14.5,7.2,2.8Hz,1H),4.77(dd,J=15.2,7.1Hz,1H),4.64(dd,J=15.2,2.6Hz,1H),4.46(dt,J=13.8,7.0Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.93(d,J=13.6Hz,1H),3.77(d,J=13.5Hz,1H),2.97(d,J=11.1Hz,1H),2.84(d,J=11.2Hz,1H),2.74–2.65(m,1H),2.59–2.54(m,1H),2.48(d,J=0.8Hz,3H),2.43(ddd,J=11.1,9.0,5.6Hz,1H),2.19(dt,J=32.3,10.5Hz,2H),1.80–1.60(m,4H).
实施例9:(S)-2-((4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物6)的制备(按照方案二线路制备)
步骤9a:4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-6)的制备:在氮气保护和-70℃下,往4-(6-((4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-1)(180毫克,0.416毫摩尔,1当量)的10毫升四氢呋喃溶液中滴加二异丙基氨基锂(0.42毫升,2摩尔/升四氢呋喃,0.843毫摩尔,2当量)。混合物在-70℃下搅拌1小时。将六氯乙烷(98.5毫克,0.416毫摩尔,1当量)的四氢呋喃(1毫升)溶液加入到混合物中。混合物在-70℃下搅拌1小时。反应用氯化铵淬灭。混合物用乙酸乙酯萃取。有机相用饱和食盐水洗涤和硫酸钠干燥。将混合物减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:石油醚/乙酸乙酯=5/1)得到透明油状物4-(6
-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(54毫克,产率:27.74%)。LCMS(ESI):m/z=468(M+H)
+.
步骤9b:2-氯-7
-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-腈4-甲基苯磺酸盐(化合物0203-6)的制备:在4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁 酯(0202-6)(54毫克,0.115毫摩尔,1.0当量)的乙酸乙酯(10毫升)溶液中加入对甲苯磺酸一水合物(59毫克,0.346毫摩尔,3.0当量)。混合物在60℃下搅拌过夜。混合物减压浓缩得到粗产品2-氯-7
-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-腈4-甲基苯磺酸盐(93毫克,粗品)。该产品不需要进一步纯化直接用于下一步。
步骤9c:(S)-2-((4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-6)的制备:将2-氯-7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-4-腈4-甲基苯磺酸盐(0203-6)(93毫克,0.173毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(34毫克,0.115毫摩尔,1.0当量)和碳酸钾(63.6毫克,0.461毫摩尔,4.0当量)的乙腈(10毫升)混合物在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-((4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(60毫克,收率:83.34%)。LCMS(ESI):m/z=626(M+H)
+.
步骤9d:(S)-2
-((4-(6
-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物6)的制备:将(S)-2-((4-(6-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-6)(60毫克,0.096毫摩尔,1.0当量)和一水合氢氧化锂(12毫克,0.288毫摩尔,3当量)的四氢呋喃/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的稀硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1)得白色固体(S)-2
-((4-(6
-((2-氯-4-氰基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(32.7毫克,收率:55.66%)。LCMS(ESI):m/z=612(M+H)
+.熔点:125~130℃;
1H NMR(500MHz,DMSO)δ12.70(s,1H),8.27(d,J=0.7Hz,1H),7.87–7.76(m,2H),7.70–7.60(m,2H),7.55(d,J=7.9Hz,1H),7.36(s,1H),6.87(d,J=7.3Hz,1H),6.73(d,J=8.1Hz,1H),5.68(s,2H),5.10(qd,J=7.2,2.8Hz,1H),4.78(dd,J=15.2,7.2Hz,1H),4.65(dd,J=15.2,2.7Hz,1H),4.47(dt,J=13.8,7.0Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.93(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.96(d,J=10.8Hz,1H),2.84(d,J=11.0Hz,1H),2.74–2.65(m,1H),2.59–2.53(m,1H),2.43(ddd,J=11.1,8.9,5.6Hz,1H),2.18(dt,J=29.7,11.0Hz,2H),1.77–1.54(m,4H).
实施例10:(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧 杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物8)的制备(按照方案二线路制备)
步骤10a:7-(羟甲基)苯并[b]噻吩-4-腈(化合物0201-8)的制备:
将2-氨基-4-溴苯甲酸甲酯(2.3克,10.0毫摩尔,1.0当量)加入到稀盐酸(2毫升浓盐酸和8毫升水)。混合物在80℃下搅拌15分钟,然后冷却到0℃。亚硝酸钠(828毫克,12毫摩尔,1.2当量)溶解于8毫升水,滴加到上述混合物中,混合物在0℃下搅拌2小时。将乙基黄原酸钾(2.72克,17毫摩尔,1.7当量)加入到8毫升水中,在65℃下搅拌。将上述所得重氮盐混合物在20分钟内加到该混合物中,混合物在65℃下搅拌2小时。加入二氯甲烷萃取,用水和饱和食盐水洗。有机相用无水硫酸钠干燥,减压浓缩。将残留物加入到氢氧化钾(5.6克,100毫摩尔,10.0当量)的10毫升乙醇溶液中,混合物在室温下搅拌1小时。混合物减压浓缩,加入水。通过加入浓盐酸调节水相pH值到1。加入乙酸乙酯萃取,用饱和食盐水洗。有机相经无水硫酸钠干燥,减压浓缩至干,得到3-溴丙炔(619毫克,5.2毫摩尔,1.3当量)和碳酸钾(884毫克,6.4毫摩尔,1.6当量)的N,N-二甲基甲酰胺混合物置于50℃下搅拌3小时。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩,得到红色油状物4-溴-2-巯基苯甲酸(2.19克,粗品),该产品不需要进一步纯化直接用于下一步。MS(ES
-):m/z=231(M-H)
-.
将上述得到的4-溴-2-巯基苯甲酸(2.19克,9.48毫摩尔,1.0当量)溶解于50毫升甲醇中,在0℃下滴加二氯亚砜(3.38克,28.44毫摩尔,3.0当量)。混合物在75℃下搅拌3小时。混合物减压浓缩,加入乙酸乙酯萃取。有机相经水和饱和食盐水洗,无水硫酸钠干燥。有机相减压浓缩得到黄色油状物4-溴-2-巯基苯甲酸甲酯(2.23克,粗品),该产品不需要进一步纯化直接用于下一步。MS(ES
-):m/z=245(M-H)
-。
将上述得到的4-溴-2-巯基苯甲酸甲酯(2.23克,9.03毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(2.13克,10.84毫摩尔,1.2当量)和碳酸钾(2.49克,18.03毫摩尔,2.0当量)的35毫升N,N-二甲基甲酰胺混合物在70℃下搅拌3小时。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用食饱和盐水洗涤,用无水硫酸钠干燥。有机相真空浓缩,残留 物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=30/1到10/1)得到黄色油状物4-溴-2-((2,2-二乙氧基乙基)硫基)苯甲酸甲酯(1.46克,收率:44.5%)。
将上述得到的4-溴-2-((2,2-二乙氧基乙基)硫基)苯甲酸甲酯(1.26克,3.47毫摩尔,1.0当量)和1.29克多聚磷酸的甲苯混合物置于120℃下搅拌过夜。冷却到室温后,加入水,用乙酸乙酯和是有名混合物通过加入浓盐酸进行酸化,加入乙酸乙酯和石油醚的混合溶剂萃取混合物。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂:石油醚/乙酸乙酯=100/1到50/1)得到红色固体4-溴苯并[b]噻吩-7-羧酸甲酯(849毫克,收率:90.6%)。
将上述得到的4-溴苯并[b]噻吩-7-羧酸甲酯(800毫克,2.96摩尔,1.0当量)溶解于25毫升乙醇,混合物在45℃下搅拌。加入硼氢化钠(1.14克,30毫摩尔,10当量),混合物搅拌过夜。混合物减压浓缩,加入乙酸乙酯萃取。有机相用饱和食盐水洗,无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=20/1到5/1)得到黄色固体(4-溴苯并[b]噻吩-7-基)甲醇(470毫克,收率:65.6%)。LCMS(ESI):m/z=225(M+H-H
2O)
+.
在氮气保护下,将上述得到的(4-溴苯并[b]噻吩-7-基)甲醇(440毫克,1.82毫摩尔,1.0当量)和氰化亚铜(1.63克,18.2毫摩尔,10.0当量)的N-甲基吡咯烷酮(15毫升)混合物置于190℃下搅拌8小时。冷却到室温后,混合物用乙酸乙酯稀释。混合物经硅藻土过滤,滤液用饱和食盐水洗,然后用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=10/1到4/1),得到7-(羟甲基)苯并[b]噻吩-4-腈(125毫克,收率:36.3%)。LCMS(ESI):m/z=172(M+H-H
2O)
+.
步骤10b:4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-8)的制备:氮气保护下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(138毫克,0.46毫摩尔,1.0当量)、7-(羟甲基)苯并[b]噻吩-4-腈(0201-8)(105毫克,0.56毫摩尔,1.2当量)、碳酸铯(378毫克,1.16毫摩尔,2.5当量),2-双环已基膦-2',6'-二异丙氧基联苯(33毫克,0.07毫摩尔,0.15当量)和三(二亚苄基丙酮)二钯(0)(38毫克,0.042毫摩尔,0.09当量)的甲苯(50毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=10/1到6/1),得到黄色固体4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(192毫克,收率:92.3%)。LCMS(ESI):m/z=450(M+H)
+.
步骤10c:7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并[b]噻吩-4-甲腈盐酸盐(化合物0203-8)的制备:向4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-8)(192毫克,0.43毫摩尔,1.0当量)在5毫升二氧六环的混合物中加入1毫升4M 氯化氢的二氧六环溶液。混合物在室温下搅拌过夜。混合物减压浓缩至干,得到白色固体7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并[b]噻吩-4-甲腈盐酸盐(240毫克,粗品)。LCMS(ESI):m/z=350(M+H)
+.
步骤10d:(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-8)的制备:将7-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并[b]噻吩-4-甲腈盐酸盐(0203-8)(240毫克,0.43毫摩尔,2.5当量)加入到5毫升N-甲基吡咯烷酮中,再加入N,N-二异丙基乙胺(175毫克,1.36毫摩尔,8.0当量)。混合物在室温下搅拌5分钟。加入(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量),然后混合物在60℃下搅拌过夜。混合物用乙酸乙酯稀释,用水和饱和食盐水洗。有机相减压浓缩,残留物经制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=20/1),得到黄色固体(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(89毫克,收率:86.1%)。m/z=608(M+H)
+.
步骤10e:(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物8)的制备:(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-8)(80毫克,0.13毫摩尔,1.0当量)和一水合氢氧化锂(44毫克,1.05毫摩尔,8.0当量)在5毫升乙腈和1毫升水的混合溶剂中的混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。加入稀硫酸调节残留物的pH值至6,加入乙酸乙酯萃取,用饱和食盐水洗。有机相经过无水硫酸钠干燥,减压浓缩,残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=10/1)得到黄色固体(S)-2-((4-(6-((4-氰基苯并[b]噻吩-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(49毫克,收率:62.0%)。LCMS(ESI):m/z=594(M+H)
+,熔点:124~126℃。
1H NMR(500MHz,DMSO)δ12.73(s,1H),8.28(s,1H),8.12(d,J=5.5Hz,1H),7.94(d,J=7.6Hz,1H),7.81(dd,J=8.4,1.0Hz,1H),7.71–7.55(m,4H),6.88(d,J=7.3Hz,1H),6.75(d,J=8.2Hz,1H),5.71(s,2H),5.10(qd,J=7.2,2.8Hz,1H),4.79(dd,J=15.2,7.1Hz,1H),4.66(dd,J=15.2,2.4Hz,1H),4.46(dd,J=13.7,7.6Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.94(d,J=13.6Hz,1H),3.80(s,1H),2.95(d,J=10.7Hz,1H),2.83(d,J=10.8Hz,1H),2.75–2.65(m,1H),2.56(t,J=11.5Hz,1H),2.47–2.38(m,1H),2.28–2.10(m,2H),1.75–1.55(m,4H).
实施例11:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物12)的制备(按照方案二线路制备)
步骤11a:(4-氯苯并呋喃-7-基)甲醇(化合物0201-12)的制备:
氮气保护条件下,5-氯-2-甲基苯酚(2.0克,14.03毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(3.31克,16.83毫摩尔,1.2当量),和碳酸钾(2.9克,21.04毫摩尔,1.5当量)的N,N-二甲基甲酰胺混合物在120℃下搅拌过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相真空浓缩,得到4-氯-2-(2,2-二乙氧基乙氧基)-1-甲基苯(4克,粗品)。该产品不需要进一步纯化直接用于下一步。
氮气保护条件下,将上述得到的4-氯-2-(2,2-二乙氧基乙氧基)-1-甲基苯(4.18克,14.03毫摩尔,1.0当量)和多聚磷酸(7.09克,21.04毫摩尔,1.5当量)的二氯乙烷混合物回流过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到透明油状物4-氯-7-甲基苯并呋喃(1.98克,产率:84.98%)。
氮气保护条件下,将上述得到的4-氯-7-甲基苯并呋喃(1.98克,11.93毫摩尔,1.0当量)、N-溴代琥珀酰亚胺(2.54克,14.31毫摩尔,1.2当量)和偶氮二异丁腈(391毫克,2.38毫摩尔,0.2当量)的二氯乙烷(10毫升)溶液在72℃下搅拌过夜。冷却至室温后,减压除去溶剂。残留物用水稀释,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚)纯化,得到黄色油状物7-(溴甲基)-4-氯苯并呋喃(2.54克,收率:87.28%)。
上述得到的7-(溴甲基)-4-氯苯并呋喃(2.54克,10.37毫摩尔,1.0当量)和醋酸钾(10.16克,103.7毫摩尔,10.0当量)的N,N-二甲基甲酰胺混合物(20毫升)在室温下搅拌3小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到乙酸(4-氯苯并呋喃-7-基)甲基酯(2.29克,粗品),该产品不需要进一步纯化直接用于下一步。
往上述得到的乙酸(4-氯苯并呋喃-7-基)甲基酯(2.29克,10.22毫摩尔,1.0当量)的四氢呋喃(10毫升)溶液中加入的甲醇钠的甲醇溶液(5.4摩尔/升,3.8毫升,20.44毫摩尔,2.0当 量)。混合物在常温下搅拌1小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=200/1-4/1)纯化,得到(4-氯苯并呋喃-7-基)甲醇(1.3克,收率:69.89%)为黄色固体。LCMS(ESI):m/z=183(M+H)
+.
步骤11b:4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯tert-butyl(化合物0202-12)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(160毫克,0.548毫摩尔,1当量),(4-氯苯并呋喃-7-基)甲醇(0201-12)(120毫克,0.66毫摩尔,1.2当量)、碳酸铯(356毫克,1.096毫摩尔,2.0当量),4,5-双二苯基膦-9,9-二甲基氧杂蒽(76毫克,0.131毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(60毫克,0.065毫摩尔,0.1当量)的甲苯(10毫升)的混合物在125℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化粗产物,得到黄色油状物4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(235毫克,产率:98.74%)。LCMS(ESI):m/z=443(M+H)
+.
步骤11c:2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(化合物0203-12)的制备:向4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-12)(235毫克,0.53毫摩尔,1.0当量)和氯化氢的二氧六环溶液(4M,1毫升)的混合物中加入二氧六环(2毫升),混合物在室温下搅拌过夜。混合物过滤。残留物用二氧六环洗涤。残留物干燥,得到黄色固体2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(142毫克,收率:70.64%).LCMS(ESI):m/z=343(M+H)
+.
步骤11d:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-12)的制备:2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(0203-12)(142毫克,0.374毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(73毫克,0.249毫摩尔,1.0当量)和N,N-二异丙基乙胺(161毫克,1.248毫摩尔,4.0当量)的N-甲基吡咯烷酮(5毫升)溶液在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色固体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(115毫克,收率:77.18%)。LCMS(ESI):m/z=601(M+H)
+.
步骤11e:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物12)的制备:(S)-2-((4-(6-((4-氯苯并呋喃-7-基) 甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-12)(115毫克,0.19毫摩尔,1.0当量)和一水合氢氧化锂(16毫克,0.38毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,然后形成固体沉淀物。混合物过滤。残留物用水洗。混合物用甲醇打浆得到白色固体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(88毫克,收率:78.57%)。LCMS(ESI):m/z=587(M+H)
+.
1HNMR(500MHz,DMSO)δ12.74(s,1H),8.29(s,1H),8.15(d,J=2.2Hz,1H),7.82(s,1H),7.75–7.60(m,2H),7.44(d,J=7.9Hz,1H),7.34(d,J=8.0Hz,1H),7.03(d,J=2.1Hz,1H),6.88(d,J=7.1Hz,1H),6.69(d,J=7.9Hz,1H),5.63(s,2H),5.10(d,J=5.6Hz,1H),4.80(dd,J=15.3,7.2Hz,1H),4.72–4.63(m,1H),4.46(dd,J=13.7,7.4Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.95(s,1H),3.78(d,J=10.6Hz,1H),2.93(d,J=71.7Hz,2H),2.76–2.56(m,2H),2.42(s,1H),2.34–2.03(m,2H),1.80(s,4H).
实施例12:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物14)的制备(按照方案二线路制备)
步骤12a:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物0204-14)的制备:将2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(0203-12)(139毫克,0.366毫摩尔,1.5当量),(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0116-1)(72毫克,0.244毫摩尔,1.0当量)和N,N-二异丙基乙胺(126毫克,0.976毫摩尔,4.0当量)的N-甲基吡咯烷酮(5毫升)溶液在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色固体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(70毫克,收率:47.62%)。LCMS(ESI):m/z=602(M+H)
+.
步骤12b:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物14)的制备:将(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0204-14)(70毫克,0.116毫摩尔,1.0当量)和一水合氢氧化锂(10毫克,0.232毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1)得到黄色 固体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(30毫克,收率:44.12%)。LCMS(ESI):m/z=588(M+H)
+.
1H NMR(500MHz,DMSO)δ12.99(s,1H),8.39–7.93(m,3H),7.61(d,J=6.7Hz,1H),7.41(s,1H),7.32(d,J=6.9Hz,1H),7.01(s,1H),6.87(s,1H),6.67(d,J=7.7Hz,1H),5.61(s,2H),5.29(d,J=93.9Hz,1H),4.80(d,J=53.8Hz,2H),4.42(d,J=50.8Hz,2H),3.89(d,J=105.4Hz,2H),2.97(s,2H),2.75–2.51(m,3H),2.31(d,J=53.9Hz,2H),1.77(d,J=15.7Hz,4H).
实施例13:(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物15)的制备(按照方案二线路制备)
步骤13a:4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-15)的制备:在氮气保护和-70℃下,往4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-12)(200毫克,0.452毫摩尔,1当量)的10毫升四氢呋喃溶液中加入二异丙基氨基锂(0.45毫升,2摩尔/升四氢呋喃,0.905毫摩尔,2当量)。混合物在-70℃下搅拌1小时。往混合物中加入六氯乙烷(107毫克,0.452毫摩尔,1当量)的四氢呋喃(1毫升)。混合物在-70℃下搅拌1小时。反应用氯化铵淬灭。混合物用乙酸乙酯萃取。有机相用饱和食盐水洗涤和硫酸钠干燥。将混合物减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化,得到透明油状物4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(180毫克,产率:83.72%)。LCMS(ESI):m/z=477(M+H)
+.
步骤13b:2-((2,4-二氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0203-15)的制备:将4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-15)(180毫克,0.377毫摩尔,1.0当量)和对甲苯磺酸(195毫克,1.132毫摩尔,3.0当量)的乙酸乙酯(15毫升)溶液在60℃下搅拌过夜。混合物冷却至室温。混合物过滤。残留物用乙酸乙酯洗涤。残留物干燥,得到白色固体2-((2,4-二氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(253毫克,粗品).LCMS(ESI):m/z=377(M+H)
+.
步骤13c:(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-15)的制备:2-((2,4-二氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0203-15)(206毫克,0.377毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(92毫克,0.314毫摩尔,1.0当量)和碳酸钾(173毫克,1.256毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃的下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯),得到白色固体(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂 环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(180毫克,收率:90.9%)。LCMS(ESI):m/z=635(M+H)
+.
步骤13d:(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物15)的制备:将(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-15)(64毫克,0.1毫摩尔,1.0当量)和一水合氢氧化锂(13毫克,0.3毫摩尔,3.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1),得到白色固体(S)-2-((4-(6-((2,4-二氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(55毫克,收率:88.71%)。LCMS(ESI):m/z=621(M+H)
+.
1HNMR(500MHz,DMSO)δ12.67(s,1H),8.26(s,1H),7.80(d,J=8.2Hz,1H),7.63(dd,J=12.7,8.1Hz,2H),7.44(d,J=8.0Hz,1H),7.37(d,J=8.1Hz,1H),7.15(s,1H),6.86(d,J=7.2Hz,1H),6.68(d,J=8.1Hz,1H),5.59(s,2H),5.11(d,J=5.0Hz,1H),4.79(dd,J=15.2,7.0Hz,1H),4.65(d,J=14.0Hz,1H),4.46(dd,J=13.5,7.1Hz,1H),4.41–4.31(m,1H),3.94(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.99(d,J=10.4Hz,1H),2.85(d,J=10.7Hz,1H),2.76–2.66(m,1H),2.58(s,1H),2.45(d,J=8.9Hz,1H),2.20(dt,J=21.7,10.4Hz,2H),1.83–1.64(m,4H).
实施例14:(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物16)的制备(按照方案二线路制备)
步骤14a:4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-16)的制备:在氮气保护和-70℃下,往4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-12)(500毫克,1.13毫摩尔,1当量)的10毫升四氢呋喃溶液中加入二异丙基氨基锂(1.13毫升,2摩尔/升四氢呋喃,2.26毫摩尔,2当量)。混合物在-70℃下搅拌1小时。往混合物中加入N-氟代双苯磺酰胺(356毫克,1.13毫摩尔,1当量)的四氢呋喃(1毫升)。混合物在-70℃下搅拌1小时。反应用氯化铵淬灭。混合物用乙酸乙酯萃取。有机相用饱和食盐水洗涤和硫酸钠干燥。将混合物减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化,得到透明油状物4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(200毫克,产率:38.38%)。LCMS(ESI):m/z=461(M+H)
+.
步骤14b:2-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0203-16)的制备:将4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-16)(200毫克,0.43毫摩尔,1.0当量)和对甲苯磺酸(224毫克,1.3毫摩尔,3.0当量) 的乙酸乙酯(15毫升)溶液在60℃下搅拌过夜。混合物冷却至室温。混合物过滤。残留物用乙酸乙酯洗涤。残留物干燥,得到白色固体2-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(208毫克,粗品).LCMS(ESI):m/z=361(M+H)
+.
步骤14c:(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-16)的制备:2-((4-氯-2-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0203-16)(104毫克,0.203毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.169毫摩尔,1.0当量)和碳酸钾(93毫克,0.676毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃的下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯),得到白色固体(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(76毫克,收率:72.38%)。LCMS(ESI):m/z=619(M+H)
+.
步骤14d:(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物16)的制备:(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-16)(76毫克,0.123毫摩尔,1.0当量)和一水合氢氧化锂(15毫克,0.369毫摩尔,3.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1),得到黄色固体(S)-2-((4-(6-((4-氯-2-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(54毫克,收率:72.97%)。LCMS(ESI):m/z=605(M+H)
+.
1HNMR(500MHz,DMSO)δ12.64(s,1H),8.26(d,J=0.8Hz,1H),7.80(dd,J=8.4,1.5Hz,1H),7.68–7.57(m,2H),7.42(d,J=8.2Hz,1H),7.38(d,J=8.2Hz,1H),6.86(d,J=7.3Hz,1H),6.68(d,J=8.2Hz,1H),6.49(d,J=6.4Hz,1H),5.56(s,2H),5.11(qd,J=7.2,2.7Hz,1H),4.79(dd,J=15.2,7.2Hz,1H),4.65(dd,J=15.2,2.7Hz,1H),4.47(dt,J=13.7,7.0Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),4.00–3.89(m,1H),3.78(d,J=13.5Hz,1H),2.99(d,J=11.2Hz,1H),2.85(d,J=11.3Hz,1H),2.74–2.66(m,1H),2.62–2.54(m,1H),2.43(ddd,J=11.1,8.9,5.6Hz,1H),2.28–2.11(m,2H),1.84–1.60(m,4H).
实施例15:(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物17)的制备(按照方案二线路制 备)
步骤15a:(4-氯-2-甲基苯并呋喃-7-基)甲醇(化合物0201-17)的制备:
氮气保护条件下,4-氯-2-羟基苯甲酸甲酯(1.87克,10.0毫摩尔,1.0当量),3-溴丙炔(1.42克,12毫摩尔,1.2当量),和碳酸钾(2.1克,15毫摩尔,1.5当量)的N,N-二甲基甲酰胺混合物在50℃下搅拌5小时。反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用N,N-二乙基苯胺(15毫升)溶解。往混合物中加入氟化铯(2.67克,17.63毫摩尔,1.3当量)。混合物在220℃下搅拌3小时。冷却到室温后,反应用水淬灭,残留物的pH值用2摩尔/升的盐酸调节至6,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=10/1)得到黄色固体4-氯-2-甲基苯并呋喃-7-羧酸甲酯(1.34克,产率:59.56%)。LCMS(ESI):m/z=225(M+H)
+.
氮气保护条件下,将上述得到的4-氯-2-甲基苯并呋喃-7-羧酸甲酯(1.34克,5.98毫摩尔,1.0当量),硼氢化钠(4.55克,119.64毫摩尔,20当量)的甲醇(13毫升)溶液在室温下搅拌3小时。反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化,得到黄色固体(4-氯-2-甲基苯并呋喃-7-基)甲醇(1.1克,收率:93.86%)。LCMS(ESI):m/z=196(M+H)
+.
步骤15b:4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-17)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(137毫克,0.46摩尔,1.0当量),(4-氯-2-甲基苯并呋喃-7-基)甲醇(0201-17)(100毫克,0.51毫摩尔,1.1当量)、碳酸铯(333毫克,1.02毫摩尔,2.0当量),4,5-双二苯基膦-9,9-二甲基氧杂蒽(59毫克,0.05毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(47毫克,0.148毫摩尔,0.2当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到黄色油状物4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(145毫克,产率:69.13%)。LCMS(ESI):m/z=456(M+H)
+.
步骤15c:2-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0203-17)的制备:将4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁 酯(0202-17)(145毫克,0.31毫摩尔,1.0当量)和对甲苯磺酸(159毫克,0.93毫摩尔,3.0当量)的乙酸乙酯(10毫升)溶液在60℃下搅拌过夜。混合物用水洗涤,残留物的pH用2摩尔/升的氢氧化钠溶液调节酯至8,并用乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩,得到2-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(92毫克,粗品),该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=357(M+H)
+.
步骤15d:(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-17)的制备:将2-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0203-17)(90毫克,0.24毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(60毫克,0.20毫摩尔,1.0当量)和碳酸钾(110毫克,0.80毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃的条件下搅拌16小时。在冷却至室温后,混合物用水稀释,并用乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯/石油醚=2/1)得白色固体(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(100毫克,收率:81.30%)。LCMS(ESI):m/z=615(M+H)
+.
步骤15e:(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物17)的制备:(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-17)(100毫克,0.16毫摩尔,1.0当量)和一水合氢氧化锂(21毫克,0.49毫摩尔,3.0当量)的乙腈/水=5/1(12毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤,残留物用水洗。残留物用厚制备薄层硅胶色谱法纯化(洗脱剂为:二氯甲烷/甲醇=10/1),得到黄色固体(S)-2-((4-(6-((4-氯-2-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(56毫克,收率:58.24%)。LCMS(ESI):m/z=601(M+H)
+.
1H NMR(500MHz,DMSO)δ12.67(s,1H),8.27(s,1H),7.80(s,1H),7.64(d,J=7.2Hz,2H),7.33(d,J=7.8Hz,1H),7.26(d,J=8.0Hz,1H),6.87(d,J=7.0Hz,1H),6.67(d,J=13.6Hz,2H),5.59(s,2H),5.10(s,1H),4.78(s,1H),4.66(d,J=14.2Hz,1H),4.46(dd,J=13.7,7.5Hz,1H),4.36(dt,J=8.9,5.9Hz,1H),3.94(s,1H),3.79(s,1H),2.99(s,1H),2.86(s,1H),2.70(dt,J=16.1,8.0Hz,1H),2.62(d,J=18.8Hz,1H),2.40(d,J=42.1Hz,4H),2.21(d,J=33.5Hz,2H),1.76(s,4H).
实施例16:(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲 基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物20)的制备(按照方案二线路制备)
步骤16a:4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-20)的制备:
往4-氯-2-甲基苯并呋喃-7-羧酸甲酯(885毫克,3.95毫摩尔,1当量)的10毫升四氢呋喃溶液中加入2N氢氧化钠溶液(5毫升)。混合物在40℃下搅拌16小时。反应冷却至室温。混合物的pH用2N盐酸调节至1,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物干燥得到黄色固体4-氯-2-甲基苯并呋喃-7-羧酸(700毫克,产率:84.03%)。LCMS(ESI):m/z=211(M+H)
+.
氮气保护条件下,将6-溴吡啶-2-胺(519毫克,3毫摩尔,1.0当量),4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1113毫克,3.6毫摩尔,1.2当量),碳酸钠(636毫克,6毫摩尔,2.0当量)和双三苯基膦二氯化钯(210毫克,0.3毫摩尔,0.1当量)的甲苯/乙醇/水(10/5/5毫升)的混合物在110℃下搅拌16小时。冷却至室温后,将反应液用乙酸乙酯萃取。有机相用饱和食盐水洗,和硫酸钠干燥。混合物减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-2/1)纯化,得到黄色油状物6-氨基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(600毫克,产率:72.46%)。LCMS(ESI):m/z=276(M+H)
+.
将6-氨基-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(600毫克,2.18毫摩尔,1.0当量)和钯碳(60毫克,Wt%=10%)的甲醇(15毫升)溶液在室温下搅拌5小时。混合物过滤。残留物用甲醇洗涤。残留物减压浓缩得到白色固体4-(6-氨基吡啶-2-基)哌啶-1-羧酸叔丁酯(553毫克,粗品).LCMS(ESI):m/z=278(M+H)
+.
在氮气保护和冰浴下,往4-氯-2-甲基苯并呋喃-7-羧酸(100毫克,0.476毫摩尔,1当量)的二氯甲烷/四氢呋喃/N,N-二甲基甲酰胺(10/5/0.01毫升)溶液中滴加入草酰氯(181毫克,1.428毫摩尔,3当量)。混合物在室温下搅拌5小时。混合物减压浓缩。残留物溶解于5毫升的二氯甲烷。往溶液里加入4-(6-氨基吡啶-2-基)哌啶-1-羧酸叔丁酯(131毫克,0.476毫摩尔,1当量)和三乙胺(144毫克,1.428毫摩尔,3当量)。混合物在室温下搅拌3小时。反应用水淬灭。混合物用二氯甲烷萃取。有机相用饱和食盐水洗涤和硫酸钠干燥。将混合物减压浓缩。残留物 用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-2/1)纯化,得到白色固体4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-羧酸叔丁酯(143毫克,产率:64.41%)。LCMS(ESI):m/z=470(M+H)
+.
步骤16b:4-氯-2-甲基-N-(6-(哌啶-4-基)吡啶-2-基)苯并呋喃-7-甲酰胺4-甲基苯磺酸盐(化合物0203-20)的制备:将4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-20)(143毫克,0.305毫摩尔,1.0当量)和对甲苯磺酸(158毫克,0.915毫摩尔,3.0当量)的乙酸乙酯(5毫升)溶液在60℃下搅拌过夜。混合物冷却至室温。混合物过滤。残留物用乙酸乙酯洗涤。残留物干燥,得到白色固体4-氯-2-甲基-N-(6-(哌啶-4-基)吡啶-2-基)苯并呋喃-7-甲酰胺4-甲基苯磺酸盐(200毫克,粗品).LCMS(ESI):m/z=370(M+H)
+.
步骤16c:(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-20)的制备:4-氯-2-甲基-N-(6-(哌啶-4-基)吡啶-2-基)苯并呋喃-7-甲酰胺4-甲基苯磺酸盐(0203-20)(106毫克,0.203毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.169毫摩尔,1.0当量)和碳酸钾(93毫克,0.676毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯),得到白色固体(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(70毫克,收率:66.03%)。LCMS(ESI):m/z=628(M+H)
+.
步骤16d:(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物20)的制备:将(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-20)(70毫克,0.11毫摩尔,1.0当量)和一水合氢氧化锂(14毫克,0.33毫摩尔,3.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1),得到白色固体(S)-2-((4-(6-(4-氯-2-甲基苯并呋喃-7-甲酰氨基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(48毫克,收率:70.03%)。LCMS(ESI):m/z=614(M+H)
+.
1HNMR(500MHz,DMSO)δ12.57(s,1H),10.33(s,1H),8.26(d,J=0.8Hz,1H),8.04(d,J=8.2Hz,1H),7.79(dd,J=8.7,7.2Hz,2H),7.72(d,J=8.2Hz,1H),7.64(d,J=8.4Hz,1H),7.42(d,J=8.2Hz,1H),7.09(d,J=7.5Hz,1H),6.79(d,J=1.0Hz,1H),5.09(ddd,J=14.4,7.2,2.8Hz,1H),4.82 (dd,J=15.2,7.2Hz,1H),4.67(dd,J=15.2,2.7Hz,1H),4.49(dd,J=13.6,7.7Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),3.95(d,J=13.5Hz,1H),3.81(d,J=13.5Hz,1H),3.01(d,J=11.2Hz,1H),2.89(d,J=11.2Hz,1H),2.78–2.62(m,2H),2.55(s,3H),2.42(ddd,J=15.9,11.1,7.0Hz,1H),2.23(dt,J=29.5,10.7Hz,2H),1.86(t,J=13.5Hz,2H),1.81–1.67(m,2H).
实施例17:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸(化合物23)的制备(按照方案一和二线路制备)
步骤17a:3-((2-甲氧基乙基)氨基)-4-硝基苯甲酸甲酯(化合物0118-23)的制备:往3-氟-4-硝基苯甲酸甲酯(0107-23)(1.0克,5.02毫摩尔,1.0当量)和N,N-二异丙基乙胺(1.34毫升,7.53毫摩尔,1.5当量)在四氢呋喃(15毫升)的混合物中加入2-甲氧基乙胺(0.45克,6.03毫摩尔,1.2当量)。混合物加热到55℃反应过夜。减压除去溶剂。残余物用水(30毫升)稀释。水层用乙酸乙酯(30毫升×4)萃取。合并的有机层用饱和食盐水(30毫升×1)洗涤,经无水硫酸钠干燥并浓缩,得到黄色固体3-((2-甲氧基乙基)氨基)-4-硝基苯甲酸甲酯(1.17克,产率:91%)。LCMS(ESI):m/z 255[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=5:1)。
步骤17b:4-氨基-3-((2-甲氧基乙基)氨基)苯甲酸甲酯(化合物0119-23)的制备:往3-((2-甲氧基乙基)氨基)-4-硝基苯甲酸甲酯(0118-23)(1.17克,4.61毫摩尔,1.0当量)在甲醇(30毫升)的混合物中加入钯碳(0.22g)。混合物在氢气球压力下室温搅拌3.5小时。混合物过滤。滤液在减压下浓缩,得到白色固体4-氨基-3-((2-甲氧基乙基)氨基)苯甲酸甲酯(1.03克,产率:100%)。LCMS(ESI):m/z 225[M+1]
+;TLC:Rf0.3(石油醚:乙酸乙酯=5:1)。
步骤17c:2-(氯甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0120-23)的制备:往4-氨基-3-((2-甲氧基乙基)氨基)苯甲酸甲酯(0119-23)(1.03克,4.60毫摩尔,1.0当量)和对甲苯磺酸一水合物(17.5毫克,0.09毫摩尔,0.02当量)在四氢呋喃(20毫升)的混合物中加入2-氯-1,1,1-三甲氧基乙烷(0.78克,5.06毫摩尔,1.1当量)。混合物加热到45℃反应过夜。减压除去溶剂。残余物在硅胶上进行柱色谱分离(石油醚∶乙酸乙酯5∶1),得到白色固体2-(氯甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(1.25克,产率:93%)。LCMS(ESI):m/z 283[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=2:1)。
步骤17d:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0205-23)的制备:往2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶对甲苯磺酸盐(0203-12)(90毫克,0.18毫摩尔,1.1当量)和2-(氯甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(0120-23)(45毫克,0.16毫摩尔,1.0当量)在乙腈(6毫升)的混合物中加入碳酸钾(66毫克,0.48毫摩尔,3.0当量)。混合物加热到60℃反应过夜。减压除去溶剂。残余物通过制备薄层色谱(石油醚:乙 酸乙酯1:1)纯化,得到白色固体2
-((4-(6
-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(69毫克,收率:74%)。LCMS(ESI):m/z 589[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=1:1)。
步骤17e:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸(化合物23)的制备:往2
-((4-(6
-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸甲酯(0205-23)(69毫克,0.12毫摩尔,1.0当量)在四氢呋喃(6毫升)和水(3毫升)的混合物中加入氢氧化锂一水合物(15毫克,0.36毫摩尔,3.0当量)。混合物加热到40℃反应过夜。混合物用水(15毫升)稀释。加入1N稀盐酸溶液调节pH=5,然后水层用乙酸乙酯(20毫升×3)萃取。合并的有机层用饱和食盐水(20毫升×1)洗涤,经无水硫酸钠干燥并浓缩。残余物通过制备薄层色谱(二氯甲烷∶甲醇=10∶1)纯化,得到白色固体2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧基乙基)-1H-苯并[d]咪唑-6-羧酸(52毫克,收率:78%)。LCMS(ESI):m/z 575[M+1]
+;TLC:Rf0.5(二氯甲烷:甲醇=10:1);熔点:123-126℃。
1H NMR(500MHz,DMSO)δ12.75(s,1H),8.24–8.11(m,2H),7.81(d,J=8.2Hz,1H),7.62(t,J=7.8Hz,2H),7.42(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.02(d,J=2.1Hz,1H),6.86(d,J=7.3Hz,1H),6.67(d,J=8.2Hz,1H),5.61(s,2H),4.60(s,2H),3.84(s,2H),3.75(t,J=5.0Hz,2H),3.21(s,3H),2.92(d,J=10.8Hz,2H),2.61(dd,J=19.2,7.7Hz,1H),2.21(t,J=10.7Hz,2H),1.75(dd,J=33.6,10.7Hz,4H).
实施例18:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24)的制备(按照方案一和二线路制备)
步骤18a:(S)-4-硝基-3-((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(化合物0118-24)的制备:氮气保护下,将3-氟-4-硝基苯甲酸甲酯(0107-23)(894.8毫克,4.4937毫摩尔,1.0当量),(S)-(四氢呋喃-2-基)甲胺(500毫克,4.9431毫摩尔,1.1当量)和碳酸钾(1242毫克,8.987毫摩尔,2.0当量)的N,N-二甲基甲酰胺混合物(10毫升)溶液在常温下搅拌3小时。反应用水淬灭,加入乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=5/1)纯化,得到(S)-4-硝基-3-((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(1120毫克,收率:88.96%)为黄色固体。LCMS(ESI):m/z=281(M+H)
+.
步骤18b:(S)-4-氨基-3-(((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(化合物0119-24)的制备:氢气下,(S)-4-硝基-3-((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(0118-24)(1120毫克,3.996毫摩尔,1.0当量)和钯/碳(112毫克,10%质量比)的四氢呋喃混合物(13毫升)在室温下搅拌过夜。 将反应液过滤,滤液减压浓缩得到黄色油状物(S)-4-氨基-3-(((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(1090毫克,产率109%)。该产品不需要进一步纯化直接用于下一步。
步骤18c:((S)-2-(氯甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0120-24)的制备:在氮气下,(S)-4-氨基-3-(((四氢呋喃-2-基)甲基)氨基)苯甲酸甲酯(0119-24)(1090毫克,4.35毫摩尔,1.0当量),2-氯-1,1,1-三甲氧基乙烷(807毫克,5.55毫摩尔,1.2单量)和一水合对甲苯磺酸(89.889毫克,0.522毫摩尔,0.12单量)的四氢呋喃(10毫升)溶液加热至45℃并搅拌过夜。冷却至室温后,反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,得到(S)-2-(氯甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(609.5毫克,收率:45.44%)为黄色固体。LCMS(ESI):m/z=309(M+H)
+.
步骤18d:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备(化合物0205-24)的制备:将2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0203-12)(96.82毫克,0.1948毫摩尔,1.2当量)和碳酸钾(89.5896毫克,0.6492毫摩尔,4.0当量)在乙腈(5毫升)中的混合物在60℃下搅拌至pH 7~8,然后将(S)-2-(氯甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0120-24)(50毫克,0.1623毫摩尔,1.0当量)加入到混合物中搅拌过夜。冷却至室温后,将反应液加水淬灭,用乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂:乙酸乙酯)得黄色固体化合物(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(79.8毫克,产率79.94)。LCMS(ESI):m/z=616(M+H)
+.
步骤18e:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24)的制备:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0205-24)(79.8毫克,0.1298毫摩尔,1.0当量)和一水合氢氧化锂(10.98毫克,0.1298毫摩尔,10单量)的乙腈/水=5/1(6毫升)混合物在40℃搅拌过夜。然后将混合物冷却至室温,通过加入1.0M H2SO4将酸碱℃调节至约6,之后形成固体沉淀。混合物过滤。残留物用水洗。混合物用甲醇打浆得到黄色固体(S)-2-(4-(6-(4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((四氢呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(49.8毫克,产率63.86%).LCMS(ESI):m/z=602(M+H)
+.
1HNMR(500MHz,DMSO)δ12.72(s,1H),8.21(s,1H),8.14(d,J=2.2Hz,1H),7.81(d,J=8.4Hz,1H),7.62(dd,J=14.0,6.4Hz,2H),7.42(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.02(d,J=2.2Hz,1H),6.86(d,J=7.3Hz,1H),6.67(d,J=8.2Hz,1H), 5.61(s,2H),4.55(d,J=13.6Hz,1H),4.44(dd,J=14.6,8.1Hz,1H),4.32–4.23(m,1H),3.99(d,J=13.6Hz,1H),3.77(dt,J=22.8,10.4Hz,2H),3.60(dd,J=14.0,7.3Hz,1H),3.01(d,J=11.2Hz,1H),2.85(d,J=10.8Hz,1H),2.61(td,J=11.2,5.6Hz,1H),2.27(t,J=10.7Hz,1H),2.17(t,J=10.6Hz,1H),2.11–2.01(m,1H),1.76(dd,J=15.5,8.4Hz,5H),1.71–1.61(m,2H).
实施例19:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物25)的制备(按照方案一和二线路制备)
步骤19a:4-氨基-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)苯甲酸甲酯(化合物0119-25)的制备:
1-乙基-1H-咪唑-5-羧酸(500毫克,3.6毫摩尔,1.0当量)的氯化亚砜(5毫升)溶液回流两个小时。冷却到室温后,真空下旋出溶剂,残留物溶于(6毫升)四氢呋喃,0℃下,滴加0.4摩尔每升的氨二氧六环溶液(1毫升)。滴加完后,混合物搅拌30分钟。加入碳酸钾(1克),混合物搅拌30分钟。混合物过滤,滤液真空浓缩,得到白色固体1-乙基-1H-咪唑-5-甲酰胺(500毫克,收率:100%)。LCMS(ESI):m/z=140(M-H)
+.
往1-乙基-1H-咪唑-5-甲酰胺(500毫克,3.6毫摩尔,1.0当量)的四氢呋喃(10毫升)溶液加入10摩尔每升的硼烷二甲硫醚溶液(0.72毫升,7.2毫摩尔,2.0当量)。混合物室温搅拌3小时。加入甲醇(2毫升),混合物搅拌30分钟。混合物真空浓缩,加入5摩尔每升的盐酸甲醇(5毫升),混合物搅拌10分钟。混合物真空浓缩得到白色固体(1-乙基-1H-咪唑-5-)甲胺盐酸盐(550毫克,收率:94.8%)。LCMS(ESI):m/z=126(M+H)
+.
将3-氟-4-硝基苯甲酸甲酯(367毫克,1.85毫摩尔,1.0当量),碳酸钾(511克,3.70毫摩尔,2.0当量)和(1-乙基-1H-咪唑-5-)甲胺盐酸盐(300毫克,1.85毫摩尔,1.0当量)的N-甲基吡咯烷酮(10毫升)混合物室温下搅拌过夜。加入乙酸乙酯和水,混合物分液,有机层用饱和食盐水洗、浓缩。残留物用硅胶柱层析纯化(洗脱剂为:二氯甲烷/甲醇=100/1到30/1)得到黄色固体3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)-4-硝基苯甲酸甲酯(340毫克,收率:60.5%)。LCMS(ESI):m/z=305(M+H)
+.
氢气条件下,将3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)-4-硝基苯甲酸甲酯(340毫克,1.1毫摩尔,1.0当量)和Pd/C(34毫克,10%质量比)的甲醇(6毫升)混合物室温下搅拌过夜。混合物过滤,滤液真空浓缩,得到白色固体4-氨基-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)苯甲酸甲酯(300毫克,收率:98.0%)。LCMS(ESI):m/z=275(M+H)
+.
步骤19b:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0205-25)的制备:
2-((4-氯苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0203-12)(231毫克,0.45毫摩尔,1.5当量),2-溴乙酸乙酯(50毫克,0.30毫摩尔,1.0当量)和碳酸钾(165毫克,1.20毫摩尔,4.0当量)在N,N-二甲基甲酰胺(10毫升)溶液中60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=20/1-1/1)纯化得白色固体2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酸乙酯(120毫克,收率:93.24%)。LCMS(ESI):m/z=429(M+H)
+.
在2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酸乙酯(120毫克,0.28毫摩尔,1.0当量)的甲醇/四氢呋喃=2/1(9毫升)溶液中加入氢氧化钠的水溶液(2摩尔/升,5毫升)。混合物在常温下搅拌3小时。混合物的pH值用1摩尔/升的稀盐酸调节至7,之后形成固体沉淀。混合物用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到粗产品2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酸(120毫克,粗品)。该产品不需要进一步纯化直接用于下一步。
在2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酸(120毫克,0.30毫摩尔,1.0当量)的N,N-二甲基甲酰胺(10毫升)溶液中加入4-氨基-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)苯甲酸甲酯(0119-25)(73毫克,0.27毫摩尔,0.9当量)和N,N-二异丙基乙胺(109毫克,0.84毫摩尔,2.8当量)。2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(136.8毫克,0.36毫摩尔,1.2当量)最后才加入到反应中。混合物在室温下搅拌过夜。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=15/1)得到黄色油状物4-(2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酰氨基)-3-((((1-乙基-1H-咪唑)-5-基)甲基)氨基)苯甲酸甲酯(50毫克,产率:28.19%)。LCMS(ESI):m/z=657(M+H)
+.
4-(2-(4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)乙酰氨基)-3-((((1-乙基-1H-咪唑)-5-基)甲基)氨基)苯甲酸甲酯在醋酸(10毫升)溶液中55℃下搅拌16小时。冷却至室温后,溶剂减压旋干。残留物用水稀释,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1)得黄色固体甲基2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(34毫克,收率:69.96%)。LCMS(ESI):m/z=639(M+H)
+.
步骤19c:2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物25)的制备:甲基2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0205-25)(34毫克,0.053毫摩尔,1.0当量)和一水合氢氧化锂(6.7毫克,0.16毫摩尔,3当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的稀硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1)得黄色固体2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸(18.3毫克,收率:55.25%)。LCMS(ESI):m/z=625(M+H)
+.
1H NMR(500MHz,DMSO)δ12.69(s,1H),8.15(d,J=1.9Hz,1H),8.06(s,1H),7.81(d,J=8.3Hz,1H),7.76–7.55(m,3H),7.42(d,J=8.0Hz,1H),7.34(d,J=7.9Hz,1H),7.03(d,J=1.9Hz,1H),6.81(d,J=7.2Hz,1H),6.67(t,J=7.1Hz,1H),6.46(s,1H),5.73(s,2H),5.61(s,2H),3.98(q,J=7.2Hz,2H),3.81(s,2H),2.87(d,J=10.8Hz,2H),2.53(d,J=11.4Hz,1H),2.15(t,J=11.1Hz,2H),1.72(d,J=11.8Hz,2H),1.60–1.42(m,2H),1.14(t,J=7.2Hz,3H).
实施例20:(S)-2-((4-(6-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物28)的制备(按照方案二线路制备)
步骤20a:(4-氟苯并呋喃-7-基)甲醇(化合物0201-28)的制备:
氮气保护条件下,将5-氟-2-甲基苯酚(3.0克,23.8毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(5.63克,28.5毫摩尔,1.2当量),碳酸钾(4.92克,35.7毫摩尔,1.5当量)和碘化钾(0.3克,10%质量比)的N,N-二甲基甲酰胺混合物在120℃下搅拌过夜。冷却到室温后,反应用水淬灭,加入乙酸乙酯萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩得到粗产品2-(2,2-二乙氧基乙氧基)-4-氟-1-甲基苯(5.3克,产率:92.0%)。该产品不需要进一步纯化直接用于下一步。
氮气保护条件下,将上述得到的2-(2,2-二乙氧基乙氧基)-4-氟-1-甲基苯(1.0克,4.13毫摩 尔,1.0当量),和多聚磷酸(3.5克,10.3毫摩尔,2.5当量)的1,2-二氯乙烷(20毫升)的混合物回流过夜。冷却到室温后,反应用水(40毫升)淬灭,并用乙酸乙酯(50毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到黄色油状4-氟-7-甲基苯并呋喃(300毫克,产率:49.0%)。LCMS(ESI):m/z=151(M+H)
+.
氮气保护条件下,将上述得到的4-氟-7-甲基苯并呋喃(300毫克,2.00毫摩尔,1.0当量)、N-溴代琥珀酰亚胺(415毫克,2.40毫摩尔,1.2当量)和偶氮二异丁腈(66毫克,0.4毫摩尔,0.2当量)的1,2-二氯乙烷(10毫升)混合物在72℃搅拌过夜。冷却至室温后,减压除去溶剂。残留物用水(20毫升)稀释,并用石油醚/乙酸乙酯=2/1(30毫升)萃取。有机层用饱和食盐水洗涤,用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体7-(溴甲基)-4-氟苯并呋喃(400毫克,收率:87.3%)。LCMS(ESI):m/z=229(M+H)
+.
将上述得到的7-(溴甲基)-4-氟苯并呋喃(400毫克,1.73毫摩尔,1.0当量)和醋酸钾(1.67克,17.3毫摩尔,10.0当量)的N,N-二甲基甲酰胺(15毫升)的混合物在室温下搅拌3小时。反应用水(20毫升)淬灭,加入乙酸乙酯(30毫升)萃取。有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到粗产品乙酸(4-氟苯并呋喃-7-基)甲基酯(500毫克粗品)。该产品不需要进一步纯化直接用于下一步。
往上述得到的乙酸(4-氟苯并呋喃-7-基)甲基酯(500毫克,2.42毫摩尔,1.0当量)的四氢呋喃(10毫升)溶液中加入的甲醇钠的甲醇溶液(5.4摩尔/升,0.7毫升,3.64毫摩尔,1.5当量)。混合物在常温下搅拌1小时。反应用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(15毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。残留物用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=4/1)纯化,得到黄色固体(4-氟苯并呋喃-7-基)甲醇(195毫克,收率:67.9%)。LCMS(ESI):m/z=167(M+H)
+.
步骤20b:4-(6
-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-28)的制备:氮气保护条件下,将4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(195毫克,0.66毫摩尔,1.0当量),(4-氟苯并呋喃-7-基)甲醇(0201-28)(132毫克,0.79毫摩尔,1.2当量)、碳酸铯(430毫克,1.32毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(61毫克,0.132毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(55毫克,0.06毫摩尔,0.1当量)的甲苯(10毫升)的混合物在120℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯(15毫升)洗涤。将滤液用水(20毫升)稀释,并用乙酸乙酯(20毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体4-(6
-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯 (230毫克,产率:82.1%)。LCMS(ESI):m/z=427(M+H)
+.
步骤20c:2-((4-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(化合物0203-28)的制备:将4-(6
-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-28)(110毫克,0.258毫摩尔,1.0当量)加入盐酸二氧六环(15毫升)溶液在室温下搅拌30分钟。将反应溶液减压浓缩得到白色固体2
-((4-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(84毫克粗品).LCMS(ESI):m/z=327(M+H)
+.
步骤20d:(S)-2-((4-(6
-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-28)的制备:将2-((4-氟苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(0203-28)(84毫克,0.257毫摩尔,1.2当量)、(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0116-3)(60毫克,0.21毫摩尔,1.0当量)和N,N-二异丙基乙胺(0.5毫升)的N-甲基吡咯烷酮(5毫升)的混合物在60℃下搅拌4小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2
-((4-(6
-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(99毫克,收率:80.4%)。LCMS(ESI):m/z=585(M+H)
+.
步骤20e:(S)-2-((4-(6-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物28)的制备:将(S)-2
-((4-(6-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-28)(99毫克,0.184毫摩尔,1.0当量)和一水合氢氧化锂(24毫克,0.553毫摩尔,3.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(12毫升)稀释,搅拌4小时,然后通过过滤收集固体。固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤,将滤液用无水硫酸钠干燥并减压浓缩。残留物真空干燥得到得到白色固体(S)-2-((4-(6-((4-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(42毫克,收率:40.0%)。LCMS(ESI):m/z=571(M+H)
+.熔点:131~143℃;
1H NMR(500MHz,DMSO)δ12.71(s,1H),8.27(s,1H),8.08(s,1H),7.80(d,J=8.3Hz,1H),7.70–7.56(m,2H),7.44(dd,J=7.8,5.5Hz,1H),7.08(dd,J=8.9,5.5Hz,2H),6.86(d,J=7.2Hz,1H),6.66(d,J=8.1Hz,1H),5.60(s,2H),5.11(d,J=5.2Hz,1H),4.79(dd,J=15.1,7.1Hz,1H),4.66(d,J=13.7Hz,1H),4.46(dd,J=13.6,7.2Hz,1H),4.37(dd,J=14.3,5.8Hz,1H),3.95(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),3.00(d,J=10.5Hz,1H),2.86(d,J=10.7Hz,1H),2.70(dt,J=16.0,7.8Hz,1H),2.61(t,J=11.5Hz,1H),2.44(t,J=13.0Hz,1H), 2.22(dt,J=21.6,10.6Hz,2H),1.86–1.65(m,4H).
实施例21:(S)-2-((4-(6-((4-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物30)的制备(按照方案二线路制备)
步骤21a:(4-甲基苯并呋喃-7-基)甲醇(化合物0201-30)的制备:
将2-羟基-4-甲基苯甲酸甲酯(831毫克,5.0毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(1.48克,7.5毫摩尔,1.5当量)和碳酸钾(1.73克,12.5毫摩尔,2.5当量)的N,N-二甲基甲酰胺混合物置于120℃下搅拌过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩,得到黄色油状物2-(2,2-二乙氧基乙氧基)-4-甲基苯甲酸甲酯(4克,粗品),该产品不需要进一步纯化直接用于下一步。
将上述得到的2-(2,2-二乙氧基乙氧基)-4-甲基苯甲酸甲酯(1.72克,5.0毫摩尔,1.0当量)和多聚磷酸(300毫克,0.88毫摩尔,0.18当量)的甲苯混合物回流过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=50/1)得到无色油状物4-甲基苯并呋喃-7-羧酸甲酯(496毫克,收率:52.2%)。
氮气保护下,将上述得到的4-甲基苯并呋喃-7-羧酸甲酯(430毫克,2.26毫摩尔,1.0当量)溶解于无水四氢呋喃中.混合物冷却至0℃。加入氢化铝锂(129毫克,3.39毫摩尔,1.5当量),混合物搅拌1.5小时。在0℃下依次加入0.13毫升水,0.13毫升15%氢氧化钠水溶液和0.39毫升水。混合物搅拌15分钟。加入1.6克无水硫酸钠,然后混合物在室温下搅拌0.5小时。混合物经减压过滤。滤液减压浓缩得到黄色固体(4-甲基苯并呋喃-7-基)甲醇(391毫克,粗品)。LCMS(ESI):m/z=145(M+H-H
2O)
+.
步骤21b:(S)-2-((4-(6-氯吡啶-2-基)哌啶1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-20)的制备:向4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(200毫克,0.67毫摩尔,1.0当量)在4毫升二氧六环的混合物中加入1.5毫升4M氯化氢的二氧六环溶液。混合物在室温下搅拌过夜。混合物减压浓缩至干。残留物加入到5毫升N-甲基吡咯烷酮中,再加入N,N-二异丙基乙胺(432毫克,3.35毫摩尔,5.0当量)。混合物在室温下搅拌5分钟。加入(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯 (化合物0116-3)(180毫克,0.61毫摩尔,0.9当量),然后混合物在60℃下搅拌过夜。混合物用乙酸乙酯稀释,用水和饱和食盐水洗。有机相减压浓缩,残留物经硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=5/1到1/1)得到黄色固体(S)-2-((4-(6-氯吡啶-2-基)哌啶1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(245毫克,收率:80.3%)。LCMS(ESI):m/z=455(M+H)
+.氮气保护下,将上述得到的(S)-2-((4-(6-氯吡啶-2-基)哌啶1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(120毫克,0.264毫摩尔,1.0当量)、(4-甲基苯并呋喃-7-基)甲醇(0201-30)(52毫克,0.317毫摩尔,1.2当量)、碳酸铯(215毫克,0.66毫摩尔,2.5当量),2-双环已基膦-2',6'-二异丙氧基联苯(12毫克,0.026毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(60毫克,0.013毫摩尔,0.05当量)的甲苯(20毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=33/1)得到黄色固体(S)-2-((4-(6-((4-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(68毫克,收率:44.4%)。LCMS(ESI):m/z=581(M+H)
+.
步骤21c:(S)-2-((4-(6-((4-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物30)的制备:(S)-2-((4-(6-((4-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-30)(68毫克,0.12毫摩尔,1.0当量)和一水合氢氧化锂(10毫克,0.23毫摩尔,2.0当量)在5毫升乙腈和1毫升水的混合溶剂中的混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用稀硫酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。混合物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=15/1)得到黄色固体(S)-2-((4-(6-((4-甲基苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(45毫克,收率:67.1%)。LCMS(ESI):m/z=567(M+H)
+,熔点:105~107℃。
1H NMR(500MHz,DMSO)δ12.70(s,1H),8.28(s,1H),7.98(d,J=2.2Hz,1H),7.81(d,J=8.1Hz,1H),7.73–7.56(m,2H),7.31(d,J=7.4Hz,1H),7.03(t,J=4.5Hz,2H),6.86(d,J=7.2Hz,1H),6.65(d,J=8.1Hz,1H),5.59(s,2H),5.11(d,J=5.2Hz,1H),4.79(dd,J=15.3,7.2Hz,1H),4.66(dd,J=15.2,2.6Hz,1H),4.46(dd,J=13.7,7.6Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.96(s,1H),3.79(s,1H),3.03(s,1H),2.87(s,1H),2.76–2.56(m,2H),2.45(d,J=16.4Hz,4H),2.20(dd,J=29.0,21.6Hz,2H),1.79(d,J=30.1Hz,4H).
实施例22:(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物31)的制备(按照方案二线路 制备)
步骤22a:(2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲醇(化合物0201-31)的制备:
将2-溴-5-(三氟甲基)苯酚(964毫克,4.0毫摩尔,1.0当量),3-溴丙炔(619毫克,5.2毫摩尔,1.3当量)和碳酸钾(884毫克,6.4毫摩尔,1.6当量)的N,N-二甲基甲酰胺混合物在50℃下搅拌3小时。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩,得到1-溴-2-(丙-2-炔-1-基氧基)-4-(三氟甲基)苯(920毫克,收率:82.1%),该产品不需要进一步纯化直接用于下一步。
在氮气保护下,将上述得到的1-溴-2-(丙-2-炔-1-基氧基)-4-(三氟甲基)苯(920毫克,3.3毫摩尔,1.0当量)和氟化铯(752毫克,4.95毫摩尔,14.5当量)的N,N-二乙基苯胺混合物置于220℃下搅拌5小时。冷却到室温后,混合物加入浓盐酸进行酸化,加入乙酸乙酯和石油醚的混合物溶剂萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂:石油醚)纯化,得到7-溴-2-甲基-4-(三氟甲基)苯并呋喃(650毫克,收率:70.6%)。
将上述得到的7-溴-2-甲基-4-(三氟甲基)苯并呋喃(580毫克,2.08毫摩尔,1.0当量)、1,3-二(二苯基膦)丙烷(172毫克,0.42毫摩尔,0.2当量),醋酸钯(95毫克,0.42毫摩尔,0.2当量)和三乙胺(2.1克,20.8毫摩尔,10.0当量)在25毫升甲醇和5毫升N,N-二甲基甲酰胺混合溶剂中的混合物加入到加压反应釜。反应釜中充入0.3兆帕的一氧化碳,在80℃下搅拌过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=50/1到20/1)得到黄色固体2-甲基-4-(三氟甲基)苯并呋喃-7-羧酸甲酯(521毫克,收率:97.1%)。
氮气保护下,将上述得到的2-甲基-4-(三氟甲基)苯并呋喃-7-羧酸甲酯(521毫克,2.0摩尔,1.0当量)溶解于无水四氢呋喃中.混合物冷却至0℃。加入氢化铝锂(116毫克,3.0毫摩尔,1.5当量),混合物搅拌1.5小时。在0℃下依次加入0.12毫升水,0.12毫升15%氢氧化钠水溶液和0.36毫升水。混合物搅拌15分钟。加入1.5克无水硫酸钠,然后混合物在室温下 搅拌0.5小时。混合物经减压过滤。滤液减压浓缩得到黄色油状物(2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲醇(507毫克,粗品)。LCMS(ESI):m/z=175(M+H-H
2O)
+.
步骤22b:4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-31)的制备:氮气保护下,将4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(150毫克,0.51毫摩尔,1.0当量)、(2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲醇(0201-31)(140毫克,0.61毫摩尔,1.2当量)、碳酸铯(416毫克,1.28毫摩尔,2.5当量),2-双环已基膦-2',6'-二异丙氧基联苯(36毫克,0.077毫摩尔,0.15当量)和三(二亚苄基丙酮)二钯(0)(42毫克,0.046毫摩尔,0.09当量)的甲苯(50毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用制备硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=20/1到6/1),得到黄色固体4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(220毫克,收率:88.0%)。LCMS(ESI):m/z=491(M+H)
+.
步骤22c:2-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(化合物0203-31)的制备:向4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-31)(220毫克,0.45毫摩尔,1.0当量)在5毫升二氧六环的混合物中加入1毫升4M氯化氢的二氧六环溶液。混合物在室温下搅拌过夜。混合物减压浓缩至干,得到白色固体2-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(250毫克,粗品)。LCMS(ESI):m/z=391(M+H)
+.
步骤22d:(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-31)的制备:将2-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)-6-(哌啶-4-基)吡啶盐酸盐(0203-21)(250毫克,0.45毫摩尔,2.6当量)加入到10毫升N-甲基吡咯烷酮中,再加入N,N-二异丙基乙胺(171毫克,1.25毫摩尔,7.3当量)。混合物在室温下搅拌5分钟。加入(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量),然后混合物在60℃下搅拌过夜。混合物用乙酸乙酯稀释,用水和饱和食盐水洗。有机相减压浓缩,残留物经制备薄层色谱纯化(洗脱剂:石油醚/乙酸乙酯=2/1),得到黄色固体(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(74毫克,收率:67.2%)。m/z=649(M+H)
+.
步骤22e:(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物31)的制备:(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲 基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-31)(74毫克,0.11毫摩尔,1.0当量)和一水合氢氧化锂(12毫克,0.8毫摩尔,2.5当量)在5毫升乙腈和1毫升水的混合溶剂中的混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。加入稀硫酸调节残留物的pH值至6,加入乙酸乙酯萃取,用饱和食盐水洗。有机相经过无水硫酸钠干燥,减压浓缩,残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=10/1)得到黄色固体(S)-2-((4-(6-((2-甲基-4-(三氟甲基)苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(55毫克,收率:75.3%)。LCMS(ESI):m/z=635(M+H)
+,熔点:126~128℃。
1H NMR(500MHz,DMSO)δ12.72(s,1H),8.27(s,1H),7.81(dd,J=8.4,1.4Hz,1H),7.64(t,J=7.8Hz,2H),7.54(d,J=7.9Hz,1H),7.47(d,J=7.8Hz,1H),6.87(d,J=7.3Hz,1H),6.78–6.67(m,2H),5.68(s,2H),5.10(qd,J=7.2,2.8Hz,1H),4.78(dd,J=15.2,7.2Hz,1H),4.64(dd,J=15.2,2.6Hz,1H),4.45(dt,J=13.9,7.0Hz,1H),4.35(dt,J=9.0,5.9Hz,1H),3.95(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.98(d,J=10.6Hz,1H),2.85(d,J=10.9Hz,1H),2.73–2.64(m,1H),2.62–2.54(m,1H),2.49–2.39(m,4H),2.21(dt,J=21.7,10.6Hz,2H),1.81–1.62(m,4H).
实施例23:(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物32)的制备(按照方案四线路制备)
步骤23a:(5-氟苯并呋喃-6-基)甲醇(化合物0401-32)的制备:
氮气保护下,向2-氟-5-羟基苯甲酸甲酯(2.0克,11.76毫摩尔,1.0当量)的乙酸(20毫升)的溶液中加入N-碘代丁二酰亚胺(2.9克,12.94毫摩尔,1.1当量),混合物在室温下搅拌过夜。将反应液倒入水中,并搅拌30分钟。将混合物过滤,然后滤饼用水洗涤并减压干燥得到白色固体2-氟-5-羟基-4-碘苯甲酸甲酯(2.7克,收率:77.59%)。LCMS(ESI):m/z=297(M+H)+.
氮气保护下,向上述得到的2-氟-5-羟基-4-碘苯甲酸甲酯(2.7克,9.12毫摩尔,1.0当量),三乙胺(2.76克,27.36毫摩尔,3.0当量),碘化亚铜(26毫克,0.137毫摩尔,0.02当量)和二(三苯基膦)二氯化钯(192毫克,0.274毫摩尔,0.03当量)的四氢呋喃(20毫升)的溶液中加入三甲基乙炔基硅烷(1.79克,18.24毫摩尔,2.0当量),混合物在70℃下搅拌过夜。冷却到室温后,减压除去溶剂,加入甲醇(20毫升),二异丙基乙胺(3.5克,27.36毫摩尔,3.0当量)和碘化亚铜(1.7克,9.12毫摩尔,1.0当量)。将混合物回流2小时。冷却到室温后,将混合物倒入水中。加入PE/EA=2/1的溶液进行萃取,将有机层减压浓缩。加入四氢呋喃(20毫升)和四丁基氟化铵三水合物(1.19克,4.56毫摩尔,0.5当量),混合物回流1小时。冷却到室温后, 混合物用水洗,并减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=100/1到20/1)得到黄色固体5-氟苯并呋喃-6-羧酸甲酯(1克,收率:55.87%)。LCMS(ESI):m/z=195(M+H)
+.
氮气保护条件下,在5-氟苯并呋喃-6-羧酸甲酯(241毫克,1.24毫摩尔,1.0当量)的四氢呋喃(20毫升)溶液中加入四氢锂铝(94.3毫克,2.48毫摩尔,2当量)。混合物在常温下搅拌3小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=20/1到5/1)得到黄色固体(5-氟苯并呋喃-6-基)甲醇(200毫克,收率:97.08%)。LCMS(ESI):m/z=167(M+H)
+.
步骤23b:4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0402-32)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(297毫克,1.0毫摩尔,1.0当量),(5-氟苯并呋喃-6-基)甲醇(0401-32(200毫克,1.2毫摩尔,1.2当量)、碳酸铯(652毫克,2.0毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(46.7毫克,0.1毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(45.8毫克,0.05毫摩尔,0.05当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=20/1-5/1)纯化粗产物,得到黄色油状物4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(250毫克,产率:58.55%)。LCMS(ESI):m/z=427(M+H)
+.
步骤23c:2-((5-氟苯并呋喃-6-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0403-32)的制备:在4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0402-32)(250毫克,0.587毫摩尔,1.0当量)的乙酸乙酯(10毫升)溶液中加入对甲苯磺酸一水合物(303毫克,1.76毫摩尔,3当量)。混合物在60℃下搅拌过夜。混合物过滤。残留物用乙酸乙酯洗涤。残留物干燥,得到白色固体2-((5-氟苯并呋喃-6-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(254毫克,收率:86.99%).LCMS(ESI):m/z=327(M+H)
+.
步骤23d:(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0404-32)的制备:将2-((5-氟苯并呋喃-6-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0403-32)(203毫克,0.407毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(80毫克,0.27毫摩尔,1.0当量)和碳酸钾(149毫克,1.08毫摩尔,4.0当量)的乙腈(10毫升)溶液在60℃的条件下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色油状物(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲 基)-1H-苯并[d]咪唑-6-羧酸甲酯(100毫克,收率:63.29%)。LCMS(ESI):m/z=585(M+H)
+.
步骤23e:(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物32)的制备:(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0404-32)(100毫克,0.17毫摩尔,1.0当量)和一水合氢氧化锂(11毫克,0.26毫摩尔,1.5当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗并减压干燥得白色固体(S)-2-((4-(6-((5-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(70毫克,收率:72.16%)。LCMS(ESI):m/z=571(M+H)
+.1H NMR(500MHz,DMSO)δ8.25(s,1H),8.01(d,J=2.2Hz,1H),7.80(dd,J=8.4,1.4Hz,1H),7.76(d,J=5.7Hz,1H),7.62(dd,J=12.2,4.8Hz,2H),7.49(d,J=9.9Hz,1H),6.94(dd,J=2.1,0.8Hz,1H),6.86(d,J=7.3Hz,1H),6.67(d,J=8.1Hz,1H),5.46(s,2H),5.11(qd,J=7.3,2.8Hz,1H),4.80(dd,J=15.2,7.2Hz,1H),4.66(dd,J=15.2,2.6Hz,1H),4.46(dt,J=13.9,7.0Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),3.95(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),3.00(d,J=11.2Hz,1H),2.86(d,J=11.3Hz,1H),2.74–2.66(m,1H),2.62(tt,J=11.4,4.0Hz,1H),2.48–2.40(m,1H),2.29–2.22(m,1H),2.22–2.14(m,1H),1.85–1.69(m,4H).
实施例24:(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物33)的制备(按照方案五线路制备)
步骤24a:(6-氟苯并呋喃-5-基)甲醇(化合物0501-33)的制备:
向2-氟-4-羟基苯甲醛(5.0克,35.7毫摩尔,1.0当量)的浓硫酸(30毫升)溶液中加入N-碘代丁二酰亚胺(8.84克,39.3毫摩尔,1.1当量),混合物在室温下搅拌3小时。将反应液倒入冰水中并搅拌1小时。将混合物过滤,然后滤饼用水洗涤并减压干燥得到粗产品2-氟-4-羟基-5-碘代苯甲醛(5.6克,粗品),该产品不需要进一步纯化直接用于下一步。
氮气保护下,向上述得到的2-氟-4-羟基-5-碘代苯甲醛(5.6克,20.8毫摩尔,1.0当量),三乙胺(6.3克,62.4毫摩尔,3.0当量),碘化亚铜(59.3毫克,0.31毫摩尔,0.02当量)和二(三苯基膦)二氯化钯(438毫克,0.62毫摩尔,0.03当量)的四氢呋喃(50毫升)的溶液中加入三甲基乙炔基硅烷(4.08克,41.6毫摩尔,2.0当量),混合物在70℃下搅拌过夜。冷却到室温后,减压除去溶剂,加入甲醇(150毫升),二异丙基乙胺(8.06克,62.4毫摩尔,3.0当量)和碘化亚 铜(4.0克,20.8毫摩尔,1.0当量)。将混合物回流2小时。冷却到室温后,将混合物倒入水中。加入PE/EA=2/1的溶液进行萃取,将有机层减压浓缩。加入四氢呋喃(50毫升)和四丁基氟化铵三水合物(2.7克,10.4毫摩尔,0.5当量),混合物回流1小时。冷却到室温后,混合物用水洗,并减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=100/1到20/1)得到黄色固体6-氟苯并呋喃-5-甲醛(2.1克,收率:61.19%)。LCMS(ESI):m/z=165(M+H)
+.
在6-氟苯并呋喃-5-甲醛(1克,6.10毫摩尔,1.0当量)的甲醇(25毫升)溶液中加入硼氢化钠(277毫克,7.32毫摩尔,1.2当量)。混合物在常温下搅拌1小时。反应用水淬灭,用乙酸乙酯萃取。有机相用食饱和盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到(6-氟苯并呋喃-5-基)甲醇(947毫克,收率:93.58%)为黄色固体。LCMS(ESI):m/z=167(M+H)
+.
步骤24b:4-(6
-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0502-33)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(350毫克,1.18毫摩尔,1.0当量),(6-氟苯并呋喃-5-基)甲醇(0501-33)(235毫克,1.416毫摩尔,1.2当量)、碳酸铯(769毫克,2.36毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(55毫克,0.118毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(54毫克,0.059毫摩尔,0.05当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1-5/1)纯化粗产物,得到黄色油状物4-(6
-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(450毫克,产率:89.64%)。LCMS(ESI):m/z=427(M+H)
+.
步骤24c:2-((6-氟苯并呋喃-5-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化合物0503-33)的制备:在4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0502-33)(450毫克,1.06毫摩尔,1.0当量)的乙酸乙酯(10毫升)溶液中加入对甲苯磺酸一水合物(546毫克,3.17毫摩尔,3当量)。混合物在60℃下搅拌过夜。混合物过滤。残留物用乙酸乙酯洗涤。残留物干燥,得到白色固体2-((6-氟苯并呋喃-5-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(510毫克,收率:96.59%).LCMS(ESI):m/z=327(M+H)
+.
步骤24d:(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物0504-33)的制备:将2-((6-氟苯并呋喃-5-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0503-33)(127毫克,0.255毫摩尔,1.5当量),(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(0116-1)(50毫克,0.17毫摩尔,1.0当量)和碳酸钾(94毫克,0.68毫摩尔,4.0当量)的乙腈(10毫升)溶液在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白 色固体(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(66毫克,收率:66.37%)。LCMS(ESI):m/z=586(M+H)
+.
步骤24e:(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物33)的制备:(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯)0504-33)(66毫克,0.11毫摩尔,1.0当量)和一水合氢氧化锂(5毫克,0.12毫摩尔,1.1当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗并减压干燥得白色固体(S)-2-((4-(6-((6-氟苯并呋喃-5-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(40毫克,收率:63.49%)。LCMS(ESI):m/z=572(M+H)
+.
1HNMR(500MHz,DMSO)δ8.04(d,J=8.1Hz,1H),7.97(dd,J=14.1,5.2Hz,2H),7.81(d,J=7.3Hz,1H),7.66–7.53(m,2H),6.97–6.91(m,1H),6.86(d,J=7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.44(s,2H),5.03(d,J=4.6Hz,1H),4.87(dd,J=14.7,7.4Hz,1H),4.69(dd,J=14.7,3.0Hz,1H),4.41(dd,J=14.0,7.1Hz,1H),4.32(dt,J=12.2,6.1Hz,1H),4.05(d,J=13.6Hz,1H),3.82(d,J=13.6Hz,1H),3.00(d,J=11.2Hz,1H),2.87(d,J=11.2Hz,1H),2.61(td,J=11.0,5.5Hz,1H),2.50(s,1H),2.37–2.16(m,3H),1.88–1.66(m,4H).
实施例25:(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物44)的制备(按照方案六线路制备)
步骤25a:(7-氟苯并呋喃-6-基)甲醇(化合物0601-44)的制备
氮气保护条件下,2-氟-3-甲基苯酚(2.5克,19.84毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(4.69克,23.81毫摩尔,1.2当量),碳酸钾(4.11克,21.4毫摩尔,1.5当量)的N,N-二甲基甲酰胺(50毫升)混合物在120℃下搅拌过夜。冷却到室温后,反应液加水稀释,用乙酸乙 酯萃取。有机层用饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=10/1至5/1)纯化得到黄色油状产物1-(2,2-二乙氧基乙氧基)-2-氟-3-甲基苯(4.78克,产率:99.6%)。
氮气保护条件下,向多聚磷酸(15.89克,47.00毫摩尔,2.5当量)的甲苯(100毫升)溶液中加入1-(2,2-二乙氧基乙氧基)-2-氟-3-甲基苯(4.55克,18.80毫摩尔,1.0当量),混合物在120℃下搅拌过夜。冷却到室温后,反应液加水稀释,用乙酸乙酯萃取。有机层干燥并减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚)得到黄色油状产物7-氟-6-甲基苯并呋喃(2.08克,产率:70.2%)。
氮气保护条件下,7-氟-6-甲基苯并呋喃(2.0克,13.33毫摩尔,1.0当量)、N-溴代丁二酰亚胺(2.85克,15.99毫摩尔,1.2当量)和偶氮二异丁腈(437毫克,2.67毫摩尔,0.2当量)的1,2-二氯乙烷(25毫升)溶液在72℃下搅拌过夜。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(洗脱剂:石油醚)纯化,得到白色固体产物6-(溴甲基)-7-氟苯并呋喃(2.13克,收率:69.8%)。
6-(溴甲基)-7-氟苯并呋喃(2.03克,8.86毫摩尔,1.0当量)和醋酸钾(8.7克,88.6毫摩尔,10.0当量)的N,N-二甲基甲酰胺混合物(40毫升)在室温下搅拌3小时。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物不经过进一步纯化,直接用于下一步。
氮气保护下,向乙酸(7-氟苯并呋喃-6-基)甲基酯(1.87克,8.99毫摩尔,1.0当量)的四氢呋喃溶液中加入甲醇钠的甲醇溶液(5.4摩尔/升,3.33毫升,17.98毫摩尔,2.0当量),混合物搅拌在室温下搅拌1.0小时。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=15/1至5/1)纯化,得到黄色固体产物(7-氟苯并呋喃-6-基)甲醇(1.2克,收率:80.4%)。
步骤25b:4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0602-44)的制备:氮气保护下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(178.8毫克,0.602毫摩尔,1.0当量),(7-氟苯并呋喃-6-基)甲醇(0601-44)(120毫克,0.722毫摩尔,1.2当量)、碳酸铯(391毫克,1.2毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(56毫克,0.12毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(55毫克,0.06毫摩尔,0.1当量)的甲苯(10毫升)混合物在120℃下搅拌过夜。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=20/1至10/1)纯化,得到黄色固体产物4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(254毫克,收率:98.8%)。LCMS(ESI):m/z=427[M+1]+.
步骤25c:2-((7-氟苯并呋喃-6-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(化 合物0603-44)的制备:在4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0602-44)(254毫克,0.596毫摩尔,1.0当量)的乙酸乙酯(10毫升)溶液加入一水合对甲苯磺酸(206毫克,1.19毫摩尔,2.0当量),混合物在60℃下搅拌过夜。反应液减压浓缩,残留物不经过进一步纯化,直接用于下一步。LCMS(ESI):m/z=327(M+H)
+.
步骤25d:(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0604-44)的制备:2-((7-氟苯并呋喃-6-基)甲氧基)-6-(哌啶-4-基)吡啶4-甲基苯磺酸盐(0603-44)(72毫克,0.22毫摩尔,1.3当量)、(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.169毫摩尔,1.0当量)和碳酸钾(93.5毫克,0.678毫摩尔,4.0当量)的乙腈(10毫升)溶液在60℃的条件下搅拌过夜。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用制备薄层色谱(二氯甲烷/甲醇=16/1)纯化,得到白色固体产物(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(89毫克,收率:90.3%)。LCMS(ESI):m/z=584(M+H)
+.
步骤25e:(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物44)的制备:(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0704-44)(89毫克,0.147毫摩尔,1.0当量)和一水合氢氧化锂(16.3毫克,0.388毫摩尔,2.5当量)的乙腈/水=5/1(12毫升)混合物在40℃下搅拌过夜。反应液用2摩尔/升的盐酸调节pH至6,用乙酸乙酯萃取,所得有机相经干燥,减压浓缩得到白色固体(S)-2-((4-(6-((7-氟苯并呋喃-6-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(76毫克,收率:87.7%)。LCMS(ESI):m/z=571(M+H)
+.
1H NMR(500MHz,DMSO)δ12.88(s,1H),8.36(s,1H),8.10(d,J=1.6Hz,1H),7.89(d,J=8.3Hz,1H),7.79(d,J=8.2Hz,1H),7.68(t,J=7.7Hz,1H),7.53–7.41(m,2H),7.12–7.04(m,1H),6.92(d,J=5.6Hz,1H),6.72(d,J=8.2Hz,1H),5.54(s,2H),5.05(d,J=5.9Hz,1H),4.84(dd,J=15.4,6.9Hz,2H),4.70(d,J=14.6Hz,1H),4.49(dd,J=13.5,7.2Hz,1H),4.35(dd,J=14.7,5.9Hz,1H),3.81(s,2H),3.35(s,3H),2.96(s,1H),2.71(dt,J=16.3,8.0Hz,1H),2.35(d,J=7.8Hz,1H),2.29–2.01(m,4H).
实施例26:(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物46)的制备(按照方案三线路制备)
步骤26a:7-(羟甲基)-3-甲基苯并呋喃-4-腈(化合物0201-46)的制备:
氮气保护条件下,4-溴-2-羟基苯甲酸甲酯(1.0克,4.33毫摩尔,1.0当量),1-溴丙-2-酮(711毫克,5.19毫摩尔,1.2当量),和碳酸钾(896毫克,6.49毫摩尔,1.5当量)的N,N-二甲基甲酰胺混合物在室温下搅拌1小时。反应用水淬灭,然后有固体析出。混合物过滤。残留物用水洗,干燥得到粗产品4-溴-2-(2-氧代丙氧基)苯甲酸甲酯(1克,粗品)。该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=287(M+H)
+.
氮气保护条件下,4-溴-2-(2-氧代丙氧基)苯甲酸甲酯(1克,3.48毫摩尔,1.0当量),和多聚磷酸(1.76克,5.23毫摩尔,1.5当量)的二氯乙烷混合物回流过夜。冷却到室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到黄色固体4-溴-3-甲基苯并呋喃-7-羧酸甲酯(357毫克,产率:38.26%)。LCMS(ESI):m/z=269(M+H)
+.
氮气保护条件下,4-溴-3-甲基苯并呋喃-7-羧酸甲酯(320毫克,1.19毫摩尔,1.0当量),四三苯基膦钯(137毫克,0.12毫摩尔,0.1当量)和氰化锌(208毫克,1.78毫摩尔,1.5当量)的N,N-二甲基甲酰胺(5毫升)溶液在90℃下搅拌过夜。冷却至室温后,反应用水淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化,得到黄色固体4-氰基-3-甲基苯并呋喃-7-羧酸甲酯(242毫克,收率:95.01%)。LCMS(ESI):m/z=216(M+H)
+.
在氮气保护和冰浴条件下,往四氢锂铝(55毫克,1.44毫摩尔,1.2当量)的四氢呋喃混合物中加入4-氰基-3-甲基苯并呋喃-7-羧酸甲酯(259毫克,1.2毫摩尔,1.0当量)。混合物在冰浴下搅拌1小时。反应用水淬灭。混合物用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=100/1-2/1)得到黄色固体7-(羟甲基)-3-甲基苯并呋喃-4-腈(135毫克,产率:60%)。LCMS(ESI):m/z=188(M+H)
+.
步骤26b:6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(化合物0303-46)的制备:氮气保护条件下,6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(0302-2)(174毫克,0.59毫摩尔,1.2当量),7-(羟甲基)-3-甲基苯并呋喃-4-腈(0201-46) (92毫克,0.492毫摩尔,1.0当量)、碳酸铯(320毫克,0.984毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(92毫克,0.197毫摩尔,0.4当量)和三(二亚苄基丙酮)二钯(0)(89毫克,0.098毫摩尔,0.2当量)的甲苯(10毫升)的混合物在125℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化粗产物,得到黄色油状物6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(123毫克,产率:56.16%)。LCMS(ESI):m/z=446(M+H)
+.
步骤26c:3-甲基-7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(化合物0304-46)的制备:将6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(0303-46)(123毫克,0.276毫摩尔,1.0当量)和盐酸的二氧六环溶液(4M,1毫升)的二氧六环(4毫升)溶液在室温下搅拌过夜。混合物减压浓缩,得到粗品3-甲基-7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(105毫克,粗品)。该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=346(M+H)
+.
步骤26d:(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0305-46)的制备:3-甲基-7-(((1',2',3',6'-四氢-[2,4'-联吡啶]]-6-基)氧基)甲基)苯并呋喃-4-甲腈盐酸盐(0304-46)(105毫克,0.276毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(54毫克,0.184毫摩尔,1.0当量)和N,N-二异丙基乙胺(95毫克,0.736毫摩尔,4.0当量)的N-甲基吡咯烷酮(5毫升)溶液在60℃下搅拌16小时。在冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色固体(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80毫克,收率:72.26%)。LCMS(ESI):m/z=604(M+H)
+.
步骤26e:(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物46)的制备:将(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0305-46)(80毫克,0.13毫摩尔,1.0当量)和一水合氢氧化锂(11毫克,0.26毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,然后形成固体沉淀物。混合物过滤。残留物用水洗。混合物用甲醇打浆得到黄色固体(S)-2-((6-((4-氰基-3-甲基苯并呋喃-7-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧 杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(66毫克,收率:78.14%)。LCMS(ESI):m/z=590(M+H)
+.
1H NMR(500MHz,DMSO)δ8.25(s,1H),8.05(s,1H),7.82(d,J=8.4Hz,1H),7.76–7.60(m,3H),7.50(d,J=7.8Hz,1H),7.06(d,J=7.5Hz,1H),6.76(d,J=8.2Hz,1H),6.61(s,1H),5.70(s,2H),5.05(qd,J=7.2,2.8Hz,1H),4.78(dd,J=15.2,7.2Hz,1H),4.63(d,J=13.0Hz,1H),4.46(dd,J=13.7,7.5Hz,1H),4.35(dt,J=8.9,5.9Hz,1H),4.05(d,J=13.6Hz,1H),3.91(d,J=13.5Hz,1H),3.19(d,J=12.6Hz,2H),2.65(ddd,J=17.7,14.8,12.1Hz,3H),2.45–2.31(m,6H).
实施例27:(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物47)的制备(按照方案七线路制备)
步骤27a:4-(羟甲基)苯并呋喃-7-腈(化合物0701-47)的制备:
氮气保护条件下,4-甲基苯并呋喃-7-腈(960毫克,6.11毫摩尔,1.0当量)、N-溴代琥珀酰亚胺(1300毫克,7.33毫摩尔,1.2当量)和偶氮二异丁腈(200毫克,1.22毫摩尔,0.2当量)的二氯乙烷(10毫升)溶液在72℃下搅拌过夜。冷却至室温后,减压除去溶剂。残留物用水稀释,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=200/1-10/1)纯化,得到4-(溴甲基)苯并呋喃-7-腈(968毫克,收率:67.22%)为白色固体。LCMS(ESI):m/z=236(M+H)
+.
4-(溴甲基)苯并呋喃-7-腈(968毫克,4.1毫摩尔,1.0当量)和醋酸钾(4克,41毫摩尔,10.0当量)的N,N-二甲基甲酰胺混合物(10毫升)在室温下搅拌3小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到粗产品乙酸(7-氰基苯并呋喃-4-基)甲基酯(766毫克,粗品)。该产品不需要进一步纯化直接用于下一步。
在乙酸(7-氰基苯并呋喃-4-基)甲基酯(766毫克,3.56毫摩尔,1.0当量)的四氢呋喃(5毫升)溶液中加入的甲醇钠的甲醇溶液(5.4摩尔/升,1.32毫升,7.12毫摩尔,2.0当量)。混合物在常温下搅拌1小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=200/1-2/1)纯化,得到4-(羟甲基)苯并呋喃-7-腈(968毫克,收率:66.23%)为黄色固体。LCMS(ESI):m/z=174(M+H)
+.
步骤27b:4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0702-47)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(178毫 克,0.6毫摩尔,1.2当量),4-(羟甲基)苯并呋喃-7-腈(0701-47(87毫克,0.5毫摩尔,1.0当量)、碳酸铯(325毫克,1毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(93毫克,0.2毫摩尔,0.4当量)和三(二亚苄基丙酮)二钯(0)(91毫克,0.1毫摩尔,0.2当量)的甲苯(10毫升)的混合物在125℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-10/1)纯化粗产物,得到黄色油状物4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(94毫克,产率:43.32%)。LCMS(ESI):m/z=434(M+H)
+.
步骤27c:4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-7-甲腈盐酸盐(化合物0703-47)的制备:将4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0702-47)(94毫克,0.217毫摩尔,1.0当量)和盐酸的二氧六环溶液(4M,1毫升)的二氧六环(4毫升)的混合物在室温下搅拌过夜。混合物减压浓缩,得到粗品4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-7-甲腈盐酸盐(100毫克,粗品).该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=334(M+H)
+.
步骤27d:(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0704-47)的制备:4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)苯并呋喃-7-甲腈盐酸盐(0703-47)(80毫克,0.217毫摩尔,1.3当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量)和N,N-二异丙基乙胺(88毫克,0.68毫摩尔,4.0当量)的N-甲基吡咯烷酮(5毫升)溶液在60℃下搅拌16小时。在冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色固体(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(40毫克,收率:40%)。LCMS(ESI):m/z=592(M+H)
+.
步骤27e:(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物47)的制备:(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0704-47)(40毫克,0.068毫摩尔,1.0当量)和一水合氢氧化锂(6毫克,0.136毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,然后形成固体沉淀物。混合物过滤。残留物用水洗。混合物用甲醇打浆并过滤得到白色固体(S)-2-((4-(6-((7-氰基苯并呋喃-4-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(33毫克,收率:84.61%)。LCMS(ESI):m/z=578(M+H)
+.
1H NMR(500MHz,DMSO)δ8.26(d,J=1.0Hz,1H), 8.22(d,J=2.2Hz,1H),7.84–7.77(m,2H),7.64(dd,J=8.0,6.9Hz,2H),7.47(d,J=7.8Hz,1H),7.28(d,J=2.2Hz,1H),6.87(d,J=7.3Hz,1H),6.73(d,J=8.1Hz,1H),5.69(s,2H),5.10(ddd,J=14.5,7.2,2.8Hz,1H),4.78(dd,J=15.2,7.2Hz,1H),4.65(dd,J=15.2,2.8Hz,1H),4.46(td,J=7.8,5.9Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),3.93(d,J=13.5Hz,1H),3.77(d,J=13.5Hz,1H),2.96(d,J=11.4Hz,1H),2.83(d,J=11.3Hz,1H),2.73–2.64(m,1H),2.56(tt,J=11.8,3.7Hz,1H),2.46–2.38(m,1H),2.18(ddd,J=31.6,11.8,9.6Hz,2H),1.74(t,J=13.5Hz,2H),1.70–1.56(m,2H).
实施例28:(S)-2-((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物49)的制备(按照方案八线路制备)
步骤28a:4-(羟甲基)-1-萘腈(化合物0801-49)的制备:
氮气保护下,1-溴-4-甲基萘(1.5克,6.78毫摩尔,1.0当量)和氰化亚铜(1.2克,13.57毫摩尔,2当量)的N,N-二甲基甲酰胺(20毫升)混合溶液在120℃下搅拌过夜。冷却至室温后,反应用水淬灭,用乙酸乙酯萃取。将混合物通过硅藻土过滤,固体用乙酸乙酯洗涤。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=15/1-10/1)纯化,得到4-甲基-1-萘腈(889毫克,收率:78.53%)为黄色固体。LCMS(ESI):m/z=168(M+H)+
氮气保护下,4-甲基-1-萘腈(400毫克,2.4毫摩尔,1.0当量)、N-溴代琥珀酰亚胺(511毫克,2.87毫摩尔,1.2当量)和偶氮二异丁腈(78.6毫克,0.479毫摩尔,0.2当量)的二氯乙烷(10毫升)溶液在72℃下搅拌过夜。冷却至室温后,减压除去溶剂。残留物用水稀释,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到粗产品4-(溴甲基)-1-萘腈(678毫克,粗品)。该产品不需要进一步纯化直接用于下一步。
4-(溴甲基)-1-萘腈(678毫克,2.76毫摩尔,1.0当量)和醋酸钾(2.7克,27.6毫摩尔,10.0当量)的N,N-二甲基甲酰胺混合物(10毫升)在室温下搅拌3小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩得到粗产品乙酸(4-氰基萘-1-基)甲基酯(823毫克,粗品)。该产品不需要进一步纯化直接用于下一步。
在乙酸(4-氰基萘-1-基)甲基酯(823毫克,3.65毫摩尔,1.0当量)的四氢呋喃(5毫升)溶液中加入的甲醇钠的甲醇溶液(5.4摩尔/升,1.35毫升,7.31毫摩尔,2.0当量)。混合物在常温下搅拌1小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸 钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=20/1-2/1)纯化,得到4-(羟甲基)-1-萘腈(300毫克,收率:44.91%)为黄色固体。LCMS(ESI):m/z=184(M+H)
+.
步骤28b:4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0802-49)的制备:氮气保护条件下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(202毫克,0.68毫摩尔,1当量),4-(羟甲基)-1-萘腈(0801-49)(150毫克,0.82毫摩尔,1.2当量)、碳酸铯(443.36毫克,1.36毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(32毫克,0.068毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(31毫克,0.034毫摩尔,0.05当量)的甲苯(10毫升)的混合物在125℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=100/1-8/1)纯化粗产物,得到黄色油状物4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(272毫克,产率:90.37%)。LCMS(ESI):m/z=444(M+H)
+.
步骤28c:4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1-萘甲腈盐酸盐(化合物0803-49)的制备:将4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0802-49)(272毫克,0.614毫摩尔,1.0当量)和盐酸的二氧六环溶液(4M,5毫升)在室温下搅拌过夜。混合物过滤。残留物用二氧六环洗涤。残留物干燥,得到黄色固体4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1-萘甲腈盐酸盐(215毫克,收率:92.28%).LCMS(ESI):m/z=344(M+H)
+.
步骤28d:(S)-2-(((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0804-49)的制备:4
-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)-1-萘甲腈盐酸盐(0803-49)(96毫克,0.254毫摩尔,1.5当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量)和碳酸钾(93.5毫克,0.678毫摩尔,4.0当量)的乙腈(5毫升)溶液在60℃下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得白色固体(S)-2-(((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(50毫克,收率:49.02%)。LCMS(ESI):m/z=602(M+H)
+.
步骤28e:(S)-2-((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物49)的制备:(S)-2-(((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0804-49)(50毫克,0.083毫摩尔,1.0当量)和一水合氢氧化锂(7毫克,0.17毫摩尔,2.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值 用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗并减压干燥得到白色固体(S)-2-((4-(6-((4-氰基萘-1-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(35毫克,收率:71.75%)。LCMS(ESI):m/z=588(M+H)
+.
1H NMR(500MHz,DMSO)δ12.68(s,1H),8.30(d,J=8.3Hz,2H),8.17(t,J=7.0Hz,2H),7.81(ddd,J=15.3,14.3,7.0Hz,4H),7.67(d,J=7.1Hz,2H),6.91(d,J=6.7Hz,1H),6.74(d,J=7.8Hz,1H),5.93(s,2H),5.07(d,J=5.1Hz,1H),4.78(dd,J=15.1,6.7Hz,1H),4.64(d,J=14.8Hz,1H),4.44(d,J=6.3Hz,1H),4.33(dt,J=9.0,5.9Hz,1H),3.94(s,1H),3.77(s,1H),2.97(s,1H),2.85(s,1H),2.74–2.55(m,2H),2.44–2.31(m,1H),2.18(s,2H),1.91(d,J=102.8Hz,4H).
实施例29:(S)-2-((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物53)的制备(按照方案二线路制备)
步骤29a:6-氟-7-(羟甲基)苯并呋喃-4-腈(化合物0201-53)的制备:
氮气保护下,向4-溴-2,6-二氟苯甲酸甲酯(2.5克,9.96毫摩尔,1.0当量)的甲醇溶液中加入甲醇钠的甲醇溶液(5.4摩尔/升,5.5毫升,29.88毫摩尔,3.0当量),混合物搅拌在室温下搅拌16.0小时。反应液加水稀释,用2摩尔/升盐酸调pH=5并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=10/1至5/1)纯化,得到无色油状产物4-溴-2-氟-6-甲氧基苯甲酸甲酯(2.5克,收率:96.2%)。
氮气保护下,向4-溴-2-氟-6-甲氧基苯甲酸甲酯(2.4克,9.12毫摩尔,1.0当量)的二氯甲烷(120毫升)溶液中加入三溴化硼(3.4克,13.69毫摩尔,1.5当量),混合物搅拌在0℃下搅拌1.5小时。反应液加甲醇淬灭,加水稀释并用二氯甲烷萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(展开剂:二氯甲烷)纯化,得到白色固体产物4-溴-2-氟-6-羟基苯甲酸甲酯(2.03克,收率:89.4%)。LCMS(ESI):m/z=247[M+1]
-。
氮气保护条件下,4-溴-2-氟-6-羟基苯甲酸甲酯(1.5克,6.02毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(1.42克,7.23毫摩尔,1.2当量),碳酸钾(1.25克,9.03毫摩尔,1.5当量)的N,N-二甲基甲酰胺(15毫升)混合物在120℃下搅拌过夜。冷却到室温后,反应液加水稀释, 用乙酸乙酯萃取。有机层用饱和盐水洗涤,用无水硫酸钠干燥,并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=10/1至8/1)纯化得到黄色油状产物4-溴-2-(2,2-二乙氧基乙氧基)-6-氟苯甲酸酯(2.15克,产率:98.2%)。
氮气保护条件下,向多聚磷酸(4.98克,14.73毫摩尔,2.5当量)的甲苯(80毫升)溶液加入4-溴-2-(2,2-二乙氧基乙氧基)-6-氟苯甲酸酯(2.15克,5毫摩尔,1.0当量),混合物在120℃下搅拌过夜。冷却到室温后,反应液加水稀释,用乙酸乙酯萃取。有机层干燥并减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚)得到黄色油状产物4-溴-6-氟苯并呋喃-7-羧酸甲酯(1.34克,产率:83.4%)。LCMS(ESI):m/z=273[M+1]
+。
氮气保护条件下,0℃下,向4-溴-6-氟苯并呋喃-7-羧酸甲酯(950毫克,3.48毫摩尔,1.0当量)的甲醇(30毫升)溶液中加入硼氢化钠(2.6克,69.60毫摩尔,20.0当量),混合物在室温下搅拌3.0小时。反应液加水淬灭并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(洗脱剂:石油醚/乙酸乙酯=10/1至2/1)纯化,得到黄色固体产物(4-溴-6-氟苯并呋喃-7-基)甲醇(850毫克,收率:99.6%)。
氮气保护条件下,向(4-溴-6-氟苯并呋喃-7-基)甲醇(630毫克,2.57毫摩尔,1.0当量)的N-甲基吡咯烷酮(20毫升)溶液加入氰化亚铜(2.3克,25.71毫摩尔,10.0当量)在190℃下搅拌8小时。冷却到室温后,反应液加水稀释,用乙酸乙酯萃取。有机层干燥并减压浓缩。残留物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=10/1至2/1)得到白色固体产物6-氟-7-(羟甲基)苯并呋喃-4-腈(92毫克,产率:18.8%)。
步骤29b:4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(化合物0202-53)的制备:氮气保护下,4-(6-氯吡啶-2-基)哌啶-1-羧酸叔丁酯(0104-1)(143毫克,0.482毫摩尔,1.0当量),6-氟-7-(羟甲基)苯并呋喃-4-腈(0201-53)(92毫克,0.482毫摩尔,1.0当量)、碳酸铯(314毫克,0.964毫摩尔,2.0当量)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(45毫克,0.0964毫摩尔,0.2当量)和三(二亚苄基丙酮)二钯(0)(44毫克,0.0482毫摩尔,0.1当量)的甲苯(10毫升)混合物在120℃下搅拌过夜。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用硅胶柱(石油醚/乙酸乙酯=10/1至5/1)纯化,得到黄色固体产物4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(180毫克,收率:82.6%)。LCMS(ESI):m/z=452[M+1]+.
步骤29c:6-氟-7-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基]苯并呋喃-4-甲腈盐酸盐(化合物0203-53)的制备:在4-(6-(((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯(0202-53)(180毫克,0.40毫摩尔,1.0当量)的二氧六环(4毫升)溶液中加入盐酸-二氧六环溶液(4摩尔溶液,1毫升),混合物在室温下搅拌过夜。反应液减压浓缩, 残留物不经过进一步纯化,直接用于下一步。LCMS(ESI):m/z=352(M+H)
+.
步骤29d:(S)-2-(((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0204-53)的制备:6-氟-7-(((6-(哌啶-4-基)吡啶基-2-基)氧基)甲基]苯并呋喃-4-甲腈盐酸盐(0203-53)(77毫克,0.220毫摩尔,1.3当量)、(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.169毫摩尔,1.0当量)和碳酸钾(93.5毫克,0.678毫摩尔,4.0当量)的乙腈(10毫升)溶液在60℃的条件下搅拌过夜。反应液加水稀释并用乙酸乙酯萃取,将有机相干燥并减压浓缩。残留物用制备薄层色谱(二氯甲烷/甲醇=16/1)纯化,得到黄色固体产物(S)-2-((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(55毫克,收率:53.4%)。LCMS(ESI):m/z=610(M+H)
+.
步骤29e:(S)-2-((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物53)的制备:(S)-2-((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶基-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0204-53)(55毫克,0.09毫摩尔,1.0当量)和一水合氢氧化锂(5.7毫克,0.135毫摩尔,1.5当量)的乙腈/水=5/1(6毫升)混合物在42℃下搅拌过夜。反应液用2摩尔/升的盐酸调节pH至6,用乙酸乙酯萃取,所得有机相经干燥,减压浓缩得到白色固体(S)-2-((4-(6-((4-氰基-6-氟苯并呋喃-7-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(39毫克,收率:72.8%)。LCMS(ESI):m/z=596(M+H)
+.
1H NMR(500MHz,DMSO)δ12.71(s,1H),8.35(d,J=2.1Hz,1H),8.26(s,1H),7.89(d,J=10.0Hz,1H),7.81(d,J=8.4Hz,1H),7.62(dd,J=16.8,8.9Hz,2H),7.20(d,J=2.1Hz,1H),6.87(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.69(s,2H),5.12(dd,J=7.1,2.5Hz,1H),4.80(dd,J=15.1,7.1Hz,1H),4.67(d,J=12.9Hz,1H),4.47(dd,J=13.7,7.6Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),3.95(d,J=13.6Hz,1H),3.80(d,J=13.6Hz,1H),2.99(d,J=10.9Hz,1H),2.86(d,J=11.0Hz,1H),2.76–2.68(m,1H),2.56(t,J=11.5Hz,1H),2.44(dd,J=18.8,8.1Hz,1H),2.20(dt,J=21.1,10.4Hz,2H),1.78–1.59(m,4H).
实施例30:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物54)的制备(按照方案九线路制备)
步骤30a:2-溴-6-((4-氯苯并呋喃-7-基)甲氧基)吡啶(化合物0901-54)的制备:氮气保护下,往(4-氯苯并呋喃-7-基)甲醇(0201-12)(230毫克,1.26毫摩尔,1.0当量)在四氢呋喃的混合物中在10-15℃加入六甲基二硅基胺基钾(1摩尔/升,3.78毫摩尔,3.0eq),混合物在15℃下搅拌1 小时。将2-溴-6-氟吡啶用四氢呋喃溶解,滴加入到反应体系中。混合物在15℃下搅拌1小时。混合物加水淬灭,用乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到黄色固体2-溴-6-((4-氯苯并呋喃-7-基)甲氧基)吡啶(140毫克,产率:32.87%)。LCMS(ESI):m/z=338(M+H)
+.
步骤30b:4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(化合物0902-54)的制备:氮气保护下,2-溴-6-((4-氯苯并呋喃-7-基)甲氧基)吡啶(0901-54)(150毫克,0.44毫摩尔,1.0当量),1-叔丁氧羰基哌嗪(92毫克,0.49毫摩尔,1.1当量)、碳酸铯(290毫克,0.89毫摩尔,2.0当量)、1,1'-联萘-2,2'-双二苯膦(31毫克,0.05毫摩尔,0.1当量)和三(二亚苄基丙酮)二钯(0)(28毫克,0.03毫摩尔,0.05当量)的甲苯(15毫升)的混合物在125℃下搅拌过夜。冷却至室温后,将反应液通过硅藻土过滤,固体用乙酸乙酯洗涤。将滤液减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到黄色油状液体4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(71毫克,产率:36.43%)。LCMS(ESI):m/z=443(M+H)
+.
步骤30c:1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪盐酸盐(化合物0903-54)的制备:将4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(0902-54)(71毫克,0.16毫摩尔,1.0当量)和盐酸的乙酸乙酯溶液(2M,4毫升)的甲醇(4毫升)溶液在40℃下搅拌2小时。混合物减压浓缩,得到粗品1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪盐酸盐(55毫克,粗品).该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=343(M+H)
+.
步骤30d:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0904-54)的制备:1-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪盐酸盐(0903-54)(55毫克,0.16毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(40毫克,0.13毫摩尔,1.0当量)和N,N-二异丙基乙胺(1毫升)的N-甲基吡咯烷酮(10毫升)溶液在60℃的下搅拌过夜。将反不混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯:石油醚=3/1)得黄色油状液体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(85毫克,收率:100%)。LCMS(ESI):m/z=603(M+H)
+.
步骤30e:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物54)的制备:(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0904-58)(85毫克,0.14毫摩尔,1.0当量)和一水合氢氧化锂(18毫克,0.43毫摩尔,3.0当量) 的乙腈/水=5/1(12毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。混合物用水洗涤,残留物pH值用1摩尔/升的盐酸调节至6。残留物加乙酸乙酯萃取并减压浓缩。粗产品用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷:甲醇=10/1),得到黄色固体(S)-2-((4-(6-((4-氯苯并呋喃-7-基)甲氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(71毫克,收率:86.25%)。LCMS(ESI):m/z=588(M+H)
+.
1H NMR(500MHz,DMSO)δ8.14(d,J=2.2Hz,1H),8.09(s,1H),7.81(d,J=8.3Hz,1H),7.49–7.42(m,2H),7.38(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.03(d,J=2.2Hz,1H),6.31(d,J=8.1Hz,1H),6.09(d,J=7.8Hz,1H),5.55(s,2H),5.15–5.08(m,1H),4.71(dd,J=15.2,7.0Hz,1H),4.59(dd,J=15.3,3.1Hz,1H),4.49(dd,J=13.3,8.0Hz,1H),4.37(dt,J=9.0,5.9Hz,1H),3.92(d,J=13.5Hz,1H),3.77(d,J=13.4Hz,1H),3.43(dd,J=12.0,7.3Hz,4H),3.29–3.24(m,4H),2.73–2.65(m,1H),2.47–2.41(m,1H).
实施例31:(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物55)的制备(按照方案三线路制备)
步骤31a:2-(4-氯苯并呋喃-7-基)乙烷-1-醇(化合物0201-55)的制备:
氮气保护下,往7-(溴甲基)-4-氯苯并呋喃(1克,4.08毫摩尔,1.0当量)和碳酸钾(1.12克,8.16毫摩尔,2当量)的四氢呋喃(10毫升)溶液中加入三甲基硅氰(808毫克,8.16毫摩尔,2当量)。混合物在90℃下搅拌4小时。反应冷却至室温。反应用水淬灭,用乙酸乙酯萃取。有机相用食饱和盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=50/1-10/1)纯化,得到黄色油状物2-(4-氯苯并呋喃-7-基)乙腈(880毫克,粗品)。LCMS(ESI):m/z=192(M+H)+.
往2-(4-氯苯并呋喃-7-基)乙腈(880毫克,6.24毫摩尔,1.0当量)的乙醇/水(10/10毫升)溶液中加入氢氧化钾(1.74克,31.2毫摩尔,5当量)。混合物在90℃下搅拌16小时。反应冷却至室温。混合物的pH值用2N盐酸调节至1,之后形成固体沉淀。混合物过滤。残留物用水洗涤和干燥,得到黄色固体2-(4-氯苯并呋喃-7-基)乙酸(510毫克,产率:38.75%)。LCMS(ESI):m/z=211(M+H)+.
氮气保护下,在0到10℃之间,往2-(4-氯苯并呋喃-7-基)乙酸(510毫克,2.43毫摩尔,1.0当量)的四氢呋喃(10毫升)溶液中滴加硼烷(0.64毫升,10摩尔/升的二甲硫醚,6.375毫摩 尔,2.5当量)。混合物在室温下搅拌1小时。反应用甲醇淬灭,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=20/1-5/1)纯化粗产物,得到透明油状物2-(4-氯苯并呋喃-7-基)乙烷-1-醇(397毫克,产率:41.18%)。LCMS(ESI):m/z=197(M+H)+.
步骤31b:6-((2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(化合物0303-55)的制备:氮气保护下,在0到10℃之间,在2-(4-氯苯并呋喃-7-基)乙烷-1-醇(0201-55)(338毫克,1.724毫摩尔,1.0当量)的四氢呋喃(20毫升)溶液中加入六甲基二硅基胺基钾(3.5毫升,1摩尔/升的四氢呋喃,3.448毫摩尔,2当量)。混合物在10℃下搅拌45分钟。2-溴-6-氟吡啶(0301-2)(303毫克,1.724毫摩尔,1当量)在10℃时分批加入到反应混合物中,混合物在室温下搅拌1小时。反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=200/1-20/1)纯化,得到黄色固体2-溴-6-(2-(4-氯苯并呋喃-7-基)乙氧基)吡啶(383毫克,产率:63.09%)。LCMS(ESI):m/z=352(M+H)
+.氮气保护下,上述得到的2-溴-6-(2-(4-氯苯并呋喃-7-基)乙氧基)吡啶(272毫克,0.77毫摩尔,1.05当量),4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(226毫克,0.73毫摩尔,1当量),碳酸钠(155毫克,1.46毫摩尔,2.0当量),二(三苯基膦)二氯化钯(51毫克,0.073毫摩尔,0.1当量)的N,N-二甲基甲酰胺/水=10/1(11毫升)混合物在92℃下搅拌过夜。在冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=20/1-10/1)纯化,得到透明油状物6-((2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(123毫克,收率:37.05%)。LCMS(ESI):m/z=455(M+H)
+.
步骤31c:6-((2-(4-氯苯并呋喃-7-基)乙氧基)-1',2',3',6'-四氢-2,4'-联吡啶4-甲基苯磺酸盐(化合物0304-55)的制备:往6-((2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(0303-55)(100毫克,0.22毫摩尔,1.0当量)的乙酸乙酯(5毫升)溶液中加入对甲苯磺酸一水合物(114毫克,0.66毫摩尔,3当量)。混合物在60℃下搅拌过夜。混合物冷却至室温。混合物减压浓缩。残留物不纯化直接用于下一步(103毫克,粗品)。LCMS(ESI):m/z=355(M+H)
+.
步骤31d:(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物0305-55)的制备:将6-((2-(4-氯苯并呋喃-7-基)乙氧基)-1',2',3',6'-四氢-2,4'-联吡啶4-甲基苯磺酸盐(0304-55)(103毫克,0.203毫摩尔,1.2当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(50毫克,0.17毫摩尔,1.0当量)和碳酸钾(94毫克,0.68毫摩尔,4.0当量)的乙腈 (10毫升)溶液在60℃的条件下搅拌16小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙酯)得黄色油状物(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(69毫克,收率:66.34%)。LCMS(ESI):m/z=613(M+H)
+.
步骤31e:(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物55)的制备:(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0604-55)(69毫克,0.11毫摩尔,1.0当量)和一水合氢氧化锂(14毫克,0.33毫摩尔,3当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。残留物的pH值用1摩尔/升的盐酸调节至6,之后形成固体沉淀。混合物过滤。残留物用水洗。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=10/1)得到黄色固体(S)-2-((6-(2-(4-氯苯并呋喃-7-基)乙氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(27毫克,收率:40.29%)。LCMS(ESI):m/z=599(M+H)
+.
1H NMR(500MHz,DMSO)δ12.72(s,1H),8.25(s,1H),8.08(d,J=2.2Hz,1H),7.81(dd,J=8.4,1.4Hz,1H),7.70–7.60(m,2H),7.25(q,J=8.0Hz,2H),7.03(d,J=7.4Hz,1H),6.98(d,J=2.2Hz,1H),6.70(s,1H),6.59(d,J=8.2Hz,1H),5.06(ddd,J=14.4,7.3,2.8Hz,1H),4.79(dd,J=15.2,7.3Hz,1H),4.70–4.55(m,3H),4.46(dd,J=13.6,7.7Hz,1H),4.35(dt,J=9.0,5.9Hz,1H),4.07(d,J=13.6Hz,1H),3.92(d,J=13.5Hz,1H),3.27–3.21(m,2H),2.80–2.69(m,2H),2.65(ddd,J=16.2,8.7,5.4Hz,1H),2.51(s,2H),2.44–2.34(m,1H).
实施例32:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-((((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-甲酸(化合物56)的制备(按照方案十线路制备)
步骤32a:4-(2,3-二羟基苯基)哌啶-1-羧酸叔丁酯(化合物1003-56)的制备:
0℃下往3-溴邻苯二酚(1.2克,6.35毫摩尔,1.0当量)和N,N-二异丙基乙胺(2.82 毫升,15.87毫摩尔,2.5当量)在二氯甲烷(20毫升)的混合物中逐滴加入2-(三甲基甲硅烷基)乙氧基甲基氯(2.65克,15.87毫摩尔,2.5当量)。混合物升到室温并搅拌2小时。减压除去溶剂。残余物在硅胶上进行柱色谱分离(石油醚:乙酸乙酯30:1),得到无色油状物(((((3-溴-1,2-亚苯基)双(氧基))双(亚甲基))双(氧基))双(乙烷-2,1-二基))双(三甲基硅烷)(2.27克,收率:79%)。TLC:Rf0.5(石油醚:乙酸乙酯=30:1)。
往(((((3-溴-1,2-亚苯基)双(氧基))双(亚甲基)双(氧基))双(乙烷-2,1-二基))双(三甲基硅烷)(2.27克,5.04毫摩尔,1.0当量),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(221毫克,0.302毫摩尔,0.06当量)和碳酸钠(1.60克,15.12毫摩尔,3.0当量)在二氧六环(30毫升)和水(7.5毫升)的混合物中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.87克,6.05毫摩尔,1.2当量)。混合物在氮气氛围下加热至85℃并搅拌16小时。减压下除去溶剂。残余物在硅胶上进行柱色谱分离(石油醚∶乙酸乙酯30∶1),得到淡黄色油状物4-(2,3-双((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(2.37克,产率:85%)。LCMS(ESI):m/z 552[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=10:1).
往4-(2,3-双((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.0克,1.81毫摩尔,1.0当量)在甲醇(15毫升)的混合物中加入钯碳(0.2g)。混合物在氢气球压力下室温搅拌过夜。混合物过滤。滤液在减压下浓缩。残余物在硅胶上进行柱色谱分离(石油醚∶乙酸乙酯30∶1),得到白色固体4-(2,3-双((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)哌啶-1-羧酸叔丁酯(0.48克,产率:48%)。LCMS(ESI):m/z554[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=10:1)。
4-(2,3-双((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)哌啶-1-羧酸叔丁酯(1.1克,1.99毫摩尔,1.0当量)在氯化氢甲醇溶液(4M溶液,15毫升)的混合物在室温下搅拌过夜。减压除去溶剂并在真空下干燥,得到白色固体4-(2,3-二羟基苯基)哌啶盐酸盐(601毫克,粗品)。LCMS(ESI):m/z 194[M+1]
+;TLC:Rf0.3(二氯甲烷:甲醇=10:1)。
往4-(2,3-二羟基苯基)哌啶盐酸盐(454毫克,1.99毫摩尔,1.0当量)和碳酸氢钠(502毫克,5.97毫摩尔,3.0当量)在甲醇(6毫升)中的混合物中加入二碳酸二叔丁酯(456毫克,2.09毫摩尔,1.05当量)。混合物在室温下搅拌3小时。减压除去溶剂。残余物经硅胶柱色谱纯化(二氯甲烷∶甲醇30∶1),得到灰色固体4-(2,3-二羟基苯基)哌啶-1-羧酸叔丁酯(583毫克,收率:100%)。LCMS(ESI):m/z 294[M+1]
+;TLC:Rf0.5(二氯甲烷:甲醇=10:1)。
步骤32b:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧 酸叔丁酯(化合物1004-56)的制备:往4-(2,3-二羟基苯基)哌啶-1-羧酸叔丁酯(1003-56)(0.25克,0.85毫摩尔,1.0当量),十二羰基三钌(27毫克,0.043毫摩尔,0.05当量)和碳酸氢钠(72毫克,0.85毫摩尔,1.0当量)在甲苯(10毫升)的混合物中加入4-氯-7-乙炔基苯并呋喃(化合物1101-57)(150毫克,0.85毫摩尔,1.0当量)。混合物在氮气氛围下加热到120℃并搅拌过夜。减压除去溶剂。残余物在硅胶上进行柱色谱分离(石油醚:乙酸乙酯30:1),得到淡黄色油状物4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧酸叔丁酯(70毫克,收率:18%)。LCMS(ESI):m/z 470[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=10:1)。
步骤32c:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶盐酸盐(化合物1005-56)的制备:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧酸叔丁酯(1004-56)(70毫克,0.15毫摩尔,1.0当量)在氯化氢二氧六环溶液(4M溶液,1.5毫升)的混合物在室温下搅拌1小时。减压除去溶剂并在真空下干燥,得到白色固体4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶盐酸盐(61毫克,粗品)。LCMS(ESI):m/z 370[M+1]
+;TLC:Rf0.3(二氯甲烷:甲醇=10:1)。
步骤32d:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物1006-56)的制备:往4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶盐酸盐(1005-56)(61毫克,0.15毫摩尔,1.0当量)和(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(0116-3)(44毫克,0.15毫摩尔,1.0当量)在乙腈(5毫升)的混合物中加入碳酸钾(51毫克,0.37毫摩尔,2.5当量)。混合物在60℃加热过夜。减压除去溶剂。残余物在硅胶上进行柱色谱分离(石油醚:乙酸乙酯3:1),得到白色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(81毫克,收率:87%)。LCMS(ESI):m/z 628[M+1]
+;TLC:Rf0.5(石油醚:乙酸乙酯=1:1)。
步骤32e:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物56)的制备:往2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(1006-56)(81毫克,0.13毫摩尔,1.0当量)在四氢呋喃(5毫升)和水(2毫升)的混合物中加入氢氧化锂一水合物(16毫克,0.39毫摩尔,3.0当量)。混合物在40℃加热过夜。混合物用水(15毫升)稀释。加入1N稀盐酸溶液调节pH=5然后水层用乙酸乙酯(15毫升×3)萃取。 合并的有机层用饱和食盐水(15毫升×1)洗涤,经无水硫酸钠干燥并浓缩。残余物通过制备薄层色谱(乙酸乙酯∶甲醇=10∶1)纯化,得到白色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(53毫克,收率:66%)。LCMS(ESI):m/z 614[M+1]
+;TLC:Rf0.5(乙酸乙酯:甲醇=10:1);熔点:165-167℃。
1H NMR(500MHz,DMSO)δ12.70(s,1H),8.27(d,J=2.1Hz,1H),8.21(d,J=6.3Hz,1H),7.80(d,J=8.5Hz,1H),7.64(d,J=8.4Hz,1H),7.44(dd,J=8.1,2.9Hz,1H),7.37(d,J=8.1Hz,1H),7.06(s,1H),6.75(dd,J=16.6,4.4Hz,3H),5.17–5.03(m,1H),4.78(dd,J=15.1,7.2Hz,1H),4.65(d,J=15.7Hz,1H),4.44(dt,J=13.0,7.6Hz,1H),4.41–4.32(m,1H),3.96(dd,J=13.5,3.6Hz,1H),3.78(d,J=13.5Hz,1H),3.01(s,1H),2.86(d,J=10.5Hz,1H),2.67(dd,J=23.9,16.3Hz,2H),2.44(s,1H),2.26(s,1H),2.16(s,4H),1.82–1.67(m,4H).
实施例33:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物57)的制备(按照方案十线路制备)
步骤33a:4-氯-7-乙炔基苯并呋喃(化合物1001-57)的制备:
2-溴-5-氯苯酚(5.0克,24.1毫摩尔,1.0当量),2-溴-1,1-二乙氧基乙烷(5.7克,28.9毫摩尔,1.2当量)和碳酸钾(6.7克,48.2毫摩尔,2.0当量)的N,N-二甲基甲酰胺(70毫升)溶液120℃搅拌过夜。冷却到室温后,混合物倒入水中,加入乙酸乙酯萃取,有机层用饱和食盐水洗、浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=200/1到100/1)得到黄色油状物1-溴-4-氯-2-(2,2-二乙氧基乙氧基)苯(8.0克,收率:102%)。
氮气保护下,1-溴-4-氯-2-(2,2-二乙氧基乙氧基)苯(8.0克,19.8毫摩尔,1.0当量)和多聚磷酸(12.5克,37.1毫摩尔,1.5当量)的二氯乙烷(150毫升)溶液在72℃下搅拌过夜。冷却到室温后,加入水,混合物搅拌30分钟。分液后,有机层用饱和食盐水洗、浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到无色液体7-溴-4-氯苯并呋喃(4.2克,收率:73.7%)。
氮气保护下,7-溴-4-氯苯并呋喃(2.0克,8.6毫摩尔,1.0当量),二三苯基膦二氯化钯(303毫克,0.43毫摩尔,0.05当量),碘化亚铜(41毫克,0.215毫摩尔,0.025当量),三甲基硅乙炔(4.2克,43.0毫摩尔,5.0当量)和三乙胺(15毫升)的四氢呋喃(20毫升)混合物在90℃下搅拌过夜。冷却到室温后,混合物过滤,滤液浓缩。残留物溶于乙酸乙酯,加入碳酸钾(1.0克), 混合物室温下搅拌2小时。加入水,混合物分液。有机层浓缩,残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到黄色固体4-氯-7-乙炔基苯并呋喃(1.4克,收率:92.1%)。
步骤33b:4-溴-2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环(化合物1002-57)的制备:氮气保护下,4-氯-7-乙炔基苯并呋喃(1001-57)(1.3克,7.4毫摩尔,1.0当量),3-溴-1,2-苯二酚(1.5克,8.1毫摩尔,1.1当量),碳酸氢钠(622毫克,7.4毫摩尔,1.0当量)和十二羰基钌(236毫克,0.37毫摩尔,0.05当量)的甲苯(50毫升)混合物在120℃下搅拌过夜。冷却到室温后,混合物过滤,滤液真空浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚)得到黄色固体4-溴-2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环(0.66克,收率:24.4%)。
步骤33c:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(化合物1004-57)的制备:氮气保护条件下,4-溴-2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环(1002-57)(660毫克,1.8毫摩尔,1.0当量),4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(612克,1.98毫摩尔,1.1当量),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(132毫克,0.18毫摩尔,0.1当量)和碳酸钠(572毫克,5.4毫摩尔,3.0当量)的二氧六环/水=10/1(11毫升)混合物在90℃下搅拌过夜。冷却到室温后,加入水和乙酸乙酯。混合物分液,有机层真空浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=200/1到30/1)得到黄色固体4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(680毫克,收率:80.5%)。LCMS(ESI):m/z=468(M+H)
+.
步骤33d:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶盐酸盐(化合物1005-57)的制备:4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1004-57)(100毫克,0.21毫摩尔,1.0当量)的4摩尔每升盐酸二氧六环(4毫升)溶液在室温下搅拌过夜。真空下旋出溶剂得到黄色固体4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶盐酸盐,该产品不需要进一步纯化直接用于下一步。
步骤33e:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物1006-57)的制备:将4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-1,2,3,6-四氢吡啶盐酸盐(1005-57)(80克,0.2毫摩尔,1.0当量),(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(35克,0.12毫摩尔,0.6当量)和碳酸钾(138毫克,1.0毫摩尔,5.0当量)的乙腈(6毫升)溶液在60℃下搅拌过夜。冷却到室温后,加入乙酸乙酯和水,混合物分液。有机层浓缩,残留物用硅胶薄层层析制备板纯化(洗脱剂为:乙酸乙 酯/甲醇=30/1)得白色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(55毫克,收率:44.4%)。LCMS(ESI):m/z=626(M+H)
+.
步骤33f:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物57)的制备:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(1006-57)(55毫克,0.09毫摩尔,1.0当量)和一水合氢氧化锂(19毫克,0.45毫摩尔,5.0当量)的乙腈/水=5/1(6毫升)混合物在40℃下搅拌过夜。冷却到室温后,加入水,加入1.0摩尔每升的盐酸调节pH=6-7。加入二氯甲烷萃取,有机层真空浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:二氯甲烷/甲醇=12/1)得白色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(40毫克,收率:74.1%)。LCMS(ESI):m/z=612(M+H)
+.
1H NMR(500MHz,DMSO)δ12.53(s,1H),8.25(s,1H),8.21(d,J=2.2Hz,1H),7.82(d,J=8.4Hz,1H),7.65(d,J=8.1Hz,1H),7.43(d,J=8.1Hz,1H),7.36(d,J=8.1Hz,1H),7.06(d,J=2.2Hz,1H),6.90–6.79(m,3H),6.39(d,J=3.5Hz,1H),5.11–5.02(m,1H),4.83–4.74(m,1H),4.64(d,J=13.1Hz,1H),4.49–4.40(m,1H),4.34(tt,J=11.8,5.9Hz,1H),4.06(d,J=13.7Hz,1H),3.92(d,J=13.6Hz,1H),3.25–3.19(m,2H),2.75(s,2H),2.65(dd,J=17.6,8.4Hz,1H),2.54(s,1H),2.47–2.35(m,2H),2.15(s,3H).
实施例34:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物58)(按照方案十线路制备)
步骤34a:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(化合物1006-58)的制备:往4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶盐酸盐(1005-56)(33毫克,0.08毫摩尔,1.0当量)和(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸甲酯(0116-1)(24毫克,0.08毫摩尔,1.0当量)在乙腈(4毫升)的混合物中加入碳酸钾(28毫克,0.20毫摩尔,2.5当量)。混合物在60℃加热过夜。减压除去溶剂。残余物通过制备薄层色谱(乙酸乙酯:甲醇60:1)纯化,得到淡黄色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(29毫克,收率:57%)。LCMS(ESI):m/z 629[M+1]
+;TLC:Rf0.5(二氯甲烷:甲醇=30:1)。
步骤34b:2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(化合物58)的制备:往2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸甲酯(1006-58)(29毫克,0.05毫摩尔,1.0当量)在四氢呋喃(4毫升)和水(2毫升)的混合物中加入氢氧化锂一水合物(6毫克,0.15毫摩尔,3.0当量)。混合物在40℃加热过夜。混合物用水(15毫升)稀释。加入1N稀盐酸溶液调节pH=5然后水层用乙酸乙酯(20毫升×3)萃取。合并的有机层用饱和食盐水(20毫升×1)洗涤,经无水硫酸钠干燥并浓缩。残余物通过制备薄层色谱(二氯甲烷∶甲醇=6∶1)纯化,得到白色固体2-((4-(2-(4-氯苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-3-(((S)-氧杂环丁烷-2-基)甲基)-3H-咪唑并[4,5-b]吡啶-5-羧酸(18毫克,收率:64%)。LCMS(ESI):m/z 615[M+1]
+;TLC:Rf0.5(二氯甲烷:甲醇=6:1);熔点:129-132℃。
1H NMR(500MHz,DMSO)δ8.22(s,1H),8.08(s,1H),7.99(d,J=7.5Hz,1H),7.44(d,J=8.0Hz,1H),7.37(d,J=8.0Hz,1H),7.06(s,1H),6.76(d,J=11.1Hz,3H),5.19(s,1H),4.82(s,1H),4.72(s,1H),4.45(s,1H),4.36(s,1H),3.98(s,1H),3.87(d,J=13.9Hz,1H),2.99(s,1H),2.90(s,1H),2.67(s,2H),2.52(s,1H),2.24(dd,J=26.5,14.2Hz,2H),2.17(d,J=12.3Hz,3H),1.87–1.63(m,4H).
实施例35:2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物61)的制备(按照方案十线路制备)
步骤35a:7-乙炔基苯并呋喃-4-腈(化合物1001-61)的制备:
将7-(羟甲基)苯并呋喃-4-腈(441毫克,2.55毫摩尔,1.0当量)和二氧化锰(3.33克,38.26毫摩尔,15.0当量)的二氯甲烷(10毫升)混合物在室温下搅拌过夜。反应液通过硅藻土过滤,并用二氯甲烷(15毫升)洗涤。滤液减压浓缩得到粗产品。粗产品用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=10/1)得到白色固体7-甲酰基苯并呋喃-4-腈(288毫克,产率:65.7%)。LCMS(ESI):m/z=172(M+H)
+.
氮气保护条件下,将7-甲酰基苯并呋喃-4-腈(251毫克,1.47毫摩尔,1.0当量),(1-重氮基-2-氧代丙基)膦酸二甲酯(338毫克,1.76毫摩尔,1.2当量)和碳酸钾(405毫克,2.94毫摩尔, 2.0当量)的甲醇(6毫升)混合物搅拌过夜。反应用水淬灭,并用乙酸乙酯萃取。有机层用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩。残留物用硅胶柱层析纯化(洗脱剂为:石油醚/乙酸乙酯=10/1)得到白色固体7-乙炔基苯并呋喃-4-腈(228毫克,产率:92.3%)。LCMS(ESI):m/z=168(M+H)
+.
步骤35b:4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧酸叔丁酯(化合物1004-61)的制备:氮气保护条件下,7-乙炔基苯并呋喃-4-腈(1001-61)(228毫克,1.37毫摩尔,1.0当量),4-(2,3-二羟基苯基)哌啶-1-羧酸叔丁酯(1003-56)(442毫克,1.51毫摩尔,1.1当量)、碳酸氢钠(115毫克,1.37毫摩尔,1.0当量)和十二羰基三钌(44毫克,0.07毫摩尔,0.05当量)的甲苯(6毫升)混合物在120℃下回流过夜。冷却至室温后,将反应液通过硅藻土过滤,并用乙酸乙酯(12毫升)洗涤。将滤液用水(15毫升)稀释,并用乙酸乙酯(10毫升)萃取。有机层用无水硫酸钠干燥,并减压浓缩。用柱色谱法(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化粗产物,得到白色固体4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧酸叔丁酯(80毫克,产率:12.7%)。LCMS(ESI):m/z=461(M+H)
+.
步骤35c:7-(2-甲基-4-(哌啶-4-基)苯并[d][1,3]二氧杂戊环-2-基)苯并呋喃-4-腈盐酸盐(化合物1005-61)的制备:往4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-羧酸叔丁酯(1004-61)(80毫克,0.17毫摩尔,1.0当量)的二氧六环(2毫升)溶液加入氯化氢的二氧六环溶液(4.0摩尔/升,4毫升),混合物在室温下搅拌过夜。减压除去溶剂得到粗产品7-(2-甲基-4-(哌啶-4-基)苯并[d][1,3]二氧杂戊环-2-基)苯并呋喃-4-腈盐酸盐。该产品不需要进一步纯化直接用于下一步。LCMS(ESI):m/z=361(M+H)
+.
步骤35d:2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(化合物1006-61)的制备:将7-(2-甲基-4-(哌啶-4-基)苯并[d][1,3]二氧杂戊环-2-基)苯并呋喃-4-腈盐酸盐(1005-61)(80毫克,假定为0.17毫摩尔,1.0当量)、(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(0116-3)(52毫克,0.17毫摩尔,1.0当量)和碳酸钾(96毫克,0.70毫摩尔,4.0当量)的乙腈(5毫升)的混合物在60℃下搅拌4小时。将反应混合物冷却至室温后加水,加乙酸乙酯萃取。有机相用饱和食盐水洗涤,用无水硫酸钠干燥并减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂为:石油醚/乙酸乙酯=1/10)得白色固体2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(50毫克,收率:46.7%)。LCMS(ESI):m/z=619(M+H)
+.
步骤35e:2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物61)的制备:将 2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(1006-61)(50毫克,0.08毫摩尔,1.0当量)和一水合氢氧化锂(7毫克,0.16毫摩尔,2.0当量)的乙腈/水=5/1(3毫升)混合物在40℃下搅拌过夜。混合物冷却到室温后,用1摩尔/升的盐酸调节pH约至6,然后形成固体沉淀物。浆液用水(12毫升)稀释,搅拌4小时,然后通过过滤收集固体。固体用水洗涤,然后在真空下干燥。将固体溶解在二氯甲烷/甲醇=1/2(5毫升)中,然后过滤,将滤液用无水硫酸钠干燥并减压浓缩。残留物真空干燥得到白色固体2-((4-(2-(4-氰基苯并呋喃-7-基)-2-甲基苯并[d][1,3]二氧杂戊环-4-基)哌啶-1-基)甲基)-1-(((S)-氧杂环丁烷-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(40毫克,收率:81.6%)。LCMS(ESI):m/z=605(M+H)
+.
1H NMR(500MHz,DMSO)δ12.72(s,1H),8.38(dd,J=7.9,2.2Hz,1H),8.27(d,J=3.0Hz,1H),7.82(t,J=7.9Hz,2H),7.64(d,J=8.3Hz,1H),7.59(dd,J=7.9,2.9Hz,1H),7.24(t,J=2.1Hz,1H),6.79(dd,J=6.6,3.4Hz,2H),6.77–6.73(m,1H),5.12(tt,J=12.1,3.6Hz,1H),4.78(dd,J=14.6,6.6Hz,1H),4.65(dd,J=12.5,4.7Hz,1H),4.50–4.42(m,1H),4.37(td,J=12.2,6.1Hz,1H),3.96(dd,J=13.5,4.7Hz,1H),3.79(d,J=13.6Hz,1H),3.02(d,J=9.2Hz,1H),2.87(d,J=8.9Hz,1H),2.68(dt,J=18.9,6.5Hz,2H),2.53(d,J=8.0Hz,1H),2.48–2.42(m,1H),2.25(d,J=10.9Hz,1H),1.74(dd,J=29.5,15.3Hz,4H).
实施例36 生物活性试验
本发明所用的对照化合物为PF-06882961,结构如下:
并且,本发明还合成了以下4个对照化合物:
其合成方法如下:
1.(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24067)的制备
步骤1-1:2-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-6-溴吡啶的制备:
在氮气保护下,将(苯并[d][1,3]二氧杂戊环-5-基)甲醇(304毫克,2.0毫摩尔,1.0当量)加入到无水四氢呋喃(10毫升)中,冷却至0℃。将1M六甲基二硅基氨基钾的四氢呋喃溶液(4.0毫升,4.0毫摩尔,2.0当量)滴加到混合物中,在0℃下搅拌一小时。将2-溴-6-氟吡啶(388毫克,2.2毫摩尔,1.1当量)的四氢呋喃溶液滴加到上述混合物中,在室温下搅拌一小时。加入氯化铵水溶液淬灭,用乙酸乙酯萃取。有机相经过水和饱和食盐水洗,无水硫酸钠干燥。有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=20/1)得到白色固体2-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-6-溴吡啶(600毫克,收率:97.4%)。LCMS(ESI):m/z=308(M+H)
+.
步骤1-2:6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯的制备:
在氮气保护下,将2-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-6-溴吡啶(600毫克,1.95毫摩尔,1.0当量)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(723毫克,2.34毫摩尔,1.2当量)、二氯二(三苯基膦)钯(69毫克,0.098毫摩尔,0.05当量)和碳酸钠(414毫克,3.9毫摩尔,2.0当量)加入到甲苯(20毫升)、乙醇(10毫升)和水(10毫升)的混合溶剂中,在110℃下搅拌反应两小时。用乙酸乙酯萃取,经水和饱和食盐水洗,无水硫酸钠干燥,有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=10/1到3/1)得到无水油状物6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(815毫克,收率:96%)。LCMS(ESI):m/z=411(M+H)
+。
步骤1-3:(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备:
在室温下,将6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(200毫克,0.49毫摩尔,1.8当量)溶解于5毫升二氧六环中,加入1毫升4M氯化氢的二氧六环溶液,混合物在室温下搅拌50分钟。混合物经过减压浓缩至干,所得残留物加入到5毫升N-甲基吡咯烷酮。加入1毫升二异丙基乙胺和(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80毫克,0.27毫摩尔,1.0当量),混合物在60℃下搅拌过夜。加入乙酸乙酯,用水和饱和食盐水洗,经过无水硫酸钠干燥,有机相减压浓缩,经制备薄层色谱纯化(展开剂:石油醚/乙酸乙酯=1/1)得到黄色固体(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(46毫克,收率:29.8%)。LCMS(ESI):m/z=569(M+H)
+。
步骤1-4:(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24067)的制备:
将(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(46毫克,0.081毫摩尔,1.0当量)和一水合氢氧化锂(11毫克,0.243毫摩尔,3.0当量)加入到5毫升乙腈和1毫升水的混合溶剂中,混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。加入稀硫酸调节残留物的pH值至6,加入乙酸乙酯萃取,用饱和食盐水洗。有机相经过无水硫酸钠干燥,减压浓缩,残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=15/1)得到黄色固体(S)-2-((6-(苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(22毫克,收率:48.8%)。LCMS(ESI):m/z=555(M+H)
+,熔点:144~146℃。
1H NMR(500MHz,DMSO)δ12.71(s,1H),8.26(s,1H),7.81(d,J=8.4Hz,1H),7.65(dd,J=8.0,5.8Hz,2H),7.06(d,J=7.5Hz,1H),7.00(s,1H),6.93(d,J=8.0Hz,1H),6.87(d,J=7.9Hz,1H),6.75(s,1H),6.68(d,J=8.2Hz,1H),5.99(s,2H),5.26(s,2H),5.06(dt,J=7.2,4.8Hz,1H),4.80(dd,J=15.2,7.2Hz,1H),4.66(dd,J=15.2,2.3Hz,1H),4.47(dd,J=13.7,7.6Hz,1H),4.36(dt,J=8.9,5.9Hz,1H),4.07(d,J=13.5Hz,1H),3.93(d,J=13.5Hz,1H), 3.21(d,J=17.6Hz,2H),2.81–2.71(m,2H),2.66(dt,J=16.3,7.7Hz,1H),2.54(s,2H),2.44–2.34(m,1H).
2.(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24068)的制备
步骤2-1:2-溴-6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)吡啶的制备:
在氮气保护下,将2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲醇(376毫克,2.0毫摩尔,1.0当量)加入到无水四氢呋喃(10毫升)中,冷却至0℃。将1M六甲基二硅基氨基钾的四氢呋喃溶液(4.0毫升,4.0毫摩尔,2.0当量)滴加到混合物中,在0℃下搅拌一小时。将2-溴-6-氟吡啶(388毫克,2.2毫摩尔,1.1当量)的四氢呋喃溶液滴加到上述混合物中,在室温下搅拌一小时。加入氯化铵水溶液淬灭,用乙酸乙酯萃取。有机相经过水和饱和食盐水洗,无水硫酸钠干燥。有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=20/1)得到无色固体2-溴-6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)吡啶(626毫克,收率:90.9%)。LCMS(ESI):m/z=344(M+H)
+.
步骤2-2:6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯的制备:
在氮气保护下,将2-溴-6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)吡啶(626毫克,1.82毫摩尔,1.0当量)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(675毫克,2.18毫摩尔,1.2当量)、二氯二(三苯基膦)钯(64毫克,0.09毫摩尔,0.05当量)和碳酸钠(386毫克,3.64毫摩尔,2.0当量)加入到甲苯(20毫升)、乙醇(10毫升)和水(10毫升)的混合溶剂中,在110℃下搅拌反应两小时。用乙酸乙酯萃取,经水和饱和食盐水洗,无水硫酸钠干燥,有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=10/1到3/1)得到黄色固体6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(800毫克,收率:98.4%)。LCMS(ESI):m/z=447(M+H)
+。
步骤2-3:(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备:
在室温下,将6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(300毫克,0.67毫摩尔,3.3当量)溶解于5毫升二氧六环中,加入1毫升4M氯化氢的二氧六环溶液,混合物在室温下搅拌60分钟。混合物经过减压浓缩至干,所得残留物加入到5毫升N-甲基吡咯烷酮。加入1毫升二异丙基乙胺和(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(60毫克,0.20毫摩尔,1.0当量),混合物在60℃下搅拌过夜。加入乙酸乙酯,用水和饱和食盐水洗,经过无水硫酸钠干燥,有机相减压浓缩,经制备薄层色谱纯化(展开剂:乙酸乙酯)得到黄色油状物(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(57毫克,收率:46.3%)。LCMS(ESI):m/z=605(M+H)
+。
步骤2-4:(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24068)的制备:
将(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(57毫克,0.094毫摩尔,1.0当量)和一水合氢氧化锂(12毫克,0.284毫摩尔,3.0当量)加入到5毫升乙腈和1毫升水的混合溶剂中,混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。加入稀硫酸调节残留物的pH值至6,加入乙酸乙酯萃取,用饱和食盐水洗。有机相经过无水硫酸钠干燥,减压浓缩,残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=12/1)得到黄色固体(S)-2-((6-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(36毫克,收率:64.8%)。LCMS(ESI): m/z=591(M+H)
+,熔点:102~104℃。
1H NMR(500MHz,DMSO)δ12.69(s,1H),8.26(s,1H),7.81(d,J=8.4Hz,1H),7.67(dd,J=12.3,7.9Hz,2H),7.49(s,1H),7.38(d,J=8.2Hz,1H),7.30(d,J=8.2Hz,1H),7.07(d,J=7.4Hz,1H),6.78–6.68(m,2H),5.36(s,2H),5.07(d,J=7.1Hz,1H),4.80(dd,J=15.1,7.2Hz,1H),4.65(d,J=14.8Hz,1H),4.46(dd,J=13.9,6.9Hz,1H),4.36(dd,J=14.2,6.2Hz,1H),4.07(d,J=13.5Hz,1H),3.93(d,J=13.5Hz,1H),3.21(d,J=17.1Hz,2H),2.75(s,2H),2.66(dd,J=17.6,7.9Hz,1H),2.52(s,2H),2.39(dd,J=17.6,8.5Hz,1H).
3.(S)-2-((6-((1-甲基-1H-苯并[d]咪唑-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24069)的制备
步骤3-1:(1-甲基-1H-苯并[d]咪唑-6-基)甲醇的制备:
在氮气保护下,将1-甲基-1H-苯并[d]咪唑-6-羧酸(300毫克,1.7毫摩尔,1.0当量)加入到无水四氢呋喃(10毫升)中,冷却至0℃。将氢化锂铝(260毫克,6.8毫摩尔,4.0当量)加入到混合物中,在室温下搅拌三小时。在冰浴下,依次滴加0.26毫升水、0.26毫升15%氢氧化钠水溶液和0.78毫升水,升至室温,加入无水硫酸钠搅拌,抽滤,滤液减压浓缩,经过硅胶柱层析纯化(洗脱剂:二氯甲烷/甲醇=20/1)得到白色固体(1-甲基-1H-苯并[d]咪唑-6-基)甲醇(126毫克,收率:45.6%)。LCMS(ESI):m/z=163(M+H)
+.
步骤3-2:6-(((6-溴吡啶-2-基)氧基)甲基)-1-甲基-1H-苯并[d]咪唑的制备:
在氮气保护下,将(1-甲基-1H-苯并[d]咪唑-6-基)甲醇(159毫克,1.0毫摩尔,1.0当量)加入到无水四氢呋喃(10毫升)中,冷却至0℃。将1M六甲基二硅基氨基钾的四氢呋喃溶液(2.0毫升,2.0毫摩尔,2.0当量)滴加到混合物中,在0℃下搅拌一小时。将2-溴-6-氟吡啶(194毫克,1.1毫摩尔,1.1当量)的四氢呋喃溶液滴加到上述混合物中,在室温下搅拌一小时。加入氯化铵水溶液淬灭,用乙酸乙酯萃取。有机相经过水和饱和食盐水洗,无水硫酸钠干燥。有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:二氯甲烷/甲醇=20/1)得到白色固体6-(((6-溴吡啶-2-基)氧基)甲基)-1-甲基-1H-苯并[d]咪唑(288毫克,收率:91.1%)。LCMS(ESI):m/z=318(M+H)
+.
步骤3-3:6-(1-甲基-1H-苯并[d]咪唑-6-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯的制备:
在氮气保护下,将6-(((6-溴吡啶-2-基)氧基)甲基)-1-甲基-1H-苯并[d]咪唑(288毫克,0.91毫摩尔,1.0当量)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(337毫克,1.09毫摩尔,1.2当量)、二氯二(三苯基膦)钯(32毫克,0.046毫摩尔,0.05当量)和碳酸钠(193毫克,1.82毫摩尔,2.0当量)加入到甲苯(10毫升)、乙醇(5毫升)和水(5毫升)的混合溶剂中,在110℃下搅拌反应两小时。用乙酸乙酯萃取,经水和饱和食盐水洗,无水硫酸钠干燥,有机相减压浓缩,经过硅胶柱层析纯化(洗脱剂:二氯甲烷/甲醇=33/1)得到黄色固体6-(1-甲基-1H-苯并[d]咪唑-6-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(374毫克,收率:97.3%)。LCMS(ESI):m/z=421(M+H)
+。
步骤3-4:(S)-2-((6-(1-甲基-1H-苯并[d]咪唑-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备:
在室温下,将6-(1-甲基-1H-苯并[d]咪唑-6-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(187毫克,0.45毫摩尔,2.25当量)溶解于5毫升二氧六环中,加入1毫升4M氯化氢的二氧六环溶液,混合物在室温下搅拌60分钟。混合物经过减压浓缩至干,所得残留物加入到5毫升N-甲基吡咯烷酮。加入1毫升二异丙基乙胺和(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(60毫克,0.20毫摩尔,1.0当量),混合物在60℃下搅拌过夜。加入乙酸乙酯,用水和饱和食盐水洗,经过无水硫酸钠干燥,有机相减压浓缩,经制备薄层色谱纯化(展开剂:二氯甲烷/甲醇=15/1)得到黄色油状物(S)-2-((6-(1-甲基-1H-苯并[d]咪唑-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(67毫克,收率:57.8%)。LCMS(ESI):m/z=579(M+H)
+。
步骤3-5:(S)-2-((6-((1-甲基-1H-苯并[d]咪唑-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24069)的制备:
将(S)-2-((6-(1-甲基-1H-苯并[d]咪唑-5-基甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(67毫克,0.116毫摩尔,1.0当量)和一水合氢氧化锂(19毫克,0.46毫摩尔,4.0当量)加入到5毫升乙腈和1毫升水的混合溶剂中,混合物在40℃下搅拌过夜。混合物冷却到室温,并减压浓缩。加入稀硫酸调节残留物的pH值至6,加入乙酸乙酯萃取,用饱和食盐水洗。有机相经过无水硫酸钠干燥,减压浓缩,残留物用制备薄层色谱纯化(洗脱剂:二氯甲烷/甲醇=12/1)得到黄色固体(S)-2-((6-((1-甲基-1H-苯并[d]咪唑-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(41毫克,收率:62.5%)。LCMS(ESI):m/z=565(M+H)
+,熔点:135~137℃。
1H NMR(500MHz,DMSO)δ12.61(s,1H),8.26(s,1H),8.17(s,1H),7.82(dd,J=8.4,1.5Hz,1H),7.70–7.64(m,3H),7.62(d,J=8.2Hz,1H),7.31(dd,J=8.3,1.3Hz,1H),7.06(d,J=7.4Hz,1H),6.78(s,1H),6.71(d,J=8.2Hz,1H),5.49(s,2H),5.07(ddd,J=14.5,7.3,2.8Hz,1H),4.80(dd,J=15.3,7.3Hz,1H),4.66(dd,J=15.2,2.7Hz,1H),4.47(dt,J=14.0,7.1Hz,1H),4.36(dt,J=9.0,5.9Hz,1H),4.08(d,J=13.5Hz,1H),3.97–3.90(m,1H),3.81(s,3H),3.26(d,J=12.6Hz,2H),2.80–2.74(m,2H),2.70–2.62(m,1H),2.60–2.53(m,2H),2.45–2.38(m,1H).
4.(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24070)的制备
步骤4-1:6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯的制备:
氮气保护条件下,将2-溴-6-氯吡啶(1.0克,5.20毫摩尔,1.0当量),4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.6克,5.20毫摩尔,1.0当量),1,1'-双(二苯基膦)二茂铁]二氯化钯和碳酸钠加入到二氧六环与水(10:1)的混合溶剂(11毫升)中,在90℃搅拌过夜。反应液冷却至室温,然后用水淬灭,加入乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。有机相减压浓缩,残留物用硅胶柱层析(洗脱剂为:石油醚/乙酸乙酯=10/1)纯化,得到黄色固体6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(3.26克,收率:214%)。LCMS(ESI):m/z=295(M+H)
+.
步骤4-2:6-氯-1',2',3',6'-四氢-2,4'-联吡啶对甲苯磺酸盐的制备:
6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯(2.94毫克,9.99毫摩尔,1.0当量)和对甲苯磺酸(4.3克,24.97毫摩尔,2.5单量)的乙酸乙酯混合物(50毫升)在60℃下搅拌30分钟。将反应液过滤,滤饼得到白色固体6-氯-1',2',3',6'-四氢-2,4'-联吡啶对甲苯磺酸盐(232毫克,产率12%)。该产品不需要进一步纯化直接用于下一步。
步骤4-3:(S)-2-((6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备:
将6-氯-1',2',3',6'-四氢-2,4'-联吡啶对甲苯磺酸盐(232毫克,0.634毫摩尔,1.2当量)和碳酸钾(291毫克,2.11毫摩尔,4.0单量)的乙腈(10毫升)混合物加热至60℃,直到pH到7~8,然后将(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(150毫克,0.528毫摩尔,1.0单量)加入到混合物并搅拌过夜。冷却至室温后,反应用水淬灭,用乙酸乙酯萃取。有机相用饱和食盐水洗涤,并用无水硫酸钠干燥。将有机相减压浓缩,得到(S)-2-((6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(188.5毫克,收率:81.74%)为黄色固体。LCMS(ESI):m/z=453.9(M+H)
+.
步骤4-4:(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备:
将(S)-2-((6-氯-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(188.5毫克,0.417毫摩尔,1.0当量),(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲醇(83.1毫克,0.500毫摩尔,1.2当量),三(二亚苄基丙酮)二钯(19.23毫克,0.021毫摩尔,0.05当量),2-双环已基膦-2',6'-二异丙氧基联苯(19.46毫克,0.0417毫摩尔,0.1当量)和碳酸铯(382.86毫克,1.175毫摩尔,2.5当量)的甲苯(70毫升)的混合物在120℃ 下搅拌过夜。冷却至室温后,将反应液过滤并将滤液减压浓缩。残留物用硅胶薄层层析制备板纯化(洗脱剂:石油醚/乙酸乙酯=1/2)得黄色固体化合物(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(20毫克,产率8.44%)。LCMS(ESI):m/z=583.6(M+H)
+.
步骤4-5:(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(化合物24070)的制备:
将(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(20毫克,0.034毫摩尔,1.0当量)和一水合氢氧化锂(2.85毫克,0.068毫摩尔,2.0单量)的乙腈/水=5/1(6毫升)的混合物在40℃搅拌过夜。然后将混合物冷却至室温,通过加入1.0M硫酸将pH调节至约6,之后形成固体沉淀。将混合物过滤。残留物用水洗。混合物用甲醇打浆得到黄色固体(S)-2-((6-((2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)甲氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(18毫克,产率92.4%)。LCMS(ESI):m/z=569(M+H)
+.
1H NMR(500MHz,DMSO)δ12.67(s,1H),8.26(s,1H),7.81(dd,J=8.4,1.2Hz,1H),7.65(t,J=8.2Hz,2H),7.05(d,J=7.5Hz,1H),6.92(d,J=1.8Hz,1H),6.89(dd,J=8.2,1.9Hz,1H),6.81(d,J=8.2Hz,1H),6.74(s,1H),6.67(d,J=8.2Hz,1H),5.24(s,2H),5.07(qd,J=7.2,2.8Hz,1H),4.80(dd,J=15.2,7.3Hz,1H),4.65(dd,J=15.2,2.6Hz,1H),4.47(dd,J=13.6,7.7Hz,1H),4.36(dt,J=8.9,5.9Hz,1H),4.20(s,4H),4.07(d,J=13.5Hz,1H),3.93(d,J=13.5Hz,1H),3.23(s,2H),2.79–2.72(m,2H),2.66(ddd,J=8.8,8.2,5.5Hz,1H),2.54(s,2H),2.40(ddd,J=16.1,11.2,7.1Hz,1H).
一、hGLP-1R 293Ta细胞株中环磷酸腺苷(cAMP)水平测定
1.实验材料
名称 | 来源 | 货号 |
cAMP检测试剂盒 | Cisbio | 62AM6PEB(1,000tests) |
IBMX | Cisbio | 62AMXADA |
FBS | Biological Industries | 04-001-1ACS |
DMEM | GIBCO | C11995500BT |
低容量白色微孔板 | Cisbio | 66PL96025 |
帝肯INFINITE F NANO+酶标仪 | 帝肯 | Infinite 200 PRO |
2.实验原理
Cisbio公司的环磷酸腺苷检测试剂盒是一种竞争性免疫分析方法,旨在测量细胞内环磷酸腺苷的积累。该原理基于
技术,细胞产生的天然环磷酸腺苷或未标记的环磷酸腺苷(标准曲线)与d2标记的环磷酸腺苷(红色受体)竞争结合单克隆环磷酸腺苷Europium Cryptate标记抗体(Europium供体)。特定信号与标准品或样品中的环磷酸腺苷浓度成反比。
对于所有其他HTRF分析,荧光比(665nm/620nm)的计算消除了任何可能的光物理干扰,这意味着该分析不受实验培养基条件(例如培养基,血清,生物素,有色化合物等)的影响。
3.实验准备
1)hGLP-1R 293Ta稳转细胞株构建:
a)委托苏州金唯智生物科技有限公司合成hGLP-1R全长序列,并与慢病毒载体pLEX-MCS进行连接。
b)将连接hGLP-1R序列的慢病毒质粒pLEX-MCS分别转染293Ta细胞产生慢病毒;
c)用慢病毒感染293Ta细胞,用嘌呤霉素进行筛选从而得到含hGLP-1R序列的293Ta稳转细胞系。
2)试剂准备:
a)配制环磷酸腺苷检测试剂(试剂需要置于室温30min)
b)3-异丁基-1-甲基黄嘌呤:3-异丁基-1-甲基黄嘌呤(500mM)用DMSO稀释到50mM,分装20ul每管,4℃保存。20ul加2ml刺激Buffer 1稀释为0.5mM使用。
4.细胞实验
1)化合物稀释:2mM母液用DMSO稀释到200nM(40X),然后取2ul加38ul刺激Buffer 1(含3-异丁基-1-甲基黄嘌呤0.5mM)稀释到10nM(2X),反应体系终浓度为5nM。用刺激Buffer 1(含3-异丁基-1-甲基黄嘌呤0.5mM)依次5倍稀释,共8个浓度点。
2)消化离心收集hGLP-1R 293Ta细胞,加入DMEM培养基(含10%FBS)吹打重悬细胞,用Scepter自动细胞计数仪(Millipore#PHCC00000)计数。调整细胞数为1X10
6cells/ml,96孔微孔白板每孔加入5ul(即每孔5000个细胞)。
3)向96孔中加入5ul稀释好的8个浓度梯度2X化合物,另在一孔中加入5ul刺激Buffer 1(含3-异丁基-1-甲基黄嘌呤0.5mM)作为对照。盖上盖子,37℃培养30min。
4)取50ul环磷酸腺苷-d2和50ulAnti-环磷酸腺苷Eu-Cryptate分别加入200ul裂解&检测Buffer 1配置工作液。96孔板每孔加入5ul环磷酸腺苷-d2工作液,然后加入5ul Anti-环磷酸腺苷Eu-Cryptate工作液。混匀,用封板膜封好96孔板,室温孵育2小时。
5)取下封板膜,用帝肯INFINITE F NANO+酶标仪读取HTRF信号。用公式Ratio=Signal 665nm/Signal 620nm*10000计算每个单孔的受体和供体激发信号的比率。以HTRF信号比率以及对应的化合物浓度,用GraphPad Prism软件处理数据,通过S形剂量-反应曲线拟合计算EC50值。测试结果如表1所示。
表1.测定化合物对hGLP-1R 293Ta细胞环磷酸腺苷水平影响
化合物 | 测定EC50pM | 化合物 | 测定EC50pM | |
1 | 11.19 | 2 | 6.10 | |
3 | 11.62 | 4 | 5.82 | |
5 | 34.66 | 6 | 3.56 | |
8 | 55.23 | 12 | 10.35 | |
14 | 15.60 | 15 | 32.03 | |
16 | 6.57 | 17 | 21.65 | |
20 | 2681.00 | 23 | 909.30 | |
24 | 1029.00 | 25 | 5.39 | |
28 | 81.10 | 30 | 41.96 | |
31 | 244.80 | 32 | 313.00 | |
33 | 127.90 | 44 | 1512.00 | |
46 | 11.01 | 47 | 117.80 |
49 | 944.90 | 53 | 262.00 | |
54 | 32.72 | 55 | 1686.00 | |
56 | 206.50 | 57 | 68.49 | |
58 | 9.40 | 61 | 109.60 | |
PF-06882961 | 31.44 | 24067 | 394.9 | |
24068 | 669.0 | 24069 | 1100.0 | |
24070 | 342.8 |
从上表中可以看出,本发明的化合物可激活hGLP-1R 293Ta细胞中cAMP水平,且比对照化合物PF-06882961、24067、24068、24069和24070的活性更高。
二、药代动力学(PK)实验
1.实验方法
雄性SD大鼠,体重180-320克,试验前禁食过夜。待测化合物溶解在30%磺丁基-β-环糊精(SBE-β-CD)中,以20mg/kg单次灌胃给药。给药后15分钟、30分钟和1、2、4、6、8及24小时尾端断口取血,每时间点约0.3ml,置于含K2-EDTA的离心管中,离心处理(2000g,10分钟,4℃)取血浆,储存在-70℃至-80℃的超低温冰箱中。50μL的血浆样品用135μL乙腈(含内标0.5μg/mL)涡旋混合进行蛋白沉淀,离心,取上清进行LC-MS/MS分析。
2.实验结果
本发明提供的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物各化合物在大鼠经口服给药后,吸收良好,血液暴露量较高,结果见图1、2和表2。本发明的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物的T
max为0.5-2.67小时,C
max为180-2553.33ng/ml,AUC
0-24h为934.28-9583.02ng/ml*h。C
max是指最大血药浓度,T
1/2为半衰期,AUC
0-24是指0-24小时时间-浓度曲线下面积,AUC
0-inf是指0-Inf时间-浓度曲线下面积。
表2.大鼠灌胃给药(20mg/kg)药代动力学参数
三、药效学实验
1.实验方法
基因工程hGLP1R小鼠,雄性,7周,购于百奥赛图江苏基因生物技术有限公司。实验动物均饲养于水平流独立通风笼具内,温度在20-26℃,相对湿度在40-70%RH,换气次数为15-30次/小时、空气洁净度为7级、昼夜明暗交替时间为12h/12h;持续供给钴60放射灭菌鼠全价颗粒饲料(广东省医学实验动物中心,大、小鼠维持饲料),不限量自由摄取;饮用自来水(高压蒸汽灭菌后使用),不间断供水,自由摄取。饲养笼具是透明的聚醚酰亚胺笼盒(苏州艾可林净化设备有限公司,水平流小鼠笼盒),无病原微生物;垫料是玉米芯(广东省医学实验动物中心,高压蒸汽灭菌后使用),每笼2-5只动物,笼卡上标明IACUC批准号、实验编号、实验开始时间、课题负责人、实验人员、动物来源、组别和动物编号等。本试验的动物使用方法经由广州必贝特医药技术有限公司IACUC批准。
hGLP1R小鼠口服葡萄糖耐量试验:动物禁食过夜,不禁水,口服单次给溶媒或相应的化合物,给溶媒或化合物前测血糖(相当于-60min血糖值),给溶媒或化合物60分钟后口服给葡萄糖(2g/kg),给葡萄糖前测血糖(相当于0min血糖值),给葡萄糖后15min、30min、60min、90min、120min测血糖值。溶媒为40%PEG400+60%MCT(0.5%MC/0.1%Tween80)水溶液,化合物剂量分别为0.3mg/kg(n=2-4),1mg/kg(n=2-4)。
2.实验结果
如图3和图4所示,化合物12和化合物16与PF-06882961在同剂量(1mg/kg)单次口服给药时,从血糖曲线和血糖AUC(0-2h)来看,化合物12与PF-06882961的降糖效果相当;化合物16的降糖效果优于PF-06882961。
如图5和图6所示,化合物6和化合物16与PF-06882961在同剂量(0.3mg/kg)单次口服给药时,从血糖曲线和血糖AUC(0-2h)来看,化合物6比PF-06882961的降糖效果略好;化合物16的降糖效果明显优于PF-06882961。
如图7和图8所示,化合物3、化合物16和化合物58在同剂量(0.3mg/kg)单次口服给药时,从血糖曲线和血糖AUC(0-2h)来看,化合物16的降糖效果表现最好。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (26)
- 式(I)所示的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体:其中:R 1和R 2分别独立选自:H,卤素,C1-C6烷基,C1-C6烷氧基;R 3和R 4分别独立选自:H,C1-C6烷基,C1-C6烷氧基;或者R 3和R 4相连组成3-8元碳环或3-8元杂环;R 5选自:3-8元杂环基取代的C1-C4烷基,5-10元杂芳基取代的C1-C4烷基,C1-C6烷氧基取代的C1-C4烷基;其中,所述R 5中的3-8元杂环基和5-10元杂芳基可以独立任选的被一个或多个R 10取代;R 6和R 7分别独立选自:H,C1-C6烷基;或者R 6和R 7一起形成G,G选自=O;各R 8和R 9分别独立选自:H,卤素,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烷基甲基,卤素取代的C1-C6烷基,羟基取代的C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,氨基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基,芳基,杂芳基,硝基,氰基,-OR,-N(R) 2,-SR,-C(O)OR,-C(O)N(R) 2,-C(O)R,-S(O)R,-S(O) 2R,-S(O) 2N(R) 2,-N(R)C(O)R;R选自:H,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C8环烷基,C3-C8环烷基甲基,卤素取代的C1-C6烷基,羟基取代的C1-C6烷基,C1-C6烷氧基取代的C1-C6烷基,氨基取代的C1-C6烷基,C1-C6烷基胺基取代的C1-C6烷基;n选自:0,1或2;p选自:1或2;m选自:1,2或3;W选自:O,S,NR 10;W 1选自:O,S;Q选自:C,CH,N;X选自:N,CR 10;Y选自:N,CR 11;R 10选自:H,C1-C6烷基,C1-C6烷氧基;R 11选自:H,C1-C6烷基,C1-C6烷氧基;或者R 11和R 6相连组成5-8元杂环;Q与相邻C之间的虚线表示所述Q与相邻C之间的化学键可选单键或双键。
- 根据权利要求1所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,W为O,R 6和R 7分别独立选自:H,C1-C6烷基。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,W 1为O。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,Q选自:C,CH。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,X选自:N,CH。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 1和R 2分别独立选自:H,卤素,C1-C3烷基,C1-C3烷氧基。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 3和R 4分别独立选自:H,C1-C3烷基,C1-C3烷氧基。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 5选自:3-4元杂环基取代的C1-C4烷基,5-6元杂芳基取代的C1-C4烷基,C1-C3烷氧基取代的C1-C4烷基;其中,所述R 5中的3-4 元杂环基和5-6元杂芳基可以独立任选的被一个或多个R 10取代。
- 根据权利要求11所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 5选自:3-4元杂环基取代的甲基,3-4元杂环基取代的乙基,5-6元杂芳基取代的甲基,5-6元杂芳基取代的乙基;其中,所述R 5中的3-4元杂环基和5-6元杂芳基可以独立任选的被一个或多个R 10取代,R 10选自:H、C1-C3烷基。
- 根据权利要求12所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 5选自:氧杂环丁烷取代的甲基,氧杂环丁烷取代的乙基,乙基咪唑取代的甲基,乙基咪唑取代的乙基。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,R 6和R 7分别独立选自:H,C1-C3烷基。
- 根据权利要求1-5任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,各R 8和R 9分别独立选自:H,卤素,氰基,C1-C3烷基,卤素取代的C1-C3烷基。
- 根据权利要求15所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,各R 8分别独立选自:H,卤素,C1-C3烷基;各R 9分别独立选自:H,卤素,氰基,C1-C3烷基,三氟甲基。
- 根据权利要求16所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体,其特征在于,各R 8分别独立选自:H、Cl、F、甲基;各R 9分别独立选自:氰基、Cl、甲基。
- 权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备GLP-1R激动剂中的应用。
- 权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备用于预防和/或治疗与GLP-1R下游信号通路相关的疾病和/或症状的药物中的应用。
- 根据权利要求20所述的应用,其特征在于,与GLP-1R下游信号通路相关的疾病和/或症状选自:糖尿病,糖尿病视网膜病变,糖尿病性脑血管病变,糖尿病性神经病变,胰岛素抵抗,高血糖症,糖尿病性肾病,高血压,白内障,骨质疏松症,高尿酸血症以及糖尿病引起的感染、肥胖症、代谢综合征、血脂异常、非酒精性脂肪肝病、非酒精性脂肪性肝炎、纤维化、心脏病、中风、肝硬化、肝癌、代谢性酸中毒、酮病、心血管不适、癫痫、动脉粥 样硬化、帕金森氏病和阿尔兹海默病。
- 权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备促进胰岛素分泌的药物中的应用。
- 权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备降血糖的药物中的应用。
- 权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体在制备预防和/或治疗糖尿病的药物中的应用。
- 根据权利要求24所述的应用,其特征在于,所述糖尿病为1型糖尿病、2型糖尿病、妊娠糖尿病、特发性1型糖尿病、早发型2型糖尿病、青年人的成年型糖尿病、青少年发作的非典型糖尿病、营养不良相关性糖尿病、成人隐匿性自身免疫性糖尿病。
- 一种预防和/或治疗糖尿病及其并发症的药物组合物,其特征在于,包括活性成分以及药学上可接受的辅料和/或载体,所述活性成分包括有权利要求1-18任一项所述的苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物或者其药学上可接受的盐或者其立体异构体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110839013.8A CN113480534B (zh) | 2021-07-23 | 2021-07-23 | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 |
CN202110839013.8 | 2021-07-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023000834A1 true WO2023000834A1 (zh) | 2023-01-26 |
Family
ID=77943500
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/096230 WO2023000834A1 (zh) | 2021-07-23 | 2022-05-31 | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN113480534B (zh) |
TW (1) | TWI816437B (zh) |
WO (1) | WO2023000834A1 (zh) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11702404B2 (en) | 2019-10-25 | 2023-07-18 | Gilead Sciences, Inc. | GLP-1R modulating compounds |
JP2023537501A (ja) | 2020-08-06 | 2023-09-01 | ガシャーブラム・バイオ・インコーポレイテッド | ヘテロ環glp-1アゴニスト |
EP4204415A1 (en) | 2020-08-28 | 2023-07-05 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
WO2022068772A1 (zh) * | 2020-09-29 | 2022-04-07 | 深圳信立泰药业股份有限公司 | 一种苯并咪唑类衍生物及其制备方法和医药用途 |
US11851419B2 (en) | 2020-11-20 | 2023-12-26 | Gilead Sciences, Inc. | GLP-1R modulating compounds |
CA3200245A1 (en) * | 2020-11-27 | 2022-06-02 | Junjun Wu | Benzimidazole derivative and preparation method therefor and medical use thereof |
EP4304712A1 (en) * | 2021-03-11 | 2024-01-17 | Gilead Sciences, Inc. | Glp-1r modulating compounds |
EP4317142A1 (en) * | 2021-03-22 | 2024-02-07 | Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd. | Thiophene glp-1 receptor agonist and use thereof |
WO2022202864A1 (ja) | 2021-03-24 | 2022-09-29 | 塩野義製薬株式会社 | 縮合環を有するglp-1受容体作動薬を含有する医薬組成物 |
CR20230495A (es) | 2021-04-21 | 2023-11-30 | Gilead Sciences Inc | Compuestos moduladores del glp-ir carboxibenzimidazólicos. |
KR20230173166A (ko) | 2021-05-20 | 2023-12-26 | 일라이 릴리 앤드 캄파니 | 마크로시클릭 글루카곤-유사 펩티드 1 수용체 효능제 |
CN113480534B (zh) * | 2021-07-23 | 2022-05-13 | 广州必贝特医药股份有限公司 | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 |
CA3231153A1 (en) | 2021-09-08 | 2023-03-16 | Kosuke Takemoto | Medicine for prevention and treatment of diseases linked to anti-obesity activity |
WO2023057429A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes and octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
CA3233131A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain 2,5-diazabicyclo[4.2.0]octanes as glp-1 receptor modulators |
WO2023057414A1 (en) | 2021-10-05 | 2023-04-13 | Astrazeneca Ab | Certain octahydrofuro[3,4- b]pyrazines as glp-1 receptor modulators |
WO2023111144A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
WO2023111145A1 (en) | 2021-12-16 | 2023-06-22 | Astrazeneca Ab | Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators |
CN116354945A (zh) * | 2021-12-27 | 2023-06-30 | 长春金赛药业有限责任公司 | 一种稠合咪唑羧酸类化合物及其制备方法和应用 |
WO2023169436A1 (zh) * | 2022-03-08 | 2023-09-14 | 广州市联瑞制药有限公司 | 苯并双环类化合物及其制备方法和应用 |
CN114716423A (zh) * | 2022-05-20 | 2022-07-08 | 中国科学院上海药物研究所 | 5,6-二氢-1,2,4-三嗪类化合物及其作为glp-1受体激动剂的药学用途 |
CN116574092A (zh) * | 2022-05-20 | 2023-08-11 | 成都地奥九泓制药厂 | 苯并咪唑或氮杂苯并咪唑类化合物、其制备方法及其应用 |
WO2024041609A1 (zh) * | 2022-08-24 | 2024-02-29 | 广州市联瑞制药有限公司 | 苯并双环类化合物及其制备方法和应用 |
WO2024046342A1 (zh) * | 2022-08-30 | 2024-03-07 | 广州市联瑞制药有限公司 | 苯并双环类化合物及其制备方法和应用 |
WO2024102625A1 (en) | 2022-11-11 | 2024-05-16 | Eli Lilly And Company | Glucagon-like peptide 1 receptor agonists |
WO2024107781A1 (en) | 2022-11-16 | 2024-05-23 | Eli Lilly And Company | Glucagon-like peptide 1 receptor agonists |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110325530A (zh) * | 2016-12-16 | 2019-10-11 | 辉瑞大药厂 | Glp-1受体激动剂及其用途 |
WO2020103815A1 (en) * | 2018-11-22 | 2020-05-28 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
WO2020207474A1 (en) * | 2019-04-12 | 2020-10-15 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
WO2021018023A1 (zh) * | 2019-08-01 | 2021-02-04 | 济南泰达领创医药技术有限公司 | 小分子glp-1受体调节剂 |
CN113480534A (zh) * | 2021-07-23 | 2021-10-08 | 广州必贝特医药技术有限公司 | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10934279B2 (en) * | 2018-06-13 | 2021-03-02 | Pfizer Inc. | GLP-1 receptor agonists and uses thereof |
KR102538572B1 (ko) * | 2018-06-15 | 2023-06-01 | 화이자 인코포레이티드 | Glp-1 수용체 효능제 및 그의 용도 |
US11702404B2 (en) * | 2019-10-25 | 2023-07-18 | Gilead Sciences, Inc. | GLP-1R modulating compounds |
WO2021160127A1 (en) * | 2020-02-13 | 2021-08-19 | Gasherbrum Bio, Inc. | Heterocyclic glp-1 agonists |
-
2021
- 2021-07-23 CN CN202110839013.8A patent/CN113480534B/zh active Active
-
2022
- 2022-05-31 WO PCT/CN2022/096230 patent/WO2023000834A1/zh unknown
- 2022-06-16 TW TW111122480A patent/TWI816437B/zh active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110325530A (zh) * | 2016-12-16 | 2019-10-11 | 辉瑞大药厂 | Glp-1受体激动剂及其用途 |
WO2020103815A1 (en) * | 2018-11-22 | 2020-05-28 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
WO2020207474A1 (en) * | 2019-04-12 | 2020-10-15 | Qilu Regor Therapeutics Inc. | Glp-1r agonists and uses thereof |
WO2021018023A1 (zh) * | 2019-08-01 | 2021-02-04 | 济南泰达领创医药技术有限公司 | 小分子glp-1受体调节剂 |
CN113480534A (zh) * | 2021-07-23 | 2021-10-08 | 广州必贝特医药技术有限公司 | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
TW202306569A (zh) | 2023-02-16 |
CN113480534A (zh) | 2021-10-08 |
TWI816437B (zh) | 2023-09-21 |
CN113480534B (zh) | 2022-05-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2023000834A1 (zh) | 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用 | |
JP2022527607A (ja) | Glp-1rアゴニスト及びその使用 | |
WO2023222124A1 (zh) | 5,6-二氢-1,2,4-三嗪类化合物及其作为glp-1受体激动剂的药学用途 | |
KR102085121B1 (ko) | 이미다조[1,2-b]피리다진계 화합물, 그를 포함하는 조성물 및 그의 용도 | |
JP6395731B2 (ja) | ブロモドメイン阻害剤として有用なカルバゾール化合物 | |
WO2021259309A1 (zh) | Glp-1受体激动剂及其药物组合物和用途 | |
KR101689421B1 (ko) | 치환된 이미다조피리디닐-아미노피리딘 화합물 | |
CN106661002B (zh) | 用于治疗炎性、代谢性、肿瘤性和自身免疫性疾病的嘧啶衍生物 | |
CN104059039B (zh) | 具有gpr40受体功能调节作用的稠环化合物 | |
TW201038560A (en) | Fused ring inhibitors of hepatitis C | |
TW202142538A (zh) | 雜環glp-1促效劑 | |
KR20080048062A (ko) | 리파제 및 포스포리파제 억제제로서 디아실 인다졸 유도체 | |
TW201010977A (en) | Amide compound | |
KR20140075775A (ko) | 과증식성 질환 치료시 Bub1 키나제 저해제로 사용하기 위한 치환된 벤질인다졸 | |
KR20130049766A (ko) | 트리사이클릭 피라졸 아민 유도체 | |
BRPI0617712A2 (pt) | derivados de triazolopiridina como inibidores de lipases e fosfolipases | |
JP2008526701A (ja) | 有機化合物 | |
WO2011093501A1 (ja) | Gpr119作動薬 | |
KR20080013933A (ko) | 레닌 억제제로서의 치환된 피페리딘 | |
TW200800907A (en) | Novel aminoalcohol-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments | |
WO2021219078A1 (zh) | 基于杂环和戊二酰亚胺骨架的化合物及其应用 | |
KR20180127979A (ko) | 화합물 (s)-4-((s)-3-플루오로-3-(2-(5,6,7,8-테트라히드로-1,8-나프티리딘-2-일)에틸)피롤리딘-1-일)-3-(3-(2-메톡시에톡시)페닐) 부탄산의 시트레이트 염 | |
KR20070094918A (ko) | 3,4,(5)-치환 테트라히드로피리딘 | |
JP4685861B2 (ja) | ドーパミンアゴニストとしての3−ピペリジニルイソクロマン−5−オール | |
BR112020001978A2 (pt) | derivados de tiazolopiridina como antagonistas de receptor de adenosina |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22845001 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |