JPWO2021222858A5 - - Google Patents
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- JPWO2021222858A5 JPWO2021222858A5 JP2022566301A JP2022566301A JPWO2021222858A5 JP WO2021222858 A5 JPWO2021222858 A5 JP WO2021222858A5 JP 2022566301 A JP2022566301 A JP 2022566301A JP 2022566301 A JP2022566301 A JP 2022566301A JP WO2021222858 A5 JPWO2021222858 A5 JP WO2021222858A5
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- JP
- Japan
- Prior art keywords
- alkyl
- compound
- phenyl
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 claims description 716
- 238000002360 preparation method Methods 0.000 claims description 306
- -1 -CF 3 Chemical group 0.000 claims description 247
- 239000000203 mixture Substances 0.000 claims description 202
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 128
- 150000003839 salts Chemical class 0.000 claims description 97
- 229910052736 halogen Inorganic materials 0.000 claims description 62
- 150000002367 halogens Chemical class 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 125000001424 substituent group Chemical group 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 101001009541 Homo sapiens G-protein coupled receptor 39 Proteins 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 102100030280 G-protein coupled receptor 39 Human genes 0.000 claims description 36
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 206010020772 Hypertension Diseases 0.000 claims description 20
- 125000006413 ring segment Chemical group 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 230000002708 enhancing effect Effects 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 208000025865 Ulcer Diseases 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- 102000000591 Tight Junction Proteins Human genes 0.000 claims description 4
- 108010002321 Tight Junction Proteins Proteins 0.000 claims description 4
- 125000003725 azepanyl group Chemical group 0.000 claims description 4
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 210000001578 tight junction Anatomy 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 230000004888 barrier function Effects 0.000 claims description 3
- 230000000112 colonic effect Effects 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003193 general anesthetic agent Substances 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 238000012384 transportation and delivery Methods 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 333
- 238000003786 synthesis reaction Methods 0.000 description 330
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 286
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 242
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 164
- 238000006243 chemical reaction Methods 0.000 description 142
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000005160 1H NMR spectroscopy Methods 0.000 description 121
- 239000000047 product Substances 0.000 description 114
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 101
- 239000000243 solution Substances 0.000 description 99
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 96
- 238000005481 NMR spectroscopy Methods 0.000 description 90
- 238000000034 method Methods 0.000 description 73
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 68
- 239000011541 reaction mixture Substances 0.000 description 65
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 64
- 239000012267 brine Substances 0.000 description 63
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 229910001868 water Inorganic materials 0.000 description 61
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 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 34
- 235000019253 formic acid Nutrition 0.000 description 34
- 239000013078 crystal Substances 0.000 description 33
- 239000011734 sodium Substances 0.000 description 33
- 235000017557 sodium bicarbonate Nutrition 0.000 description 32
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 239000007832 Na2SO4 Substances 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 28
- 235000011152 sodium sulphate Nutrition 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- 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 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000007821 HATU Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 238000007920 subcutaneous administration Methods 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000005406 washing Methods 0.000 description 17
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 16
- 239000000463 material Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- CFOSWOHHDVSXCR-UHFFFAOYSA-N n-[3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl]cyclopropanecarboxamide Chemical compound C1CC1C(=O)NC(C=C1N2CCCCCC2)=CC=C1C(=O)N1CCCCC1 CFOSWOHHDVSXCR-UHFFFAOYSA-N 0.000 description 14
- 230000002378 acidificating effect Effects 0.000 description 13
- 238000010828 elution Methods 0.000 description 13
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 13
- 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 12
- 241000699670 Mus sp. Species 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 230000036772 blood pressure Effects 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 230000000155 isotopic effect Effects 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- IRMBVBDXXYXPEW-UHFFFAOYSA-N 1-methyl-3-phenylpiperazine Chemical compound C1N(C)CCNC1C1=CC=CC=C1 IRMBVBDXXYXPEW-UHFFFAOYSA-N 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 150000003857 carboxamides Chemical class 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WJXYUEOVOQGJGV-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2CC21 WJXYUEOVOQGJGV-UHFFFAOYSA-N 0.000 description 9
- JSLZVOHJJVVYMP-UHFFFAOYSA-N 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid Chemical compound OC(C(C=CC(NC(C1CC1)=O)=C1)=C1N1CCCC1)=O JSLZVOHJJVVYMP-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 241000282412 Homo Species 0.000 description 9
- CASFZFNWKPATAU-UHFFFAOYSA-N N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide Chemical compound O=C(C1CC1)NC(C=C1)=CC(N2CCCCCC2)=C1C(N(CCNC1)C1C1=CC=CS1)=O CASFZFNWKPATAU-UHFFFAOYSA-N 0.000 description 9
- JLBKDWJZLAMRDR-UHFFFAOYSA-N N-[3-(azepan-1-yl)-4-[4-(1,2-oxazol-3-ylmethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide Chemical compound O=C(C1CC1)NC(C=C1)=CC(N2CCCCCC2)=C1C(N1CCN(CC2=NOC=C2)CC1)=O JLBKDWJZLAMRDR-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- 238000011894 semi-preparative HPLC Methods 0.000 description 9
- CFBUTNFXRFULBP-UHFFFAOYSA-N tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCNC1C1=CC=C(F)C=C1 CFBUTNFXRFULBP-UHFFFAOYSA-N 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- YTPQLWVHCBATKO-UHFFFAOYSA-N 1-propylpiperazine;dihydrobromide Chemical compound Br.Br.CCCN1CCNCC1 YTPQLWVHCBATKO-UHFFFAOYSA-N 0.000 description 8
- BFVCDPJJFUPNAQ-UHFFFAOYSA-N 2-thiophen-2-ylpiperazine Chemical compound C1NCCNC1C1=CC=CS1 BFVCDPJJFUPNAQ-UHFFFAOYSA-N 0.000 description 8
- HMXLFEQWPFPEEX-UHFFFAOYSA-N 3-propan-2-ylpyrrolidine;hydrochloride Chemical compound Cl.CC(C)C1CCNC1 HMXLFEQWPFPEEX-UHFFFAOYSA-N 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- AYUDZYWOGMAMOR-UHFFFAOYSA-N CC(CC(C)C1)CN1C(C=C(C=C1)N)=C1C(OC)=O Chemical compound CC(CC(C)C1)CN1C(C=C(C=C1)N)=C1C(OC)=O AYUDZYWOGMAMOR-UHFFFAOYSA-N 0.000 description 8
- DVEINEMEAYTTCR-UHFFFAOYSA-N N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide Chemical compound CCCN(CC1)CCN1C(C(C=CC(NC(C1CC1)=O)=C1)=C1Br)=O DVEINEMEAYTTCR-UHFFFAOYSA-N 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 229950011148 cyclopropane Drugs 0.000 description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- WLVKIYAGOIQBBX-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(C=C2)=CC=C2F)N1C(C(C=CC(NC(C1CC1)=O)=C1)=C1N1CCCC1)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(C=C2)=CC=C2F)N1C(C(C=CC(NC(C1CC1)=O)=C1)=C1N1CCCC1)=O)=O WLVKIYAGOIQBBX-UHFFFAOYSA-N 0.000 description 7
- ZILHLXYAAOZDSF-UHFFFAOYSA-N CC(CC(C)C1)CN1C(C=C(C=C1)[N+]([O-])=O)=C1C(OC)=O Chemical compound CC(CC(C)C1)CN1C(C=C(C=C1)[N+]([O-])=O)=C1C(OC)=O ZILHLXYAAOZDSF-UHFFFAOYSA-N 0.000 description 7
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- KVKQGAFQQHJUSF-UHFFFAOYSA-N O=C(C1CC1)NC(C=C1)=CC(N2CCCC2)=C1C(N(CCNC1)C1C(C=CC=C1)=C1F)=O Chemical compound O=C(C1CC1)NC(C=C1)=CC(N2CCCC2)=C1C(N(CCNC1)C1C(C=CC=C1)=C1F)=O KVKQGAFQQHJUSF-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000004088 microvessel Anatomy 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- BNDYLIJOOZNIHE-UHFFFAOYSA-N 2-thiophen-2-ylpyrazine Chemical compound C1=CSC(C=2N=CC=NC=2)=C1 BNDYLIJOOZNIHE-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 6
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- LJLSDTNXERYHDT-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(C=CC=C2)=C2F)N1C(C(C=CC(NC(C1CC1)=O)=C1)=C1N1CCCC1)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(C=CC=C2)=C2F)N1C(C(C=CC(NC(C1CC1)=O)=C1)=C1N1CCCC1)=O)=O LJLSDTNXERYHDT-UHFFFAOYSA-N 0.000 description 6
- CAFZYKVSKYVDSH-UHFFFAOYSA-N CC(CC(C)C1)CN1C(C=C(C=C1)NC(C2CC2)=O)=C1C(OC)=O Chemical compound CC(CC(C)C1)CN1C(C=C(C=C1)NC(C2CC2)=O)=C1C(OC)=O CAFZYKVSKYVDSH-UHFFFAOYSA-N 0.000 description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
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