RU2712621C2 - Азотсодержащие гетероциклические производные, полезные в качестве ингибитора калликреина плазмы - Google Patents

Info

Publication number

RU2712621C2

RU2712621C2 RU2015154987A RU2015154987A RU2712621C2 RU 2712621 C2 RU2712621 C2 RU 2712621C2 RU 2015154987 A RU2015154987 A RU 2015154987A RU 2015154987 A RU2015154987 A RU 2015154987A RU 2712621 C2 RU2712621 C2 RU 2712621C2

Authority

RU

Russia

Prior art keywords

ylmethyl

carboxylic acid

pyrazole

amide

aminoisoquinolin

Prior art date

2013-05-23

Links

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• 229940126155 plasma kallikrein inhibitor Drugs 0.000 title description 9
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 184
• 150000001875 compounds Chemical class 0.000 claims abstract description 164
• -1 ethylenedioxy Chemical group 0.000 claims abstract description 129
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 93
• 125000003118 aryl group Chemical group 0.000 claims abstract description 91
• 125000001424 substituent group Chemical group 0.000 claims abstract description 73
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 66
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 54
• 150000002367 halogens Chemical class 0.000 claims abstract description 54
• 108090000113 Plasma Kallikrein Proteins 0.000 claims abstract description 52
• 102000003827 Plasma Kallikrein Human genes 0.000 claims abstract description 51
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 47
• 238000000034 method Methods 0.000 claims abstract description 42
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 41
• 150000003839 salts Chemical class 0.000 claims abstract description 41
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 32
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 30
• 230000000694 effects Effects 0.000 claims abstract description 28
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 23
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 22
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 20
• 201000010099 disease Diseases 0.000 claims abstract description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 16
• LWDVTRXNUGVQES-UHFFFAOYSA-N 6-(aminomethyl)isoquinolin-1-amine Chemical compound NC1=NC=CC2=CC(CN)=CC=C21 LWDVTRXNUGVQES-UHFFFAOYSA-N 0.000 claims abstract description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 12
• 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 11
• 229930195733 hydrocarbon Natural products 0.000 claims abstract description 11
• 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 8
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 3
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 3
• 239000000203 mixture Substances 0.000 claims description 105
• 229910052801 chlorine Inorganic materials 0.000 claims description 34
• 125000004432 carbon atom Chemical group C* 0.000 claims description 23
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
• 238000011282 treatment Methods 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 17
• 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 16
• 201000011190 diabetic macular edema Diseases 0.000 claims description 16
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 15
• MVXVYAKCVDQRLW-UHFFFAOYSA-N azain Natural products C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 15
• 150000001408 amides Chemical class 0.000 claims description 14
• SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 13
• 150000005258 1H-pyrrolo(2,3-b)pyridines Chemical class 0.000 claims description 12
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 11
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 10
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 10
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 10
• 230000008728 vascular permeability Effects 0.000 claims description 10
• 206010012601 diabetes mellitus Diseases 0.000 claims description 9
• 208000028185 Angioedema Diseases 0.000 claims description 8
• 206010010356 Congenital anomaly Diseases 0.000 claims description 8
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 230000002207 retinal effect Effects 0.000 claims description 7
• 238000001356 surgical procedure Methods 0.000 claims description 7
• 150000002473 indoazoles Chemical class 0.000 claims description 6
• 150000002475 indoles Chemical class 0.000 claims description 6
• RAUIBWGXUJDXBK-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-ethyl-4-methyl-5-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]pyrrole-2-carboxamide Chemical compound CCN1C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=CC(C)=C1CC(C=C1)=CC=C1CN1C=CC=CC1=O RAUIBWGXUJDXBK-UHFFFAOYSA-N 0.000 claims description 6
• 229930195734 saturated hydrocarbon Natural products 0.000 claims description 6
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 5
• 208000020658 intracerebral hemorrhage Diseases 0.000 claims description 5
• SLRCFYCDNOSNHM-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(6-pyrrolidin-1-ylpyridin-3-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=N1)=CC=C1N1CCCC1 SLRCFYCDNOSNHM-UHFFFAOYSA-N 0.000 claims description 5
• BMLMQNFIWXYERL-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-ethyl-4-methyl-5-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]pyrrole-2-carboxamide Chemical compound CC=1C=C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)N(CC)C=1CC(C=C1)=CC=C1CN1C=C(C)C=N1 BMLMQNFIWXYERL-UHFFFAOYSA-N 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 5
• 208000032843 Hemorrhage Diseases 0.000 claims description 4
• 230000000740 bleeding effect Effects 0.000 claims description 4
• 239000008280 blood Substances 0.000 claims description 4
• 210000004369 blood Anatomy 0.000 claims description 4
• 230000002612 cardiopulmonary effect Effects 0.000 claims description 4
• 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 4
• XECHFZNCWDDSAE-UHFFFAOYSA-N N-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-ylmethyl)-1-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound FC(F)(F)c1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCC1CCCC2NNCC12 XECHFZNCWDDSAE-UHFFFAOYSA-N 0.000 claims description 3
• NVEZCZPWINYFRQ-UHFFFAOYSA-N N-(2,3,3a,4,5,6,7,7a-octahydro-1H-indazol-4-ylmethyl)-3-amino-1-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide Chemical compound Nc1nn(Cc2ccc(Cn3ccccc3=O)cc2)cc1C(=O)NCC1CCCC2NNCC12 NVEZCZPWINYFRQ-UHFFFAOYSA-N 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 3
• DAOSBZHACYXGLP-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(2-pyrrolidin-1-ylpyridin-4-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=1)=CC=NC=1N1CCCC1 DAOSBZHACYXGLP-UHFFFAOYSA-N 0.000 claims description 3
• AKRGGXIRZBHZIN-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(5-chloro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-3-cyclopropylpyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=C1Cl)=CN=C1N1CCCC1 AKRGGXIRZBHZIN-UHFFFAOYSA-N 0.000 claims description 3
• XCDBZZWRWFCHFE-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(5-fluoro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=C1F)=CN=C1N1CCCC1 XCDBZZWRWFCHFE-UHFFFAOYSA-N 0.000 claims description 3
• GGVYRGRBULRJBJ-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(6-ethoxy-5-fluoropyridin-3-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1=C(F)C(OCC)=NC=C1CN1N=C(C(F)(F)F)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 GGVYRGRBULRJBJ-UHFFFAOYSA-N 0.000 claims description 3
• GKPBRBZRCXWGEQ-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(6-ethoxypyridin-3-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1=NC(OCC)=CC=C1CN1N=C(C(F)(F)F)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 GKPBRBZRCXWGEQ-UHFFFAOYSA-N 0.000 claims description 3
• NTKGSHJOYRJNMU-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[2-(pyrazol-1-ylmethyl)-1,3-thiazol-4-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(N=1)=CSC=1CN1C=CC=N1 NTKGSHJOYRJNMU-UHFFFAOYSA-N 0.000 claims description 3
• NWLUWTWQKQUQDZ-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[4-[(4-carbamoylpyrazol-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1=C(C(=O)N)C=NN1CC(C=C1)=CC=C1CN1N=C(C(F)(F)F)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 NWLUWTWQKQUQDZ-UHFFFAOYSA-N 0.000 claims description 3
• ZSWFNMZXDBXLIE-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[4-[(4-cyanopyrazol-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=C1)=CC=C1CN1C=C(C#N)C=N1 ZSWFNMZXDBXLIE-UHFFFAOYSA-N 0.000 claims description 3
• HXLUIKPALDGUQR-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1=C(C)C=NN1CC(C=C1)=CC=C1CN1N=C(C(F)(F)F)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 HXLUIKPALDGUQR-UHFFFAOYSA-N 0.000 claims description 3
• LQCMCNVSZTUNJE-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[6-[3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=N1)=CC=C1N1CCC(CO)C1 LQCMCNVSZTUNJE-UHFFFAOYSA-N 0.000 claims description 3
• JPOJBUJCQDGKSB-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-cyclopropyl-1-[[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]methyl]pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=N1)=CC=C1N1CCC(F)(F)C1 JPOJBUJCQDGKSB-UHFFFAOYSA-N 0.000 claims description 3
• UAXGFNOVXFRLLA-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-4-methyl-2-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-1,3-thiazole-5-carboxamide Chemical compound C1=C(C)C=NN1CC(C=C1)=CC=C1CC1=NC(C)=C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)S1 UAXGFNOVXFRLLA-UHFFFAOYSA-N 0.000 claims description 3
• QIPKJJHSPMUFFY-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridin-5-ylmethanamine Chemical compound NCC1=CN=C2NC=CC2=C1 QIPKJJHSPMUFFY-UHFFFAOYSA-N 0.000 claims description 2
• 206010047571 Visual impairment Diseases 0.000 claims description 2
• 230000023555 blood coagulation Effects 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 230000001771 impaired effect Effects 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• PNKCTJJHKZQMAW-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[2-[(4-methylpyrazol-1-yl)methyl]-1,3-thiazol-4-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1=C(C)C=NN1CC1=NC(CN2N=C(C(C(=O)NCC=3C=C4C=CN=C(N)C4=CC=3)=C2)C(F)(F)F)=CS1 PNKCTJJHKZQMAW-UHFFFAOYSA-N 0.000 claims description 2
• 208000029257 vision disease Diseases 0.000 claims description 2
• 230000004304 visual acuity Effects 0.000 claims description 2
• 230000004393 visual impairment Effects 0.000 claims description 2
• XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims 2
• OWQPOVKKUWUEKE-UHFFFAOYSA-N 1,2,3-benzotriazine Chemical class N1=NN=CC2=CC=CC=C21 OWQPOVKKUWUEKE-UHFFFAOYSA-N 0.000 claims 1
• GDAXJBDYNVDMDF-UHFFFAOYSA-N 1,2,4-benzotriazine Chemical class N1=NC=NC2=CC=CC=C21 GDAXJBDYNVDMDF-UHFFFAOYSA-N 0.000 claims 1
• 150000005057 1,7-naphthyridines Chemical class 0.000 claims 1
• 150000005058 1,8-naphthyridines Chemical class 0.000 claims 1
• RXNOUICOGMOLSP-UHFFFAOYSA-N 1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-3-thiophen-3-ylpyrazole-4-carboxylic acid Chemical compound CC=1C=NN(C=1)CC1=CC=C(CN2N=C(C(=C2)C(=O)O)C2=CSC=C2)C=C1 RXNOUICOGMOLSP-UHFFFAOYSA-N 0.000 claims 1
• CYSBHVWWJOJGFG-UHFFFAOYSA-N 1-[[6-(pyrazol-1-ylmethyl)pyridin-3-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound OC(=O)c1cn(Cc2ccc(Cn3cccn3)nc2)nc1C(F)(F)F CYSBHVWWJOJGFG-UHFFFAOYSA-N 0.000 claims 1
• WQCOGVPGBAAMER-UHFFFAOYSA-N 6-(aminomethyl)isoquinolin-1-amine 1-[(6-propoxypyridin-3-yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxylic acid Chemical compound NCc1ccc2c(N)nccc2c1.CCCOc1ccc(Cn2cc(C(O)=O)c(n2)C(F)(F)F)cn1 WQCOGVPGBAAMER-UHFFFAOYSA-N 0.000 claims 1
• HXXRJXFBBAXPEU-UHFFFAOYSA-N CCOC1=CC=C(CN(C=C2C(O)=O)N=C2N)C=N1.NCC1=CC=C2C(N)=NC=CC2=C1 Chemical compound CCOC1=CC=C(CN(C=C2C(O)=O)N=C2N)C=N1.NCC1=CC=C2C(N)=NC=CC2=C1 HXXRJXFBBAXPEU-UHFFFAOYSA-N 0.000 claims 1
• XJQGNQVJHOCMPX-UHFFFAOYSA-N COC1=CC(=NC=C1CN2C(=C(C(=N2)C3CC3)C(=O)N)CC4=CC5=C(C=C4)C(=NC=C5)N)N6CCCC6 Chemical compound COC1=CC(=NC=C1CN2C(=C(C(=N2)C3CC3)C(=O)N)CC4=CC5=C(C=C4)C(=NC=C5)N)N6CCCC6 XJQGNQVJHOCMPX-UHFFFAOYSA-N 0.000 claims 1
• SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 1
• 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 claims 1
• 230000015271 coagulation Effects 0.000 claims 1
• 238000005345 coagulation Methods 0.000 claims 1
• 125000004122 cyclic group Chemical group 0.000 claims 1
• 125000001153 fluoro group Chemical group F* 0.000 claims 1
• 150000002537 isoquinolines Chemical class 0.000 claims 1
• QRXZKSAIEGYFFV-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide Chemical compound C1=C(C)C=NN1CC(C=C1)=CC=C1CN1N=C(C2=C(ON=C2C)C)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 QRXZKSAIEGYFFV-UHFFFAOYSA-N 0.000 claims 1
• LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims 1
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 claims 1
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• 239000000126 substance Substances 0.000 abstract description 11
• 230000004071 biological effect Effects 0.000 abstract description 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 3
• 239000011737 fluorine Substances 0.000 abstract description 3
• 150000002391 heterocyclic compounds Chemical class 0.000 abstract 2
• FFKVFWOGKQYLEU-UHFFFAOYSA-N 3-cyclopropyl-1-[(6-phenoxypyridin-3-yl)methyl]pyrazole-4-carboxylic acid Chemical compound OC(=O)c1cn(Cc2ccc(Oc3ccccc3)nc2)nc1C1CC1 FFKVFWOGKQYLEU-UHFFFAOYSA-N 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 272
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 183
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• 239000012267 brine Substances 0.000 description 70
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• 239000012044 organic layer Substances 0.000 description 46
• 238000005481 NMR spectroscopy Methods 0.000 description 44
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• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000004246 zinc acetate Substances 0.000 description 1
• 239000011592 zinc chloride Substances 0.000 description 1
• 235000005074 zinc chloride Nutrition 0.000 description 1