JP2010508362A

JP2010508362A - Ｃ型肝炎ウイルスの阻害剤

Ｃ型肝炎ウイルスの阻害剤 Download PDF

Info

Publication number: JP2010508362A
Authority: JP; Japan
Prior art keywords: alkyl; hcv; mmol; compound; tert
Prior art date: 2006-11-01
Legal status : Withdrawn

Application number

JP2009535436A

Other languages

English (en)

Japanese (ja)

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JP2010508362A5 (US07714131-20100511-C00001.png

Inventor

スタンリー・ダンドレア

ポール・マイケル・スコーラ

Current Assignee

Bristol Myers Squibb Co

Original Assignee

Bristol Myers Squibb Co

Priority date

2006-11-01

Filing date

2007-10-31

Publication date

2010-03-18

2007-10-31 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

2010-03-18 Publication of JP2010508362A publication Critical patent/JP2010508362A/ja

2010-10-28 Publication of JP2010508362A5 publication Critical patent/JP2010508362A5/ja

Status Withdrawn legal-status Critical Current

Links

241000711549 Hepacivirus C Species 0.000 title description 125
239000003112 inhibitor Substances 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 277
239000000203 mixture Substances 0.000 claims abstract description 147
238000000034 method Methods 0.000 claims abstract description 96
125000000217 alkyl group Chemical group 0.000 claims description 88
-1 hydroxy, amino Chemical group 0.000 claims description 69
125000003545 alkoxy group Chemical group 0.000 claims description 45
150000003839 salts Chemical class 0.000 claims description 45
230000000694 effects Effects 0.000 claims description 37
125000003118 aryl group Chemical group 0.000 claims description 32
125000005843 halogen group Chemical group 0.000 claims description 31
229920006395 saturated elastomer Polymers 0.000 claims description 29
125000000753 cycloalkyl group Chemical group 0.000 claims description 28
229910052739 hydrogen Inorganic materials 0.000 claims description 25
125000000623 heterocyclic group Chemical group 0.000 claims description 24
102000014150 Interferons Human genes 0.000 claims description 21
108010050904 Interferons Proteins 0.000 claims description 21
229940079322 interferon Drugs 0.000 claims description 21
238000011282 treatment Methods 0.000 claims description 21
208000015181 infectious disease Diseases 0.000 claims description 20
125000004093 cyano group Chemical group *C#N 0.000 claims description 17
239000001257 hydrogen Substances 0.000 claims description 17
229910052760 oxygen Inorganic materials 0.000 claims description 17
150000001412 amines Chemical class 0.000 claims description 16
125000002877 alkyl aryl group Chemical group 0.000 claims description 15
108010047761 Interferon-alpha Proteins 0.000 claims description 14
102000006992 Interferon-alpha Human genes 0.000 claims description 14
229910052717 sulfur Inorganic materials 0.000 claims description 14
239000003937 drug carrier Substances 0.000 claims description 13
125000005842 heteroatom Chemical group 0.000 claims description 13
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 12
125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 12
HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 12
229960000329 ribavirin Drugs 0.000 claims description 12
102000012479 Serine Proteases Human genes 0.000 claims description 11
108010022999 Serine Proteases Proteins 0.000 claims description 11
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 10
150000002431 hydrogen Chemical class 0.000 claims description 10
101800001019 Non-structural protein 4B Proteins 0.000 claims description 9
125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
108060004795 Methyltransferase Proteins 0.000 claims description 8
101800001014 Non-structural protein 5A Proteins 0.000 claims description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 claims description 7
108010006035 Metalloproteases Proteins 0.000 claims description 7
102000005741 Metalloproteases Human genes 0.000 claims description 7
125000003282 alkyl amino group Chemical group 0.000 claims description 7
125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 7
125000004001 thioalkyl group Chemical group 0.000 claims description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
125000001589 carboacyl group Chemical group 0.000 claims description 6
229910052799 carbon Inorganic materials 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 5
108020005544 Antisense RNA Proteins 0.000 claims description 5
102100040018 Interferon alpha-2 Human genes 0.000 claims description 5
108010079944 Interferon-alpha2b Proteins 0.000 claims description 5
102000013462 Interleukin-12 Human genes 0.000 claims description 5
108010065805 Interleukin-12 Proteins 0.000 claims description 5
102000000588 Interleukin-2 Human genes 0.000 claims description 5
108010002350 Interleukin-2 Proteins 0.000 claims description 5
102000004889 Interleukin-6 Human genes 0.000 claims description 5
108090001005 Interleukin-6 Proteins 0.000 claims description 5
230000005867 T cell response Effects 0.000 claims description 5
DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 5
229960003805 amantadine Drugs 0.000 claims description 5
239000003184 complementary RNA Substances 0.000 claims description 5
125000004663 dialkyl amino group Chemical group 0.000 claims description 5
210000002443 helper t lymphocyte Anatomy 0.000 claims description 5
DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 claims description 5
229960002751 imiquimod Drugs 0.000 claims description 5
230000002452 interceptive effect Effects 0.000 claims description 5
229940117681 interleukin-12 Drugs 0.000 claims description 5
229940100601 interleukin-6 Drugs 0.000 claims description 5
229960000888 rimantadine Drugs 0.000 claims description 5
125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 4
108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 4
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
GRSZFWQUAKGDAV-KQYNXXCUSA-N IMP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-KQYNXXCUSA-N 0.000 claims description 3
125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
229940124186 Dehydrogenase inhibitor Drugs 0.000 claims 2
PIEXCQIOSMOEOU-UHFFFAOYSA-N 1-bromo-3-chloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Br)C(=O)N(Cl)C1=O PIEXCQIOSMOEOU-UHFFFAOYSA-N 0.000 claims 1
108090000765 processed proteins & peptides Proteins 0.000 abstract description 15
102000004196 processed proteins & peptides Human genes 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 223
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 153
239000000243 solution Substances 0.000 description 150
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
238000005481 NMR spectroscopy Methods 0.000 description 134
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 130
239000000543 intermediate Substances 0.000 description 124
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
238000004949 mass spectrometry Methods 0.000 description 94
235000019439 ethyl acetate Nutrition 0.000 description 85
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 83
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 83
239000011541 reaction mixture Substances 0.000 description 83
238000004519 manufacturing process Methods 0.000 description 79
239000002904 solvent Substances 0.000 description 79
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
229910001868 water Inorganic materials 0.000 description 70
238000002360 preparation method Methods 0.000 description 64
239000000047 product Substances 0.000 description 64
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
239000007787 solid Substances 0.000 description 62
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
238000006243 chemical reaction Methods 0.000 description 48
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
229910052943 magnesium sulfate Inorganic materials 0.000 description 41
235000019341 magnesium sulphate Nutrition 0.000 description 41
239000003921 oil Substances 0.000 description 39
235000019198 oils Nutrition 0.000 description 39
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 37
238000002953 preparative HPLC Methods 0.000 description 32
239000002253 acid Substances 0.000 description 31
101710144111 Non-structural protein 3 Proteins 0.000 description 29
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
238000003556 assay Methods 0.000 description 28
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
239000012267 brine Substances 0.000 description 26
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
102000035195 Peptidases Human genes 0.000 description 22
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239000004365 Protease Substances 0.000 description 22
238000003818 flash chromatography Methods 0.000 description 22
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 20
101800001838 Serine protease/helicase NS3 Proteins 0.000 description 20
210000004027 cell Anatomy 0.000 description 20
239000012230 colorless oil Substances 0.000 description 20
230000014759 maintenance of location Effects 0.000 description 20
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 20
230000015572 biosynthetic process Effects 0.000 description 19
GPKDGVXBXQTHRY-UHFFFAOYSA-N 3-chloropropane-1-sulfonyl chloride Chemical compound ClCCCS(Cl)(=O)=O GPKDGVXBXQTHRY-UHFFFAOYSA-N 0.000 description 18
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
239000012044 organic layer Substances 0.000 description 18
239000000284 extract Substances 0.000 description 17
229910052757 nitrogen Inorganic materials 0.000 description 17
239000012074 organic phase Substances 0.000 description 17
239000000758 substrate Substances 0.000 description 17
238000003786 synthesis reaction Methods 0.000 description 17
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
125000004432 carbon atom Chemical group C* 0.000 description 16
239000012043 crude product Substances 0.000 description 16
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
239000000872 buffer Substances 0.000 description 15
238000005859 coupling reaction Methods 0.000 description 15
238000001704 evaporation Methods 0.000 description 15
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239000010410 layer Substances 0.000 description 15
239000002585 base Substances 0.000 description 14
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230000002401 inhibitory effect Effects 0.000 description 14
125000001424 substituent group Chemical group 0.000 description 14
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
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230000006870 function Effects 0.000 description 13
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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 13
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
229940024606 amino acid Drugs 0.000 description 12
WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 12
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
150000001413 amino acids Chemical class 0.000 description 11
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
238000003776 cleavage reaction Methods 0.000 description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
NBJXCTLFPNBZSG-XPUUQOCRSA-N ethyl (1s,2r)-1-amino-2-ethenylcyclopropane-1-carboxylate Chemical compound CCOC(=O)[C@]1(N)C[C@@H]1C=C NBJXCTLFPNBZSG-XPUUQOCRSA-N 0.000 description 11
238000000746 purification Methods 0.000 description 11
230000007017 scission Effects 0.000 description 11
239000011780 sodium chloride Substances 0.000 description 11
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
239000003153 chemical reaction reagent Substances 0.000 description 10
239000013078 crystal Substances 0.000 description 10
238000003756 stirring Methods 0.000 description 10
239000000126 substance Substances 0.000 description 10
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
239000008346 aqueous phase Substances 0.000 description 9
238000001816 cooling Methods 0.000 description 9
238000002866 fluorescence resonance energy transfer Methods 0.000 description 9
239000002002 slurry Substances 0.000 description 9
229910000104 sodium hydride Inorganic materials 0.000 description 9
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
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 8
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
239000004480 active ingredient Substances 0.000 description 8
125000002618 bicyclic heterocycle group Chemical group 0.000 description 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
239000005457 ice water Substances 0.000 description 8
239000000463 material Substances 0.000 description 8
FVVKCIUZDXQPKF-UHFFFAOYSA-N n-tert-butyl-1-methylcyclopropane-1-sulfonamide Chemical compound CC(C)(C)NS(=O)(=O)C1(C)CC1 FVVKCIUZDXQPKF-UHFFFAOYSA-N 0.000 description 8
239000008194 pharmaceutical composition Substances 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
230000008569 process Effects 0.000 description 8
229920002477 rna polymer Polymers 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
0 CClCCCC(C=*)Cl Chemical compound CClCCCC(C=*)Cl 0.000 description 7
229910052681 coesite Inorganic materials 0.000 description 7
229910052906 cristobalite Inorganic materials 0.000 description 7
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
239000000843 powder Substances 0.000 description 7
238000010992 reflux Methods 0.000 description 7
239000000377 silicon dioxide Substances 0.000 description 7
235000012239 silicon dioxide Nutrition 0.000 description 7
229910052682 stishovite Inorganic materials 0.000 description 7
229940124530 sulfonamide Drugs 0.000 description 7
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ATJVVVCODTXRAE-UHFFFAOYSA-N 1-methylcyclopropane-1-sulfonamide Chemical compound NS(=O)(=O)C1(C)CC1 ATJVVVCODTXRAE-UHFFFAOYSA-N 0.000 description 6
BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 6
102000004190 Enzymes Human genes 0.000 description 6
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239000007821 HATU Substances 0.000 description 6
239000007995 HEPES buffer Substances 0.000 description 6
101800001020 Non-structural protein 4A Proteins 0.000 description 6
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
239000012131 assay buffer Substances 0.000 description 6
YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
238000004440 column chromatography Methods 0.000 description 6
238000001514 detection method Methods 0.000 description 6
201000010099 disease Diseases 0.000 description 6
239000012039 electrophile Substances 0.000 description 6
229940088598 enzyme Drugs 0.000 description 6
125000000524 functional group Chemical group 0.000 description 6
239000002609 medium Substances 0.000 description 6
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
125000006239 protecting group Chemical group 0.000 description 6
239000012312 sodium hydride Substances 0.000 description 6
238000006467 substitution reaction Methods 0.000 description 6
150000003456 sulfonamides Chemical class 0.000 description 6
239000006228 supernatant Substances 0.000 description 6
239000000725 suspension Substances 0.000 description 6
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