CN114105962A - Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof - Google Patents
Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN114105962A CN114105962A CN202111248634.5A CN202111248634A CN114105962A CN 114105962 A CN114105962 A CN 114105962A CN 202111248634 A CN202111248634 A CN 202111248634A CN 114105962 A CN114105962 A CN 114105962A
- Authority
- CN
- China
- Prior art keywords
- preparation
- substituted
- compound
- methyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 526
- 150000001875 compounds Chemical class 0.000 title claims abstract description 114
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 125000000565 sulfonamide group Chemical group 0.000 title claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 17
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002860 competitive effect Effects 0.000 claims abstract description 5
- 229910001414 potassium ion Inorganic materials 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 108
- -1 -CH2-phenyl Chemical group 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical group 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 13
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000003172 aldehyde group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 6
- 208000025865 Ulcer Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 6
- 231100000397 ulcer Toxicity 0.000 claims description 6
- 206010019375 Helicobacter infections Diseases 0.000 claims description 4
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 201000000052 gastrinoma Diseases 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 229940121819 ATPase inhibitor Drugs 0.000 claims description 3
- 208000023665 Barrett oesophagus Diseases 0.000 claims description 3
- 206010063655 Erosive oesophagitis Diseases 0.000 claims description 3
- 208000007882 Gastritis Diseases 0.000 claims description 3
- 206010020601 Hyperchlorhydria Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 claims description 3
- 201000006549 dyspepsia Diseases 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000017215 gastric mucosa-associated lymphoid tissue lymphoma Diseases 0.000 claims description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 3
- 208000000689 peptic esophagitis Diseases 0.000 claims description 3
- 230000002980 postoperative effect Effects 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- LCQZTTHYFOMGKL-UHFFFAOYSA-N 2-methoxy-1,4-dioxane Chemical compound COC1COCCO1 LCQZTTHYFOMGKL-UHFFFAOYSA-N 0.000 claims description 2
- 206010002243 Anastomotic ulcer Diseases 0.000 claims description 2
- 206010030216 Oesophagitis Diseases 0.000 claims description 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 208000000718 duodenal ulcer Diseases 0.000 claims description 2
- 208000006881 esophagitis Diseases 0.000 claims description 2
- 201000005917 gastric ulcer Diseases 0.000 claims description 2
- 229940015043 glyoxal Drugs 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 4
- 125000001624 naphthyl group Chemical group 0.000 claims 4
- 125000000466 oxiranyl group Chemical group 0.000 claims 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 4
- 230000027119 gastric acid secretion Effects 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 166
- 239000007787 solid Substances 0.000 description 160
- 238000003786 synthesis reaction Methods 0.000 description 102
- 230000015572 biosynthetic process Effects 0.000 description 101
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 91
- CMEPUAROFJSGJN-YFKPBYRVSA-N [(2s)-1,4-dioxan-2-yl]methanol Chemical compound OC[C@H]1COCCO1 CMEPUAROFJSGJN-YFKPBYRVSA-N 0.000 description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 43
- HNSFAXPMNOFMQI-UHFFFAOYSA-N 1-(oxan-4-yl)ethanol Chemical compound CC(O)C1CCOCC1 HNSFAXPMNOFMQI-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- YSNVSVCWTBLLRW-UHFFFAOYSA-N oxan-4-ylmethanol Chemical compound OCC1CCOCC1 YSNVSVCWTBLLRW-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- KIKCAPPVFQLOIU-UHFFFAOYSA-N (2,5-difluorophenyl)methanol Chemical compound OCC1=CC(F)=CC=C1F KIKCAPPVFQLOIU-UHFFFAOYSA-N 0.000 description 7
- SIYWDKQSSDBLOA-UHFFFAOYSA-N 1-(2,6-difluorophenyl)ethanol Chemical compound CC(O)C1=C(F)C=CC=C1F SIYWDKQSSDBLOA-UHFFFAOYSA-N 0.000 description 7
- BHNRGBRMCNHNQD-UHFFFAOYSA-N 3-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(C#N)=C1 BHNRGBRMCNHNQD-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- UEGDJZYKJPZJAA-UHFFFAOYSA-N 1-(3,5-difluorophenyl)ethanol Chemical compound CC(O)C1=CC(F)=CC(F)=C1 UEGDJZYKJPZJAA-UHFFFAOYSA-N 0.000 description 5
- 108091006112 ATPases Proteins 0.000 description 5
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 4
- RWEXBYKVPKGAQZ-UHFFFAOYSA-N COCCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 Chemical compound COCCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 RWEXBYKVPKGAQZ-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 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 4
- NIJZBWHOHNWJBX-UHFFFAOYSA-N 2,4-difluorobenzyl alcohol 2,4-difluoro-1-(hydroxymethyl)benzene Chemical compound OCC1=CC=C(F)C=C1F NIJZBWHOHNWJBX-UHFFFAOYSA-N 0.000 description 3
- IIQKIICAOXAXEJ-UHFFFAOYSA-N 3,5-difluorobenzenesulfonyl chloride Chemical compound FC1=CC(F)=CC(S(Cl)(=O)=O)=C1 IIQKIICAOXAXEJ-UHFFFAOYSA-N 0.000 description 3
- ONCAZCNPWWQQMW-UHFFFAOYSA-N 3-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=CC(S(Cl)(=O)=O)=C1 ONCAZCNPWWQQMW-UHFFFAOYSA-N 0.000 description 3
- YDUHIMCRFRIVFI-UHFFFAOYSA-N 3-fluoro-4-methylbenzenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1F YDUHIMCRFRIVFI-UHFFFAOYSA-N 0.000 description 3
- OKYSUJVCDXZGKE-UHFFFAOYSA-N 3-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(S(Cl)(=O)=O)=C1 OKYSUJVCDXZGKE-UHFFFAOYSA-N 0.000 description 3
- JDFDHBSESGTDAL-UHFFFAOYSA-N 3-methoxypropan-1-ol Chemical compound COCCCO JDFDHBSESGTDAL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ULXUJHZWUZJCKL-UHFFFAOYSA-N COC(C1=CNC(C(C=CC(OCC2CC2)=C2)=C2F)=C1OC)=O Chemical compound COC(C1=CNC(C(C=CC(OCC2CC2)=C2)=C2F)=C1OC)=O ULXUJHZWUZJCKL-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000005119 centrifugation Methods 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
- 238000001816 cooling Methods 0.000 description 3
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 3
- 229940107698 malachite green Drugs 0.000 description 3
- 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 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- PBLNHHSDYFYZNC-UHFFFAOYSA-N (1-naphthyl)methanol Chemical compound C1=CC=C2C(CO)=CC=CC2=C1 PBLNHHSDYFYZNC-UHFFFAOYSA-N 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-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
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- WYLYBQSHRJMURN-UHFFFAOYSA-N (2-methoxyphenyl)methanol Chemical compound COC1=CC=CC=C1CO WYLYBQSHRJMURN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 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
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 2
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- 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 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 2
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 2
- CHNYVNOFAWYUEG-UHFFFAOYSA-N 1h-pyrrole-3-carbaldehyde Chemical compound O=CC=1C=CNC=1 CHNYVNOFAWYUEG-UHFFFAOYSA-N 0.000 description 2
- WATIARBIFSKYKC-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-5-ylmethanol Chemical compound O1CCOC2=C1C=CC=C2CO WATIARBIFSKYKC-UHFFFAOYSA-N 0.000 description 2
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 2
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 2
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-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
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 2
- GKWLIQDHWRWNRS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC(N)(CO)CO.OCCN1CCN(CCS(O)(=O)=O)CC1 GKWLIQDHWRWNRS-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-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
- BTVWZWFKMIUSGS-UHFFFAOYSA-N 2-methylpropane-1,2-diol Chemical compound CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 description 2
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 2
- VEDGUZUQXIZCDH-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzenesulfonyl chloride Chemical compound COCCOc1cccc(c1)S(Cl)(=O)=O VEDGUZUQXIZCDH-UHFFFAOYSA-N 0.000 description 2
- RZQWBHXXTLMXJR-UHFFFAOYSA-N 3-(3-methoxypropoxy)benzenesulfonyl chloride Chemical compound COCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 RZQWBHXXTLMXJR-UHFFFAOYSA-N 0.000 description 2
- SUZRGLLWEFEEGF-UHFFFAOYSA-N 3-(cyclopropylmethoxy)benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(OCC2CC2)=C1 SUZRGLLWEFEEGF-UHFFFAOYSA-N 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
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 2
- OINWZUJVEXUHCC-UHFFFAOYSA-N 3-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC(S(Cl)(=O)=O)=C1 OINWZUJVEXUHCC-UHFFFAOYSA-N 0.000 description 2
- JHJKSEKUZNJKGO-UHFFFAOYSA-N 3-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=CC(S(Cl)(=O)=O)=C1 JHJKSEKUZNJKGO-UHFFFAOYSA-N 0.000 description 2
- ULLXNNNTWZMHPB-UHFFFAOYSA-N 4-(cyclopropylmethoxy)-2-fluorobenzaldehyde Chemical compound Fc1cc(OCC2CC2)ccc1C=O ULLXNNNTWZMHPB-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
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 2
- MRQYTJXVULSNIS-UHFFFAOYSA-N 4-bromo-3-fluorophenol Chemical compound OC1=CC=C(Br)C(F)=C1 MRQYTJXVULSNIS-UHFFFAOYSA-N 0.000 description 2
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 2
- XTLHTMDWLYWDEO-UHFFFAOYSA-N 5-bromo-1h-pyrrole-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CN1 XTLHTMDWLYWDEO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 2
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 2
- 238000009010 Bradford assay Methods 0.000 description 2
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- WKIQNNYMLWCFGS-UHFFFAOYSA-N CC(C=C1)=CC=C1S(C(C(C=CC(OCC1CC1)=C1)=C1F)NC=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(C(C(C=CC(OCC1CC1)=C1)=C1F)NC=O)(=O)=O WKIQNNYMLWCFGS-UHFFFAOYSA-N 0.000 description 2
- SNSKBYHARDDKFG-UHFFFAOYSA-N CC(C=C1)=CC=C1S(C(C(C=CC(OCC1CC1)=C1)=C1F)[N+]#[C-])(=O)=O Chemical compound CC(C=C1)=CC=C1S(C(C(C=CC(OCC1CC1)=C1)=C1F)[N+]#[C-])(=O)=O SNSKBYHARDDKFG-UHFFFAOYSA-N 0.000 description 2
- YHIVATLXBVGGHL-UHFFFAOYSA-N CNCC(C=C1Br)=CN1S(C1=CC(OCCCOC)=CC=C1)(=O)=O Chemical compound CNCC(C=C1Br)=CN1S(C1=CC(OCCCOC)=CC=C1)(=O)=O YHIVATLXBVGGHL-UHFFFAOYSA-N 0.000 description 2
- LFXWSJIWACDRGE-UHFFFAOYSA-N COC(C(C(OC)=C1C(C=CC(OCC2CC2)=C2)=C2F)=CN1S(C1=CC=CN=C1)(=O)=O)=O Chemical compound COC(C(C(OC)=C1C(C=CC(OCC2CC2)=C2)=C2F)=CN1S(C1=CC=CN=C1)(=O)=O)=O LFXWSJIWACDRGE-UHFFFAOYSA-N 0.000 description 2
- YGYCWPZXJJKXHP-UHFFFAOYSA-N COC(C(C=O)=C1)=C(C(C=CC(OCC2CC2)=C2)=C2F)N1S(C1=CC=CN=C1)(=O)=O Chemical compound COC(C(C=O)=C1)=C(C(C=CC(OCC2CC2)=C2)=C2F)N1S(C1=CC=CN=C1)(=O)=O YGYCWPZXJJKXHP-UHFFFAOYSA-N 0.000 description 2
- XFAFAXSGXGGOQF-UHFFFAOYSA-N COC(C(CO)=C1)=C(C(C=CC(OCC2CC2)=C2)=C2F)N1S(C1=CC=CN=C1)(=O)=O Chemical compound COC(C(CO)=C1)=C(C(C=CC(OCC2CC2)=C2)=C2F)N1S(C1=CC=CN=C1)(=O)=O XFAFAXSGXGGOQF-UHFFFAOYSA-N 0.000 description 2
- XMAMHTJZEXCFBL-UHFFFAOYSA-N COC1=CC=CC(S(N2C(Br)=CC(C=O)=C2)(=O)=O)=C1 Chemical compound COC1=CC=CC(S(N2C(Br)=CC(C=O)=C2)(=O)=O)=C1 XMAMHTJZEXCFBL-UHFFFAOYSA-N 0.000 description 2
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-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
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa 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
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 2
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 2
- YOOWCYQWQDKUAT-UHFFFAOYSA-N O=S(C1=CC(OCC2CCCC2)=CC=C1)(Cl)=O Chemical compound O=S(C1=CC(OCC2CCCC2)=CC=C1)(Cl)=O YOOWCYQWQDKUAT-UHFFFAOYSA-N 0.000 description 2
- UGPLWFMOENUGKT-UHFFFAOYSA-N OC1=CC=CC(S(N2C(Br)=CC(C=O)=C2)(=O)=O)=C1 Chemical compound OC1=CC=CC(S(N2C(Br)=CC(C=O)=C2)(=O)=O)=C1 UGPLWFMOENUGKT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 108010067973 Valinomycin Proteins 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-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
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 210000003815 abdominal wall Anatomy 0.000 description 2
- 239000011609 ammonium molybdate Substances 0.000 description 2
- 235000018660 ammonium molybdate Nutrition 0.000 description 2
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 2
- 229940010552 ammonium molybdate Drugs 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
- 125000004429 atom Chemical group 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
- 230000004071 biological effect Effects 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 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
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125936 compound 42 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
- 229940125900 compound 59 Drugs 0.000 description 2
- 229940126179 compound 72 Drugs 0.000 description 2
- FCFNRCROJUBPLU-UHFFFAOYSA-N compound M126 Natural products CC(C)C1NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC(=O)C(C(C)C)NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC(=O)C(C(C)C)NC(=O)C(C)OC(=O)C(C(C)C)NC(=O)C(C(C)C)OC1=O FCFNRCROJUBPLU-UHFFFAOYSA-N 0.000 description 2
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 2
- ISQVBYGGNVVVHB-UHFFFAOYSA-N cyclopentylmethanol Chemical compound OCC1CCCC1 ISQVBYGGNVVVHB-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-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
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 230000027125 histamine-induced gastric acid secretion Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000003350 kerosene Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 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
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000001187 pylorus Anatomy 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture 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
- 238000007423 screening assay Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- LNPNQDXXFAWSCF-UHFFFAOYSA-N tert-butyl n-[(5-bromo-1h-pyrrol-3-yl)methyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1=CNC(Br)=C1 LNPNQDXXFAWSCF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-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
- FCFNRCROJUBPLU-DNDCDFAISA-N valinomycin Chemical compound CC(C)[C@@H]1NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC(=O)[C@H](C(C)C)NC(=O)[C@H](C)OC(=O)[C@@H](C(C)C)NC(=O)[C@@H](C(C)C)OC1=O FCFNRCROJUBPLU-DNDCDFAISA-N 0.000 description 2
- 229950003825 vonoprazan Drugs 0.000 description 2
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 2
- KJZLJGZZDNGGCA-UHFFFAOYSA-N (1-methylpiperidin-4-yl)methanol Chemical compound CN1CCC(CO)CC1 KJZLJGZZDNGGCA-UHFFFAOYSA-N 0.000 description 1
- JAOYKRSASYNDGH-SCSAIBSYSA-N (1r)-1-(2,6-dichloro-3-fluorophenyl)ethanol Chemical compound C[C@@H](O)C1=C(Cl)C=CC(F)=C1Cl JAOYKRSASYNDGH-SCSAIBSYSA-N 0.000 description 1
- JAOYKRSASYNDGH-BYPYZUCNSA-N (1s)-1-(2,6-dichloro-3-fluorophenyl)ethanol Chemical compound C[C@H](O)C1=C(Cl)C=CC(F)=C1Cl JAOYKRSASYNDGH-BYPYZUCNSA-N 0.000 description 1
- 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 1
- QUIMJTKRVOBTQN-UHFFFAOYSA-N (2,4-dimethylphenyl)methanol Chemical compound CC1=CC=C(CO)C(C)=C1 QUIMJTKRVOBTQN-UHFFFAOYSA-N 0.000 description 1
- LVICICZQETYOGS-UHFFFAOYSA-N (2,6-difluorophenyl)methanol Chemical compound OCC1=C(F)C=CC=C1F LVICICZQETYOGS-UHFFFAOYSA-N 0.000 description 1
- MFGWMAAZYZSWMY-UHFFFAOYSA-N (2-naphthyl)methanol Chemical compound C1=CC=CC2=CC(CO)=CC=C21 MFGWMAAZYZSWMY-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GNQLTCVBSGVGHC-UHFFFAOYSA-N (3,4-difluorophenyl)methanol Chemical compound OCC1=CC=C(F)C(F)=C1 GNQLTCVBSGVGHC-UHFFFAOYSA-N 0.000 description 1
- LOGIHEKXJKHXEC-UHFFFAOYSA-N (3,5-difluorophenyl)methanol Chemical compound OCC1=CC(F)=CC(F)=C1 LOGIHEKXJKHXEC-UHFFFAOYSA-N 0.000 description 1
- XJZNZSLOHZLFQP-UHFFFAOYSA-N (4,4-difluorocyclohexyl)methanol Chemical compound OCC1CCC(F)(F)CC1 XJZNZSLOHZLFQP-UHFFFAOYSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 1
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-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
- RCPAVJXGLFKACE-UHFFFAOYSA-N 1-(2,5-difluorophenyl)ethanol Chemical compound CC(O)C1=CC(F)=CC=C1F RCPAVJXGLFKACE-UHFFFAOYSA-N 0.000 description 1
- NBVJYNNOTNTJRX-UHFFFAOYSA-N 1-[4-(hydroxymethyl)piperidin-1-yl]ethanone Chemical compound CC(=O)N1CCC(CO)CC1 NBVJYNNOTNTJRX-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- JMSUNAQVHOHLMX-UHFFFAOYSA-N 1-cyclohexylethanol Chemical compound CC(O)C1CCCCC1 JMSUNAQVHOHLMX-UHFFFAOYSA-N 0.000 description 1
- VOGSDFLJZPNWHY-UHFFFAOYSA-N 2,2-difluoroethanol Chemical compound OCC(F)F VOGSDFLJZPNWHY-UHFFFAOYSA-N 0.000 description 1
- FJSAJUXIHJIAMD-UHFFFAOYSA-N 2,4-difluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C(F)=C1 FJSAJUXIHJIAMD-UHFFFAOYSA-N 0.000 description 1
- CELLJWUVMKEJDY-UHFFFAOYSA-N 2,5-difluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(F)C(S(Cl)(=O)=O)=C1 CELLJWUVMKEJDY-UHFFFAOYSA-N 0.000 description 1
- QXWAUQMMMIMLTO-UHFFFAOYSA-N 2,6-difluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(F)=C1S(Cl)(=O)=O QXWAUQMMMIMLTO-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- XDZLMMDJKWJEJF-UHFFFAOYSA-N 2-(3,5-difluorophenyl)ethanol Chemical compound OCCC1=CC(F)=CC(F)=C1 XDZLMMDJKWJEJF-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
- 235000020926 24-h fasting Nutrition 0.000 description 1
- RPPATMZRVMDBEP-UHFFFAOYSA-N 3-(cyclobutylmethoxy)benzenesulfonyl chloride Chemical compound ClS(=O)(=O)c1cccc(OCC2CCC2)c1 RPPATMZRVMDBEP-UHFFFAOYSA-N 0.000 description 1
- BOWIFWCBNWWZOG-UHFFFAOYSA-N 3-Thiophenemethanol Chemical compound OCC=1C=CSC=1 BOWIFWCBNWWZOG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ASYQJYIEVNXWDV-UHFFFAOYSA-N 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(O)C=C1F ASYQJYIEVNXWDV-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RWQUWTMOHXGTNN-UHFFFAOYSA-N 9-n,10-n-bis(4-butylphenyl)-9-n,10-n-bis(4-methylphenyl)phenanthrene-9,10-diamine Chemical compound C1=CC(CCCC)=CC=C1N(C=1C2=CC=CC=C2C2=CC=CC=C2C=1N(C=1C=CC(C)=CC=1)C=1C=CC(CCCC)=CC=1)C1=CC=C(C)C=C1 RWQUWTMOHXGTNN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- NWIBPDOTXNCUJO-UHFFFAOYSA-N CCCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 Chemical compound CCCCCOC1=CC=CC(S(Cl)(=O)=O)=C1 NWIBPDOTXNCUJO-UHFFFAOYSA-N 0.000 description 1
- UUXQJNNTXGKBGG-UHFFFAOYSA-N CCCCCOC1=CC=CC(S(N2C(Br)=CC(CNC)=C2)(=O)=O)=C1 Chemical compound CCCCCOC1=CC=CC(S(N2C(Br)=CC(CNC)=C2)(=O)=O)=C1 UUXQJNNTXGKBGG-UHFFFAOYSA-N 0.000 description 1
- AVWFTOHPNISZDX-UHFFFAOYSA-N CNCC(C=C1Br)=CN1S(C1=CC(OCC2CCC2)=CC=C1)(=O)=O Chemical compound CNCC(C=C1Br)=CN1S(C1=CC(OCC2CCC2)=CC=C1)(=O)=O AVWFTOHPNISZDX-UHFFFAOYSA-N 0.000 description 1
- NGVYJQODJCZVOD-UHFFFAOYSA-N CNCC(C=C1Br)=CN1S(C1=CC(OCC2CCCC2)=CC=C1)(=O)=O Chemical compound CNCC(C=C1Br)=CN1S(C1=CC(OCC2CCCC2)=CC=C1)(=O)=O NGVYJQODJCZVOD-UHFFFAOYSA-N 0.000 description 1
- MLBTVEYCUVAJKJ-UHFFFAOYSA-N CNCC(C=C1Br)=CN1S(C1=CC(OCCCCOC)=CC=C1)(=O)=O Chemical compound CNCC(C=C1Br)=CN1S(C1=CC(OCCCCOC)=CC=C1)(=O)=O MLBTVEYCUVAJKJ-UHFFFAOYSA-N 0.000 description 1
- DDZSFXSPRUTNGE-UHFFFAOYSA-N CNCC(C=C1Br)=CN1S(C1=CC(OCCF)=CC=C1)(=O)=O Chemical compound CNCC(C=C1Br)=CN1S(C1=CC(OCCF)=CC=C1)(=O)=O DDZSFXSPRUTNGE-UHFFFAOYSA-N 0.000 description 1
- UXCGTYMZPRKSPG-UHFFFAOYSA-N COC(C1=CNC(C(C=CC(OCC2CC2)=C2)=C2F)=C1F)=O Chemical compound COC(C1=CNC(C(C=CC(OCC2CC2)=C2)=C2F)=C1F)=O UXCGTYMZPRKSPG-UHFFFAOYSA-N 0.000 description 1
- 101150003340 CYP2C19 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- ZRQVQDAWPHHSMU-IMJSIDKUSA-N [(1s,2s)-2-fluorocyclopropyl]methanol Chemical compound OC[C@@H]1C[C@@H]1F ZRQVQDAWPHHSMU-IMJSIDKUSA-N 0.000 description 1
- JJAUYEZYAXAERE-UHFFFAOYSA-N [2-(difluoromethoxy)phenyl]methanol Chemical compound OCC1=CC=CC=C1OC(F)F JJAUYEZYAXAERE-UHFFFAOYSA-N 0.000 description 1
- ICOVMLDFMWLRJO-UHFFFAOYSA-N [2-(trifluoromethoxy)phenyl]methanol Chemical compound OCC1=CC=CC=C1OC(F)(F)F ICOVMLDFMWLRJO-UHFFFAOYSA-N 0.000 description 1
- HSIDWXYUJAUALR-UHFFFAOYSA-N [4-(difluoromethoxy)phenyl]methanol Chemical compound OCC1=CC=C(OC(F)F)C=C1 HSIDWXYUJAUALR-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229960001456 adenosine triphosphate Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 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
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 0.000 description 1
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- RHFZTBSULNJWEI-UHFFFAOYSA-N dimethyl 2-(methoxymethylidene)propanedioate Chemical compound COC=C(C(=O)OC)C(=O)OC RHFZTBSULNJWEI-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- XDUKCSCITZQGGB-UHFFFAOYSA-N ethanamine;methanol Chemical compound OC.CCN XDUKCSCITZQGGB-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000020828 fasting Nutrition 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- STJIISDMSMJQQK-UHFFFAOYSA-N furan-3-ylmethanol Chemical compound OCC=1C=COC=1 STJIISDMSMJQQK-UHFFFAOYSA-N 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000011539 homogenization buffer Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- VMFMUJZRXZXYAH-UHFFFAOYSA-N n-[5-[[5-chloro-4-[2-[2-(dimethylamino)-2-oxoacetyl]anilino]pyrimidin-2-yl]amino]-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl]prop-2-enamide Chemical compound C=CC(=O)NC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)C(=O)C(=O)N(C)C)C(Cl)=CN=2)C(OC)=CC=1N1CCN(C)CC1 VMFMUJZRXZXYAH-UHFFFAOYSA-N 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- ROTONRWJLXYJBD-UHFFFAOYSA-N oxan-2-ylmethanol Chemical compound OCC1CCCCO1 ROTONRWJLXYJBD-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical compound OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000000856 sucrose gradient centrifugation Methods 0.000 description 1
- 239000002352 surface water Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 210000002417 xiphoid bone Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of medicaments, and discloses a compound containing a sulfonamide structure, a preparation method and application thereof, a pharmaceutical composition and application thereofThe compounds provided are useful as therapeutic agents, particularly as inhibitors of gastric acid secretion and potassium ion competitive acid blockers (P-CABs).
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a compound containing a sulfonamide structure, a preparation method and application thereof, and a pharmaceutical composition and application thereof.
Background
Proton Pump Inhibitors (PPIs), represented by omeprazole, strongly and persistently inhibit gastric acid secretion by inhibiting H +/K + -atpase on gastric parietal cells, and PPIs are widely used for treating acid-related diseases such as gastroesophageal reflux disease, peptic ulcer, helicobacter pylori infection, upper gastrointestinal bleeding, Zollinger-Ellison syndrome, and the like.
Since 1988, the long-term clinical application shows that PPI has the defects of instability, short half-life, influence by CYP2C19 gene polymorphism, limited administration time, slow effect and the like, and clinically needs an antacid medicament with quicker effect, stronger acid inhibition effect and longer pH maintenance time.
Potassium-Competitive Acid Blockers (P-CABs) Potassium-Competitive Acid Blockers (P-CABs) are a novel Acid-inhibitory drug that directly compete with K + for binding sites on H +/K + -ATPase in ionic form, while inhibiting H +/K + -ATPase in both resting and activated states, thereby effectively inhibiting gastric Acid secretion. Compared with the traditional proton pump inhibitor, the P-CABs have the characteristics of lipophilicity, alkalescence, high dissociation constant and stability under the condition of low pH.
Compared with a Proton Pump Inhibitor (PPI), the P-CAB is a lipophilic weak base, has quicker acid inhibition effect and lasting effect, and is not easy to generate the acid breakthrough phenomenon at night; and the P-CAB medicines have good stability, do not need to be prepared into an enteric-coated dosage form and are not influenced by gene polymorphism. .
However, the representative P-cab vonoprazan that has been marketed also presents a certain safety risk in clinical applications, such as hepatotoxicity and the like. Thus, although a series of potassium-competitive acid blockers have been disclosed, there is still a need to develop compounds with more abundant structural types, and new compounds that may have better tissue distribution and other drug-forming properties.
Disclosure of Invention
The object of the present invention is to overcome the aforementioned drawbacks of the prior art and to provide a new class of compounds having the efficacy of potassium-competitive acid blockers.
In order to achieve the above object, a first aspect of the present invention provides a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in the formula (I), the compound represented by the formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)2-phenyl, 3-furyl containing at least two halogen substitutions; r1Wherein the optional substituents are selected from halogen, hydroxy, C1-C3Alkyl of (C)1-C3At least one of aldehyde groups of (a);
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Optionally present inThe substituent is selected from halogen and C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is C1-C3Alkyl groups of (a);
R4is H, C1-C3Alkoxy, halogen of (a);
R5and R6One of H and the other selected from F, C1-C3Alkyl group of (1).
The second aspect of the present invention provides a process for preparing a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
the method comprises the following steps: carrying out contact reaction on a compound shown as a formula (II) and a compound shown as a formula (III);
wherein, in formula (I), formula (II) and formula (III), the definitions of each group are the same as those described in the first aspect.
A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
A fourth aspect of the present invention provides the use of a compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect, in the manufacture of a medicament for an H +/K + -ATPase inhibitor and/or in the manufacture of a medicament for a potassium ion competitive acid blocker.
A fifth aspect of the present invention provides the use of a compound as described in the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect, in the manufacture of a medicament for the treatment or prevention of peptic ulcer, zollinger-ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, barrett's esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, or hyperacidity or ulcers resulting from post-operative stress.
The present invention provides the aforementioned compounds as therapeutic agents, particularly as gastric acid secretion inhibitors and potassium ion competitive acid blockers (P-CABs).
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Unless stated to the contrary, the following terms used herein have the following meanings.
“C1-C6The "alkyl group" of (a) means a saturated alkyl group comprising a straight chain of 1 to 6 carbon atomsOr a branched alkyl group. Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. For "C1-C4The alkyl group "and the like have similar definitions, only in terms of the total number of carbon atoms, and the present invention will not be described in detail.
“C1-C6The "alkoxy group" of (a) means a saturated alkoxy group, including a straight or branched chain alkoxy group of 1 to 6 carbon atoms. Such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. For "C1-C4Alkoxy group of (1), "" C1-C3The "alkoxy group" and the like have similar definitions, only in terms of the total number of carbon atoms, and the present invention will not be described in detail.
"six-membered saturated heterocycloalkyl group containing 1 to 2 oxygen atoms" means that 1 to 2 ring atoms in the six-membered saturated heterocycloalkyl group are oxygen atoms, for example, tetrahydropyranyl group, dioxane group and the like.
"substituted or unsubstituted C3-C6The "cycloalkyl group" of (a) means that the number of ring-forming atoms is 3 to 6, for example, 3, 4,5 or 6, and the ring-forming atoms are all C atoms, and any position in the cycloalkyl group which may be substituted by a group defined in the present invention.
"substituted or unsubstituted piperidinyl" means that any position in the piperidine ring that can be substituted with a group as defined herein.
“-O-C1-C4alkylene-O-C of1-C2By "alkyl" is meant that the group is attached to the parent nucleus structure through O and the terminal alkyl group is methyl or ethyl.
"C substituted by 1-3 halogens1-C3Alkyl of (2) means C1-C3Any substitutable position in the alkyl group of (a) is substituted with 1 to 3 halogens.
“-O-C1-C4alkylene-C of3-C6The "cycloalkyl group" means that the group is bonded to the parent structure through O and the terminal alkyl group is C3-C6A cycloalkyl group of (a).
"halogen" means fluorine, chlorine, bromine or iodine.
The invention "optionally present" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does or does not.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like, or with organic acids including acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or is complexed with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
By "pharmaceutically acceptable carrier" is meant an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to: calcium carbonate, calcium phosphate, various sugars (e.g., lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic or methacrylic polymers, gelatin, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or hydrogenated or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, and the like.
As described above, the first aspect of the present invention provides a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
in the formula (I), the compound represented by the formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)2-phenyl, 3-furyl containing at least two halogen substitutions; r1Wherein the optional substituents are selected from halogen, hydroxy, C1-C3Alkyl of (C)1-C3At least one of aldehyde groups of (a);
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from halogen, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is C1-C3Alkyl groups of (a);
R4is H, C1-C3Alkoxy, halogen of (a);
R5and R6One of H and the other selected from F, C1-C3Alkyl group of (1).
According to a preferred embodiment, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)2-phenyl, 3-furyl containing at least two halogen substitutions; r1Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, C1-C2At least one of aldehyde groups of (a);
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, iodine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4Alkylene group of (a)O-C1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl, ethyl, n-propyl or isopropyl;
R4is H, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro or bromo;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
According to another preferred embodiment, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)2-phenyl, 3-furyl containing at least two halogen substitutions; r1Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl and glyoxal;
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4Alkylene of (A)radical-O-C1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl or ethyl;
R4is H, methoxy or fluoro;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
According to still another preferred embodiment, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, methyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, difluoromethyl, methoxy, dioxane, substituted or unsubstituted piperidinyl, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (A) a (B) a (C) a (C) b) a (C) a (C) b) a (C) a (C) a (C) and (C) a (C) a (C) a (C) a (C) a (C) a (C)2-phenyl, 3-furyl containing at least two halogen substitutions; r1Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl and aldehyde group;
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano of、-O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl or ethyl;
R4is H, methoxy or fluoro;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
According to a particularly preferred embodiment, the compound of formula (I) is selected from any one of compound 1 to compound 100.
The pharmaceutically acceptable salts of the structure of formula (I) of the present invention include, but are not limited to, the hydrochloride salt form.
The present invention does not require any particular method for preparing the compounds of the first aspect, and those skilled in the art can easily determine an appropriate preparation method by combining the features of the structural formulae provided by the present invention with the technical means known in the field of organic synthesis. Also, the examples of the present invention exemplify some of the methods for preparing specific compounds, and those skilled in the art can determine the specific methods for preparing the remaining compounds according to these exemplarily provided methods.
And, preferably, in order to obtain a compound having a higher yield and purity, the present invention provides the process described in the second aspect for preparing a compound having a sulfonamide structure, which has a structure represented by formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
the method comprises the following steps: carrying out contact reaction on a compound shown as a formula (II) and a compound shown as a formula (III);
wherein, in formula (I), formula (II) and formula (III), the definitions of the respective groups are the same as those described in the first aspect.
According to a particularly preferred embodiment, the compounds according to the invention are obtained by a process as shown in the following synthetic schemes, the conditions of the substituents involved in the synthetic schemes being in accordance with the correspondence described hereinbefore.
The present invention is not particularly limited to the parameter conditions in the aforementioned synthetic routes, and those skilled in the art can perform the synthesis by using the parameters known in the art, and the synthesis parameter conditions of some specific compounds are exemplarily given hereinafter, and those skilled in the art should not be construed as limiting the present invention.
As mentioned above, the third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the first aspect or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
The present invention does not particularly require pharmaceutically acceptable carriers, excipients or diluents, and may be various substances known in the art, and the present invention will not be described herein in detail, and those skilled in the art will not be construed as limiting the present invention.
The fourth aspect of the present invention provides the use of a compound referred to in the first aspect above, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition referred to in the third aspect, in the manufacture of a medicament for an H +/K + -ATPase inhibitor and/or in the manufacture of a medicament for a potassium ion competitive acid blocker.
A fifth aspect of the present invention provides the use of a compound according to the first aspect above, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect above, in the manufacture of a medicament for the treatment or prophylaxis of peptic ulcer, zollinger-ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, barrett's esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, or hyperacidity or ulcers resulting from post-operative stress.
Particularly preferably, the peptic ulcer includes at least one of gastric ulcer, duodenal ulcer and stomal ulcer; the symptomatic gastroesophageal reflux disease includes at least one of non-erosive reflux disease and non-esophagitis gastroesophageal reflux disease.
Preferably, the aforementioned pharmaceutical composition of the present invention and the aforementioned compound can be used for the preparation of a gastric acid secretion inhibitor.
Preferably, the present invention provides a method for inhibiting gastric acid secretion, which comprises administering to a patient in need thereof an effective amount of the aforementioned compound or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
Hereinbefore, in addition to pharmaceutically acceptable carriers, adjuvants commonly used in pharmacy may be included, such as: antibacterial agents, antifungal agents, antimicrobial agents, shelf-stable agents, hueing agents, solubilizing agents, thickening agents, surfactants, complexing agents, proteins, amino acids, fats, sugars, vitamins, minerals, trace elements, sweeteners, pigments, flavors or combinations thereof, and the like.
The present invention will be described in detail below by way of examples. In the following examples, the raw materials used below are all common commercial products unless otherwise specified.
Preparation example 1: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 1
Step 1: preparation of 5-bromo-1H-pyrrole-3-carbaldehyde
Pyrrole-3-carbaldehyde (52.6mmol) and tetrahydrofuran (THF,100mL) were added to a two-necked round-bottomed flask and cooled to-78 ℃ in a low temperature magnetic stirrer, and bromosuccinimide (NBS,52.6mmol) dissolved in N, N-dimethylformamide (DMF,30mL) was added dropwise to the reaction system. After the dropwise addition, the reaction is continued for 1h, and the temperature is increased to-10 ℃ for continuous reaction for 1 h. TLC monitored the starting material reaction was complete. Ice water was added to the system, followed by extraction with ethyl acetate (200 mL. times.2), washing with saturated brine (150 mL. times.2), merging of the organic phases, drying over anhydrous sodium sulfate, concentration under reduced pressure to give a brown solid, washing with isopropyl ether, and suction filtration to give a white solid with a yield of 49.4%.
Step 2: preparation of tert-butyl ((5-bromo-1H-pyrrol-3-yl) methyl) (methyl) carbamate
5-bromo-1H-pyrrole-3-carbaldehyde (17.2mmol), 33 wt% methylamine in methanol (34.4mmol) and methanol (40mL) were added to a single-neck round-bottom flask and stirred at room temperature (25 ℃ C., same below) for 1H, and sodium borohydride (25.8mmol) was added portionwise in an ice bath and stirring continued for 1H. TLC monitored the starting material reaction was complete. Adding 50mL of water into the system, stirring for 10min, transferring the reaction system into a separating funnel in batches by using ethyl acetate (300mL), washing by using saturated saline (150mL multiplied by 3), drying by using anhydrous sodium sulfate, dissolving the product by using acetonitrile (30mL), dropwise adding di-tert-butyl dicarbonate (20.6mmol), stirring for 30min at room temperature, monitoring by TLC that the reaction of the raw material is completely carried out, transferring the reaction system into the separating funnel in batches by using ethyl acetate (300mL), washing by using the saturated saline (150mL multiplied by 3), drying by using the anhydrous sodium sulfate of an organic phase, concentrating under reduced pressure, mixing samples, purifying by column chromatography, concentrating under reduced pressure to obtain brown oily liquid, and obtaining the yield of 79.5%.
And step 3: preparation of tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate
60mL of ultra-dry tetrahydrofuran was charged in a single-neck round-bottom flask, cooled to 0 ℃, sodium hydride (47.2mmol) was added, tert-butyl ((5-bromo-1H-pyrrol-3-yl) methyl) (methyl) carbamate (13.5mmol) dissolved in 10mL of N, N-dimethylformamide was slowly added dropwise, stirring was carried out at 0 ℃ for 30min, and then 15-crown-5 (40.5mmol) was added dropwise, then pyridine-3-sulfonyl chloride (20.2mmol) is added dropwise, stirring is continued for 30min at 0 ℃ after the addition is finished, then stirring the mixture for 30min at room temperature, monitoring the complete reaction of the raw materials by TLC, pouring the system into ice water, extracting the mixture by ethyl acetate (200mL multiplied by 2), washing the mixture by saturated saline solution (150mL multiplied by 2), combining organic phases, drying the organic phases by anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, and purifying the organic phases by column chromatography to obtain light yellow solid with the yield of 82.1 percent.
And 4, step 4: preparation of 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol
To the reaction tube were added 4-bromo-3-fluoro-phenol (262mmol), pinacol diborate (314mmol), palladium tetrakistriphenylphosphine (13.1mmol), potassium acetate (524 mmol). After nitrogen gas was purged 3 times, 400mL of 1, 4-dioxane was added, and the mixture was stirred at 130 ℃ for 12 hours, and the completion of the reaction of the starting materials was monitored by TLC. Adding ice water into the system, extracting, drying the organic phase by anhydrous sodium sulfate, decompressing, concentrating and purifying by column chromatography to obtain white solid with the yield of 51.5 percent.
And 5: preparation of tert-butyl ((5- (2-fluoro-4-hydroxyphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (2.3mmol), 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (3.49mmol), tetrakistriphenylphosphine palladium (0.233mmol), sodium bicarbonate (6.96mmol), nitrogen gas was purged 3 times, DME (20mL), H under nitrogen protection, and the reaction tube was charged with tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (3.49mmol), tetrakistriphenylphosphine palladium (0.233mmol), and sodium bicarbonate (6.96mmol)2O (5mL), reacted at 100 ℃ for 2 h. TLC monitored the starting material reaction was complete. The reaction system was transferred to a separatory funnel with ethyl acetate (150mL), washed with saturated brine (100 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give a pale yellow solid with a yield of 69.8%.
Step 6: (S) -1- (5- (4- ((1, 4-dioxan-2-yl) methoxy) -2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine hydrochloride
The stirrer was set to 80 ℃ for preheating, and tert-butyl ((5- (2-fluoro-4-hydroxyphenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.43mmol,1.0eq), triphenylphosphine (0.866mmol,2.0eq), (2S) -1, 4-dioxane-2-methanol (0.866mmol,2.0eq), and 10mL of toluene were added to a single-neck round-bottomed flask and dissolved by heating and stirring. Diisopropyl azodicarboxylate (0.866mmol,2.0eq) was added dropwise when the temperature rose to 80 ℃ and stirred for 30min at 80 ℃ with TLC monitoring of the completion of the starting material reaction. After directly concentrating the system under reduced pressure, 2mL of ethyl acetate solution of hydrogen chloride and 2mL of ethyl acetate were added, the mixture was stirred at room temperature for 12 hours, and the completion of the reaction of the starting materials was monitored by TLC. The hydrochloride salt of compound 1 was obtained by suction filtration in 50% yield as a yellow solid.
1H NMR(600MHz,Methanol-d4)δ8.88(d,J=4.8Hz,1H),8.65(s,1H),8.07(d,J=8.4Hz,1H),7.81(s,1H),7.75–7.69(m,1H),7.02(t,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),6.72(d,J=11.4Hz,1H),6.42(s,1H),4.10(s,2H),4.08–4.01(m,2H),4.00–3.95(m,1H),3.92–3.88(m,1H),3.86–3.82(m,1H),3.81–3.71(m,2H),3.67–3.61(m,1H),3.58–3.53(m,1H),2.71(s,3H).
Preparation example 2: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 2
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of cyclobutylmethanol gave the hydrochloride salt of compound 2 as a white solid in 24% yield from step 6).
1H NMR(600MHz,Methanol-d4)δ8.87–8.83(m,1H),8.61(s,1H),8.01(d,J=8.4Hz,1H),7.80(s,1H),7.68–7.63(m,1H),7.00(t,J=8.4Hz,1H),6.76(d,J=8.4Hz,1H),6.69–6.62(m,1H),6.40(d,J=1.8Hz,1H),4.10(s,2H),4.00(d,J=6.6Hz,2H),2.86–2.77(m,1H),2.72(s,3H),2.23–2.11(m,2H),2.08–1.89(m,4H).
Preparation example 3: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 3
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of cyclopentylmethanol gave the hydrochloride salt of compound 3 as a white solid in 31% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.87(d,J=4.8Hz,1H),8.63(s,1H),8.05(d,J=8.4Hz,1H),7.81(d,J=2.4Hz,1H),7.72–7.66(m,1H),7.00(t,J=8.4Hz,1H),6.76(d,J=8.4Hz,1H),6.67(d,J=11.4Hz,1H),6.41(d,J=1.8Hz,1H),4.10(s,2H),3.92(d,J=6.6Hz,2H),2.72(s,3H),2.44–2.32(m,1H),1.92–1.83(m,2H),1.75–1.58(m,4H),1.47–1.35(m,2H).
Preparation example 4: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 4
The preparation of this preparation is similar to that of preparation 1, except that: (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of cyclohexylmethanol to give the hydrochloride salt of compound 4 as a white solid in a one-step yield of 35% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.84(d,J=5.4Hz,1H),8.60(s,1H),8.06–7.99(m,1H),7.76(d,J=2.4Hz,1H),7.68–7.62(m,1H),6.97–6.90(m,1H),6.70(dd,J=8.4,2.4Hz,1H),6.63–6.57(m,1H),6.36(d,J=2.4Hz,1H),4.04(s,2H),3.78(d,J=6.6Hz,2H),2.66(s,3H),1.88–1.62(m,6H),1.35–1.15(m,3H),1.12–0.98(m,2H).
Preparation example 5: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 5
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4, 4-difluoro-cyclohexanemethanol to give the hydrochloride salt of compound 5 as a white solid in 37% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(dd,J=4.8,1.8Hz,1H),8.60(d,J=2.4Hz,1H),8.00(dt,J=8.4,1.8Hz,1H),7.79(d,J=1.8Hz,1H),7.65(dd,J=8.4,4.8Hz,1H),7.00(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.68(dd,J=11.4,2.4Hz,1H),6.40(d,J=1.8Hz,1H),4.09(s,2H),3.91(d,J=6.0Hz,2H),2.71(s,3H),2.15–2.05(m,2H),2.01–1.92(m,3H),1.91–1.75(m,2H),1.51–1.40(m,2H).
Preparation example 6:
this preparation serves to illustrate the synthesis of compound 6:
the preparation of this preparation is similar to that of preparation 1, except that: (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give compound 6 as a white solid in 34% yield in step 6).
1H NMR(400MHz,DMSO-d6)δ8.86(dd,J=4.8,1.8Hz,1H),8.57(d,J=2.4Hz,1H),7.88(dt,J=8.4,1.8Hz,1H),7.61(dd,J=8.4,4.8Hz,1H),7.45(d,J=1.8Hz,1H),7.00(t,J=8.4Hz,1H),6.85(dd,J=12.0,2.4Hz,1H),6.78(dd,J=8.4,2.4Hz,1H),6.30(d,J=1.8Hz,1H),3.90(dd,J=11.4,4.8Hz,4H),3.49(s,2H),2.24(s,3H),2.10–1.96(m,1H),1.75–1.63(m,2H),1.44–1.20(m,4H).
Preparation example 7: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 7
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of tetrahydropyran-2-methanol to give the hydrochloride of compound 7 as a white solid in a one-step yield of 40% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.89(dd,J=4.8,1.8Hz,1H),8.65(d,J=2.4Hz,1H),8.07(d,J=8.4Hz,1H),7.81(d,J=1.8Hz,1H),7.72(dd,J=8.4,4.8Hz,1H),7.01(t,J=8.4Hz,1H),6.79(dd,J=8.4,2.54Hz,1H),6.70(dd,J=11.4,2.4Hz,1H),6.42(d,J=1.8Hz,1H),4.10(s,2H),4.04–3.97(m,3H),3.79–3.72(m,1H),3.58–3.50(m,1H),2.71(s,3H),1.96–1.88(m,1H),1.76–1.43(m,5H).
Preparation example 8: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 8:
the preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 8 as a white solid in 25% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.86(dd,J=4.8,1.6Hz,1H),8.62(d,J=2.4Hz,1H),8.04–7.98(m,1H),7.81(d,J=1.8Hz,1H),7.65(dd,J=8.4,4.8Hz,1H),7.01(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.67(dd,J=12.0,2.4Hz,1H),6.41(d,J=1.8Hz,1H),4.35–4.29(m,1H),4.10(s,2H),4.01(dd,J=11.8,4.2Hz,2H),3.50–3.40(m,2H),2.72(s,3H),1.92–1.80(m,2H),1.70–1.62(m,1H),1.58–1.42(m,2H),1.32(d,J=6.0Hz,3H).
Preparation example 9: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 9
The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride as a yellow solid in a yield of 70%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3, 5-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 9 as a white solid in 28% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.74(d,J=11.4Hz,1H),7.38(t,J=9.0Hz,1H),7.09–6.95(m,3H),6.75(d,J=8.4Hz,1H),6.66(d,J=11.4Hz,1H),6.40(s,1H),4.36–4.28(m,1H),4.09(s,2H),4.02–3.92(m,2H),3.50–3.38(m,2H),2.71(s,3H),1.92–1.79(m,2H),1.69–1.39(m,3H),1.30(d,J=6.0Hz,3H).
Preparation example 10: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 10
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride as a yellow solid in a yield of 70%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-trifluoromethylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 10 as a white solid in 35% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.03(d,J=7.8Hz,1H),7.89–7.72(m,3H),7.60(s,1H),6.99(t,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),6.64(d,J=11.4Hz,1H),6.39(d,J=2.4Hz,1H),4.35–4.29(m,1H),4.11(s,2H),4.05–3.99(m,2H),3.51–3.44(m,2H),2.72(s,3H),1.95–1.85(m,2H),1.71–1.65(m,1H),1.60–1.45(m,2H),1.33(d,J=6.6Hz,3H).
Preparation example 11: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 11
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride as a yellow solid in 73% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluoro-4-methylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 11 as a white solid in 31% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.75(s,1H),7.40(t,J=7.8Hz,1H),7.24(d,J=8.4Hz,1H),7.06(d,J=8.4Hz,1H),7.00(t,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),6.69–6.64(m,1H),6.38(s,1H),4.37–4.30(m,1H),4.10(s,2H),4.04–3.99(m,2H),3.47(t,J=12.0Hz,2H),2.72(s,3H),2.34(s,3H),1.96–1.83(m,2H),1.71–1.63(m,1H),1.57–1.43(m,2H),1.33(d,J=6.0Hz,3H).
Preparation example 12: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 12
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 5-difluorobenzenesulfonyl chloride as a yellow solid in a yield of 72%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 5-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 12 as a white solid in 40% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.76(s,1H),7.52–7.45(m,1H),7.35–7.28(m,1H),6.93(t,J=8.4Hz,1H),6.89–6.84(m,1H),6.67(dd,J=8.4,2.4Hz,1H),6.51(dd,J=11.4,2.4Hz,1H),6.39(d,J=2.4Hz,1H),4.28–4.20(m,1H),4.10(s,2H),3.97(dd,J=11.4,4.2Hz,2H),3.46–3.34(m,2H),2.70(s,3H),1.88–1.77(m,2H),1.65–1.55(m,1H),1.54–1.36(m,2H),1.26(d,J=6.0Hz,3H).
Preparation example 13: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 13
The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-cyanobenzenesulfonyl chloride as a yellow solid in 71% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 13 as a white solid in 36% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.84(s,1H),8.59(s,1H),7.94(d,J=6.6Hz,1H),7.79(s,1H),7.60(s,1H),6.97(d,J=8.4Hz,1H),6.73(d,J=7.2Hz,1H),6.62(d,J=11.4Hz,1H),6.39(s,1H),4.33–4.24(m,1H),4.10(s,2H),2.71(s,3H),1.99–1.90(m,1H),1.85–1.76(m,3H),1.73–1.68(m,1H),1.66–1.56(m,1H),1.38–1.05(m,8H).
Preparation example 14: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 14
Step 1: preparation of 5-bromo-1- ((3-methoxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde
Adding pyrrole-3-formaldehyde (11.5mmol) into a single-neck round-bottom flask, dissolving in 25mL of ultra-dry tetrahydrofuran, cooling to 0 ℃, slowly adding sodium hydride (1.61g, 60% in kerosene, 40.0mmol), then dropwise adding 3-methoxybenzenesulfonyl chloride (17.2mmol), continuing stirring at 0 ℃ for 30min after the dropwise adding is finished, then stirring at room temperature for 30min, monitoring the completion of the reaction of the raw materials by TLC, pouring the system into ethyl acetate (200mL multiplied by 2) in ice water for extraction, washing with saturated saline (150 multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying by column chromatography to obtain a light yellow solid with the yield of 90.0%.
Step 2: preparation of 5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde
A three-necked round bottom flask was charged with 5-bromo-1- ((3-methoxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde (10.3mmol) and ultra-dry dichloromethane (CH)2Cl250mL) was placed in a low temperature magnetic stirrer and cooled to-78 deg.C, then BBr was added3(51.7mmol) was added dropwise to the reaction system. After the dropwise addition, the mixture is transferred to an ice bath condition to be stirred for 30 min. TLC monitored the starting material reaction was complete. Adding ice water into the system, extracting with EA (200mL multiplied by 2), washing with saturated brine (150mL multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, mixing samples, purifying by column chromatography, and concentrating under reduced pressure to obtain yellow solid with the yield of 58.0%.
And step 3: preparation of tert-butyl ((5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate
To a single neck round bottom flask was added methylamine hydrochloride (15.2mmol) and methanol (CH)3OH, 50mL) was placed in a low temperature magnetic stirrer and cooled to-40 deg.C, then 5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrole-3-carbaldehyde (15.1mmol) and sodium cyanoborohydride (52.5mmol) were added and the temperature was naturally raised to room temperature. TLC monitored the completion of the reaction of the starting material, the reaction system was transferred in portions to a separatory funnel with ethyl acetate (300mL), washed with saturated brine (150 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown yellow oil, the product was dissolved in acetonitrile (30mL), di-tert-butyl dicarbonate (17.3mmol) and sodium bicarbonate (42.8mmol) were added, and stirred overnight at 50 ℃ in an oil bath, TLC monitored the completion of the reaction of the starting material with ethyl acetate (300mL), the reaction system was transferred in portions to a separatory funnel with saturated brine (150 mL. times.3), dried over anhydrous sodium sulfate of the organic phase, concentrated under reduced pressure and stirred, purified by column chromatography, and concentrated under reduced pressure to give a brown oil with a yield of 44.0%.
And 4, step 4: preparation of tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate
The stirrer was set to 80 ℃ and preheated, and tert-butyl ((5-bromo-1- ((3-hydroxyphenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.89mmol), triphenylphosphine (1.79mmol), ethylene glycol monomethyl ether (1.79mmol) and toluene (10 mL) were added to a single-neck round-bottom flask and dissolved by heating with stirring. Diisopropyl azodicarboxylate (1.79mmol) was added dropwise when the temperature rose to 80 deg.C, stirred at 80 deg.C for 10min and TLC monitored for completion of the starting material reaction. The system is directly decompressed and concentrated, dichloromethane with 2mL is loaded by a wet method, and the white solid is obtained by column chromatography purification, with the yield of 70.0%.
And 5: preparation of 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol
To the reaction tube were added 4-bromo-3-fluoro-phenol (262mmol), pinacol diborate (314mmol), palladium tetrakistriphenylphosphine (13.1mmol), potassium acetate (524 mmol). After nitrogen gas was purged 3 times, 400mL of 1, 4-dioxane was added, and the mixture was stirred at 130 ℃ for 12 hours, and the completion of the reaction of the starting materials was monitored by TLC. Adding ice water into the system, extracting, drying the organic phase by anhydrous sodium sulfate, decompressing, concentrating and purifying by column chromatography to obtain white solid with the yield of 51.5 percent.
Step 6: preparation of tert-butyl ((1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -5- (2-fluoro-4-hydroxyphenyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (2.0mmol), 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol (3.0mmol), tetrakistriphenylphosphine palladium (0.1mmol), sodium bicarbonate (6.10mmol), nitrogen purged 3 times, DME (20mL), H under nitrogen protection2O (5mL), reacted at 100 ℃ for 2 h. TLC monitored the starting material reaction was complete. The reaction system was transferred to a separatory funnel with ethyl acetate (150mL), washed with saturated brine (100mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give a pale yellow solid in a yield of 69.3%.
And 7: 1- (5- (2-fluoro-4- (1- (tetrahydro-2H-pyran-4-yl) ethoxy) phenyl) -1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine-hydrochloride
The stirrer was set to 90 ℃ and preheated, and tert-butyl ((1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -5- (2-fluoro-4-hydroxyphenyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate (0.64mmol), triphenylphosphine (1.28mmol), 1- (tetrahydro-2H-pyran-4-yl) ethanol (1.12mmol) and toluene (10 mL) were added to the single-neck round-bottom flask and dissolved by heating and stirring. Diisopropyl azodicarboxylate (1.28mmol) was added dropwise when the temperature rose to 80 deg.C, stirred at 80 deg.C for 5min and TLC monitored for completion of the starting material reaction. Directly concentrating the system under reduced pressure to obtain a crude product, adding 2mL of ethyl acetate solution of hydrochloric acid and 2mL of ethyl acetate, stirring at room temperature for 12h, and monitoring the completion of the raw material reaction by TLC. The mixture was filtered by suction to give a yellow oil in 29% yield.
1H NMR(600MHz,Methanol-d4)δ7.69(s,1H),7.38(s,1H),7.25–7.18(m,1H),7.11–7.05(m,1H),6.92(d,J=24.0Hz,2H),6.75–6.69(m,1H),6.66(d,J=11.4Hz,1H),6.32(s,1H),4.34–4.26(m,1H),4.08–3.96(m,7H),3.72(s,2H),3.50–3.36(m,2H),2.66(s,3H),1.88–1.81(m,2H),1.69–1.60(m,1H),1.57–1.43(m,2H),1.30(s,5H).
Preparation example 15: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 15
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-methoxybenzenesulfonyl chloride as a yellow solid in 69% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-methoxybenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 55% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 15 as a gray solid in 45% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.72(s,1H),7.37(t,J=8.4Hz,1H),7.17(d,J=8.4Hz,1H),7.07(d,J=7.8Hz,1H),6.93(t,J=8.4Hz,1H),6.84(s,1H),6.69(d,J=9.0Hz,1H),6.62(d,J=11.4Hz,1H),6.33(s,1H),4.31–4.23(m,1H),4.06(s,2H),3.98(dd,J=11.4,4.2Hz,2H),3.73(s,3H),3.47–3.38(m,2H),2.68(s,3H),1.90–1.78(m,2H),1.67–1.59(m,1H),1.55–1.39(m,2H),1.28(d,J=6.0Hz,3H).
Preparation example 16: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 16
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 6-difluorobenzenesulfonyl chloride as a yellow solid in 67% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 6-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 16 as a white solid in 41% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.71–7.57(m,2H),6.95(t,J=9.0Hz,2H),6.82(t,J=8.4Hz,1H),6.55(d,J=9.0Hz,1H),6.44(d,J=11.4Hz,1H),6.31(s,1H),4.19–4.14(m,1H),4.03(s,2H),3.90(dd,J=11.4,4.2Hz,2H),3.34(dt,J=15.6,7.8Hz,2H),2.63(s,3H),1.81–1.70(m,2H),1.57–1.50(m,1H),1.46–1.30(m,2H),1.18(d,J=6.0Hz,3H).
Preparation example 17: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 17
The preparation of this preparation is similar to that of preparation 1, except that: pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 2, 4-difluorobenzenesulfonyl chloride as a yellow solid in 68% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (2, 4-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 17 as a white solid in 42% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.92(s,1H),7.53–7.45(m,1H),7.42–7.34(m,1H),7.16–7.09(m,2H),6.86–6.81(m,1H),6.73–6.67(m,1H),6.57–6.53(m,1H),4.47–4.36(m,1H),4.27(s,2H),4.15(dd,J=11.4,4.2Hz,2H),3.65–3.54(m,2H),2.87(s,3H),2.05–1.94(m,2H),1.82–1.76(m,1H),1.72–1.55(m,2H),1.44(d,J=6.0Hz,3H).
Preparation example 18: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 18
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 4-cyanobenzenesulfonyl chloride as a yellow solid in 66% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (4-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 18 as a white solid in 43% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.02(d,J=8.4Hz,2H),7.95–7.90(m,1H),7.79(d,J=8.4Hz,2H),7.12(t,J=8.4Hz,1H),6.89(dd,J=8.4,2.4Hz,1H),6.81(dd,J=12.0,2.4Hz,1H),6.55–6.51(m,1H),4.50–4.44(m,1H),4.24(s,2H),4.15(dd,J=11.4,4.2Hz,2H),3.65–3.56(m,2H),2.86(s,3H),2.08–1.96(m,2H),1.82–1.77(m,1H),1.72–1.57(m,2H),1.46(d,J=6.0Hz,3H).
Preparation example 19: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 19
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluorobenzenesulfonyl chloride as a yellow solid in 68% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluorophenylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 19 as a white solid in 48% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.75(d,J=1.8Hz,1H),7.53(td,J=8.14,5.4Hz,1H),7.44(td,J=8.4,2.4Hz,1H),7.34(d,J=7.8Hz,1H),7.12(dt,J=8.4,2.4Hz,1H),6.97(t,J=8.4Hz,1H),6.73(dd,J=8.4,2.4Hz,1H),6.64(dd,J=11.4,2.4Hz,1H),6.38(d,J=2.4Hz,1H),4.33–4.26(m,1H),4.09(s,2H),3.99(dd,J=11.4,4.2Hz,2H),3.48–3.37(m,2H),2.70(s,3H),1.91–1.81(m,2H),1.68–1.60(m,1H),1.56–1.42(m,2H),1.30(d,J=6.0Hz,3H).
Preparation example 20: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 20
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-cyclohexylethanol to give the hydrochloride of compound 20 as a white solid in 49% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.84(s,1H),8.59(s,1H),7.94(d,J=6.6Hz,1H),7.79(s,1H),7.60(s,1H),6.97(d,J=8.4Hz,1H),6.73(d,J=7.2Hz,1H),6.62(d,J=11.4Hz,1H),6.39(s,1H),4.33–4.24(m,1H),4.10(s,2H),2.71(s,3H),1.99–1.90(m,1H),1.85–1.76(m,3H),1.73–1.68(m,1H),1.66–1.56(m,1H),1.38–1.05(m,8H).
Preparation example 21: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 21
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylpiperidine to give the hydrochloride salt of compound 21 as a yellow solid in a one-step yield of 33% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.79(d,J=4.8Hz,1H),8.50(s,1H),7.96(d,J=8.4Hz,1H),7.75(s,1H),7.63–7.54(m,2H),6.97(t,J=8.4Hz,1H),6.74(d,J=8.4Hz,1H),6.66(d,J=11.4Hz,1H),6.36(s,1H),4.05(s,2H),3.93(d,J=6.0Hz,2H),3.46–3.38(m,2H),3.09–2.99(m,2H),2.66(s,3H),2.20–2.12(m,1H),2.09–2.02(m,2H),1.70–1.52(m,2H).
Preparation example 22: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 22
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-methyl-4-piperidinemethanol to give the hydrochloride salt of compound 22 as a gray solid in 40% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.83(d,J=5.4Hz,1H),8.54(s,1H),7.98(d,J=8.4Hz,1H),7.80(s,1H),7.62(s,1H),7.01(d,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),6.71(d,J=11.2Hz,1H),6.41(d,J=2.4Hz,1H),3.99(d,J=5.4Hz,2H),3.63–3.56(m,2H),3.12–3.04(m,2H),2.90(s,2H),2.71(s,3H),2.20–2.12(m,2H),2.01(s,3H),1.77–1.66(m,2H),1.63–1.57(m,1H).
Preparation example 23:
this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 23:
the preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (4- (hydroxymethyl) piperidin-1-yl) ethanone to give the hydrochloride salt of compound 23 as a white solid in 20% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.81(dd,J=4.8,1.8Hz,1H),8.54(d,J=2.4Hz,1H),8.00–7.94(m,1H),7.77(d,J=1.8Hz,1H),7.64–7.57(m,1H),6.97(t,J=8.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.65(dd,J=11.4,2.4Hz,1H),6.37(d,J=1.8Hz,1H),4.55(d,J=13.3Hz,1H),4.06(s,2H),3.99(d,J=14.0Hz,1H),3.90(d,J=6.2Hz,2H),3.19(t,J=13.3Hz,1H),2.79–2.62(m,4H),2.14(s,3H),2.13–2.05(s,1H),2.02–1.84(m,2H),1.47–1.32(m,2H).
Preparation example 24: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 24
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluorobenzenesulfonyl chloride as a yellow solid in 71% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluorophenylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 68% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 24 as a white solid in 45% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.74(d,J=1.8Hz,1H),7.68(dd,J=7.8,1.8Hz,1H),7.53–7.41(m,2H),7.30(d,J=2.4Hz,1H),6.97(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.66(dd,J=11.4,2.4Hz,1H),6.36(d,J=1.8Hz,1H),4.08(s,2H),3.99(dd,J=11.4,4.2Hz,2H),,3.90(d,J=6.6Hz,2H),3.48(td,J=12.0,2.4Hz,2H),,2.70(s,3H),2.15–2.07(m,1H),1.84–1.72(m,2H),1.54–1.41(m,2H).
Preparation example 25: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 25
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-chlorobenzenesulfonyl chloride as a yellow solid in a yield of 72%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-chlorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 25 as a white solid in a one-step yield of 42% in step 6).
1H NMR(600MHz,Methanol-d4)δ7.74(d,J=1.8Hz,1H),7.56–7.39(m,2H),7.32(d,J=7.8Hz,1H),7.16–7.09(m,1H),7.00–6.93(m,1H),6.74(dd,J=8.4,2.4Hz,1H),6.66(dd,J=11.4,2.4Hz,1H),6.36(d,J=1.8Hz,1H),4.08(s,2H),3.99(dd,J=11.4,4.2Hz,2H),3.89(d,J=6.6Hz,2H),3.48(td,J=12.0,2.4Hz,2H),,2.70(s,3H),2.15–2.03(m,1H),1.82–1.71(m,2H),1.53–1.41(m,2H).
Preparation example 26: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 26
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride as a yellow solid in a yield of 72%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-fluoro-4-methylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 26 as a white solid in 44% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.71(d,J=1.8Hz,1H),7.37(t,J=7.8Hz,1H),7.20(dd,J=8.4,1.8Hz,1H),7.06(dd,J=8.4,1.8Hz,1H),6.98(t,J=8.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.67(dd,J=11.4,2.4Hz,1H),6.34(d,J=1.8Hz,1H),4.07(s,2H),4.02–3.96(m,2H),3.89(d,J=6.6Hz,2H),3.48(td,J=12.0,2.4Hz,2H),,2.69(s,3H),2.31(s,3H),2.15–2.06(m,1H),1.83–1.74(m,2H),1.54–1.41(m,2H).
Preparation example 27: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 27
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride as a yellow solid in 71% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3, 5-difluorobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 61% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 27 as a white solid in 49% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ7.75(d,J=1.8Hz,1H),7.43–7.34(m,1H),7.10–6.99(m,3H),6.77(dd,J=8.4,2.4Hz,1H),6.68(dd,J=11.4,2.4Hz,1H),6.40(d,J=2.4Hz,1H),4.09(s,2H),3.99(dd,J=11.4,4.2Hz,2H),3.90(d,J=6.6Hz,2H),3.48(td,J=12.0,1.8Hz,2H),2.71(s,3H),2.15–2.05(m,1H),1.83–1.74(m,2H),1.53–1.42(m,2H).
Preparation example 28: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 28
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-cyanobenzenesulfonyl chloride as a yellow solid in a yield of 70%.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 63% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 28 as a white solid in 51% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.02(d,J=7.8Hz,1H),7.81–7.74(m,2H),7.69(t,J=7.8Hz,1H),7.59(s,1H),6.98(t,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.66(d,J=11.4Hz,1H),6.36(d,J=1.8Hz,1H),4.08(s,2H),3.99(d,J=11.4Hz,2H),3.92(d,J=6.6Hz,2H),3.48(t,J=12.0Hz,2H),2.70(s,3H),2.15–2.05(m,1H),1.82–1.74(m,2H),1.54–1.44(m,2H).
Preparation example 29: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 29
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 4-cyanobenzenesulfonyl chloride as a yellow solid in 68% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (4-cyanobenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 59% yield.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride salt of compound 29 as a white solid in a one-step yield of 42% in step 6).
1H NMR(600MHz,Methanol-d4)δ7.91–7.84(m,2H),7.76(d,J=1.8Hz,1H),7.65–7.60(m,2H),6.96(t,J=8.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.67(dd,J=11.4,2.4Hz,1H),6.37(d,J=1.8Hz,1H),4.08(s,2H),3.99(dd,J=11.4,4.2Hz,2H),3.89(d,J=6.6Hz,2H),3.48(td,J=12.0,2.4Hz,2H),2.70(s,2H),2.14–2.04(m,1H),1.83–1.73(m,2H),1.53–1.40(m,2H).
Preparation example 30: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 30
The preparation of this preparation is similar to that of preparation 14, except that:
replacing ethylene glycol methyl ether in the step 4) with 2-fluoroethanol with an equimolar amount, and obtaining yellow solid with the yield of 60%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- ((3- (2-fluoroethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 60% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 30 as the hydrochloride salt as a white solid in 43% yield in step 7).
1H NMR(600MHz,Methanol-d4)δ7.74(d,J=1.8Hz,1H),7.40(t,J=8.4Hz,1H),7.24(dd,J=8.4,2.6Hz,1H),7.11(d,J=8.4Hz,1H),6.94(t,J=8.4Hz,1H),6.89(t,J=2.4Hz,1H),6.72(dd,J=8.4,2.4Hz,1H),6.65(dd,J=11.4,2.4Hz,1H),6.34(d,J=1.8Hz,1H),4.80–4.64(m,2H),4.22–4.11(m,2H),4.08(s,2H),4.03–3.95(m,2H),3.88(d,J=6.0Hz,2H),3.53–3.44(m,2H),2.69(s,3H),2.17–2.02(m,1H),1.85–1.72(m,2H),1.54–1.39(m,2H).
Preparation example 31: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 31
The preparation of this preparation is similar to that of preparation 14, except that:
ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-pentanol, a yellow solid, yield 62%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- ((3- (pentyloxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 62% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 31 as the hydrochloride salt as a white solid in 20% yield in step 7).
1H NMR(600MHz,Methanol-d4)δ7.72(d,J=1.8Hz,1H),7.37(t,J=8.4Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.08(d,J=7.8Hz,1H),6.96(t,J=8.4Hz,1H),6.82(t,J=2.4Hz,1H),6.72(dd,J=8.4,2.4Hz,1H),6.66(dd,J=11.4,2.4Hz,1H),6.32(d,J=2.4Hz,1H),4.07(s,2H),4.00(dd,J=12.0,4.2Hz,2H),3.91–3.81(m,4H),3.48(t,J=12.0Hz,2H),2.69(s,3H),2.16–2.05(m,1H),1.83–1.71(m,4H),1.54–1.36(m,6H),0.96(t,J=7.0Hz,3H).
Preparation example 32: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 32
The preparation of this preparation is similar to that of preparation 14, except that:
replacing ethylene glycol methyl ether in step 4) with an equimolar amount of 3-methoxy-1-propanol as a yellow solid with a yield of 64%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 64% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 32 as the hydrochloride salt as a white solid in 25% yield in step 7).
1H NMR(600MHz,Methanol-d4)δ7.71(s,1H),7.38(t,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H),7.09(d,J=7.8Hz,1H),6.96(t,J=8.4Hz,1H),6.87–6.81(m,1H),6.73(d,J=8.4Hz,1H),6.68–6.61(m,1H),6.32(s,1H),4.07(s,2H),4.02–3.94(m,4H),3.89(d,J=6.6Hz,2H),3.55(t,J=6.0Hz,2H),3.49(t,J=12.0Hz,2H),3.35(s,3H),2.69(s,3H)2.15–2.06(m,1H),2.04–1.96(m,2H),1.82–1.74(m,2H),1.53–1.43(m,2H).
Preparation example 33: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 33
The preparation of this preparation is similar to that of preparation 14, except that:
ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of cyclopropylmethanol as a yellow solid in 61% yield.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (cyclobutylmethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 62% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 33 as a white solid in 34% yield in step 7).
1H NMR(400MHz,Methanol-d4)δ7.75(d,J=1.8Hz,1H),7.39(t,J=8.4Hz,1H),7.21(dd,J=8.4,2.54z,1H),7.13–7.07(m,1H),6.97(t,J=8.4Hz,1H),6.88(t,J=2.4Hz,1H),6.73(dd,J=8.4,2.4Hz,1H),6.67(dd,J=11.4,2.4Hz,1H),6.36(d,J=2.4Hz,1H),4.38–4.29(m,1H),4.10(s,2H),4.02(dd,J=11.4,4.2Hz,2H),3.88(d,J=6.6Hz,2H),3.53–3.40(m,2H),2.82–2.67(m,4H),2.20–2.10(m,2H),2.08–1.80(m,6H),1.70–1.62(m,1H),1.60–1.42(m,2H),1.33(d,J=6.0Hz,3H).
Preparation example 34: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 34
The preparation of this preparation is similar to that of preparation 14, except that:
ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of cyclopentyl methanol as a yellow solid in 61% yield.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (cyclopentylmethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 62% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 4-hydroxymethyltetrahydropyran, giving compound 34 as the hydrochloride salt as a white solid in a one-step yield of 46% in step 7).
1H NMR(400MHz,Methanol-d4)δ7.72(d,J=2.0Hz,1H),7.37(t,J=8.4Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.09(dd,J=7.6,1.6Hz,1H),6.96(t,J=8.4Hz,1H),6.81(t,J=2.4Hz,1H),6.72(dd,J=8.4,2.4Hz,1H),6.66(dd,J=11.4,2.4Hz,1H),6.33(d,J=1.6Hz,1H),4.07(s,2H),3.99(dd,J=11.4,4.2Hz,2H),3.88(d,J=6.6Hz,2H),3.75(d,J=6.6Hz,2H),3.48(td,J=12.0,1.8Hz,2H),2.69(s,3H),2.38–2.25(m,1H),2.15–2.01(m,1H),1.91–1.74(m,4H),1.73–1.56(m,4H),1.54–1.41(m,2H),1.40–1.29(m,2H).
Preparation example 35: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 35
The preparation of this preparation is similar to that of preparation 14, except that:
replacing ethylene glycol methyl ether in the step 4) with an equimolar amount of 2-fluoroethanol, a yellow solid, yield 62%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (2-fluoroethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of cyclohexylmethanol gave compound 35 as the hydrochloride salt as a white solid in 45% yield in step 7).
1H NMR(600MHz,Methanol-d4)δ7.73(d,J=1.8Hz,1H),7.40(t,J=8.4Hz,1H),7.24(dd,J=8.4,2.4Hz,1H),7.10(d,J=7.8Hz,1H),6.94(t,J=8.4Hz,1H),6.89(t,J=2.4Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.62(dd,J=11.4,2.4Hz,1H),6.33(d,J=1.8Hz,1H),4.80–4.62(m,2H),4.21–4.11(m,2H),4.08(s,2H),3.81(d,J=6.6Hz,2H),2.69(s,3H),1.94–1.77(m,6H),1.41–1.21(m,4H),1.18–1.07(m,2H).
Preparation example 36: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 36
The preparation of this preparation is similar to that of preparation 14, except that:
ethylene glycol methyl ether in step 4) was replaced by an equimolar amount of n-pentanol, a yellow solid, yield 64%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (pentyloxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine as a yellow solid in 60% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of cyclohexylmethanol gave compound 36 as the hydrochloride salt as a white solid in 19% yield in one step in step 7).
1H NMR(600MHz,Methanol-d4)δ7.73(d,J=1.8Hz,1H),7.37(t,J=7.8Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.09(d,J=7.8Hz,1H),6.94(t,J=8.4Hz,1H),6.80(t,J=2.4Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.62(dd,J=11.4,2.4Hz,1H),6.33(d,J=1.8Hz,1H),4.08(s,2H),3.85(t,J=6.6Hz,2H),3.81(d,J=6.0Hz,2H),2.70(s,3H),1.94–1.86(m,2H),1.86–1.68(m,6H),1.50–1.20(m,7H),1.18–1.07(m,2H),0.97(t,J=7.0Hz,3H).
Preparation example 37: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 37
The preparation of this preparation is similar to that of preparation 14, except that:
ethylene glycol methyl ether in step 4) was replaced with an equimolar amount of 3-methoxy-1-propanol as a yellow solid with a yield of 61%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 37 as a white solid in 44% yield in step 7).
1H NMR(400MHz,Methanol-d4)δ7.73(d,J=1.8Hz,1H),7.38(t,J=8.4Hz,1H),7.19(dd,J=8.4,2.4Hz,1H),7.12–7.07(m,1H),6.96(t,J=8.4Hz,1H),6.87(t,J=2.4Hz,1H),6.72(dd,J=8.4,2.4Hz,1H),6.66(dd,J=11.4,2.4Hz,1H),6.34(d,J=1.8Hz,1H),4.36–4.27(m,1H),4.08(s,2H),4.04–3.94(m,4H),3.55(t,J=6.0Hz,2H),3.50–3.41(m,2H),3.35(s,3H),2.70(s,3H),2.06–1.97(m,2H),1.93–1.82(m,2H),1.70–1.62(m,1H),1.59–1.41(m,2H),1.31(d,J=6.0Hz,3H).
Preparation example 38: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 38
The preparation of this preparation is similar to that of preparation 14, except that:
replacing ethylene glycol methyl ether in the step 4) with an equimolar amount of-methoxy-1-butanol as a yellow solid with a yield of 58%.
Tert-butyl ((5-bromo-1- ((3- (2-methoxyethoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 6) was replaced with an equimolar amount of 1- (5-bromo-1- ((3- (4-methoxybutoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine as a yellow solid in 61% yield.
Replacing 1- (tetrahydro-2H-pyran-4-yl) ethanol in step 7) with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 38 as a yellow solid in 20% yield in step 7).
1H NMR(400MHz,Methanol-d4)δ7.67(d,J=1.8Hz,1H),7.35(t,J=8.4Hz,1H),7.16(dd,J=8.4,2.4Hz,1H),7.09–7.05(m,1H),6.94(t,J=8.4Hz,1H),6.84(t,J=2.4Hz,1H),6.69(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.4,2.4Hz,1H),6.31(d,J=1.8Hz,1H),4.34–4.23(m,1H),4.04–3.95(m,4H),3.91(t,J=6.0Hz,2H),3.48–3.41(m,4H),3.33(s,3H),2.62(s,3H),1.87–1.76(m,4H),1.75–1.67(m,2H),1.67–1.60(m,1H),1.56–1.41(m,4H),1.29(d,J=6.0Hz,3H).
Preparation example 39: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 39
The preparation of this preparation is similar to that of preparation 1, except that:
pyridine-3-sulfonyl chloride in step 3) was replaced with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride as a yellow solid in 68% yield.
Tert-butyl ((5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate in step 5) was replaced with an equimolar amount of tert-butyl ((5-bromo-1- (3-trifluoromethylbenzenesulfonyl) -1H-pyrrol-3-yl) methyl) (methyl) carbamate as a yellow solid in 65% yield.
The (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give the hydrochloride of compound 39 as a white solid in 54% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.99(d,J=7.8Hz,1H),7.86–7.68(m,3H),7.56(s,1H),6.97(t,J=8.4Hz,1H),6.73(dd,J=8.4,2.4Hz,1H),6.62(dd,J=11.4,2.4Hz,1H),6.37(d,J=1.8Hz,1H),4.09(s,2H),4.00(dd,J=10.8,4.2Hz,2H),3.88(d,J=6.6Hz,2H),3.49(td,J=12.0,2.4Hz,2H),2.70(s,3H),2.15–2.05(m,1H),1.83–1.73(m,2H),1.53–1.42(m,2H).
Preparation example 40: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 40
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of methanol to give the hydrochloride of compound 40 as a white solid in a one-step yield of 46% in step 6).
1H NMR(600MHz,Methanol-d4)δ9.01(d,J=5.4Hz,1H),8.81(s,1H),8.35(d,J=8.4Hz,1H),7.96(dd,J=8.4,5.4Hz,1H),7.89–7.82(m,1H),7.04(t,J=8.4Hz,1H),6.78(dd,J=8.4,2.4Hz,1H),6.71(dd,J=11.4,2.4Hz,1H),6.47(d,J=1.8Hz,1H),4.12(s,2H),3.87(s,3H),2.72(s,3H).
Preparation example 41: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 41
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of ethanol to give the hydrochloride salt of compound 41 as a white solid in 53% yield in one step in step 6).
1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.56(s,1H),7.86(d,J=7.8Hz,1H),7.66–7.49(m,2H),7.04–6.93(m,1H),6.88–6.71(m,2H),6.34(s,1H),4.19–3.97(m,2H),3.61(s,2H),2.30(s,3H),1.30–1.22(m,3H).
Preparation example 42: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 42
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 2-difluoroethanol to give the hydrochloride of compound 42 as a white solid in a one-step yield of 47% in step 6).
1H NMR(600MHz,DMSO-d6)δ8.86(d,J=4.8Hz,1H),8.57(d,J=2.4Hz,1H),7.87(d,J=8.4Hz,1H),7.61(dd,J=8.4,4.8Hz,1H),7.48(s,1H),7.04(t,J=8.4Hz,1H),6.97(d,J=11.4Hz,1H),6.86(dd,J=8.4,2.4Hz,1H),6.43(t,J=55.2Hz,1H),6.32(s,1H),4.46–4.35(m,2H),3.51(s,2H),2.24(s,3H).
Preparation example 43: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 43
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3-methoxypropanol to give the hydrochloride salt of compound 43 as a yellow solid in 51% yield in step 6).
1H NMR(600MHz,DMSO-d6)δ8.86(d,J=4.8Hz,1H),8.56(s,1H),7.87(d,J=8.4Hz,1H),7.61(t,J=6.6Hz,1H),7.45(s,1H),6.99(t,J=8.4Hz,1H),6.83(d,J=11.4Hz,1H),6.77(d,J=8.4Hz,1H),6.30(s,1H),4.12–4.03(m,2H),3.49(d,J=6.0Hz,4H),3.26(s,3H),2.24(s,3H),2.02–1.93(m,2H).
Preparation example 44: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 44
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of isopropanol to give the hydrochloride salt of compound 44 as a white solid in 50% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.81(d,J=4.8Hz,1H),8.55(s,1H),7.90(d,J=8.4Hz,1H),7.78(s,1H),7.59–7.52(m,1H),6.99(t,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),6.65(d,J=11.4Hz,1H),6.38(s,1H),4.09(s,2H),3.80(d,J=6.6Hz,2H),2.71(s,3H),2.15–2.04(m,1H),1.06(dd,J=6.7,2.4Hz,6H).
Preparation example 45: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 45
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of neopentyl alcohol to give the hydrochloride salt of compound 45 as a white solid in one step yield of 38% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(d,J=4.8Hz,1H),8.65–8.58(m,1H),8.01(d,J=8.4Hz,1H),7.79(s,1H),7.65(dd,J=8.4,4.8Hz,1H),6.99(t,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.71–6.64(m,1H),6.44–6.35(m,1H),4.09(s,2H),3.69(s,2H),2.71(s,3H),1.07(s,9H).
Preparation example 46: this preparation is illustrative of the procedure for the synthesis of compound 46
The preparation of this preparation is similar to that of preparation 1, except that:
the 33% methylamine methanol solution in step 2) was replaced with an equimolar amount of ethylamine methanol, a brown oily liquid, yield 70%.
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethyltetrahydropyran to give compound 46 as a white solid in 48% yield in step 6).
1H NMR(600MHz,Chloroform-d)δ8.75(dd,J=4.8,1.8Hz,1H),8.60(d,J=2.4Hz,1H),7.81–7.71(m,1H),7.47(s,1H),7.34(dd,J=8.4,4.8Hz,1H),7.01(t,J=8.4Hz,1H),6.65(dd,J=8.4,2.4Hz,1H),6.55(dd,J=11.4,2.4Hz,1H),6.30(d,J=1.8Hz,1H),4.08–3.99(m,2H),3.81(d,J=6.6Hz,2H),3.76(s,2H),3.52–3.41(m,3H),2.81–2.72(m,2H),2.13–2.04(m,1H),1.81–1.72(m,2H),1.53–1.42(m,2H),1.21(t,J=7.2Hz,3H).
Preparation example 47: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 47
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1- (tetrahydro-2H-pyran-4-yl) ethanol to give the hydrochloride salt of compound 47 as a white solid in 38% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.86(dd,J=4.8,1.6Hz,1H),8.62(d,J=2.4Hz,1H),8.04–7.98(m,1H),7.81(d,J=1.8Hz,1H),7.65(dd,J=8.4,4.8Hz,1H),7.01(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.67(dd,J=12.0,2.4Hz,1H),6.41(d,J=1.8Hz,1H),4.35–4.29(m,1H),4.10(s,2H),4.01(dd,J=11.8,4.2Hz,2H),3.50–3.40(m,2H),2.72(s,3H),1.92–1.80(m,2H),1.70–1.62(m,1H),1.58–1.42(m,2H),1.32(d,J=6.0Hz,3H).
Preparation example 48: this preparation is illustrative of the procedure for the synthesis of Compound 48
Step 1: preparation of 4- (cyclopropylmethoxy) -2-fluorobenzaldehyde
A single neck round bottom flask was charged with 2-fluoro-4-hydroxybenzaldehyde (14.2mmol), (bromomethyl) cyclopropane (20.7mmol), potassium carbonate (42.7mmol), DMF (40mL), stirred overnight at 60 deg.C, TLC monitored the starting material reaction to completion. Purification by column chromatography gave 2.7g of a white oily liquid in 99% yield.
Step 2: preparation of N- ((4- (cyclopropylmethoxy) -2-fluorophenyl) (tosyl) methyl) carboxamide
A round bottom flask was charged with a reaction mixture of sodium 4-methylbenzenesulfonate (32.0mmol), (15) - (+) -10-camphorsulfonic acid (, 0.320mmol), 4- (cyclopropylmethoxy) -2-fluorobenzaldehyde (35.2mmol) and formamide (160mmol) which was solidified overnight at about 65 deg.C for about 16 h. The solids were broken down and suspended in methanol. The solid block was ground to a powder with a spatula, filtered and washed with methanol. The filter cake was dried under vacuum at about 60 ℃ to give a white powder with a yield of 79%.
And step 3: preparation of 4- (cyclopropylmethoxy) -2-fluoro-1- (isocyano (tosyl) methyl) benzene
Dissolving N- ((4- (cyclopropylmethoxy) -2-fluorophenyl) (tosyl) methyl) formamide (105.2mmol) with 500ml of anhydrous tetrahydrofuran, adding phosphorus oxychloride (210.4mmol) into a reaction bottle, reducing the temperature in an ice bath under the protection of nitrogen, dropwise adding triethylamine (631.1mmol) at the temperature of 0-10 ℃, and stirring for 60min after the addition in the ice bath. TLC detection, and after the raw material disappears, processing: quenched by dropping 500mL of water, extracted with MTBE (200 mL. times.3), combined organic phases, washed with 300mL of saturated brine X2, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent to give a yellow semisolid. 120mL of petroleum ether, 6mL of ethyl acetate were added. Stirring at room temperature for 30min, and filtering. And drying the product at room temperature. A pale yellow solid was obtained in a yield of 72%.
And 4, step 4: preparation of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylate
NaH (67.5mmol), 250mL of diethyl ether, nitrogen protection, ice-bath cooling, 250mL of acetonitrile-dissolved 4- (cyclopropylmethoxy) -2-fluoro-1- (isocyano (tosyl) methyl) benzene (225.0mmol) and dimethyl 2- (methoxymethylene) malonate (13.5mmol) were added dropwise at-10 deg.C, after the addition, the temperature was raised to 40 deg.C and stirred for 48 h. After the reaction is finished, 500mL of water is added, 100mL of MTBE is used for extraction for three times, organic phases are combined, 300mL of saturated saline solution is used for washing, anhydrous sodium sulfate is used for drying, filtration and reduced pressure rotary evaporation are carried out to remove the solvent, an oily substance is obtained, 1.5 times of weight of 100-fold silica gel and 200-fold silica gel are added for mixing sample preparation and sand preparation, 4 times of weight of 200-fold silica gel and 300-fold silica gel are used for packing a column and column chromatography, a product point is collected, 50mL of n-heptane is added after reduced pressure concentration and drying, 2mL of ethyl acetate is used for pulping at room temperature for 1h, and yellow powdery solid is obtained through filtration, wherein the yield is 45%.
And 5: preparation of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxylate
Adding 60mL of ultra-dry tetrahydrofuran into a single-neck round-bottom flask, cooling to 0 ℃, adding sodium hydride (60% in kerosene and 47.2mmol), slowly dropwise adding 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (13.5mmol) dissolved in 10mL of N, N-dimethylformamide, stirring at 0 ℃ for 30min, dropwise adding 15 crown 5(40.5mmol), dropwise adding pyridine-3-sulfonyl chloride (20.2mmol), continuously stirring at 0 ℃ for 30min after dropwise adding is finished, stirring at room temperature for 30min, detecting the completion of the reaction of raw materials by TLC, pouring the system into ethyl acetate (200mL multiplied by 2) in ice water for extraction, washing with saturated saline (150mL multiplied by 2), combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, purifying by column chromatography to obtain a light yellow solid, the yield thereof was found to be 71.5%.
Step 6: preparation of (5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methanol
Methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxylate (60.8mmol) was dissolved in tetrahydrofuran. To the resulting solution was added diisobutylaluminum hydride (1.0M n-hexane solution) (182.2mmol) at 0 ℃ and then stirred at room temperature for 1 h. Water was added to the reaction mixture at 0 ℃ and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 1:4(v/v)) to obtain a yellow compound in a yield of 50%.
And 7: preparation of 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde
(5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) methanol (50.0mmol) was dissolved in dichloromethane. To the resulting solution was added pyridinium chlorochromate (150.0mmol), stirred at room temperature for 30min, and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a yellow compound in a yield of 63.5%.
And 8: preparation of 1- (5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine
5- (4- (Cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (0.23mmol), methylamine (33 wt% in methanol, 2.3mmol), and methanol (3mL) were added to a single-neck round-bottom flask in an ice-water bath and stirred for 30 min. The ice bath was removed and the temperature was raised naturally to ambient temperature and stirred overnight. The next day sodium borohydride (1.2mmol) was added and the reaction was continued at room temperature (25 ℃ C.) for 3 h. TLC monitored the starting material reaction was complete. The system was added to ice water, extracted with dichloromethane (50mL × 4), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give a white solid with a one-step yield of 33%.
1H NMR(600MHz,Methanol-d4)δ8.89(d,J=4.8Hz,1H),8.60(s,1H),8.07(d,J=7.8Hz,1H),7.80–7.67(m,2H),7.02(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.4,2.4Hz,1H),4.08(s,2H),3.88(d,J=6.6Hz,2H),3.44(s,3H),2.72(s,3H),1.32–1.28(m,1H),0.69–0.61(m,2H),0.46–0.31(m,2H).
Preparation example 49: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 49:
the preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of (S) -glycidol to give the hydrochloride salt of compound 49 as a gray solid in 45% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.82(d,J=4.8Hz,1H),8.57(s,1H),7.92(d,J=8.0Hz,1H),7.79(s,1H),7.59(dd,J=8.4,4.8Hz,1H),7.02(t,J=8.4Hz,1H),6.85–6.77(m,1H),6.72(dd,J=11.6,2.4Hz,1H),6.40(d,J=2.0Hz,1H),4.20–4.06(m,5H),3.82–3.75(m,1H),3.75–3.67(m,1H),2.71(s,3H).
Preparation example 50: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 50
The preparation of this preparation is similar to that of preparation 1, except that:
replacement of (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of (R) -glycidol provided the hydrochloride salt of compound 50 as a grey solid in 46% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.89(d,J=5.2Hz,1H),8.67(s,1H),8.13–8.05(m,1H),7.82(d,J=2.0Hz,1H),7.72(dd,J=8.4,5.2Hz,1H),7.04(t,J=8.4Hz,1H),6.82(dd,J=8.4,2.4Hz,1H),6.74(dd,J=11.2,2.4Hz,1H),6.43(d,J=1.6Hz,1H),4.20–4.07(m,5H),3.78(dd,J=11.2,4.8Hz,1H),3.71(dd,J=11.2,5.2Hz,1H),2.71(s,3H).
Preparation example 51: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 51
The preparation of this preparation is similar to that of preparation 48, except that:
the methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-methoxy-1H-pyrrole-3-carboxylate in step 4) was replaced with an equimolar amount of methyl 5- (4- (cyclopropylmethoxy) -2-fluorophenyl) -4-fluoro-1H-pyrrole-3-carboxylate to give the hydrochloride salt of compound 51 as a brown solid in 46% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.90(d,J=5.4Hz,1H),8.70(d,J=2.4Hz,1H),8.20(d,J=9.0Hz,1H),7.85–7.79(m,2H),7.04(t,J=8.4Hz,1H),6.82–6.78(m,1H),6.49–6.44(m,1H),4.10(s,2H),3.84(s,2H),2.73(s,3H),1.33(s,6H).
Preparation example 52: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 52
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-methylpropane-1, 2-diol to give the hydrochloride of compound 52 as a brown solid in a one-step yield of 46% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.94(d,J=5.4Hz,1H),8.72(d,J=2.4Hz,1H),8.20(d,J=9.0Hz,1H),7.89–7.79(m,2H),7.03(t,J=8.4Hz,1H),6.86–6.79(m,1H),6.77–6.70(m,1H),6.48–6.42(m,1H),4.11(s,2H),3.86(s,2H),2.72(s,3H),1.34(s,6H).
Preparation example 53: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 53
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of cis-2-fluorocyclopropyl) methanol to give the hydrochloride salt of compound 53 as a white solid in 46% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.93(d,J=5.2Hz,1H),8.75–8.66(m,1H),8.16(d,J=7.8Hz,1H),7.88–7.75(m,2H),7.03(dd,J=9.5,7.6Hz,1H),6.81(dd,J=8.6,2.5Hz,1H),6.72(dd,J=11.4,2.5Hz,1H),6.44(d,J=2.1Hz,1H),4.34–4.25(m,1H),4.17–4.02(m,3H),2.74(s,3H),1.05–0.97(m,1H),0.95–0.81(m,1H).
Preparation example 54: this preparation is illustrative of the procedure for the synthesis of compound 54
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 5-difluorobenzyl alcohol to give compound 54 as a white solid in 48% yield in step 6).
1H NMR(600MHz,Chloroform-d)δ8.74(d,J=4.8Hz,1H),8.63(s,1H),7.71(d,J=8.4Hz,1H),7.38(s,1H),7.32(dd,J=8.4,4.8Hz,1H),7.25–7.21(m,1H),7.10–7.05(m,2H),7.04–6.98(m,1H),6.75(d,J=8.4Hz,1H),6.66(d,J=11.4Hz,1H),6.24(s,1H),5.12(s,2H),3.63(s,2H),2.45(s,3H).
Preparation example 55: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 55
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 4-difluorobenzyl alcohol to give the hydrochloride of compound 55 as a yellow oil in 45% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85–8.79(m,1H),8.57(s,1H),7.91(d,J=8.4Hz,1H),7.80(s,1H),7.64–7.53(m,2H),7.10–7.00(m,3H),6.86(d,J=8.4Hz,1H),6.79(d,J=11.4Hz,1H),6.40(d,J=2.4Hz,1H),5.18(s,2H),4.10(s,2H),2.72(s,3H).
Preparation example 56: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 56
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 6-difluorobenzyl alcohol to give the hydrochloride salt of compound 56 as a white solid in 45% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(d,J=4.8Hz,1H),8.63(s,1H),7.97(d,J=8.4Hz,1H),7.81(s,1H),7.62(t,J=6.6Hz,1H),7.54–7.43(m,1H),7.15–6.98(m,3H),6.87(d,J=8.4Hz,1H),6.81(d,J=11.4Hz,1H),6.42(s,1H),5.21(s,2H),4.10(s,2H),2.72(s,3H).
Preparation example 57: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 57
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3, 4-difluorobenzyl alcohol to give the hydrochloride salt of compound 57 as a white solid in 56% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(d,J=4.8Hz,1H),8.60(d,J=2.4Hz,1H),7.99(d,J=8.4Hz,1H),7.81(s,1H),7.67–7.60(m,1H),7.43(t,J=9.6Hz,1H),7.31(m,2H),7.04(t,J=8.4Hz,1H),6.86(d,J=9.0Hz,1H),6.78(d,J=11.4Hz,1H),6.42(d,J=2.1Hz,1H),5.14(s,2H),4.10(s,2H),2.71(s,4H).
Preparation example 58: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 58
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3, 5-difluorobenzyl alcohol to give the hydrochloride of compound 58 as a white solid in 55% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.84(d,J=4.8Hz,1H),8.59(s,1H),7.94(d,J=8.4Hz,1H),7.82(s,1H),7.64–7.55(m,1H),7.16–7.10(m,2H),7.06(t,J=8.4Hz,1H),6.99–6.93(m,1H),6.88(d,J=8.4Hz,1H),6.81(d,J=11.4Hz,1H),6.43(d,J=2.4Hz,1H),5.21(s,2H),4.12(s,2H),2.73(s,3H).
Preparation example 59: this preparation serves to illustrate the synthesis of compound 59:
the preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-difluoromethoxybenzyl alcohol to give compound 59 as a yellow powder in 49% yield in one step in step 6).
1H NMR(400MHz,Methanol-d4)δ8.75(dd,J=4.8,1.6Hz,1H),8.53(d,J=2.4Hz,1H),7.87–7.81(m,1H),7.58(dd,J=7.6,1.6Hz,1H),7.51(d,J=1.8Hz,1H),7.50–7.46(m,1H),7.42(td,J=7.6,1.6Hz,1H),7.34–7.22(m,2H),7.01(t,J=8.4Hz,1H),6.88(t,J=73.6Hz,1H),6.81(dd,J=8.4,2.4Hz,1H),6.74(dd,J=11.2,2.4Hz,1H),6.29(d,J=1.6Hz,1H),5.19(s,2H),3.63(s,2H),2.39(s,3H).
Preparation example 60: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 60
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-trifluoromethoxy benzyl alcohol to give the hydrochloride salt of compound 60 as a white solid in 56% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.88(d,J=5.2Hz,1H),8.67(s,1H),8.04(ddd,J=8.4,2.4,1.6Hz,1H),7.82(d,J=2.0Hz,1H),7.71–7.63(m,2H),7.52–7.46(m,1H),7.45–7.36(m,2H),7.05(t,J=8.4Hz,1H),6.85(dd,J=8.4,2.4Hz,1H),6.77(dd,J=11.2,2.4Hz,1H),6.44(d,J=2.0Hz,1H),5.23(s,2H),4.11(s,2H),2.72(s,3H).
Preparation example 61: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 61
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-difluoromethoxybenzyl alcohol to give the hydrochloride of compound 61 as a white solid in 55% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.87–8.80(m,1H),8.60(d,J=2.4Hz,1H),7.96(d,J=7.8Hz,1H),7.81(s,1H),7.64–7.57(m,1H),7.56–7.51(m,2H),7.24–7.18(m,2H),7.02(t,J=8.4Hz,1H),6.86(t,J=66.0Hz,1H),6.86–6.84(m,1H),6.79–6.75(m,1H),6.41(d,J=2.4Hz,1H),5.16(s,2H),4.10(s,2H),2.72(s,3H).
Preparation example 62: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 62
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 1-hydroxymethylnaphthalene to give the hydrochloride of compound 62 as a white solid in 53% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.83–8.78(m,1H),8.61(s,1H),8.13(d,J=8.4Hz,1H),7.98–7.84(m,3H),7.80(s,1H),7.67(d,J=6.6Hz,1H),7.64–7.46(m,3H),7.04(t,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.85(d,J=11.4Hz,1H),6.41(s,1H),5.62(s,2H),4.10(s,2H),2.72(s,3H).
Preparation example 63: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of Compound 63
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1-hydroxymethylnaphthalene gave the hydrochloride salt of compound 63 as a white solid in 43% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.19–8.12(m,1H),8.05–8.00(m,1H),7.94(dd,J=12.6,8.4Hz,2H),7.84–7.73(m,2H),7.72–7.66(m,2H),7.65–7.48(m,4H),7.09–7.01(m,1H),6.98–6.91(m,1H),6.89–6.83(m,1H),6.41(s,1H),5.63(s,2H),4.11(s,2H),2.73(s,3H).
Preparation example 64: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 64
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylbenzoic acid to give the hydrochloride salt of compound 64 as a white solid in a one-step yield of 25% in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(d,J=5.4Hz,1H),8.63(s,1H),8.07(d,J=7.8Hz,2H),8.00(d,J=7.2Hz,1H),7.80(s,1H),7.68–7.52(m,3H),7.08–6.97(m,1H),6.86(d,J=8.4Hz,1H),6.78(d,J=11.4Hz,1H),6.41(s,1H),5.25(s,2H),4.09(s,2H),2.71(s,3H).
Preparation example 65: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 65
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1- (2, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 65 as a white solid in 48% yield in one step of step 6).
1H NMR(600MHz,Methanol-d4)δ8.84(d,J=4.8Hz,1H),8.61(d,J=2.4Hz,1H),7.93(d,J=8.4Hz,1H),7.79(s,1H),7.63–7.56(m,1H),7.23–7.16(m,2H),7.11–7.05(m,1H),6.98(t,J=8.4Hz,1H),6.73(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.4,2.4Hz,1H),6.39(s,1H),5.76(q,J=6.4Hz,1H),4.08(s,2H),2.70(s,3H),1.68(d,J=6.4Hz,3H).
Preparation example 66: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 66
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-Dioxane-2-methanol in step 6) was replaced with an equimolar amount of (S) -1- (2, 6-dichloro-3-fluorophenyl) ethanol to give the hydrochloride salt of compound 66 as a white solid in 56% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.89(dd,J=5.4,1.8Hz,1H),8.65(d,J=2.4Hz,1H),8.02–7.97(m,1H),7.81(d,J=1.8Hz,1H),7.70–7.65(m,1H),7.50–7.45(m,1H),7.28(t,J=8.4Hz,1H),6.98(t,J=8.4Hz,1H),6.69(dd,J=8.4,2.4Hz,1H),6.59(dd,J=11.4,2.4Hz,1H),6.40(d,J=1.8Hz,1H),6.16(q,J=6.6Hz,1H),4.10(s,2H),2.71(s,3H),1.84(d,J=6.6Hz,3H).
Preparation example 67: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 67
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 67 as a white solid in 53% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.92–8.88(m,1H),8.68(d,J=2.4Hz,1H),8.04–7.97(m,1H),7.82(d,J=1.8Hz,1H),7.67(dd,J=8.4,5.4Hz,1H),7.45–7.32(m,1H),7.02(t,J=8.4Hz,2H),6.98(t,J=8.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1H),6.65(dd,J=11.4,2.4Hz,1H),6.40(d,J=2.4Hz,1H),5.88(q,J=6.6Hz,1H),4.10(s,2H),2.72(s,3H),1.81(d,J=6.6Hz,3H).
Preparation example 68: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 68
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 68 as a white solid in 55% yield in one step of step 6).
1H NMR(400MHz,Methanol-d4)δ8.84(dd,J=4.8,1.6Hz,1H),8.60(d,J=2.4Hz,1H),7.93(dt,J=8.4,2.0Hz,1H),7.79(d,J=1.6Hz,1H),7.59(dd,J=8.4,4.8Hz,1H),7.10–7.01(m,2H),6.96(t,J=8.4Hz,1H),6.87(tt,J=9.2,2.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.65(dd,J=11.2,2.4Hz,1H),6.38(d,J=2.0Hz,1H),5.54(q,J=6.4Hz,1H),4.08(s,2H),2.70(s,3H),1.64(d,J=6.4Hz,3H).
Preparation example 69: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 69
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 69 as a white solid in 43% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.00(dt,J=7.6,1.6Hz,1H),7.76(d,J=2.0Hz,1H),7.70–7.65(m,1H),7.64–7.53(m,2H),7.42–7.32(m,1H),7.00(t,J=8.4Hz,2H),6.93(t,J=8.4Hz,1H),6.74(dd,J=8.8,2.4Hz,1H),6.60(dd,J=11.2,2.4Hz,1H),6.35(d,J=2.0Hz,1H),5.87(q,J=6.4Hz,1H),4.07(s,2H),2.70(s,3H),1.80(d,J=6.4Hz,3H).
Preparation example 70: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 70
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 70 as a white solid in 45% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ8.01(dt,J=7.6,1.2Hz,1H),7.76(d,J=2.0Hz,1H),7.71–7.67(m,1H),7.64–7.58(m,2H),7.11–7.01(m,2H),6.94(t,J=8.4Hz,1H),6.86(tt,J=9.2,2.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.2,2.4Hz,1H),6.35(d,J=2.0Hz,1H),5.54(q,J=6.4Hz,1H),4.07(s,2H),2.69(s,3H),1.64(d,J=6.4Hz,3H).
Preparation example 71: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 71
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (cyclopropylmethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) ethanol gave the hydrochloride salt of compound 71 as a white solid in 47% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.71(d,J=1.8Hz,1H),7.34–7.24(m,1H),7.15(dd,J=8.4,2.4Hz,1H),7.09–7.04(m,2H),6.98–6.94(m,1H),6.94–6.85(m,2H),6.81(t,J=2.4Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.4,2.4Hz,1H),6.31(d,J=2.4Hz,1H),5.53(q,J=6.6Hz,1H),4.06(s,2H),3.81–3.65(m,2H),2.68(s,3H),1.64(d,J=6.6Hz,3H),1.26–1.17(m,1H),0.67–0.59(m,2H),0.39–0.32(m,2H).
Preparation example 72: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 72
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (cyclopropylmethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) ethanol gave the hydrochloride salt of compound 72 as a yellow oil in 45% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.67(d,J=2.0Hz,1H),7.44–7.31(m,1H),7.24(t,J=8.0Hz,1H),7.14(dd,J=8.4,2.4Hz,1H),7.04–6.97(m,2H),6.94–6.85(m,2H),6.81(t,J=2.0Hz,1H),6.69(dd,J=8.4,2.4Hz,1H),6.59(dd,J=11.4,2.4Hz,1H),6.27(d,J=2.0Hz,1H),5.85(q,J=6.4Hz,1H),4.00(s,2H),3.73(d,J=7.2Hz,2H),2.65(s,3H),1.80(d,J=6.4Hz,3H),1.28–1.11(m,1H),0.71–0.54(m,2H),0.42–0.27(m,2H).
Preparation example 73: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 73:
the preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2, 4-dimethylbenzyl alcohol to give the hydrochloride of compound 73 as a white solid in 56% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.89(s,1H),8.69(s,1H),8.05(d,J=7.8Hz,1H),7.81(s,1H),7.68(s,1H),7.27(d,J=7.8Hz,1H),7.11–6.96(m,3H),6.84(d,J=8.4Hz,1H),6.76(d,J=11.4Hz,1H),6.42(s,1H),5.10(s,2H),4.10(s,2H),2.71(s,3H),2.33(d,J=26.8Hz,6H).
Preparation example 74: this preparation is illustrative of the procedure for the synthesis of compound 74
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 4-hydroxymethylpyridine to give compound 74 as a white solid in 57% yield in step 6).
1H NMR(400MHz,DMSO-d6)δ8.87–8.84(m,1H),8.64–8.59(m,2H),8.56(d,J=2.4Hz,1H),7.88–7.82(m,1H),7.59(dd,J=8.4,4.8Hz,1H),7.49–7.43(m,3H),7.04(t,J=8.4Hz,1H),6.96(dd,J=11.2,2.4Hz,1H),6.88(dd,J=8.4,2.4Hz,1H),6.31(d,J=2.0Hz,1H),5.27(s,2H),3.48(s,2H),2.23(s,3H).
Preparation example 75: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 75
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 2-methoxybenzyl alcohol to give the hydrochloride salt of compound 75 as a white solid in 49% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.89(d,J=4.8Hz,1H),8.70(s,1H),8.07(d,J=5.4Hz,1H),7.83(s,1H),7.70(dd,J=8.4,4.8Hz,1H),7.46–7.40(m,1H),7.38–7.32(m,1H),7.09–6.95(m,3H),6.77(dd,J=8.4,2.4Hz,1H),6.68(dd,J=11.4,2.4Hz,1H),6.43(s,1H),5.17(s,2H),4.11(s,2H),3.90(s,3H),2.72(s,3H).
Preparation example 76: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 76
The preparation of this preparation is similar to that of preparation 1, except that:
(2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of (R) -1- (2, 6-dichloro-3-fluorophenyl) ethanol to give the hydrochloride salt of compound 76 as a white solid in 44% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.85(d,J=4.8Hz,1H),8.62(d,J=2.4Hz,1H),7.97(d,J=8.4Hz,1H),7.77(s,1H),7.68–7.62(m,1H),7.46–7.41(m,1H),7.24(t,J=8.5Hz,1H),6.94(t,J=8.4Hz,1H),6.65(dd,J=8.4,2.4Hz,1H),6.55(dd,J=11.4,2.4Hz,1H),6.36(d,J=1.8Hz,1H),6.12(q,J=6.6Hz,1H),4.05(s,2H),2.67(s,3H),1.79(d,J=6.6Hz,3H).
Preparation example 77: this preparation is illustrative of the procedure for the synthesis of Compound 77
The preparation of this preparation is similar to that of preparation 1, except that:
the (2S) -1, 4-dioxane-2-methanol in step 6) was replaced with an equimolar amount of 3-hydroxymethylthiophene to give compound 77 as a yellow solid in 40% yield in step 6).
1H NMR(600MHz,DMSO-d6)δ8.86(d,J=4.8Hz,1H),8.57(s,1H),7.85(d,J=8.4Hz,1H),7.66–7.46(m,4H),7.22(d,J=4.8Hz,1H),7.00(t,J=8.4Hz,1H),6.93(dd,J=11.4,2.4Hz,1H),6.85(dd,J=8.4,2.4Hz,1H),6.32(s,1H),5.16(s,2H),3.55(s,2H),2.27(s,3H).
Preparation example 78: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 78
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-chlorobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 78 as a white solid in 40% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.75(s,1H),7.68(d,J=8.4Hz,1H),7.52–7.45(m,1H),7.43(d,J=8.4Hz,1H),7.33–7.30(m,2H),7.24–7.17(m,1H),7.17–7.12(m,1H),7.05–7.00(m,1H),6.87(d,J=9.0Hz,1H),6.78(d,J=10.8Hz,1H),6.37(s,1H),5.21(s,2H),4.09(s,2H),2.71(s,3H).
Preparation example 79: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 79
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-fluorobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 79 as a white solid in a one-step yield of 36% in step 6).
1H NMR(600MHz,Methanol-d4)δ7.75(s,1H),7.54–7.48(m,1H),7.47–7.41(m,1H),7.35–7.28(m,2H),7.23–7.11(m,3H),7.02(t,J=8.4Hz,1H),6.85(dd,J=8.4,2.4Hz,1H),6.81–6.76(m,1H),6.38(s,1H),5.20(s,2H),4.09(s,2H),2.71(s,3H).
Preparation example 80: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 80
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3, 5-difluorobenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 80 as a white solid in 44% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.76(s,1H),7.41–7.36(m,1H),7.33–7.29(m,1H),7.22–7.17(m,1H),7.16–7.11(m,1H),7.10–7.04(m,3H),6.88(d,J=8.4Hz,1H),6.81(d,J=10.8Hz,1H),6.42(s,1H),5.20(s,2H),4.10(s,2H),2.71(s,3H).
Preparation example 81: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 81
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-fluoro-4-methylbenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 81 as a white solid in 36% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.73(s,1H),7.37–7.29(m,2H),7.25–7.12(m,3H),7.09(d,J=9.0Hz,1H),7.06–7.00(m,1H),6.87–6.84(m,1H),6.79(dd,J=11.4,2.4Hz,1H),6.36(s,1H),5.20(s,2H),4.08(s,2H),2.70(s,3H),2.31(s,3H).
Preparation example 82: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 82
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-pentyloxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 5-difluorobenzyl alcohol gave the hydrochloride salt of compound 82 as a white solid in 36% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ7.74(s,1H),7.40–7.29(m,2H),7.24–7.12(m,3H),7.06(d,J=7.8Hz,1H),7.03–6.98(m,1H),6.89–6.75(m,3H),6.35(s,1H),5.19(s,2H),4.08(s,2H),3.91–3.81(m,2H),2.70(s,3H),1.82–1.62(m,2H),1.51–1.28(m,4H),0.97–0.87(m,3H).
Preparation example 83: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 83:
the preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclobutylmethoxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave the hydrochloride salt of compound 83 as a yellow oil in 41% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.60(d,J=2.0Hz,1H),7.29–7.19(m,1H),7.13(t,J=8.4Hz,1H),7.01(dd,J=8.4,2.4Hz,1H),6.92–6.75(m,4H),6.72(t,J=2.4Hz,1H),6.57(dd,J=8.4,2.4Hz,1H),6.49(dd,J=11.4,2.4Hz,1H),6.21(d,J=1.8Hz,1H),5.71(q,J=6.4Hz,1H),3.91(s,2H),3.72(d,J=6.4Hz,2H),2.54(s,3H),2.07–1.95(m,3H),1.92–1.71(m,4H),1.66(d,J=6.4Hz,3H).
Preparation example 84: this preparation is illustrative of the synthesis of the hydrochloride salt of compound 84
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclopentylmethoxybenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 4-difluorobenzyl alcohol gave the hydrochloride salt of compound 84 as a white solid in 40% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.75(d,J=1.6Hz,1H),7.40–7.28(m,2H),7.24–7.10(m,3H),7.10–7.06(m,1H),7.01(t,J=8.4Hz,1H),6.86–6.81(m,2H),6.78(dd,J=11.2,2.4Hz,1H),6.36(d,J=1.6Hz,1H),5.19(s,2H),4.09(s,2H),3.75(d,J=6.8Hz,2H),2.70(s,3H),2.40–2.22(m,1H),1.90–1.74(m,2H),1.69–1.51(m,4H),1.42–1.27(m,2H).
Preparation example 85: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 85
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyclopentylmethoxybenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave the hydrochloride salt of compound 85 as a yellow oil in 23% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.67(d,J=2.0Hz,1H),7.42–7.31(m,1H),7.25(t,J=8.0Hz,1H),7.14(dd,J=8.4,2.4Hz,1H),7.05–6.95(m,2H),6.94–6.87(m,2H),6.80(t,J=2.0Hz,1H),6.69(dd,J=8.4,2.4Hz,1H),6.59(dd,J=11.2,2.4Hz,1H),6.26(d,J=2.0Hz,1H),5.84(q,J=6.4Hz,1H),4.01(s,2H),3.75(d,J=6.8Hz,2H),2.65(s,3H),2.37–2.25(m,1H),1.90–1.75(m,5H),1.72–1.58(m,4H),1.42–1.32(m,2H).
Preparation example 86: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 86
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (2-methoxy-ethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 4-difluorobenzyl alcohol gave the hydrochloride salt of compound 86 as a white solid in 45% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.75(d,J=2.0Hz,1H),7.41–7.29(m,2H),7.25–7.11(m,3H),7.12–7.05(m,1H),7.00(t,J=8.4Hz,1H),6.88(t,J=2.0Hz,1H),6.84(dd,J=8.4,2.4Hz,1H),6.78(dd,J=11.2,2.4Hz,1H),6.36(d,J=2.0Hz,1H),5.20(s,2H),4.09(s,2H),4.06–4.01(m,2H),3.74–3.67(m,2H),3.38(s,3H),2.70(s,3H).
Preparation example 87: this preparation is illustrative of the procedure for the synthesis of compound 87
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (2-methoxy-ethoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2-methoxybenzyl alcohol gave compound 87 as a white solid in 39% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.68(d,J=2.0Hz,1H),7.46–7.40(m,1H),7.38–7.30(m,2H),7.20(dd,J=8.4,2.4Hz,1H),7.07–7.02(m,2H),7.00–6.92(m,2H),6.87(t,J=2.0Hz,1H),6.78(dd,J=8.4,2.4Hz,1H),6.71(dd,J=11.2,2.4Hz,1H),6.31(d,J=2.0Hz,1H),5.15(s,2H),4.04–3.98(m,4H),3.89(s,3H),3.71–3.65(m,2H),3.36(s,3H),2.65(s,3H).
Preparation example 88: this preparation is illustrative of the procedure for the synthesis of compound 88
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (3-methoxy-propoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave compound 88 as a yellow oil in 44% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.67(d,J=2.0Hz,1H),7.42–7.31(m,1H),7.25(t,J=8.0Hz,1H),7.18–7.12(m,1H),7.04–6.96(m,2H),6.94–6.87(m,2H),6.83(t,J=2.0Hz,1H),6.70(dd,J=8.8,2.4Hz,1H),6.60(dd,J=11.2,2.4Hz,1H),6.27(d,J=2.0Hz,1H),5.85(q,J=6.4Hz,1H),4.01(s,2H),3.96(t,J=6.4Hz,2H),3.54(t,J=6.0Hz,2H),3.35(s,3H),2.64(s,3H),2.04–1.95(m,2H),1.79(d,J=6.4Hz,3H).
Preparation example 89: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of Compound 89
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (3-methoxy-propoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 89 as a white solid in 46% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.63(d,J=2.0Hz,1H),7.21(t,J=8.0Hz,1H),7.08(dd,J=8.4,2.4Hz,1H),7.01–6.94(m,2H),6.93–6.88(m,1H),6.86–6.74(m,3H),6.62(dd,J=8.4,2.4Hz,1H),6.55(dd,J=11.2,2.4Hz,1H),6.23(d,J=2.0Hz,1H),5.44(q,J=6.4Hz,1H),3.98(s,2H),3.89(t,J=6.4Hz,2H),3.46(t,J=6.0Hz,2H),3.27(s,3H),2.60(s,3H),1.96–1.85(m,2H),1.55(d,J=6.4Hz,3H).
Preparation example 90: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 90
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2-hydroxymethylnaphthalene gave the hydrochloride salt of compound 90 as a white solid in 51% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.08(d,J=8.4Hz,1H),7.94–7.85(m,2H),7.73–7.69(m,1H),7.64(d,J=6.6Hz,1H),7.59–7.45(m,3H),7.28(t,J=7.8Hz,1H),7.13(dd,J=8.4,2.4Hz,1H),7.03(d,J=7.8Hz,1H),6.97(t,J=8.4Hz,1H),6.85(dd,J=8.4,2.4Hz,1H),6.81(d,J=11.4Hz,2H),6.32(d,J=2.4Hz,1H),5.56(s,2H),4.05(s,2H),3.85(t,J=6.0Hz,2H),3.26(s,3H),3.21–3.18(m,2H),2.67(s,3H),1.75–1.68(m,2H),1.65–1.58(m,2H).
Preparation example 91: this preparation is illustrative of the procedure for the synthesis of Compound 91
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (2, 6-difluorophenyl) -ethanol gave compound 91 as a white solid in 48% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.69(d,J=2.0Hz,1H),7.42–7.32(m,1H),7.25(t,J=8.0Hz,1H),7.15(dd,J=8.4,2.4Hz,1H),7.04–6.96(m,2H),6.95–6.86(m,2H),6.82(t,J=2.0Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.60(dd,J=11.4,2.4Hz,1H),6.29(d,J=2.0Hz,1H),5.84(q,J=6.4Hz,1H),4.04(s,2H),3.90(t,J=6.4Hz,2H),3.46(t,J=6.4Hz,2H),3.34(s,3H),2.66(s,3H),1.88–1.67(m,7H).
Preparation example 92: this preparation serves to illustrate the synthesis of the hydrochloride salt of compound 92:
the preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 92 as a yellow solid in 41% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.71(d,J=2.0Hz,1H),7.29(t,J=8.0Hz,1H),7.16(dd,J=8.4,2.54Hz,1H),7.09–7.02(m,2H),7.01–6.96(m,1H),6.95–6.84(m,2H),6.82(t,J=2.0Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.63(dd,J=11.2,2.4Hz,1H),6.31(d,J=2.0Hz,1H),5.52(q,J=6.4Hz,1H),4.06(s,2H),3.91(t,J=6.4Hz,2H),3.45(t,J=6.4Hz,2H),3.34(s,3H),2.68(s,3H),1.85–1.76(m,2H),1.76–1.68(m,2H),1.63(d,J=6.3Hz,3H).
Preparation example 93: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 93
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3- (4-methoxy-butoxy) benzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1, 3-benzodioxolane-4-alkylmethanol gave the hydrochloride salt of compound 93 as a white solid in 40% yield in one step in step 6).
1H NMR(400MHz,Methanol-d4)δ7.73(d,J=2.0Hz,1H),7.33(t,J=8.0Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.04(d,J=8.0Hz,1H),7.00–6.94(m,2H),6.92–6.77(m,4H),6.73(dd,J=11.2,2.4Hz,1H),6.34(d,J=2.0Hz,1H),6.01(s,2H),5.11(s,2H),4.08(s,2H),3.90(t,J=6.4Hz,2H),3.41(t,J=6.4Hz,2H),3.30(s,3H),2.70(s,3H),1.86–1.75(m,2H),1.74–1.63(m,2H).
Preparation 94: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 94
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol of step 6) with an equimolar amount of 1, 3-benzodioxol-4-alkylmethanol gave the hydrochloride salt of compound 94 as a white solid in 50% yield in one step of step 6).
1H NMR(600MHz,DMSO-d6)δ9.14(s,2H),8.89(d,J=3.6Hz,1H),8.59(s,1H),7.89(d,J=8.4Hz,1H),7.81(s,1H),7.63–7.59(m,1H),7.01–6.94(m,4H),6.91–6.85(m,2H),6.52(s,1H),6.08(s,2H),5.11(s,2H),3.98(s,3H).
Preparation example 95: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 95
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 1, 3-benzodioxolane-4-alkylmethanol gave the hydrochloride salt of compound 95 as a white solid in 44% yield in step 6).
1H NMR(400MHz,Methanol-d4)δ7.73(d,J=2.0Hz,1H),7.33(t,J=8.0Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.04(d,J=8.0Hz,1H),7.00–6.94(m,2H),6.92–6.77(m,4H),6.73(dd,J=11.2,2.4Hz,1H),6.34(d,J=2.0Hz,1H),6.01(s,2H),5.11(s,2H),4.08(s,2H),3.90(t,J=6.4Hz,2H),3.41(t,J=6.4Hz,2H),3.30(s,3H),2.70(s,3H),1.86–1.75(m,2H),1.74–1.63(m,2H).
Preparation example 96: this preparation is illustrative of the procedure for the synthesis of hydrochloride salt of compound 96
The preparation of this preparation is similar to that of preparation 1, except that:
replacing the (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 3-dihydro-1, 4-benzodioxin-5-methanol gave the hydrochloride salt of compound 96 as a white solid in 56% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.96–8.86(m,1H),8.71(d,J=2.4Hz,1H),8.15–8.01(m,1H),7.82(d,J=2.4Hz,1H),7.71(dd,J=8.4,4.8Hz,1H),7.06–6.97(m,2H),6.87–6.80(m,3H),6.75(dd,J=11.4,2.4Hz,1H),6.43(d,J=2.4Hz,1H),5.13(s,2H),4.37–4.24(m,4H),4.11(s,2H),2.72(s,3H).
Preparation example 97: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 97
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-cyanobenzenesulfonyl chloride and replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, 3-dihydro-1, 4-benzodioxin-5-methanol gave the hydrochloride salt of compound 97 as a white solid in 43% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.03(d,J=7.7Hz,1H),7.81–7.60(m,4H),7.00(d,J=10.4Hz,2H),6.88–6.80(m,3H),6.73(d,J=11.4Hz,1H),6.40(s,1H),5.15(s,2H),4.37–4.25(m,4H),4.10(s,2H),2.72(s,3H).
Preparation example 98: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 98
The preparation of this preparation is similar to that of preparation 1, except that:
replacing pyridine-3-sulfonyl chloride in step 3) with an equimolar amount of 3-trifluoromethylbenzenesulfonyl chloride and (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2, -5-difluorobenzyl alcohol gave the hydrochloride salt of compound 98 as a white solid in 52% yield in step 6).
1H NMR(600MHz,Methanol-d4)δ8.00(d,J=7.8Hz,1H),7.80(d,J=5.4Hz,2H),7.76–7.70(m,1H),7.60(s,1H),7.34–7.27(m,1H),7.23–7.17(m,1H),7.17–7.12(m,1H),7.03(t,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),6.75(d,J=11.4Hz,1H),6.39(s,1H),5.19(s,2H),4.09(s,2H),2.70(s,3H).
Preparation example 99: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 99
The preparation of this preparation is similar to that of preparation 1, except that:
replacing (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 2- (3, 5-difluorophenyl) -ethanol gave the hydrochloride salt of compound 99 as a white solid in 48% yield in step 6).1H NMR(600MHz,Methanol-d4)δ8.80(d,J=4.8Hz,1H),8.55(d,J=2.4Hz,1H),7.98–7.92(m,1H),7.76(s,1H),7.59(dd,J=8.4,4.8Hz,1H),7.00–6.89(m,3H),6.82–6.75(m,1H),6.73(d,J=8.4Hz,1H),6.64(d,J=11.4Hz,1H),6.36(t,J=1.8Hz,1H),4.24(t,J=6.0Hz,2H),4.06(s,2H),3.10(t,J=6.0Hz,2H),2.67(s,3H).
Preparation example 100: this preparation is illustrative of the procedure for the synthesis of the hydrochloride salt of compound 100
The preparation of this preparation is similar to that of preparation 1, except that:
replacement of (2S) -1, 4-dioxane-2-methanol in step 6) with an equimolar amount of 3-hydroxymethylfuran afforded the hydrochloride salt of compound 100 as a grey solid in 51% yield in one step in step 6).
1H NMR(600MHz,Methanol-d4)δ8.89(d,J=4.8Hz,1H),8.67(s,1H),8.07(d,J=8.4Hz,1H),7.82(s,1H),7.71(dd,J=8.4,4.8Hz,1H),7.65(s,1H),7.53(s,1H),7.02(t,J=8.4Hz,1H),6.86–6.81(m,1H),6.75(d,J=11.4Hz,1H),6.55(s,1H),6.45–6.39(m,1H),5.04(s,2H),4.10(s,2H),2.71(s,3H).
Test example 1: h+/K+Biological evaluation of ATPases
This test example is to evaluate the compounds of the invention for H by in vitro screening assays+/K+Inhibition of ATPase enzymatic Activity, with Compound IC50Values (calculated from inhibition at different concentrations) are indicated.
In vitro screening assay:
(1) preparation of reagents:
compound solution: independently dissolving the products (namely the compound or the hydrochloride of the compound) obtained in the preparation examples in DMSO respectively to prepare the products with proper concentration;
buffer I: 50mmol/L HEPES-Tris, pH 6.5, 5mmol/L magnesium chloride, 10. mu. mol/L valinomycin (Bailingwei chemical technology Co., Ltd., product number: 227304);
and (2) buffer solution II: 50mmol/L HEPES-Tris, pH 6.5, 5mmol/L magnesium chloride, 10 μmol/L valinomycin, 5mmol/L potassium chloride;
adenosine 5-triphosphate (ATP, Sigma-Aldrich, cat # A2383) solution: diluting ATP to 5mM with buffer I;
malachite green solution: dissolving 0.12 wt% of malachite green (Bailingwei chemical technology Co., Ltd., product number: 913120) in 2.5mol/L sulfuric acid, 7.5 wt% of ammonium molybdate (Bailingwei chemical technology Co., Ltd., product number: 128321) and 11% of Tween 20(V/V), and mixing the sulfuric acid, the ammonium molybdate and the Tween 20 at a ratio of 100:25:2 when in use;
rabbit gastric mucosa microsomes (rich in H +/K + -ATPase, self-extracted) are extracted by a sucrose gradient centrifugation method: the stomach of the rabbit was washed with tap water and 3M NaCl solution, respectively, and then surface water was removed with filter paper. Add pre-cooled homogenization buffer (4ml/g tissue) and homogenize in tissue homogenizer for 2-5 min. After homogenizing, if larger tissue particles exist, centrifuging (600g for 10min) to remove, then transferring the supernatant into a clean centrifuge tube, centrifuging for 30min at 20000g, then transferring the supernatant into a clean centrifuge tube, further centrifuging, centrifuging for 90min at 100000g, and collecting precipitates; suspending and precipitating by using homogenate, uniformly blowing, measuring the protein concentration by using a Bradford method, and adjusting the concentration to be 10 mg/ml; adding 7.5 wt% of Ficoll layering solution in equal proportion, centrifuging 100000g for 60min, collecting the middle layer (H +/K + -ATPasenered structural membranes) in a clean centrifuge tube, diluting by 4-5 times of homogenate liquid, centrifuging 100000g for 90min, and collecting precipitate; the precipitate was suspended in a homogenate, homogenized in a glass homogenizer, and the protein concentration was measured by the Bradford method to adjust the concentration to 22.5 mg/ml. Freezing at-80 deg.C for use.
(2) The experimental process comprises the following steps:
mu.L of rabbit gastric mucosal microsome (H) was added to 45. mu.L of buffer II+/K+ATPase), 5. mu.L of the compound solution was added, and 5. mu.L of a 5mM ATP solution was added to start the reaction, followed by pre-reaction at 37 ℃ for 30 min. The reaction was stopped by adding 15. mu.L of malachite green solution, equilibrated at room temperature for 20min and the absorbance read at 620 nm.
At the same time, the same volume reaction was carried out without potassium chloride as background, and subtracted when calculating the enzyme activity, the results are shown in Table 1.
Table 1: compound pair H+/K+Inhibition of ATPase enzymatic Activity
As can be seen from Table 1, the compounds of the invention are p.H+/K+Excellent inhibition of the activity of the ATPase enzyme.
Test example 2: inhibitory Effect of Compounds on Histamine-induced gastric acid secretion in rats
70 SPF SD rats (Hangzhou medical school (production)) weighing 180-. Fasting for 24h without water. After 24h, the administration is carried out by gastric lavage, the administration volume is 1ml/100g, each group is administered once, and the negative control group and the model group are administered with physiological saline with the same volume by gastric lavage. Then, after anesthetizing the rat with chloral hydrate at 300mg/kg (1ml/100g), the rat was fixed on a rat plate, the abdominal wall was incised from the lower part of the sternal xiphoid process along the ventral midline for about 2-3 cm, and the left side of the costal margin was gently pushed upward with a finger to expose the stomach to the incision. The pylorus was ligated by threading a line under the pylorus (the other blood vessels in the vicinity were not ligated) and then closing the abdominal wall incision. Animals were administered histamine dihydrochloride (30mg/10ml/kg) subcutaneously 1h after gavage of the test compound or normal saline. 3h after histamine administration with excess CO2The rats were sacrificed by suffocation, the stomach was taken, the stomach contents were collected, centrifuged at 3000rpm/min for 10min, the acid solution was titrated with 0.1mol/L NaOH to pH7.0, and the total acid and acid inhibitory rate during 3h were calculated.
The acid inhibition rate was calculated as follows, and the results are shown in Table 2:
acid inhibition rate (%) (total acid amount in model group-total acid amount in administration group)/total acid amount in model group × 100%.
Table 2: inhibitory Effect of Compounds on Histamine-induced gastric acid secretion in rats
Compound numbering | Dosage (mg/kg) | Acid inhibitory Rate (%) |
6 | 2 | 48 |
8 | 2 | 71 |
28 | 2 | 71 |
37 | 2 | 56 |
48 | 2 | 75 |
48 | 4 | 86 |
67 | 2 | 64 |
As can be seen from Table 2, the compounds of the present invention have excellent inhibitory effects on gastric acid secretion in rats induced by histamine.
Test example 3: rat tissue distribution assay for Compound 48
Healthy male SD rats 3 (weight range of 220-. Compound 48 was administered orally at a dose of 4 mg/kg.
Vehicle for preparation of drug administration preparation: pure water. Fasting was performed 4h before administration. Plasma, heart (perfusion), liver, stomach were collected at 1h, 2h, 4h (blank tissues were taken from the remaining SD rats to the analysis group). Tissue homogenization, preparation of standard koji with corresponding blank tissue and quantification of QC. Blood samples should be centrifuged to remove plasma within 1 hour after collection and placed on crushed ice prior to centrifugation. Plasma samples obtained by centrifugation were stored in a freezer until assayed. Centrifugation conditions: 4-10 ℃, 8000rpm, 6 minutes. Sample concentrations were measured by LC-MS-MS (MS03: Shimadzu LC30AD and API 4000)) and exposure data were calculated using WINNOLIN software.
Table 3: tissue distribution of Compound 48 rats at an oral dose of 4mg/kg
Tissue of | Exposure (0-4h)/h ng/mL | Ratio of |
Blood plasma | 85.8 | 1 |
Liver disease | 7585.5 | 88.4 |
Stomach (stomach) | 14693.7 | 171.3 |
As can be seen from Table 3, the compound of the invention has very obvious gastric tissue enrichment effect, has lower exposure in plasma and lower exposure in liver, is expected to reduce the safety risks such as hepatotoxicity and the like existing in marketed drugs such as Vonoprazan and the like while improving the treatment effect by reducing systemic exposure.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A compound containing a sulfonamide structure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I),
in the formula (I), the compound represented by the formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (a), a six-membered saturated heterocycloalkyl group containing 1-2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1-2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH2-phenyl, furan-3-yl containing at least two halogen substitutions; r1Wherein the optional substituents are selected from halogen, hydroxy, C1-C3Alkyl of (C)1-C3At least one of aldehyde groups of (a);
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from halogen, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkyl of (2), C substituted by 1-6 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is C1-C3Alkyl groups of (a);
R4is H, C1-C3Alkoxy, halogen of (a);
R5and R6One of H and the other selected from F, C1-C3Alkyl group of (1).
2. The compound according to claim 1, wherein, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy, a six-membered saturated heterocycloalkyl group containing 1 to 2 oxygen atoms, a substituted or unsubstituted six-membered saturated heterocycloalkyl group containing 1 to 2 nitrogen atomsSaturated heterocycloalkyl, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH2-phenyl, furan-3-yl containing at least two halogen substitutions; r1Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, n-propyl, isopropyl, C1-C2At least one of aldehyde groups of (a);
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, iodine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl, ethyl, n-propyl or isopropyl;
R4is H, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro or bromo;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
3. The compound according to claim 2, wherein, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, substituted or unsubstituted C1-C4Alkyl of (C)1-C3Alkoxy of (1) to (2)Six-membered saturated heterocycloalkyl group having an oxygen atom, substituted or unsubstituted six-membered saturated heterocycloalkyl group having 1 to 2 nitrogen atoms, -C1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH2-phenyl, furan-3-yl containing at least two halogen substitutions; r1Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl, n-propyl, isopropyl and glyoxal;
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl or ethyl;
R4is H, methoxy or fluoro;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
4. The compound according to claim 3, wherein, in formula (I),
x is CH2Or CH (CH)3);
R1Is H, methyl, isopropyl, tert-butyl, hydroxy-substituted tert-butyl, difluoromethyl, methoxy, dioxane, substituted or unsubstituted piperidylC1-C4alkylene-O-C of1-C3Alkyl, substituted or unsubstituted C3-C6Saturated cycloalkyl groups of (a) a (b) an oxirane group, a phenyl group containing at least two halogen substitutions, a phenyl group substituted with difluoromethoxy, a phenyl group substituted with trifluoromethoxy, a phenyl group substituted with carboxyl, a naphthyl group, a phenyl group containing at least two methyl substitutions, a pyridin-4-yl group, a phenyl group substituted with methoxy, a thiophen-3-yl group, a benzodioxolyl group, -CH2-phenyl, furan-3-yl containing at least two halogen substitutions; r1Wherein the optional substituent is at least one of fluorine, chlorine, hydroxyl, methyl, ethyl and aldehyde group;
R2is 3-pyridyl, substituted or unsubstituted phenyl; r2Wherein the optional substituents are selected from the group consisting of fluorine, chlorine, bromine, C1-C6Alkyl of (C)1-C6Alkoxy of, -O-C1-C4alkylene-O-C of1-C2Alkyl of (2), C substituted by 1-3 halogens1-C3Alkyl of (2), C substituted by 1-3 halogens1-C3Alkoxy, cyano, -O-C1-C4alkylene-C of3-C6At least one of cycloalkyl groups of (a);
R3is methyl or ethyl;
R4is H, methoxy or fluoro;
R5and R6One of which is H and the other is selected from F, methyl, ethyl, n-propyl, isopropyl.
6. a process for the preparation of a compound containing a sulfonamide structure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I),
the method comprises the following steps: carrying out contact reaction on a compound shown as a formula (II) and a compound shown as a formula (III);
wherein, in formula (I), formula (II) and formula (III), the definitions of the respective groups are the same as those described in any one of claims 1 to 5.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
8. The method ofA compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of H+/K+-ATPase inhibitor drugs and/or the use for the preparation of potassium ion competitive acid blocker drugs.
9. Use of a compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment or prophylaxis of peptic ulcer, Zollinger-Ellison syndrome, gastritis, erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease, Barrett's esophagitis, functional dyspepsia, helicobacter pylori infection, gastric cancer, gastric MALT lymphoma, ulcers caused by non-steroidal anti-inflammatory drugs, or hyperacidity or ulcers caused by post-operative stress.
10. The use according to claim 9, wherein the peptic ulcer comprises at least one of a gastric ulcer, a duodenal ulcer, and a stomal ulcer; the symptomatic gastroesophageal reflux disease includes at least one of non-erosive reflux disease and non-esophagitis gastroesophageal reflux disease.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111248634.5A CN114105962A (en) | 2021-10-26 | 2021-10-26 | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111248634.5A CN114105962A (en) | 2021-10-26 | 2021-10-26 | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114105962A true CN114105962A (en) | 2022-03-01 |
Family
ID=80376920
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111248634.5A Pending CN114105962A (en) | 2021-10-26 | 2021-10-26 | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114105962A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115232107A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of high-purity Voranolan fumarate |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
CN102985422A (en) * | 2010-05-12 | 2013-03-20 | Abbvie公司 | Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases |
WO2014019442A1 (en) * | 2012-08-03 | 2014-02-06 | 上海恒瑞医药有限公司 | Benzofuran derivatives, preparation method and medical use thereof |
CN110396080A (en) * | 2018-04-24 | 2019-11-01 | 广东东阳光药业有限公司 | A kind of preparation method of Vonoprazan fumarate metabolin and its deuterated object |
CN113620930A (en) * | 2021-07-12 | 2021-11-09 | 南京烁慧医药科技有限公司 | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof |
-
2021
- 2021-10-26 CN CN202111248634.5A patent/CN114105962A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
CN102985422A (en) * | 2010-05-12 | 2013-03-20 | Abbvie公司 | Pyrrolopyridine and pyrrolopyrimidine inhibitors of kinases |
WO2014019442A1 (en) * | 2012-08-03 | 2014-02-06 | 上海恒瑞医药有限公司 | Benzofuran derivatives, preparation method and medical use thereof |
CN110396080A (en) * | 2018-04-24 | 2019-11-01 | 广东东阳光药业有限公司 | A kind of preparation method of Vonoprazan fumarate metabolin and its deuterated object |
CN113620930A (en) * | 2021-07-12 | 2021-11-09 | 南京烁慧医药科技有限公司 | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115232107A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of high-purity Voranolan fumarate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI718113B (en) | Pyridinecarboxamides derivatives, preparation process and pharmaceutical use thereof | |
WO2019149922A1 (en) | Compounds which cause degradation of egfr, for use against cancer | |
CA2935071A1 (en) | Piperidine-dione derivatives | |
JPH0739412B2 (en) | Novel sulfoxide | |
CN102770414A (en) | [5,6] heterocyclic compound | |
JP2021512161A (en) | 2H-indazole derivatives as CDK4 and CDK6 inhibitors and their therapeutic use | |
JP2021176847A (en) | Substituted five-membered and six-membered heterocyclic compound, its preparation method, combination with medicine and its usage | |
RU2507203C1 (en) | Compound, certain novel forms thereof, pharmaceutical compositions based thereon and methods of production and use | |
CN101336240A (en) | Salt of sulfinylbenzimidazole compound, and crystal and amorphous form thereof | |
EA015123B1 (en) | Pyrazole-isoquinoline urea derivatives as p38 kinase inhibitors | |
CN102325754A (en) | Cyclic compound having hetero atom | |
WO2011049127A1 (en) | 5-hydroxypyrimidine-4-carboxamide derivative having hydrocarbon ring group | |
WO2013041038A1 (en) | Pyridine compounds as inhibitors of kinase | |
WO2016015676A1 (en) | Pyridine-substituted 2-aminopyridine protein kinase inhibitors | |
CN116262741A (en) | Compounds as EGFR inhibitors | |
EP3009424B1 (en) | Bicyclic nitrogen-containing aromatic heterocyclic amide compound | |
CN114105962A (en) | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof | |
TW202342473A (en) | Parp1 inhibitors and uses thereof | |
TW202334158A (en) | Prolyl hydroxylase domain-containing protein (phd) inhibitors and uses thereof | |
JP2022515309A (en) | Substituted aryl compounds, their production methods and uses | |
CA3198096A1 (en) | Aryl derivatives for treating trpm3 mediated disorders | |
CN113880772A (en) | CDK kinase inhibitor and application thereof | |
CN113620930B (en) | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof | |
WO2020052489A1 (en) | Preparation for 6-amino-1h-pyrazolo[3,4-d]pyrimidine-based jak kinase inhibitor and application thereof | |
TW202340190A (en) | Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp1) inhibitors and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |