BR112020010216A2 - inibidores de dopamina-¿-hidroxilase - Google Patents

Info

Publication number

BR112020010216A2

BR112020010216A2 BR112020010216-4A BR112020010216A BR112020010216A2 BR 112020010216 A2 BR112020010216 A2 BR 112020010216A2 BR 112020010216 A BR112020010216 A BR 112020010216A BR 112020010216 A2 BR112020010216 A2 BR 112020010216A2

Authority

BR

Brazil

Prior art keywords

methyl

thioxo

imidazol

hydrogen

tetrahydro

Prior art date

2017-12-04

Links

• Espacenet
• Global Dossier
• Discuss

• 239000003112 inhibitor Substances 0.000 title abstract description 17
• VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title description 4
• 229960003638 dopamine Drugs 0.000 title description 2
• 102000008109 Mixed Function Oxygenases Human genes 0.000 title 1
• 108010074633 Mixed Function Oxygenases Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 282
• 150000003839 salts Chemical class 0.000 claims abstract description 36
• 239000012453 solvate Substances 0.000 claims abstract description 34
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 18
• 238000000034 method Methods 0.000 claims abstract description 16
• 108010015720 Dopamine beta-Hydroxylase Proteins 0.000 claims abstract description 9
• 102100033156 Dopamine beta-hydroxylase Human genes 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• -1 hydroxy, methylsulfonyl Chemical group 0.000 claims description 1376
• 229910052739 hydrogen Inorganic materials 0.000 claims description 1009
• 239000001257 hydrogen Substances 0.000 claims description 164
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 154
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 139
• 125000001424 substituent group Chemical group 0.000 claims description 62
• 125000001153 fluoro group Chemical group F* 0.000 claims description 48
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 37
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 36
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 30
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 29
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
• 125000004043 oxo group Chemical group O=* 0.000 claims description 26
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 23
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 22
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 21
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 19
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 18
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 18
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 18
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• 125000002757 morpholinyl group Chemical group 0.000 claims description 16
• 125000003386 piperidinyl group Chemical group 0.000 claims description 16
• 229920002472 Starch Polymers 0.000 claims description 15
• 210000003169 central nervous system Anatomy 0.000 claims description 15
• 125000002704 decyl group Chemical group [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])* 0.000 claims description 15
• 230000005764 inhibitory process Effects 0.000 claims description 15
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
• 235000019698 starch Nutrition 0.000 claims description 15
• 239000008107 starch Substances 0.000 claims description 15
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 14
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 14
• 125000004076 pyridyl group Chemical group 0.000 claims description 14
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
• 125000004432 carbon atom Chemical group C* 0.000 claims description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 9
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 9
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
• 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 7
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
• 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 7
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 125000004193 piperazinyl group Chemical group 0.000 claims description 7
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
• 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 claims description 6
• 125000003545 alkoxy group Chemical group 0.000 claims description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 claims description 5
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 5
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 5
• GSJJVNAPLSISFR-CQSZACIVSA-N (6S)-1-benzyl-6-(3,5-difluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C(C1=CC=CC=C1)C1=C2N(C(N1)=S)C[C@@H](C2)C1=CC(=CC(=C1)F)F GSJJVNAPLSISFR-CQSZACIVSA-N 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 230000015572 biosynthetic process Effects 0.000 abstract description 7
• 238000003786 synthesis reaction Methods 0.000 abstract description 3
• 239000000543 intermediate Substances 0.000 abstract description 2
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 450
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 281
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 266
• 238000005160 1H NMR spectroscopy Methods 0.000 description 219
• 238000005481 NMR spectroscopy Methods 0.000 description 213
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 195
• 239000000203 mixture Substances 0.000 description 158
• XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 152
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 143
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 135
• 239000007787 solid Substances 0.000 description 127
• 239000000243 solution Substances 0.000 description 126
• 239000000843 powder Substances 0.000 description 117
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 98
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 81
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 67
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 67
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 63
• 239000002253 acid Substances 0.000 description 60
• 239000003208 petroleum Substances 0.000 description 53
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
• 235000019439 ethyl acetate Nutrition 0.000 description 52
• 239000000047 product Substances 0.000 description 51
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 49
• 235000019341 magnesium sulphate Nutrition 0.000 description 49
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 47
• 239000012074 organic phase Substances 0.000 description 46
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
• 239000003921 oil Substances 0.000 description 42
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 30
• 238000004587 chromatography analysis Methods 0.000 description 28
• 239000006071 cream Substances 0.000 description 28
• 238000006243 chemical reaction Methods 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• 239000011541 reaction mixture Substances 0.000 description 20
• 238000010992 reflux Methods 0.000 description 20
• SOUTXPDHEIXJST-SECBINFHSA-N 2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@@H](C2)C1=C(C(=CC=C1F)Br)F)=O SOUTXPDHEIXJST-SECBINFHSA-N 0.000 description 19
• SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 208000002815 pulmonary hypertension Diseases 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• SOUTXPDHEIXJST-VIFPVBQESA-N 2-[(6R)-6-(3-bromo-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC=C1F)Br)F)=O SOUTXPDHEIXJST-VIFPVBQESA-N 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• 239000008346 aqueous phase Substances 0.000 description 16
• 125000004429 atom Chemical group 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
• VJRKXHZVHNGEHE-SECBINFHSA-N 2-[(6S)-6-(3-chloro-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@@H](C2)C1=C(C(=CC=C1F)Cl)F)=O VJRKXHZVHNGEHE-SECBINFHSA-N 0.000 description 14
• 239000006260 foam Substances 0.000 description 13
• 239000002244 precipitate Substances 0.000 description 13
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 12
• 229940116357 potassium thiocyanate Drugs 0.000 description 12
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
• 238000001816 cooling Methods 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 10
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
• 238000001704 evaporation Methods 0.000 description 10
• 230000008020 evaporation Effects 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• VDEZBFWJJWGEQP-KPZWWZAWSA-N 2-[(2R,4S)-4-(5-bromo-2-fluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-1-imidazol-1-ylethanone Chemical compound BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3C=NC=C3)=S)C1)C2)F VDEZBFWJJWGEQP-KPZWWZAWSA-N 0.000 description 8
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
• XVYBJYXRAVEJOT-GAJHUEQPSA-N N-benzyl-2-[(2R,4S)-4-(2,5-difluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-methylacetamide Chemical compound C1(=CC=C(C(=C1)[C@]12C[C@H]1C1=C(CC(=O)N(CC3=CC=CC=C3)C)NC(=S)N1C2)F)F XVYBJYXRAVEJOT-GAJHUEQPSA-N 0.000 description 8
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
• 229910052760 oxygen Inorganic materials 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 229910052717 sulfur Inorganic materials 0.000 description 8
• SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 7
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
• RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
• 206010019280 Heart failures Diseases 0.000 description 7
• 229960002748 norepinephrine Drugs 0.000 description 7
• SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 7
• 230000037081 physical activity Effects 0.000 description 7
• RKOIYCWHKHOMRR-VIFPVBQESA-N 1-pyrrolidin-1-yl-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound Fc1cc(F)c(F)c([C@H]2Cc3c(CC(=O)N4CCCC4)[nH]c(=S)n3C2)c1F RKOIYCWHKHOMRR-VIFPVBQESA-N 0.000 description 6
• NEZMBAPPFRPZGX-JTQLQIEISA-N 1-pyrrolidin-1-yl-3-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound FC1=CC(F)=C(F)C([C@@H]2CN3C(=S)NC(CCC(=O)N4CCCC4)=C3C2)=C1F NEZMBAPPFRPZGX-JTQLQIEISA-N 0.000 description 6
• UMTWGUMHQWQCFR-ORAYPTAESA-N BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3CCCC3)=S)C1)C2)F Chemical compound BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3CCCC3)=S)C1)C2)F UMTWGUMHQWQCFR-ORAYPTAESA-N 0.000 description 6
• 206010007559 Cardiac failure congestive Diseases 0.000 description 6
• 206010013975 Dyspnoeas Diseases 0.000 description 6
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
• 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 6
• WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 6
• 239000012230 colorless oil Substances 0.000 description 6
• 201000010099 disease Diseases 0.000 description 6
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 6
• 235000017557 sodium bicarbonate Nutrition 0.000 description 6
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• 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 6
• 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 6
• LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 5
• 208000000059 Dyspnea Diseases 0.000 description 5
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
• 239000012267 brine Substances 0.000 description 5
• 238000004440 column chromatography Methods 0.000 description 5
• 238000002425 crystallisation Methods 0.000 description 5
• 230000008025 crystallization Effects 0.000 description 5
• 230000000694 effects Effects 0.000 description 5
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
• 125000002950 monocyclic group Chemical group 0.000 description 5
• YZZVIKDAOTXDEB-JTQLQIEISA-N nepicastat Chemical compound NCC1=CNC(=S)N1[C@@H]1CC2=CC(F)=CC(F)=C2CC1 YZZVIKDAOTXDEB-JTQLQIEISA-N 0.000 description 5
• 238000002360 preparation method Methods 0.000 description 5
• 229920006395 saturated elastomer Polymers 0.000 description 5
• 239000012279 sodium borohydride Substances 0.000 description 5
• 229910000033 sodium borohydride Inorganic materials 0.000 description 5
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
• 208000024891 symptom Diseases 0.000 description 5
• OWNKZEBRQLFXSU-PGECJRHESA-N (1R,5S)-5-(2,5-difluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@]2(C[C@H]2C1C(O)=O)c1cc(F)ccc1F OWNKZEBRQLFXSU-PGECJRHESA-N 0.000 description 4
• MDPIXEXXHOMRAI-GFMNRZNCSA-N (1R,5S)-5-(3-chloro-5-fluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C([C@@H]2C[C@@]2(C1)C1=CC(=CC(=C1)F)Cl)C(=O)O MDPIXEXXHOMRAI-GFMNRZNCSA-N 0.000 description 4
• UIMHCFQYXSHGCG-PGECJRHESA-N (1R,5S)-5-(5-chloro-2-fluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C([C@@H]2C[C@@]2(C1)C1=C(C=CC(=C1)Cl)F)C(=O)O UIMHCFQYXSHGCG-PGECJRHESA-N 0.000 description 4
• LBERUSYMIULPAV-VUUHIHSGSA-N (4S)-4-(3,5-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@H](C1)C1=CC(=CC(=C1)F)F)C(=O)O LBERUSYMIULPAV-VUUHIHSGSA-N 0.000 description 4
• XFHFJKWXOCHYSH-SSDOTTSWSA-N (6S)-6-(3,5-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-1-carboxylic acid Chemical compound C1(=CC(F)=CC(=C1)[C@@H]1CC2=C(C(=O)O)NC(=S)N2C1)F XFHFJKWXOCHYSH-SSDOTTSWSA-N 0.000 description 4
• ODBYONWDYFNMHM-QMMMGPOBSA-N 1-imidazol-1-yl-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CC(=O)N3C=CN=C3)NC(=S)N2C1)F)F ODBYONWDYFNMHM-QMMMGPOBSA-N 0.000 description 4
• KVOBRWVAKXVLAE-YYSFKGJASA-N 2-[(2R,4S)-4-(3-chloro-2,6-difluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-1-imidazol-1-ylethanone Chemical compound ClC=1C(=C(C(=CC=1)F)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3C=NC=C3)=S)C1)C2)F KVOBRWVAKXVLAE-YYSFKGJASA-N 0.000 description 4
• NOJRGZKNRSDTEB-ORAYPTAESA-N 2-[(2R,4S)-4-(5-bromo-2-fluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-1-morpholin-4-ylethanone Chemical compound C1(=CC=C(C(=C1)[C@]12[C@H](C3=C(CC(=O)N4CCOCC4)NC(=S)N3C1)C2)F)Br NOJRGZKNRSDTEB-ORAYPTAESA-N 0.000 description 4
• LGZXHVWZGRXYRS-VIFPVBQESA-N 2-[(6R)-6-(3-bromo-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-N-(2-hydroxyethyl)-N-methylacetamide Chemical compound BrC=1C(=C(C(=CC=1)F)[C@H]1CC=2N(C(NC=2CC(=O)N(C)CCO)=S)C1)F LGZXHVWZGRXYRS-VIFPVBQESA-N 0.000 description 4
• VCAKFZGCRCEYDJ-SECBINFHSA-N 2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-N-cyclobutylacetamide Chemical compound BrC=1C(=C(C(=CC=1)F)[C@@H]1CC=2N(C(NC=2CC(=O)NC2CCC2)=S)C1)F VCAKFZGCRCEYDJ-SECBINFHSA-N 0.000 description 4
• SNVCRDUMOJKXCE-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylic acid Chemical compound OC1CC(CN1C(O)=O)c1cc(F)cc(F)c1 SNVCRDUMOJKXCE-UHFFFAOYSA-N 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
• MJYMXAOQEZXEPL-YCRPNKLZSA-N CN(C1CCCC1)C(=O)Cc1[nH]c(=S)n2C[C@]3(C[C@H]3c12)c1cc(Br)ccc1F Chemical compound CN(C1CCCC1)C(=O)Cc1[nH]c(=S)n2C[C@]3(C[C@H]3c12)c1cc(Br)ccc1F MJYMXAOQEZXEPL-YCRPNKLZSA-N 0.000 description 4
• 206010008479 Chest Pain Diseases 0.000 description 4
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
• QVLDUOYVZVMRKP-KPZWWZAWSA-N Fc1ccc(Br)cc1[C@]12C[C@H]1c1c(CC(=O)NC3CC3)[nH]c(=S)n1C2 Chemical compound Fc1ccc(Br)cc1[C@]12C[C@H]1c1c(CC(=O)NC3CC3)[nH]c(=S)n1C2 QVLDUOYVZVMRKP-KPZWWZAWSA-N 0.000 description 4
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 4
• 230000008499 blood brain barrier function Effects 0.000 description 4
• 210000001218 blood-brain barrier Anatomy 0.000 description 4
• 239000013078 crystal Substances 0.000 description 4
• AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 4
• 208000035475 disorder Diseases 0.000 description 4
• 229950005868 nepicastat Drugs 0.000 description 4
• NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 4
• 125000006413 ring segment Chemical group 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• 239000012258 stirred mixture Substances 0.000 description 4
• APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 3
• HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 3
• BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 3
• WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 3
• KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 3
• IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 3
• KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
• 229910015900 BF3 Inorganic materials 0.000 description 3
• 239000004215 Carbon black (E152) Substances 0.000 description 3
• 208000024172 Cardiovascular disease Diseases 0.000 description 3
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
• 206010020772 Hypertension Diseases 0.000 description 3
• HGAQZWAUPLDGPV-VBKZILBWSA-N N-butyl-2-[(2R,4S)-4-(2,5-difluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-methylacetamide Chemical compound C1(=CC=C(C(=C1)[C@]12C[C@H]1C1=C(CC(=O)N(CCCC)C)NC(=S)N1C2)F)F HGAQZWAUPLDGPV-VBKZILBWSA-N 0.000 description 3
• IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 3
• 208000014777 Pulmonary venoocclusive disease Diseases 0.000 description 3
• 230000001684 chronic effect Effects 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 229930195733 hydrocarbon Natural products 0.000 description 3
• 239000005457 ice water Substances 0.000 description 3
• 239000002198 insoluble material Substances 0.000 description 3
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 3
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
• CJJZCWJJAZMVCJ-UHFFFAOYSA-N n-benzyl-2,5-dimethylaniline Chemical compound CC1=CC=C(C)C(NCC=2C=CC=CC=2)=C1 CJJZCWJJAZMVCJ-UHFFFAOYSA-N 0.000 description 3
• 230000002093 peripheral effect Effects 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
• RFAKLMBNSZNUNX-UHFFFAOYSA-N potassium;isothiocyanate Chemical compound [K+].[N-]=C=S RFAKLMBNSZNUNX-UHFFFAOYSA-N 0.000 description 3
• 230000003389 potentiating effect Effects 0.000 description 3
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 3
• 210000001147 pulmonary artery Anatomy 0.000 description 3
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 3
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 3
• 238000001228 spectrum Methods 0.000 description 3
• 230000002889 sympathetic effect Effects 0.000 description 3
• 238000001665 trituration Methods 0.000 description 3
• VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 2
• MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 2
• OFZKJJCDUNPRSI-BYDSUWOYSA-N (4R)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](CC1C(O)=O)c1c(F)c(F)cc(F)c1F OFZKJJCDUNPRSI-BYDSUWOYSA-N 0.000 description 2
• OFZKJJCDUNPRSI-PVSHWOEXSA-N (4S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@H](C1)C1=C(C(=CC(=C1F)F)F)F)C(=O)O OFZKJJCDUNPRSI-PVSHWOEXSA-N 0.000 description 2
• PVMDENPNABPPBV-JTQLQIEISA-N (6R)-1-(2-pyridin-2-ylethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound N1=C(C=CC=C1)CCC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F PVMDENPNABPPBV-JTQLQIEISA-N 0.000 description 2
• CSWPSHQOPBVLOE-NSHDSACASA-N (6R)-1-(2-pyridin-3-ylethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound N1=CC(=CC=C1)CCC1=C2N(C(N1)=S)C[C@H](C2)C2=C(C(=CC(=C2F)F)F)F CSWPSHQOPBVLOE-NSHDSACASA-N 0.000 description 2
• SXAMJIQNOIIHHG-NSHDSACASA-N (6R)-1-(2-pyridin-4-ylethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound FC1=C(F)C([C@H]2CC3=C(CCC4=CC=NC=C4)NC(=S)N3C2)=C(F)C(F)=C1 SXAMJIQNOIIHHG-NSHDSACASA-N 0.000 description 2
• PRKGDVYDPMCHQA-NSHDSACASA-N (6R)-1-(3-pyrrolidin-1-ylpropyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(F)=C(F)C([C@H]2CC3=C(CCCN4CCCC4)NC(=S)N3C2)=C(F)C(F)=C1 PRKGDVYDPMCHQA-NSHDSACASA-N 0.000 description 2
• OMLOVFCTOYUMFJ-VIFPVBQESA-N (6R)-1-[2-(1-methylimidazol-2-yl)ethyl]-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound CN1C(=NC=C1)CCC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F OMLOVFCTOYUMFJ-VIFPVBQESA-N 0.000 description 2
• BEZQRLKDWAJGJY-LBPRGKRZSA-N (6R)-6-(3-bromo-2,6-difluorophenyl)-1-(2-pyridin-3-ylethyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(=CC=C(C(=C1F)[C@H]1CC2=C(CCC3=CC=CN=C3)NC(=S)N2C1)F)Br BEZQRLKDWAJGJY-LBPRGKRZSA-N 0.000 description 2
• MRTLLPSGIWSGJT-JTQLQIEISA-N (6R)-6-(3-bromo-2,6-difluorophenyl)-1-[2-(2-methylsulfonylethylamino)ethyl]-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(=CC=C(C(=C1F)[C@H]1CC2=C(CCNCCS(=O)(=O)C)NC(=S)N2C1)F)Br MRTLLPSGIWSGJT-JTQLQIEISA-N 0.000 description 2
• DOGJPYICMIVFQA-NSHDSACASA-N (6R)-6-(3-bromo-2,6-difluorophenyl)-1-[2-(4,4-difluoropiperidin-1-yl)ethyl]-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(=CC=C(C(=C1F)[C@H]1CC2=C(CCN3CCC(CC3)(F)F)NC(=S)N2C1)F)Br DOGJPYICMIVFQA-NSHDSACASA-N 0.000 description 2
• NIDWKECJIOIAFU-LBPRGKRZSA-N (6R)-6-(3-bromo-2,6-difluorophenyl)-1-[2-(4-methylsulfonylpiperidin-1-yl)ethyl]-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(Br)=C(F)C([C@H]2CC3=C(CCN4CCC(S(=O)(=O)C)CC4)NC(=S)N3C2)=C(F)C=C1 NIDWKECJIOIAFU-LBPRGKRZSA-N 0.000 description 2
• BHXSAQNCSWKTQZ-JTQLQIEISA-N (6R)-6-(3-bromo-2,6-difluorophenyl)-1-[2-[2-hydroxyethyl(methyl)amino]ethyl]-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound BrC=1C(=C(C(=CC=1)F)[C@H]1CC=2N(C(NC=2CCN(C)CCO)=S)C1)F BHXSAQNCSWKTQZ-JTQLQIEISA-N 0.000 description 2
• BQMPLYDEWYOYEA-RXMQYKEDSA-N (6S)-1-(hydroxymethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1=C(C(F)=C(C(=C1F)F)[C@@H]1CC2=C(CO)NC(=S)N2C1)F BQMPLYDEWYOYEA-RXMQYKEDSA-N 0.000 description 2
• SRXWLNZJAMUZFA-ZCFIWIBFSA-N (6S)-1-(methylsulfonylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound CS(=O)(=O)CC1=C2N(C(N1)=S)C[C@@H](C2)C1=C(C(=CC(=C1F)F)F)F SRXWLNZJAMUZFA-ZCFIWIBFSA-N 0.000 description 2
• MOOXLHRYFBGMCD-MRVPVSSYSA-N (6S)-6-(3,5-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-1-carbaldehyde Chemical compound FC1=CC(=CC(F)=C1)[C@H]1CN2C(=S)NC(C=O)=C2C1 MOOXLHRYFBGMCD-MRVPVSSYSA-N 0.000 description 2
• ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 2
• MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
• UILXGSXBVZKWRZ-OWOJBTEDSA-N 1,3-difluoro-5-[(e)-2-nitroethenyl]benzene Chemical compound [O-][N+](=O)\C=C\C1=CC(F)=CC(F)=C1 UILXGSXBVZKWRZ-OWOJBTEDSA-N 0.000 description 2
• IVHJIQYGIXNVDO-JTQLQIEISA-N 1-(4,4-difluoropiperidin-1-yl)-3-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CCC(=O)N3CCC(CC3)(F)F)NC(=S)N2C1)F)F IVHJIQYGIXNVDO-JTQLQIEISA-N 0.000 description 2
• QNTRZNVLDQJOQL-VIFPVBQESA-N 1-(4-hydroxypiperidin-1-yl)-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CC(=O)N3CCC(CC3)O)NC(=S)N2C1)F)F QNTRZNVLDQJOQL-VIFPVBQESA-N 0.000 description 2
• NHQRCCKQZWXKHY-UWVGGRQHSA-N 1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound FC1=C(F)C([C@H]2CC3=C(CC(=O)N4CCC[C@H]4CO)NC(=S)N3C2)=C(F)C(F)=C1 NHQRCCKQZWXKHY-UWVGGRQHSA-N 0.000 description 2
• ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 2
• NEKPGQOYPVESNC-NSHDSACASA-N 1-[4-(hydroxymethyl)piperidin-1-yl]-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound FC1=C(F)C([C@H]2CC3=C(CC(=O)N4CCC(CC4)CO)NC(=S)N3C2)=C(F)C(F)=C1 NEKPGQOYPVESNC-NSHDSACASA-N 0.000 description 2
• MRWNVANDLNSBLP-NSHDSACASA-N 1-piperidin-1-yl-3-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CCC(=O)N3CCCCC3)NC(=S)N2C1)F)F MRWNVANDLNSBLP-NSHDSACASA-N 0.000 description 2
• RKOIYCWHKHOMRR-SECBINFHSA-N 1-pyrrolidin-1-yl-2-[(6S)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound N1(CCCC1)C(CC1=C2N(C(N1)=S)C[C@@H](C2)C1=C(C(=CC(=C1F)F)F)F)=O RKOIYCWHKHOMRR-SECBINFHSA-N 0.000 description 2
• OKRROXQXGNEUSS-UHFFFAOYSA-N 1h-imidazol-1-ium-1-carboxylate Chemical compound OC(=O)N1C=CN=C1 OKRROXQXGNEUSS-UHFFFAOYSA-N 0.000 description 2
• MLDXPKBJYZRKOV-KSFYIVLOSA-N 2-[(2R,4S)-4-(5-bromo-2-fluorophenyl)-8-methyl-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-cyclohexylacetamide Chemical compound C1(=CC=C(F)C(=C1)[C@]12C[C@H]1C1=C(CC(=O)NC3CCCCC3)N(C(=S)N1C2)C)Br MLDXPKBJYZRKOV-KSFYIVLOSA-N 0.000 description 2
• APEGJTFVFGNKAK-JTQLQIEISA-N 2-[(6R)-6-(2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C=CC=C1F)F)=O APEGJTFVFGNKAK-JTQLQIEISA-N 0.000 description 2
• ZATQBVCJFDISQJ-GFCCVEGCSA-N 2-[(6S)-6-(3,5-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-morpholin-4-ylethanone Chemical compound C1=C(C=C(C=C1F)[C@@H]1CC2=C(CC(=O)N3CCOCC3)NC(=S)N2C1)F ZATQBVCJFDISQJ-GFCCVEGCSA-N 0.000 description 2
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
• QWUWRLDIFVZEFV-VJSCVCEBSA-N 2-methylsulfonyl-1-[(4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl]ethanone Chemical compound C1(F)=C(F)C(=C(F)C(F)=C1)[C@@H]1CC(C(=O)CS(=O)(=O)C)NC1 QWUWRLDIFVZEFV-VJSCVCEBSA-N 0.000 description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
• SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 2
• 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 2
• YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 2
• XFHFJKWXOCHYSH-UHFFFAOYSA-N 6-(3,5-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-1-carboxylic acid Chemical compound OC(=O)C1=C2CC(CN2C(=S)N1)C1=CC(F)=CC(F)=C1 XFHFJKWXOCHYSH-UHFFFAOYSA-N 0.000 description 2
• CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 2
• GFQDOBPJKGQUOF-NSHDSACASA-N BrC=1C(=C(C(=CC=1)F)[C@H]1CC=2N(C(NC=2CCNC2CCS(CC2)(=O)=O)=S)C1)F Chemical compound BrC=1C(=C(C(=CC=1)F)[C@H]1CC=2N(C(NC=2CCNC2CCS(CC2)(=O)=O)=S)C1)F GFQDOBPJKGQUOF-NSHDSACASA-N 0.000 description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
• 206010007558 Cardiac failure chronic Diseases 0.000 description 2
• IUTCNGZCGRVZJL-PPVBMBHXSA-N Cl.Cl.Fc1cc(F)c(F)c([C@@H]2CNC(C2)C(=O)CN2CCOCC2)c1F Chemical compound Cl.Cl.Fc1cc(F)c(F)c([C@@H]2CNC(C2)C(=O)CN2CCOCC2)c1F IUTCNGZCGRVZJL-PPVBMBHXSA-N 0.000 description 2
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• QDLOLBJKQDOMTM-VEDVMXKPSA-N FC=1C=C(C=C(C=1)F)[C@@H]1C(C(NC1)=O)C(=O)O Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1C(C(NC1)=O)C(=O)O QDLOLBJKQDOMTM-VEDVMXKPSA-N 0.000 description 2
• GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 2
• DGMPVYSXXIOGJY-UHFFFAOYSA-N Fusaric acid Chemical compound CCCCC1=CC=C(C(O)=O)N=C1 DGMPVYSXXIOGJY-UHFFFAOYSA-N 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• 208000019693 Lung disease Diseases 0.000 description 2
• AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 2
• 206010028980 Neoplasm Diseases 0.000 description 2
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
• 206010036653 Presyncope Diseases 0.000 description 2
• 208000031467 Pulmonary capillary hemangiomatosis Diseases 0.000 description 2
• 206010039163 Right ventricular failure Diseases 0.000 description 2
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
• BGENIXIZRRKNAO-CPCISQLKSA-N [(1R,2S)-2-(aminomethyl)-2-(2,5-difluorophenyl)cyclopropyl]methanol Chemical compound C1=C(F)C=C(C(F)=C1)[C@@]1(C[C@H]1CO)CN BGENIXIZRRKNAO-CPCISQLKSA-N 0.000 description 2
• LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 2
• 125000000217 alkyl group Chemical group 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 239000012043 crude product Substances 0.000 description 2
• 229910052805 deuterium Inorganic materials 0.000 description 2
• BLEBFDYUDVZRFG-UHFFFAOYSA-N dichloromethane;propan-2-ol Chemical compound ClCCl.CC(C)O BLEBFDYUDVZRFG-UHFFFAOYSA-N 0.000 description 2
• AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
• 229940079593 drug Drugs 0.000 description 2
• 238000001035 drying Methods 0.000 description 2
• 206010016256 fatigue Diseases 0.000 description 2
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
• 239000012458 free base Substances 0.000 description 2
• 208000019622 heart disease Diseases 0.000 description 2
• 230000033444 hydroxylation Effects 0.000 description 2
• 238000005805 hydroxylation reaction Methods 0.000 description 2
• 125000002632 imidazolidinyl group Chemical group 0.000 description 2
• 230000006872 improvement Effects 0.000 description 2
• 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 2
• 125000003965 isoxazolidinyl group Chemical group 0.000 description 2
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
• 239000000463 material Substances 0.000 description 2
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
• DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
• 239000012452 mother liquor Substances 0.000 description 2
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
• 125000000160 oxazolidinyl group Chemical group 0.000 description 2
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
• NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
• 230000000750 progressive effect Effects 0.000 description 2
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
• 238000001953 recrystallisation Methods 0.000 description 2
• XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 2
• 239000000377 silicon dioxide Substances 0.000 description 2
• XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
• 239000012312 sodium hydride Substances 0.000 description 2
• 229910000104 sodium hydride Inorganic materials 0.000 description 2
• 239000000126 substance Substances 0.000 description 2
• HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
• NQNKWMXAGSJFCM-VKCPWKDNSA-N tert-butyl (1S,5R)-1-(2,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@]12CN(C([C@@H]2C1)O)C(=O)OC(C)(C)C NQNKWMXAGSJFCM-VKCPWKDNSA-N 0.000 description 2
• MRQBYCKPXJQCFO-WAPNNBGYSA-N tert-butyl (1S,5R)-4-cyano-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Chemical compound C(#N)C1N(C[C@]2(C[C@@H]12)C1=C(C=CC(=C1)F)F)C(=O)OC(C)(C)C MRQBYCKPXJQCFO-WAPNNBGYSA-N 0.000 description 2
• NHOFTFDJHYFPOO-SNVBAGLBSA-N tert-butyl (4S)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](CC1=O)c1cc(F)cc(F)c1 NHOFTFDJHYFPOO-SNVBAGLBSA-N 0.000 description 2
• LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 2
• 125000001984 thiazolidinyl group Chemical group 0.000 description 2
• 230000009424 thromboembolic effect Effects 0.000 description 2
• ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 2
• ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
• BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
• PBRUBPPNMKLVMK-GFMNRZNCSA-N (1R,5S)-5-(3,5-difluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C([C@@H]2C[C@@]2(C1)C1=CC(=CC(=C1)F)F)C(=O)O PBRUBPPNMKLVMK-GFMNRZNCSA-N 0.000 description 1
• NKVBTSHBJCPDHN-XUHZEFJWSA-N (1R,5S)-5-(3-bromo-2,6-difluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C([C@@H]2C[C@@]2(C1)C1=C(C(=CC=C1F)Br)F)C(=O)O NKVBTSHBJCPDHN-XUHZEFJWSA-N 0.000 description 1
• NILWSRKQGPYRDH-PGECJRHESA-N (1R,5S)-5-(5-bromo-2-fluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound BrC=1C=CC(=C(C=1)[C@]12CN(C([C@@H]2C1)C(=O)O)C(=O)OC(C)(C)C)F NILWSRKQGPYRDH-PGECJRHESA-N 0.000 description 1
• SOCAXRLFGRNEPK-IFZYUDKTSA-N (1r,3s,5r)-2-n-[1-carbamoyl-5-(cyanomethoxy)indol-3-yl]-3-n-[(3-chloro-2-fluorophenyl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxamide Chemical compound O=C([C@@H]1C[C@H]2C[C@H]2N1C(=O)NC1=CN(C2=CC=C(OCC#N)C=C21)C(=O)N)NCC1=CC=CC(Cl)=C1F SOCAXRLFGRNEPK-IFZYUDKTSA-N 0.000 description 1
• DOMQFIFVDIAOOT-ROUUACIJSA-N (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide Chemical compound COC1=C(C(=CC=C1)OC)N1C(=NN=C1C=1C=NC=C(C=1)C)NS(=O)(=O)[C@@H](C)[C@H](C)C1=NC=C(C=N1)C DOMQFIFVDIAOOT-ROUUACIJSA-N 0.000 description 1
• HYFNWVABAVFIID-RYUDHWBXSA-N (3R)-1-[2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]pyrrolidine-3-carbonitrile Chemical compound CN1C(N2C(=C1CC(=O)N1C[C@@H](CC1)C#N)C[C@@H](C2)C1=C(C(=CC=C1F)F)F)=S HYFNWVABAVFIID-RYUDHWBXSA-N 0.000 description 1
• HYFNWVABAVFIID-NEPJUHHUSA-N (3S)-1-[2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]pyrrolidine-3-carbonitrile Chemical compound CN1C(N2C(=C1CC(=O)N1C[C@H](CC1)C#N)C[C@@H](C2)C1=C(C(=CC=C1F)F)F)=S HYFNWVABAVFIID-NEPJUHHUSA-N 0.000 description 1
• CKRJDFBZZYAXBV-VXGBXAGGSA-N (3S)-1-[2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-sulfanylidene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]pyrrolidine-3-carbonitrile Chemical compound BrC=1C(=C(C(=CC=1)F)[C@@H]1CC=2N(C(N(C=2CC(=O)N2C[C@H](CC2)C#N)C)=S)C1)F CKRJDFBZZYAXBV-VXGBXAGGSA-N 0.000 description 1
• FVYXSJVCWIBOGU-LLTODGECSA-N (4R)-4-(2,5-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@@H](C1)C1=C(C=CC(=C1)F)F)C(=O)O FVYXSJVCWIBOGU-LLTODGECSA-N 0.000 description 1
• AXUNGJYMNWZYOS-QHGLUPRGSA-N (4R)-4-(2,6-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@@H](C1)C1=C(C=CC=C1F)F)C(=O)O AXUNGJYMNWZYOS-QHGLUPRGSA-N 0.000 description 1
• STCHPFKGKXUFAD-YMNIQAILSA-N (4R)-4-(3-bromo-2,6-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@@H](C1)C1=C(C(=CC=C1F)Br)F)C(=O)O STCHPFKGKXUFAD-YMNIQAILSA-N 0.000 description 1
• GHTXVBKOCNUXHS-LLTODGECSA-N (4R)-4-(5-chloro-2-fluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@@H](C1)C1=C(C=CC(=C1)Cl)F)C(=O)O GHTXVBKOCNUXHS-LLTODGECSA-N 0.000 description 1
• FVYXSJVCWIBOGU-CGCSKFHYSA-N (4S)-4-(2,5-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1=C(F)C=C(C(F)=C1)[C@@H]1CC(C(=O)O)N(C1)C(=O)OC(C)(C)C FVYXSJVCWIBOGU-CGCSKFHYSA-N 0.000 description 1
• STCHPFKGKXUFAD-RZZZFEHKSA-N (4S)-4-(3-bromo-2,6-difluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@H](C1)C1=C(C(=CC=C1F)Br)F)C(=O)O STCHPFKGKXUFAD-RZZZFEHKSA-N 0.000 description 1
• OXFWXIJKQCMSSV-CGCSKFHYSA-N (4S)-4-(5-bromo-2-fluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C[C@H](C1)C1=C(C=CC(=C1)Br)F)C(=O)O OXFWXIJKQCMSSV-CGCSKFHYSA-N 0.000 description 1
• HGRWHBQLRXWSLV-DEOSSOPVSA-N (4s)-3'-(3,6-dihydro-2h-pyran-5-yl)-1'-fluoro-7'-(3-fluoropyridin-2-yl)spiro[5h-1,3-oxazole-4,5'-chromeno[2,3-c]pyridine]-2-amine Chemical compound C1OC(N)=N[C@]21C1=CC(C=3COCCC=3)=NC(F)=C1OC1=CC=C(C=3C(=CC=CN=3)F)C=C12 HGRWHBQLRXWSLV-DEOSSOPVSA-N 0.000 description 1
• ZRGRBESRTDUUAB-JTQLQIEISA-N (6R)-1-(2-pyrrolidin-1-ylethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound FC1=C(F)C([C@H]2CC3=C(CCN4CCCC4)NC(=S)N3C2)=C(F)C(F)=C1 ZRGRBESRTDUUAB-JTQLQIEISA-N 0.000 description 1
• GDQALHMQQKRIAR-VIFPVBQESA-N (6R)-1-(morpholin-4-ylmethyl)-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CN3CCOCC3)NC(=S)N2C1)F)F GDQALHMQQKRIAR-VIFPVBQESA-N 0.000 description 1
• WWJGSYURUWBJSV-NSHDSACASA-N (6R)-1-[2-(tert-butylamino)ethyl]-2-methyl-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(=CC=C(C(=C1F)[C@H]1CC2=C(CCNC(C)(C)C)N(C(=S)N2C1)C)F)F WWJGSYURUWBJSV-NSHDSACASA-N 0.000 description 1
• XMEGOAGGMRRLSS-LBPRGKRZSA-N (6R)-2-methyl-1-(2-pyridin-3-ylethyl)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-thione Chemical compound CN1C(N2C(=C1CCC=1C=NC=CC=1)C[C@@H](C2)C1=C(C(=CC(=C1F)F)F)F)=S XMEGOAGGMRRLSS-LBPRGKRZSA-N 0.000 description 1
• OSMCUMJYOFNDID-LBPRGKRZSA-N (6R)-2-methyl-1-(2-pyrrolidin-1-ylethyl)-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(F)=C(F)C([C@H]2CC3=C(CCN4CCCC4)N(C(=S)N3C2)C)=C(F)C=C1 OSMCUMJYOFNDID-LBPRGKRZSA-N 0.000 description 1
• RDCRLGVVZFZVEY-LURJTMIESA-N (6R)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound Fc1ccc(F)c([C@H]2Cc3c[nH]c(=S)n3C2)c1F RDCRLGVVZFZVEY-LURJTMIESA-N 0.000 description 1
• LVLCGOPFTYYDBR-VXGBXAGGSA-N (6S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-1-[2-[[(3R)-oxolan-3-yl]amino]ethyl]-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-3-thione Chemical compound C1(=CC=C(C(=C1F)[C@@H]1CC2=C(CCN[C@H]3COCC3)N(C(=S)N2C1)C)F)Br LVLCGOPFTYYDBR-VXGBXAGGSA-N 0.000 description 1
• WUVLJUFYEDXPIW-GFCCVEGCSA-N (6S)-6-(3-chloro-2,6-difluorophenyl)-1-(2-pyridin-3-ylethyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazole-3-thione Chemical compound ClC=1C(=C(C(=CC=1)F)[C@@H]1CC=2N(C(NC=2CCC=2C=NC=CC=2)=S)C1)F WUVLJUFYEDXPIW-GFCCVEGCSA-N 0.000 description 1
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
• UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
• QUKGLNCXGVWCJX-UHFFFAOYSA-N 1,3,4-thiadiazol-2-amine Chemical compound NC1=NN=CS1 QUKGLNCXGVWCJX-UHFFFAOYSA-N 0.000 description 1
• MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 description 1
• DETYQMJKPNWRCC-UHFFFAOYSA-N 1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid Chemical compound OC(=O)N1CC2(CC2C1C=O)c1cc(F)cc(F)c1 DETYQMJKPNWRCC-UHFFFAOYSA-N 0.000 description 1
• VEDDWQBQTNDTAL-JTQLQIEISA-N 1-(4-methylpiperazin-1-yl)-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound CN1CCN(CC1)C(CC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F)=O VEDDWQBQTNDTAL-JTQLQIEISA-N 0.000 description 1
• GFOBYXFCJDAGHW-LBPRGKRZSA-N 1-(4-methylpiperidin-1-yl)-3-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound CC1CCN(CC1)C(CCC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F)=O GFOBYXFCJDAGHW-LBPRGKRZSA-N 0.000 description 1
• NIKVQXDRUGIOQN-HIFPTAJRSA-N 1-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound CC1(C2CN(CC12)C(CCC1=C2N(C(N1C)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F)=O)C NIKVQXDRUGIOQN-HIFPTAJRSA-N 0.000 description 1
• MRBDJIITORMKOQ-OOFVQCGSSA-N 1-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-phenylpropan-1-one Chemical compound [H][C@@]12C[C@@]1(CNC2C(=O)CCC1=CC=CC=C1)C1=CC(F)=CC=C1F MRBDJIITORMKOQ-OOFVQCGSSA-N 0.000 description 1
• SQNAGQVMBBKONT-LMEFHGLZSA-N 1-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-phenylpropan-1-one hydrochloride Chemical compound Cl.FC1=C(C=C(C=C1)F)[C@]12CNC([C@@H]2C1)C(CCC1=CC=CC=C1)=O SQNAGQVMBBKONT-LMEFHGLZSA-N 0.000 description 1
• PPKHYJXXUFCNPK-RYUDHWBXSA-N 1-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound C1(=CC=C(C(=C1F)[C@H]1CC2=C(CC(=O)N3CCC[C@H]3CF)N(C(=S)N2C1)C)F)F PPKHYJXXUFCNPK-RYUDHWBXSA-N 0.000 description 1
• XDWHUJSVQIYEBR-STQMWFEESA-N 1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]propan-1-one Chemical compound C1=C(F)C(F)=C([C@H]2CC3=C(CCC(=O)N4CCC[C@H]4CO)N(C(=S)N3C2)C)C(F)=C1 XDWHUJSVQIYEBR-STQMWFEESA-N 0.000 description 1
• UKZFLUNJJOVAGB-RYUDHWBXSA-N 1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CC(=O)N3CCC[C@H]3COC)N(C(=S)N2C1)C)F)F UKZFLUNJJOVAGB-RYUDHWBXSA-N 0.000 description 1
• YJKDJHODMAZALQ-STQMWFEESA-N 1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound COC[C@@H]1CCCN1C(=O)Cc1c2C[C@@H](Cn2c(=S)n1C)c1c(F)ccc(F)c1F YJKDJHODMAZALQ-STQMWFEESA-N 0.000 description 1
• UGUPNFIAZKKDJO-WDEREUQCSA-N 1-[(3R)-3-fluoropyrrolidin-1-yl]-2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound F[C@H]1CN(CC1)C(CC1=C2N(C(N1C)=S)C[C@H](C2)C1=C(C(=CC=C1F)F)F)=O UGUPNFIAZKKDJO-WDEREUQCSA-N 0.000 description 1
• LUDKPFHJMXZJER-CQSZACIVSA-N 1-[2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-sulfanylidene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]-N,N-dimethylpiperidine-4-carboxamide Chemical compound C1(Br)=C(F)C(=C(F)C=C1)[C@@H]1CC2=C(CC(=O)N3CCC(C(=O)N(C)C)CC3)N(C(=S)N2C1)C LUDKPFHJMXZJER-CQSZACIVSA-N 0.000 description 1
• HCEHZJVPJBWUCJ-ZGTCLIOFSA-N 1-[2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-2-methyl-3-sulfanylidene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]-N,N-dimethylpyrrolidine-3-carboxamide Chemical compound C1(=CC=C(C(=C1F)[C@@H]1CC2=C(CC(=O)N3CCC(C3)C(=O)N(C)C)N(C(=S)N2C1)C)F)Br HCEHZJVPJBWUCJ-ZGTCLIOFSA-N 0.000 description 1
• LAMMGYDETCDQIV-KIYNQFGBSA-N 1-[3-(fluoromethyl)pyrrolidin-1-yl]-2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,6-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound FCC1CN(CC1)C(CC1=C2N(C(N1C)=S)C[C@H](C2)C1=C(C(=CC=C1F)F)F)=O LAMMGYDETCDQIV-KIYNQFGBSA-N 0.000 description 1
• BAMVBKWFEZCUSB-JTQLQIEISA-N 1-methyl-4-[2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]piperazin-2-one Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC2=C(CC(=O)N3CC(=O)N(CC3)C)N(C(=S)N2C1)C)F)F BAMVBKWFEZCUSB-JTQLQIEISA-N 0.000 description 1
• WTPVUCAMLWKDDD-VIFPVBQESA-N 1-morpholin-4-yl-2-[(6R)-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]ethanone Chemical compound O1CCN(CC1)C(CC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C(=CC(=C1F)F)F)F)=O WTPVUCAMLWKDDD-VIFPVBQESA-N 0.000 description 1
• LFDGRWDETVOGDT-UHFFFAOYSA-N 1h-pyrrole;hydrochloride Chemical compound Cl.C=1C=CNC=1 LFDGRWDETVOGDT-UHFFFAOYSA-N 0.000 description 1
• UIMMFRUOZOWROM-UHFFFAOYSA-N 2-(2,5-difluorophenyl)acetonitrile Chemical compound FC1=CC=C(F)C(CC#N)=C1 UIMMFRUOZOWROM-UHFFFAOYSA-N 0.000 description 1
• LKVCOMLOKZEJQB-YCRPNKLZSA-N 2-[(2R,4S)-4-(5-bromo-2-fluorophenyl)-8-methyl-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-cyclopentylacetamide Chemical compound C1(=CC=C(C(=C1)[C@]12C[C@H]1C1=C(CC(=O)NC3CCCC3)N(C(=S)N1C2)C)F)Br LKVCOMLOKZEJQB-YCRPNKLZSA-N 0.000 description 1
• ADKYNWVMFVOPPN-KPZWWZAWSA-N 2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-1-imidazol-1-ylethanone Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3C=NC=C3)=S)C1)C2)F ADKYNWVMFVOPPN-KPZWWZAWSA-N 0.000 description 1
• NRGRASKAAFQOSK-KSFYIVLOSA-N 2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-8-methyl-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-cyclohexylacetamide Chemical compound ClC1=CC(=C(F)C=C1)[C@]12C[C@H]1C1=C(CC(=O)NC3CCCCC3)N(C(=S)N1C2)C NRGRASKAAFQOSK-KSFYIVLOSA-N 0.000 description 1
• DGNDCUHLFDODIM-YCRPNKLZSA-N 2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-8-methyl-7-sulfanylidene-6,8-diazatricyclo[4.3.0.02,4]non-1(9)-en-9-yl]-N-cyclopentylacetamide Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)NC3CCCC3)C)=S)C1)C2)F DGNDCUHLFDODIM-YCRPNKLZSA-N 0.000 description 1
• SVVXQBYRWINVRQ-JTQLQIEISA-N 2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-1-morpholin-4-ylethanone Chemical compound C1(=CC(=C(C(=C1F)[C@H]1CC2=C(CC(=O)N3CCOCC3)N(C(=S)N2C1)C)F)F)F SVVXQBYRWINVRQ-JTQLQIEISA-N 0.000 description 1
• OINIVAPICCIAQZ-JTQLQIEISA-N 2-[(6R)-6-(5-chloro-2-fluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@H](C2)C1=C(C=CC(=C1)Cl)F)=O OINIVAPICCIAQZ-JTQLQIEISA-N 0.000 description 1
• YJYAESYXKDGDBU-SNVBAGLBSA-N 2-[(6S)-6-(3-bromo-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-morpholin-4-ylethanone Chemical compound BrC1=C(F)C(=C(F)C=C1)[C@@H]1CC2=C(CC(=O)N3CCOCC3)NC(=S)N2C1 YJYAESYXKDGDBU-SNVBAGLBSA-N 0.000 description 1
• AVMMVHSJTYBQNY-SSDOTTSWSA-N 2-[(6S)-6-(3-chloro-2,6-difluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-N-methylacetamide Chemical compound ClC=1C(=C(C(=CC=1)F)[C@@H]1CC=2N(C(NC=2CC(=O)NC)=S)C1)F AVMMVHSJTYBQNY-SSDOTTSWSA-N 0.000 description 1
• OBRHRERYWLMUCI-SNVBAGLBSA-N 2-[(6S)-6-(5-bromo-2-fluorophenyl)-3-sulfanylidene-2,5,6,7-tetrahydropyrrolo[1,2-c]imidazol-1-yl]-1-imidazol-1-ylethanone Chemical compound N1(C=NC=C1)C(CC1=C2N(C(N1)=S)C[C@@H](C2)C1=C(C=CC(=C1)Br)F)=O OBRHRERYWLMUCI-SNVBAGLBSA-N 0.000 description 1
• XRWHJJIAVVNAMG-UHFFFAOYSA-N 2-aminocyclopentan-1-one;hydrochloride Chemical compound Cl.NC1CCCC1=O XRWHJJIAVVNAMG-UHFFFAOYSA-N 0.000 description 1
• YMHVHZXNGIWILD-NNVMMKAESA-N 2-methylsulfonyl-1-[(4S)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl]ethanone hydrochloride Chemical compound Cl.CS(=O)(=O)CC(=O)C1NC[C@@H](C1)C1=C(C(=CC(=C1F)F)F)F YMHVHZXNGIWILD-NNVMMKAESA-N 0.000 description 1
• WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
• ASOFZHSTJHGQDT-UHFFFAOYSA-N 3,5-difluorobenzaldehyde Chemical compound FC1=CC(F)=CC(C=O)=C1 ASOFZHSTJHGQDT-UHFFFAOYSA-N 0.000 description 1
• TVXFFKOKMNNZFO-WOPFXOFLSA-N 3-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanenitrile Chemical compound C1=C(F)C=C(C(F)=C1)[C@]12C[C@H]1C(C(=O)CC#N)NC2 TVXFFKOKMNNZFO-WOPFXOFLSA-N 0.000 description 1
• ARDTYRDIXYZFDY-DBBVZMLNSA-N 3-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanenitrile hydrochloride Chemical compound Cl.FC1=C(C=C(C=C1)F)[C@]12CNC([C@@H]2C1)C(CC#N)=O ARDTYRDIXYZFDY-DBBVZMLNSA-N 0.000 description 1
• BJHOPRALYSNEJC-WOPFXOFLSA-N 3-[(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanamide Chemical compound C1(F)=CC(=CC(F)=C1)[C@]12C[C@H]1C(C(=O)CC(=O)N)NC2 BJHOPRALYSNEJC-WOPFXOFLSA-N 0.000 description 1
• NBWRAFYLSXEMPK-DBBVZMLNSA-N 3-[(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanamide hydrochloride Chemical compound Cl.FC=1C=C(C=C(C=1)F)[C@]12CNC([C@@H]2C1)C(CC(=O)N)=O NBWRAFYLSXEMPK-DBBVZMLNSA-N 0.000 description 1
• HXWMUQDSVCLXQC-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonyl]-5-thiophen-2-yl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C(C2CC2(C1)C=1SC=CC=1)C(=O)O HXWMUQDSVCLXQC-UHFFFAOYSA-N 0.000 description 1
• YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
• MKLNTBLOABOJFZ-UHFFFAOYSA-N 3-aminooxolan-2-one;hydron;bromide Chemical compound Br.NC1CCOC1=O MKLNTBLOABOJFZ-UHFFFAOYSA-N 0.000 description 1
• QDLOLBJKQDOMTM-UHFFFAOYSA-N 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid Chemical compound OC(=O)C1C(CNC1=O)c1cc(F)cc(F)c1 QDLOLBJKQDOMTM-UHFFFAOYSA-N 0.000 description 1
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
• VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
• VJFMSYZSFUWQPZ-HNBPALPRSA-N 4-[(R)-[(4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-hydroxymethyl]quinolin-6-ol Chemical compound O[C@H](C1=CC=NC2=CC=C(C=C12)O)C1N2CC[C@@H](C1)[C@H](C2)C=C VJFMSYZSFUWQPZ-HNBPALPRSA-N 0.000 description 1
• CMWFEYPMRSKTJS-VIFPVBQESA-N 4-[2-[(6R)-2-methyl-3-sulfanylidene-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]acetyl]piperazin-2-one Chemical compound CN1C(N2C(=C1CC(=O)N1CC(NCC1)=O)C[C@@H](C2)C1=C(C(=CC(=C1F)F)F)F)=S CMWFEYPMRSKTJS-VIFPVBQESA-N 0.000 description 1
• XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000006164 6-membered heteroaryl group Chemical group 0.000 description 1
• UNQYAAAWKOOBFQ-UHFFFAOYSA-N 7-[(4-chlorophenyl)methyl]-8-[4-chloro-3-(trifluoromethoxy)phenoxy]-1-(3-hydroxypropyl)-3-methylpurine-2,6-dione Chemical compound C=1C=C(Cl)C=CC=1CN1C=2C(=O)N(CCCO)C(=O)N(C)C=2N=C1OC1=CC=C(Cl)C(OC(F)(F)F)=C1 UNQYAAAWKOOBFQ-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
• 206010002383 Angina Pectoris Diseases 0.000 description 1
• XNHBKJPVXXVCDU-VBKZILBWSA-N BrC1=CC(=C(F)C=C1)[C@]12[C@H](C3=C(CC(=O)N4CCNCC4)N(C(=S)N3C1)C)C2 Chemical compound BrC1=CC(=C(F)C=C1)[C@]12[C@H](C3=C(CC(=O)N4CCNCC4)N(C(=S)N3C1)C)C2 XNHBKJPVXXVCDU-VBKZILBWSA-N 0.000 description 1
• IVLLNEKVSAQYGY-VBKZILBWSA-N BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCC3)C)=S)C1)C2)F Chemical compound BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCC3)C)=S)C1)C2)F IVLLNEKVSAQYGY-VBKZILBWSA-N 0.000 description 1
• BNWUOFDNQQCOQM-YCRPNKLZSA-N BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCCC3)C)=S)C1)C2)F Chemical compound BrC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCCC3)C)=S)C1)C2)F BNWUOFDNQQCOQM-YCRPNKLZSA-N 0.000 description 1
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
• 229910000906 Bronze Inorganic materials 0.000 description 1
• UYYVNLGLQAWNRV-ORAYPTAESA-N C1=C(Br)C=C(C(F)=C1)[C@]12C[C@H]1C1=C(CC(=O)NC3CCC3)NC(=S)N1C2 Chemical compound C1=C(Br)C=C(C(F)=C1)[C@]12C[C@H]1C1=C(CC(=O)NC3CCC3)NC(=S)N1C2 UYYVNLGLQAWNRV-ORAYPTAESA-N 0.000 description 1
• YFJMZEVXIXSWFO-QHGLUPRGSA-N C1=C(C(=C(C(=C1F)F)[C@H]1CC(C(=O)CN2CCOCC2)NC1)F)F Chemical compound C1=C(C(=C(C(=C1F)F)[C@H]1CC(C(=O)CN2CCOCC2)NC1)F)F YFJMZEVXIXSWFO-QHGLUPRGSA-N 0.000 description 1
• KHFAQXNAPADCDT-KWKNKYSRSA-N C1=C(F)C=C(C=C1F)[C@@H]1CC(C(=O)CS(=O)C)NC1 Chemical compound C1=C(F)C=C(C=C1F)[C@@H]1CC(C(=O)CS(=O)C)NC1 KHFAQXNAPADCDT-KWKNKYSRSA-N 0.000 description 1
• OIKAGJJUYUUEGA-QNGGVGCWSA-N CN(Cc1ccccc1)C(=O)CC(=O)C1NC[C@]2(C[C@@H]12)c1cc(F)ccc1F Chemical compound CN(Cc1ccccc1)C(=O)CC(=O)C1NC[C@]2(C[C@@H]12)c1cc(F)ccc1F OIKAGJJUYUUEGA-QNGGVGCWSA-N 0.000 description 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
• 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 1
• GHBOFBJZTOFWST-JWXACMMISA-N Cl.CS(=O)CC(=O)C1C[C@H](CN1)c1cc(F)cc(F)c1 Chemical compound Cl.CS(=O)CC(=O)C1C[C@H](CN1)c1cc(F)cc(F)c1 GHBOFBJZTOFWST-JWXACMMISA-N 0.000 description 1
• YCYCEGKLBGMLAC-PLOVBFIDSA-N Cl.FC=1C=C(C=C(C=1)F)[C@]12CNC([C@@H]2C1)C(C(=O)OCC)(O)O Chemical compound Cl.FC=1C=C(C=C(C=1)F)[C@]12CNC([C@@H]2C1)C(C(=O)OCC)(O)O YCYCEGKLBGMLAC-PLOVBFIDSA-N 0.000 description 1
• DVIIXOXWFPTUJE-DJDUHJHYSA-N Cl.Fc1cc(F)cc(c1)[C@H]1CNC(C1)C(=O)CC(=O)N1CCOCC1 Chemical compound Cl.Fc1cc(F)cc(c1)[C@H]1CNC(C1)C(=O)CC(=O)N1CCOCC1 DVIIXOXWFPTUJE-DJDUHJHYSA-N 0.000 description 1
• CGWQQBGYCIQPFB-VBKZILBWSA-N ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCC3)C)=S)C1)C2)F Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCC3)C)=S)C1)C2)F CGWQQBGYCIQPFB-VBKZILBWSA-N 0.000 description 1
• ZBAMNQOMPHXAQA-YCRPNKLZSA-N ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCCC3)C)=S)C1)C2)F Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCCCC3)C)=S)C1)C2)F ZBAMNQOMPHXAQA-YCRPNKLZSA-N 0.000 description 1
• WVNAKQVEPCRTCT-YCRPNKLZSA-N ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCN(CC3)C)C)=S)C1)C2)F Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(N(C=3CC(=O)N3CCN(CC3)C)C)=S)C1)C2)F WVNAKQVEPCRTCT-YCRPNKLZSA-N 0.000 description 1
• KRPSGOCFWNIQJD-VBKZILBWSA-N ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3CCCCC3)=S)C1)C2)F Chemical compound ClC=1C=CC(=C(C=1)[C@]12[C@H](C=3N(C(NC=3CC(=O)N3CCCCC3)=S)C1)C2)F KRPSGOCFWNIQJD-VBKZILBWSA-N 0.000 description 1
• MRJWUHYEZQURKE-VBKZILBWSA-N Cn1c(CC(=O)N2CCNCC2)c2[C@@H]3C[C@@]3(Cn2c1=S)c1cc(Cl)ccc1F Chemical compound Cn1c(CC(=O)N2CCNCC2)c2[C@@H]3C[C@@]3(Cn2c1=S)c1cc(Cl)ccc1F MRJWUHYEZQURKE-VBKZILBWSA-N 0.000 description 1
• 206010010356 Congenital anomaly Diseases 0.000 description 1
• XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
• 206010011703 Cyanosis Diseases 0.000 description 1
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
• SGCTWYZILNQVIR-KEKZHRQWSA-N FC1=CC(=CC(F)=C1)[C@@H]1CC(C(=O)CC(=O)N2CCOCC2)NC1 Chemical compound FC1=CC(=CC(F)=C1)[C@@H]1CC(C(=O)CC(=O)N2CCOCC2)NC1 SGCTWYZILNQVIR-KEKZHRQWSA-N 0.000 description 1
• QBLNGTDDICVLKQ-SSDOTTSWSA-N FC=1C=C(C=C(C=1)F)[C@@H]1CC(NC1)=O Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC(NC1)=O QBLNGTDDICVLKQ-SSDOTTSWSA-N 0.000 description 1
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
• 208000015872 Gaucher disease Diseases 0.000 description 1
• 208000031886 HIV Infections Diseases 0.000 description 1
• 208000037357 HIV infectious disease Diseases 0.000 description 1
• XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
• 208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 description 1
• 208000021124 Heritable pulmonary arterial hypertension Diseases 0.000 description 1
• 206010021133 Hypoventilation Diseases 0.000 description 1
• 206010021143 Hypoxia Diseases 0.000 description 1
• 208000024934 IgG4-related mediastinitis Diseases 0.000 description 1
• 208000029523 Interstitial Lung disease Diseases 0.000 description 1
• 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
• 208000008771 Lymphadenopathy Diseases 0.000 description 1
• 206010025219 Lymphangioma Diseases 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
• NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
• FEYNFHSRETUBEM-UHFFFAOYSA-N N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide Chemical compound COc1ccc(cc1)N1N=C(C)C(C(=O)Nc2cccc(c2)C(C)(F)F)C1=O FEYNFHSRETUBEM-UHFFFAOYSA-N 0.000 description 1
• VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 1
• 206010028851 Necrosis Diseases 0.000 description 1
• YTIXDLLEUKQMKT-UHFFFAOYSA-N OC(=O)N1CC(CC1C=O)c1cc(F)cc(F)c1 Chemical compound OC(=O)N1CC(CC1C=O)c1cc(F)cc(F)c1 YTIXDLLEUKQMKT-UHFFFAOYSA-N 0.000 description 1
• 206010030113 Oedema Diseases 0.000 description 1
• 206010033557 Palpitations Diseases 0.000 description 1
• 208000010378 Pulmonary Embolism Diseases 0.000 description 1
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
• 208000024799 Thyroid disease Diseases 0.000 description 1
• 208000033774 Ventricular Remodeling Diseases 0.000 description 1
• 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
• JHUYNQGHNWXETM-UHFFFAOYSA-M [Br-].[Mg+]CCCC1=CC=CC=C1 Chemical compound [Br-].[Mg+]CCCC1=CC=CC=C1 JHUYNQGHNWXETM-UHFFFAOYSA-M 0.000 description 1
• SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
• CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
• 230000004913 activation Effects 0.000 description 1
• 208000013228 adenopathy Diseases 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 description 1
• AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
• 230000001668 ameliorated effect Effects 0.000 description 1
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
• 235000019270 ammonium chloride Nutrition 0.000 description 1
• 210000003423 ankle Anatomy 0.000 description 1
• 230000006793 arrhythmia Effects 0.000 description 1
• 230000004872 arterial blood pressure Effects 0.000 description 1
• 125000003118 aryl group Chemical group 0.000 description 1
• 230000001746 atrial effect Effects 0.000 description 1
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• 125000003943 azolyl group Chemical group 0.000 description 1
• 230000008901 benefit Effects 0.000 description 1
• 210000004556 brain Anatomy 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• 229910052794 bromium Inorganic materials 0.000 description 1
• 239000010974 bronze Substances 0.000 description 1
• 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
• 230000000747 cardiac effect Effects 0.000 description 1
• 239000003054 catalyst Substances 0.000 description 1
• DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
• 239000003153 chemical reaction reagent Substances 0.000 description 1
• 239000000460 chlorine Substances 0.000 description 1
• 229910052801 chlorine Inorganic materials 0.000 description 1
• 238000007906 compression Methods 0.000 description 1
• 230000006835 compression Effects 0.000 description 1
• 208000018631 connective tissue disease Diseases 0.000 description 1
• KUNSUQLRTQLHQQ-UHFFFAOYSA-N copper tin Chemical compound [Cu].[Sn] KUNSUQLRTQLHQQ-UHFFFAOYSA-N 0.000 description 1
• 230000008878 coupling Effects 0.000 description 1
• 238000010168 coupling process Methods 0.000 description 1
• 238000005859 coupling reaction Methods 0.000 description 1
• 239000013058 crude material Substances 0.000 description 1
• 238000009109 curative therapy Methods 0.000 description 1
• 125000004122 cyclic group Chemical group 0.000 description 1
• NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
• 230000034994 death Effects 0.000 description 1
• 230000007423 decrease Effects 0.000 description 1
• 230000001419 dependent effect Effects 0.000 description 1
• 238000011161 development Methods 0.000 description 1
• 230000009547 development abnormality Effects 0.000 description 1
• 238000003745 diagnosis Methods 0.000 description 1
• 238000010586 diagram Methods 0.000 description 1
• JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
• ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
• NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
• SHVSZVYCTKMFRK-UHFFFAOYSA-N diethyl propanedioate;hydrochloride Chemical compound Cl.CCOC(=O)CC(=O)OCC SHVSZVYCTKMFRK-UHFFFAOYSA-N 0.000 description 1
• 229940116901 diethyldithiocarbamate Drugs 0.000 description 1
• LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 1
• 125000004212 difluorophenyl group Chemical group 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
• 125000000532 dioxanyl group Chemical group 0.000 description 1
• 125000005879 dioxolanyl group Chemical group 0.000 description 1
• HCDITHVDEPPNIL-UHFFFAOYSA-L dipotassium;propanedioate Chemical compound [K+].[K+].[O-]C(=O)CC([O-])=O HCDITHVDEPPNIL-UHFFFAOYSA-L 0.000 description 1
• 238000009826 distribution Methods 0.000 description 1
• 229960002563 disulfiram Drugs 0.000 description 1
• 125000005883 dithianyl group Chemical group 0.000 description 1
• 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
• 208000002173 dizziness Diseases 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 230000003828 downregulation Effects 0.000 description 1
• 230000003073 embolic effect Effects 0.000 description 1
• 230000002255 enzymatic effect Effects 0.000 description 1
• YKWNUSJLICDQEO-UHFFFAOYSA-N ethoxyethane;propan-2-ol Chemical compound CC(C)O.CCOCC YKWNUSJLICDQEO-UHFFFAOYSA-N 0.000 description 1
• GCJBUAGBDRHNEP-NFJWQWPMSA-N ethyl (4S)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1C(C(NC1)=O)C(=O)OCC GCJBUAGBDRHNEP-NFJWQWPMSA-N 0.000 description 1
• JZHUOWXHIONLEJ-PKEIRNPWSA-N ethyl 2-[(4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1C[C@H](CN1)c1cc(F)cc(F)c1 JZHUOWXHIONLEJ-PKEIRNPWSA-N 0.000 description 1
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
• 125000004494 ethyl ester group Chemical group 0.000 description 1
• DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
• 239000012065 filter cake Substances 0.000 description 1
• 125000001207 fluorophenyl group Chemical group 0.000 description 1
• 235000019253 formic acid Nutrition 0.000 description 1
• 238000009472 formulation Methods 0.000 description 1
• 229960002449 glycine Drugs 0.000 description 1
• 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
• 208000007345 glycogen storage disease Diseases 0.000 description 1
• 238000000227 grinding Methods 0.000 description 1
• 208000035474 group of disease Diseases 0.000 description 1
• 208000018578 heart valve disease Diseases 0.000 description 1
• 208000034737 hemoglobinopathy Diseases 0.000 description 1
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
• 150000004677 hydrates Chemical class 0.000 description 1
• 150000002430 hydrocarbons Chemical class 0.000 description 1
• USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
• 208000018875 hypoxemia Diseases 0.000 description 1
• XBECWGJPSXHFCS-UHFFFAOYSA-N imidazole-1-carbaldehyde Chemical compound O=CN1C=CN=C1 XBECWGJPSXHFCS-UHFFFAOYSA-N 0.000 description 1
• 125000002883 imidazolyl group Chemical group 0.000 description 1
• 239000004615 ingredient Substances 0.000 description 1
• 208000018337 inherited hemoglobinopathy Diseases 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
• 229940011051 isopropyl acetate Drugs 0.000 description 1
• 125000001786 isothiazolyl group Chemical group 0.000 description 1
• GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
• 125000000842 isoxazolyl group Chemical group 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 239000012280 lithium aluminium hydride Substances 0.000 description 1
• 230000007774 longterm Effects 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
• 229910001623 magnesium bromide Inorganic materials 0.000 description 1
• JGZKUKYUQJUUNE-UHFFFAOYSA-L magnesium;ethoxyethane;dibromide Chemical compound [Mg+2].[Br-].[Br-].CCOCC JGZKUKYUQJUUNE-UHFFFAOYSA-L 0.000 description 1
• DHZDXXLCWXHNOB-UHFFFAOYSA-M magnesium;ethylbenzene;bromide Chemical compound [Mg+2].[Br-].[CH2-]CC1=CC=CC=C1 DHZDXXLCWXHNOB-UHFFFAOYSA-M 0.000 description 1
• 239000003550 marker Substances 0.000 description 1
• 235000012054 meals Nutrition 0.000 description 1
• 230000007246 mechanism Effects 0.000 description 1
• GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
• LPONOOWGKUXHAL-KCVIPRPTSA-N methyl 3-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanoate Chemical compound [H][C@@]12C[C@@]1(CNC2C(=O)CC(=O)OC)C1=CC(F)=CC=C1F LPONOOWGKUXHAL-KCVIPRPTSA-N 0.000 description 1
• IAXWJGMNRYAPSN-KVYIEZFASA-N methyl 3-[(1R,5S)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl]-3-oxopropanoate hydrochloride Chemical compound Cl.COC(CC(=O)C1[C@@H]2C[C@@]2(CN1)C1=C(C=CC(=C1)F)F)=O IAXWJGMNRYAPSN-KVYIEZFASA-N 0.000 description 1
• 239000002480 mineral oil Substances 0.000 description 1
• 235000010446 mineral oil Nutrition 0.000 description 1
• 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
• 230000002107 myocardial effect Effects 0.000 description 1
• ITPOTYPCMARYOB-UHFFFAOYSA-N n-(2-pyridin-2-ylethyl)acetamide Chemical compound CC(=O)NCCC1=CC=CC=N1 ITPOTYPCMARYOB-UHFFFAOYSA-N 0.000 description 1
• FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 1
• VFBILHPIHUPBPZ-UHFFFAOYSA-N n-[[2-[4-(difluoromethoxy)-3-propan-2-yloxyphenyl]-1,3-oxazol-4-yl]methyl]-2-ethoxybenzamide Chemical compound CCOC1=CC=CC=C1C(=O)NCC1=COC(C=2C=C(OC(C)C)C(OC(F)F)=CC=2)=N1 VFBILHPIHUPBPZ-UHFFFAOYSA-N 0.000 description 1
• DOWVMJFBDGWVML-UHFFFAOYSA-N n-cyclohexyl-n-methyl-4-(1-oxidopyridin-1-ium-3-yl)imidazole-1-carboxamide Chemical compound C1=NC(C=2C=[N+]([O-])C=CC=2)=CN1C(=O)N(C)C1CCCCC1 DOWVMJFBDGWVML-UHFFFAOYSA-N 0.000 description 1
• NNKPHNTWNILINE-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxopyrazin-1-yl]benzamide Chemical compound CNCCOC1=CC=CC=C1C1(NC=2C(N(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=CN=2)=O)CC1 NNKPHNTWNILINE-UHFFFAOYSA-N 0.000 description 1
• RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
• XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
• 230000017074 necrotic cell death Effects 0.000 description 1
• 210000005036 nerve Anatomy 0.000 description 1
• LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
• 229960003966 nicotinamide Drugs 0.000 description 1
• 235000005152 nicotinamide Nutrition 0.000 description 1
• 239000011570 nicotinamide Substances 0.000 description 1
• LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 125000001715 oxadiazolyl group Chemical group 0.000 description 1
• DGOYLVBDCVINQZ-UHFFFAOYSA-N oxane-4-carboxamide Chemical compound NC(=O)C1CCOCC1 DGOYLVBDCVINQZ-UHFFFAOYSA-N 0.000 description 1
• 125000002971 oxazolyl group Chemical group 0.000 description 1
• AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
• 125000004430 oxygen atom Chemical group O* 0.000 description 1
• 230000020477 pH reduction Effects 0.000 description 1
• 244000045947 parasite Species 0.000 description 1
• 230000007170 pathology Effects 0.000 description 1
• 210000001428 peripheral nervous system Anatomy 0.000 description 1
• 208000004594 persistent fetal circulation syndrome Diseases 0.000 description 1
• 208000007232 portal hypertension Diseases 0.000 description 1
• LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
• 229910000027 potassium carbonate Inorganic materials 0.000 description 1
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
• WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 1
• 230000002028 premature Effects 0.000 description 1
• 230000003449 preventive effect Effects 0.000 description 1
• 238000004393 prognosis Methods 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• 230000036593 pulmonary vascular resistance Effects 0.000 description 1
• 238000000746 purification Methods 0.000 description 1
• 125000003373 pyrazinyl group Chemical group 0.000 description 1
• 125000003226 pyrazolyl group Chemical group 0.000 description 1
• 125000002098 pyridazinyl group Chemical group 0.000 description 1
• QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
• 125000000714 pyrimidinyl group Chemical group 0.000 description 1
• 125000000168 pyrrolyl group Chemical group 0.000 description 1
• 230000009467 reduction Effects 0.000 description 1
• 230000000241 respiratory effect Effects 0.000 description 1
• 238000012552 review Methods 0.000 description 1
• 201000000306 sarcoidosis Diseases 0.000 description 1
• 208000013220 shortness of breath Diseases 0.000 description 1
• 208000019116 sleep disease Diseases 0.000 description 1
• 208000020685 sleep-wake disease Diseases 0.000 description 1
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
• 238000010911 splenectomy Methods 0.000 description 1
• 239000000758 substrate Substances 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 230000008961 swelling Effects 0.000 description 1
• 206010042772 syncope Diseases 0.000 description 1
• HUZXENNYKIFAKL-YMNIQAILSA-N tert-butyl (4R)-2-(2-bromoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate Chemical compound BrCC(=O)C1N(C[C@H](C1)C1=C(C(=CC(=C1F)F)F)F)C(=O)OC(C)(C)C HUZXENNYKIFAKL-YMNIQAILSA-N 0.000 description 1
• IHKMBVDYBORZSF-YMNIQAILSA-N tert-butyl (4R)-2-(2-diazoacetyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate Chemical compound [N+](=[N-])=CC(=O)C1N(C[C@H](C1)C1=C(C(=CC(=C1F)F)F)F)C(=O)OC(C)(C)C IHKMBVDYBORZSF-YMNIQAILSA-N 0.000 description 1
• KCHSIDJMIUSGGI-ZGTOLYCTSA-N tert-butyl (4S)-4-(2,5-difluorophenyl)-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1CC(N(C1)C(=O)OC(C)(C)C)C(CC(=O)OCC)=O KCHSIDJMIUSGGI-ZGTOLYCTSA-N 0.000 description 1
• ZDBRMHHNVWQHIS-YNODCEANSA-N tert-butyl (4S)-4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](CC1C=O)c1cc(F)cc(F)c1 ZDBRMHHNVWQHIS-YNODCEANSA-N 0.000 description 1
• OAFYNQMZLMOEQG-VUUHIHSGSA-N tert-butyl (4S)-4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC(N(C1)C(=O)OC(C)(C)C)O OAFYNQMZLMOEQG-VUUHIHSGSA-N 0.000 description 1
• GQSKZYIGXYODHM-UHFFFAOYSA-N tert-butyl 2-ethylpentanoate Chemical compound CCCC(CC)C(=O)OC(C)(C)C GQSKZYIGXYODHM-UHFFFAOYSA-N 0.000 description 1
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
• 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
• 125000003831 tetrazolyl group Chemical group 0.000 description 1
• 125000001113 thiadiazolyl group Chemical group 0.000 description 1
• 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
• 125000000335 thiazolyl group Chemical group 0.000 description 1
• 150000003585 thioureas Chemical class 0.000 description 1
• 230000001732 thrombotic effect Effects 0.000 description 1
• 231100000331 toxic Toxicity 0.000 description 1
• 230000002588 toxic effect Effects 0.000 description 1
• 239000003053 toxin Substances 0.000 description 1
• 231100000765 toxin Toxicity 0.000 description 1
• 108700012359 toxins Proteins 0.000 description 1
• 125000004306 triazinyl group Chemical group 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
• 230000002861 ventricular Effects 0.000 description 1
• 239000003039 volatile agent Substances 0.000 description 1
• 210000000707 wrist Anatomy 0.000 description 1