AU773227B2 - Substituted oxoazaheterocyclyl compounds - Google Patents

Info

Publication number

AU773227B2

AU773227B2 AU64628/00A AU6462800A AU773227B2 AU 773227 B2 AU773227 B2 AU 773227B2 AU 64628/00 A AU64628/00 A AU 64628/00A AU 6462800 A AU6462800 A AU 6462800A AU 773227 B2 AU773227 B2 AU 773227B2

Authority

AU

Australia

Prior art keywords

ylmethyl

optionally substituted

formula

group

chloro

Prior art date

1999-07-28

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.)

Ceased

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 451
• 238000000034 method Methods 0.000 claims abstract description 40
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
• -1 iodo, hydroxyl Chemical group 0.000 claims description 281
• 229910052739 hydrogen Inorganic materials 0.000 claims description 101
• 125000000217 alkyl group Chemical group 0.000 claims description 95
• 239000001257 hydrogen Substances 0.000 claims description 94
• 125000003118 aryl group Chemical group 0.000 claims description 83
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 52
• 238000002360 preparation method Methods 0.000 claims description 41
• 150000003839 salts Chemical class 0.000 claims description 40
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
• 125000003545 alkoxy group Chemical group 0.000 claims description 29
• 125000002252 acyl group Chemical group 0.000 claims description 28
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 23
• 125000005843 halogen group Chemical group 0.000 claims description 23
• 125000004442 acylamino group Chemical group 0.000 claims description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
• 150000001204 N-oxides Chemical class 0.000 claims description 17
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 17
• 230000015572 biosynthetic process Effects 0.000 claims description 16
• 239000012453 solvate Substances 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 238000011282 treatment Methods 0.000 claims description 15
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 13
• CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 208000007536 Thrombosis Diseases 0.000 claims description 10
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 claims description 6
• 239000003146 anticoagulant agent Substances 0.000 claims description 6
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 6
• GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• LUEYUHCBBXWTQT-UHFFFAOYSA-N 4-phenyl-2h-triazole Chemical compound C1=NNN=C1C1=CC=CC=C1 LUEYUHCBBXWTQT-UHFFFAOYSA-N 0.000 claims description 5
• 206010051055 Deep vein thrombosis Diseases 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• KAVSMINTEBGDTI-UHFFFAOYSA-N pyridine;thiophene Chemical compound C=1C=CSC=1.C1=CC=NC=C1 KAVSMINTEBGDTI-UHFFFAOYSA-N 0.000 claims description 5
• 241000894007 species Species 0.000 claims description 5
• JEJWGAXKVFYJDN-UHFFFAOYSA-N thiadiazole;thiophene Chemical compound C=1C=CSC=1.C1=CSN=N1 JEJWGAXKVFYJDN-UHFFFAOYSA-N 0.000 claims description 5
• ULIIZNSKJMOVMX-UHFFFAOYSA-N 1,2-oxazole;thiophene Chemical compound C=1C=CSC=1.C=1C=NOC=1 ULIIZNSKJMOVMX-UHFFFAOYSA-N 0.000 claims description 4
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
• 206010000891 acute myocardial infarction Diseases 0.000 claims description 4
• 210000001367 artery Anatomy 0.000 claims description 4
• PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
• GBXYTRIBFXZUBS-UHFFFAOYSA-N oxadiazole;thiophene Chemical compound C=1C=CSC=1.C1=CON=N1 GBXYTRIBFXZUBS-UHFFFAOYSA-N 0.000 claims description 4
• 230000002093 peripheral effect Effects 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• HHNQDLUNMOECFS-UHFFFAOYSA-N thiophene;2h-triazole Chemical compound C=1C=CSC=1.C1=CNN=N1 HHNQDLUNMOECFS-UHFFFAOYSA-N 0.000 claims description 4
• 210000005166 vasculature Anatomy 0.000 claims description 4
• 206010002388 Angina unstable Diseases 0.000 claims description 3
• 206010053567 Coagulopathies Diseases 0.000 claims description 3
• 208000005189 Embolism Diseases 0.000 claims description 3
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
• 239000005977 Ethylene Substances 0.000 claims description 3
• 206010022562 Intermittent claudication Diseases 0.000 claims description 3
• 208000006011 Stroke Diseases 0.000 claims description 3
• 208000001435 Thromboembolism Diseases 0.000 claims description 3
• 208000032109 Transient ischaemic attack Diseases 0.000 claims description 3
• 208000007814 Unstable Angina Diseases 0.000 claims description 3
• 206010047249 Venous thrombosis Diseases 0.000 claims description 3
• 230000003187 abdominal effect Effects 0.000 claims description 3
• 230000001154 acute effect Effects 0.000 claims description 3
• 208000015294 blood coagulation disease Diseases 0.000 claims description 3
• 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 238000007887 coronary angioplasty Methods 0.000 claims description 3
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 3
• 208000021156 intermittent vascular claudication Diseases 0.000 claims description 3
• 210000003127 knee Anatomy 0.000 claims description 3
• 210000003141 lower extremity Anatomy 0.000 claims description 3
• 210000004789 organ system Anatomy 0.000 claims description 3
• 230000001575 pathological effect Effects 0.000 claims description 3
• BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 3
• 238000001356 surgical procedure Methods 0.000 claims description 3
• 230000009885 systemic effect Effects 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 claims description 3
• 230000002537 thrombolytic effect Effects 0.000 claims description 3
• 201000010875 transient cerebral ischemia Diseases 0.000 claims description 3
• 210000003462 vein Anatomy 0.000 claims description 3
• WZHMOWXUUOUMMU-UHFFFAOYSA-N heptoxy(nitro)carbamic acid Chemical compound CCCCCCCON(C(=O)O)[N+](=O)[O-] WZHMOWXUUOUMMU-UHFFFAOYSA-N 0.000 claims description 2
• 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims 2
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 2
• DRGIGDYIMYVIPD-TXEPZDRESA-N (3s)-1-[(4-aminoquinazolin-7-yl)methyl]-4-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-3-propylpiperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.N1([C@H](C(N(CC=2C=C3N=CN=C(N)C3=CC=2)CC1)=O)CCC)CC(=NO1)C=C1C1=CC=C(Cl)S1 DRGIGDYIMYVIPD-TXEPZDRESA-N 0.000 claims 1
• CIRUOCWGWWYEOA-UHFFFAOYSA-N 1-[(4-aminoquinazolin-7-yl)methyl]-4-[[3-(5-chlorothiophen-2-yl)-1,2-oxazol-5-yl]methyl]piperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C=1C=C2C(N)=NC=NC2=CC=1CN(C(C1)=O)CCN1CC(ON=1)=CC=1C1=CC=C(Cl)S1 CIRUOCWGWWYEOA-UHFFFAOYSA-N 0.000 claims 1
• TZASSKUFFUBNAV-UHFFFAOYSA-N 1-[(4-aminoquinazolin-7-yl)methyl]-4-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]piperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C=1C=C2C(N)=NC=NC2=CC=1CN(C(C1)=O)CCN1CC(=NO1)C=C1C1=CC=C(Cl)S1 TZASSKUFFUBNAV-UHFFFAOYSA-N 0.000 claims 1
• BOQZXGHEWNKPED-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-(1h-pyrrolo[3,2-c]pyridin-2-ylmethyl)piperazin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.S1C(Cl)=CC=C1C1=CC(CN2C(CN(CC=3NC4=CC=NC=C4C=3)CC2)=O)=NO1 BOQZXGHEWNKPED-UHFFFAOYSA-N 0.000 claims 1
• CMHHNHDPPWDNAH-UHFFFAOYSA-N 5'-acetyl-4-{[(2,4-dimethylphenyl)sulfonyl]amino}-2,2'-bithiophene-5-carboxylic acid Chemical compound S1C(C(=O)C)=CC=C1C1=CC(NS(=O)(=O)C=2C(=CC(C)=CC=2)C)=C(C(O)=O)S1 CMHHNHDPPWDNAH-UHFFFAOYSA-N 0.000 claims 1
• 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
• 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
• 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
• 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
• 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
• 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
• 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
• 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
• 240000000171 Crataegus monogyna Species 0.000 claims 1
• 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
• 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
• UKQILUDBMLHVAA-UHFFFAOYSA-N FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C(CN(CC1)CC1=NN=C(N1)C1=CC=C(C=C1)Cl)=O Chemical compound FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C(CN(CC1)CC1=NN=C(N1)C1=CC=C(C=C1)Cl)=O UKQILUDBMLHVAA-UHFFFAOYSA-N 0.000 claims 1
• FTPKMWKRAPBLAY-LTCKWSDVSA-N FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C([C@@H](N(CC1)CC1=NN=C(N1)C=1SC(=CC1)Cl)C)=O Chemical compound FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C([C@@H](N(CC1)CC1=NN=C(N1)C=1SC(=CC1)Cl)C)=O FTPKMWKRAPBLAY-LTCKWSDVSA-N 0.000 claims 1
• FCDDOSASZFZHST-LTCKWSDVSA-N FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C([C@@H](N(CC1)CC=1SC(=NN1)C=1SC(=CC1)Cl)C)=O Chemical compound FC(C(=O)O)(F)F.FC(C(=O)O)(F)F.NC1=NC=NC2=CC(=CC=C12)CN1C([C@@H](N(CC1)CC=1SC(=NN1)C=1SC(=CC1)Cl)C)=O FCDDOSASZFZHST-LTCKWSDVSA-N 0.000 claims 1
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
• 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 70
• 108010074860 Factor Xa Proteins 0.000 abstract description 36
• 230000002401 inhibitory effect Effects 0.000 abstract description 6
• 108010029144 Factor IIa Proteins 0.000 abstract 2
• 239000000243 solution Substances 0.000 description 344
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 269
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 202
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 182
• 238000005481 NMR spectroscopy Methods 0.000 description 145
• 235000019439 ethyl acetate Nutrition 0.000 description 115
• 125000001072 heteroaryl group Chemical group 0.000 description 113
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 112
• 239000000203 mixture Substances 0.000 description 96
• 239000007787 solid Substances 0.000 description 95
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
• 125000000392 cycloalkenyl group Chemical group 0.000 description 83
• 125000000623 heterocyclic group Chemical group 0.000 description 77
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 73
• 239000012044 organic layer Substances 0.000 description 73
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
• 229920006395 saturated elastomer Polymers 0.000 description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
• 150000002431 hydrogen Chemical class 0.000 description 55
• 239000002253 acid Substances 0.000 description 54
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 53
• 239000012043 crude product Substances 0.000 description 52
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
• 125000002947 alkylene group Chemical group 0.000 description 50
• 125000000753 cycloalkyl group Chemical group 0.000 description 50
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
• 229910052757 nitrogen Inorganic materials 0.000 description 46
• 239000002585 base Substances 0.000 description 45
• 239000010410 layer Substances 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 45
• 239000000047 product Substances 0.000 description 43
• 229910052760 oxygen Inorganic materials 0.000 description 42
• 229910052717 sulfur Inorganic materials 0.000 description 42
• 108090000190 Thrombin Proteins 0.000 description 41
• 125000004432 carbon atom Chemical group C* 0.000 description 41
• 238000006243 chemical reaction Methods 0.000 description 41
• 229960004072 thrombin Drugs 0.000 description 41
• 229940093499 ethyl acetate Drugs 0.000 description 40
• 239000002904 solvent Substances 0.000 description 36
• 125000003710 aryl alkyl group Chemical group 0.000 description 35
• 239000003921 oil Substances 0.000 description 33
• 235000019198 oils Nutrition 0.000 description 33
• 125000003107 substituted aryl group Chemical group 0.000 description 31
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 229910052799 carbon Inorganic materials 0.000 description 29
• 238000000746 purification Methods 0.000 description 29
• 238000004440 column chromatography Methods 0.000 description 28
• 235000019441 ethanol Nutrition 0.000 description 28
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
• 229910000104 sodium hydride Inorganic materials 0.000 description 27
• 125000004475 heteroaralkyl group Chemical group 0.000 description 26
• 230000000694 effects Effects 0.000 description 25
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
• 238000003756 stirring Methods 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 24
• 150000001721 carbon Chemical group 0.000 description 24
• 150000002500 ions Chemical class 0.000 description 24
• 239000007921 spray Substances 0.000 description 24
• 229910052727 yttrium Inorganic materials 0.000 description 24
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 23
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
• 125000000547 substituted alkyl group Chemical group 0.000 description 23
• 229940086542 triethylamine Drugs 0.000 description 23
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 239000012267 brine Substances 0.000 description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 22
• 125000006413 ring segment Chemical group 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• 125000004414 alkyl thio group Chemical group 0.000 description 21
• 238000010992 reflux Methods 0.000 description 21
• 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 20
• 239000001301 oxygen Substances 0.000 description 20
• KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-N 0.000 description 19
• 239000003153 chemical reaction reagent Substances 0.000 description 19
• 238000003818 flash chromatography Methods 0.000 description 19
• 125000001424 substituent group Chemical group 0.000 description 19
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
• 239000011734 sodium Substances 0.000 description 18
• 125000004183 alkoxy alkyl group Chemical group 0.000 description 17
• 150000001412 amines Chemical class 0.000 description 17
• 125000003435 aroyl group Chemical group 0.000 description 17
• 239000000460 chlorine Substances 0.000 description 17
• 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
• 125000004122 cyclic group Chemical group 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• 239000012442 inert solvent Substances 0.000 description 15
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 15
• 125000004433 nitrogen atom Chemical group N* 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 14
• 229960000583 acetic acid Drugs 0.000 description 14
• 125000004350 aryl cycloalkyl group Chemical group 0.000 description 14
• IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 14
• 125000005346 substituted cycloalkyl group Chemical group 0.000 description 14
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 13
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 13
• 150000002923 oximes Chemical class 0.000 description 13
• 238000006268 reductive amination reaction Methods 0.000 description 13
• 239000000741 silica gel Substances 0.000 description 13
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• 229960001866 silicon dioxide Drugs 0.000 description 13
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