CA2729656A1 - Imidazopyrimidinones and uses thereof - Google Patents

Info

Publication number

CA2729656A1

CA2729656A1 CA2729656A CA2729656A CA2729656A1 CA 2729656 A1 CA2729656 A1 CA 2729656A1 CA 2729656 A CA2729656 A CA 2729656A CA 2729656 A CA2729656 A CA 2729656A CA 2729656 A1 CA2729656 A1 CA 2729656A1

Authority

CA

Canada

Prior art keywords

oxo

group

product

3alkylene

preparation

Prior art date

2008-07-02

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• BOUNFBOFBGBYBT-UHFFFAOYSA-N purin-8-one Chemical class C1=NC=NC2=NC(=O)N=C21 BOUNFBOFBGBYBT-UHFFFAOYSA-N 0.000 title 1
• 238000000034 method Methods 0.000 claims abstract description 154
• 150000001875 compounds Chemical class 0.000 claims abstract description 115
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 239000000651 prodrug Substances 0.000 claims abstract description 19
• 229940002612 prodrug Drugs 0.000 claims abstract description 19
• 208000036142 Viral infection Diseases 0.000 claims abstract description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
• 230000009385 viral infection Effects 0.000 claims abstract description 13
• 238000011321 prophylaxis Methods 0.000 claims abstract description 7
• 238000002360 preparation method Methods 0.000 claims description 183
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• -1 C1-10alkylNR3R4 Chemical group 0.000 claims description 50
• 125000001424 substituent group Chemical group 0.000 claims description 35
• 125000004432 carbon atom Chemical group C* 0.000 claims description 33
• 229910052717 sulfur Inorganic materials 0.000 claims description 33
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 32
• 125000005843 halogen group Chemical group 0.000 claims description 29
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 24
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 24
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 22
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 21
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 20
• 230000035772 mutation Effects 0.000 claims description 20
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
• 125000000623 heterocyclic group Chemical group 0.000 claims description 16
• 230000003612 virological effect Effects 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• 208000015181 infectious disease Diseases 0.000 claims description 13
• 230000003647 oxidation Effects 0.000 claims description 13
• 238000007254 oxidation reaction Methods 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 10
• 125000001072 heteroaryl group Chemical group 0.000 claims description 10
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 108010002459 HIV Integrase Proteins 0.000 claims description 8
• 125000002947 alkylene group Chemical group 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 229940124524 integrase inhibitor Drugs 0.000 claims description 8
• 239000002850 integrase inhibitor Substances 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 7
• 229940124530 sulfonamide Drugs 0.000 claims description 7
• 125000004122 cyclic group Chemical group 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 102220076678 rs146651027 Human genes 0.000 claims description 6
• FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
• 125000006713 (C5-C10) cycloalkyl group Chemical group 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 150000003951 lactams Chemical class 0.000 claims description 3
• CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 claims description 2
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
• 229960003586 elvitegravir Drugs 0.000 claims description 2
• JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 claims description 2
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
• 150000003536 tetrazoles Chemical group 0.000 claims description 2
• VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
• 150000003852 triazoles Chemical group 0.000 claims description 2
• 239000000047 product Substances 0.000 description 213
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 208
• 238000005481 NMR spectroscopy Methods 0.000 description 151
• 239000000203 mixture Substances 0.000 description 105
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 103
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 70
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
• 239000000243 solution Substances 0.000 description 54
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• 229910001868 water Inorganic materials 0.000 description 43
• 101150041968 CDC13 gene Proteins 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• 239000007787 solid Substances 0.000 description 30
• 238000004440 column chromatography Methods 0.000 description 29
• 238000010511 deprotection reaction Methods 0.000 description 27
• 229910052740 iodine Inorganic materials 0.000 description 26
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 210000004027 cell Anatomy 0.000 description 23
• 235000019439 ethyl acetate Nutrition 0.000 description 23
• 241000700605 Viruses Species 0.000 description 22
• 239000012267 brine Substances 0.000 description 22
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• 102100034343 Integrase Human genes 0.000 description 21
• 108010061833 Integrases Proteins 0.000 description 21
• 229940093499 ethyl acetate Drugs 0.000 description 21
• 230000002829 reductive effect Effects 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• 238000003556 assay Methods 0.000 description 18
• 230000000694 effects Effects 0.000 description 18
• 241000725303 Human immunodeficiency virus Species 0.000 description 17
• 238000006243 chemical reaction Methods 0.000 description 17
• 238000004128 high performance liquid chromatography Methods 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
• 108020004414 DNA Proteins 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 239000002253 acid Substances 0.000 description 15
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 15
• 229910052938 sodium sulfate Inorganic materials 0.000 description 15
• 235000011152 sodium sulphate Nutrition 0.000 description 15
• 238000001212 derivatisation Methods 0.000 description 14
• 238000005160 1H NMR spectroscopy Methods 0.000 description 13
• SLUYEZHWAHGANQ-UHFFFAOYSA-N 3h-imidazo[1,2-a]pyrimidin-5-one Chemical compound O=C1C=CN=C2N=CCN12 SLUYEZHWAHGANQ-UHFFFAOYSA-N 0.000 description 13
• 239000000284 extract Substances 0.000 description 13
• 239000012044 organic layer Substances 0.000 description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 230000008878 coupling Effects 0.000 description 11
• 238000010168 coupling process Methods 0.000 description 11
• 238000005859 coupling reaction Methods 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
• 239000011541 reaction mixture Substances 0.000 description 11
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
• 238000001914 filtration Methods 0.000 description 10
• CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 10
• 238000010992 reflux Methods 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 9
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
• UHDHWOXRBRJTDM-UHFFFAOYSA-N 2-(aminomethyl)-5-fluoro-n,n-dimethylbenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC(F)=CC=C1CN UHDHWOXRBRJTDM-UHFFFAOYSA-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
• 230000001404 mediated effect Effects 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
• 229960004742 raltegravir Drugs 0.000 description 8
• 239000002904 solvent Substances 0.000 description 8
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
• 239000000460 chlorine Substances 0.000 description 7
• 230000007062 hydrolysis Effects 0.000 description 7
• 238000006460 hydrolysis reaction Methods 0.000 description 7
• 230000010354 integration Effects 0.000 description 7
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
• BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 229910052794 bromium Inorganic materials 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• 239000007822 coupling agent Substances 0.000 description 6
• 239000003480 eluent Substances 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
• 229910052731 fluorine Inorganic materials 0.000 description 6
• 239000004615 ingredient Substances 0.000 description 6
• 239000003112 inhibitor Substances 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• 229910052751 metal Inorganic materials 0.000 description 6
• 239000002184 metal Substances 0.000 description 6
• 235000015320 potassium carbonate Nutrition 0.000 description 6
• 239000000725 suspension Substances 0.000 description 6
• IXHNFOOSLAWRBQ-UHFFFAOYSA-N (3,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(Cl)=C1 IXHNFOOSLAWRBQ-UHFFFAOYSA-N 0.000 description 5
• BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 5
• 108091026890 Coding region Proteins 0.000 description 5
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• 108090000790 Enzymes Proteins 0.000 description 5
• 208000031886 HIV Infections Diseases 0.000 description 5
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• 239000007832 Na2SO4 Substances 0.000 description 5
• 230000010933 acylation Effects 0.000 description 5
• 238000005917 acylation reaction Methods 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 229910052801 chlorine Inorganic materials 0.000 description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 5
• 239000003921 oil Substances 0.000 description 5
• 230000001566 pro-viral effect Effects 0.000 description 5
• 238000010791 quenching Methods 0.000 description 5
• 239000013605 shuttle vector Substances 0.000 description 5
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 5
• 238000001890 transfection Methods 0.000 description 5
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• 108060001084 Luciferase Proteins 0.000 description 4
• 239000005089 Luciferase Substances 0.000 description 4
• BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• 230000009471 action Effects 0.000 description 4
• 239000004480 active ingredient Substances 0.000 description 4
• 229960004132 diethyl ether Drugs 0.000 description 4
• 201000010099 disease Diseases 0.000 description 4
• UONGQILKBBDHDJ-UHFFFAOYSA-N n,n',n'-trimethyloxamide Chemical compound CNC(=O)C(=O)N(C)C UONGQILKBBDHDJ-UHFFFAOYSA-N 0.000 description 4
• 239000002245 particle Substances 0.000 description 4
• 108090000623 proteins and genes Proteins 0.000 description 4
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
• 230000035892 strand transfer Effects 0.000 description 4
• 239000000758 substrate Substances 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• 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 3
• BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 3
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
• UUHMFGQYTIQQIS-UHFFFAOYSA-N 1h-imidazo[1,2-a]pyrimidin-5-one Chemical compound O=C1C=CN=C2NC=CN12 UUHMFGQYTIQQIS-UHFFFAOYSA-N 0.000 description 3
• YHPVIBUEXBEHPV-UHFFFAOYSA-N 2,6-dihydro-1h-pyrimidin-5-one Chemical compound O=C1CNCN=C1 YHPVIBUEXBEHPV-UHFFFAOYSA-N 0.000 description 3
• LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
• 208000030507 AIDS Diseases 0.000 description 3
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
• 208000037357 HIV infectious disease Diseases 0.000 description 3
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
• 108700008625 Reporter Genes Proteins 0.000 description 3
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
• 230000029936 alkylation Effects 0.000 description 3
• 238000005804 alkylation reaction Methods 0.000 description 3
• 125000000539 amino acid group Chemical group 0.000 description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
• 239000003153 chemical reaction reagent Substances 0.000 description 3
• 239000012024 dehydrating agents‎ Substances 0.000 description 3
• 238000003818 flash chromatography Methods 0.000 description 3
• 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
• 150000002430 hydrocarbons Chemical group 0.000 description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
• 230000005764 inhibitory process Effects 0.000 description 3
• 239000000543 intermediate Substances 0.000 description 3
• 239000007788 liquid Substances 0.000 description 3
• WLRVQBMWJDBJTI-UHFFFAOYSA-N methyl 1-[2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl]-6-hydroxy-3-(methylsulfanylmethyl)-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=C(CSC)N2C(=O)C(O)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)CC(C)C1 WLRVQBMWJDBJTI-UHFFFAOYSA-N 0.000 description 3
• LUCZHWHTIYRJIT-UHFFFAOYSA-N methyl 3-(4-fluoro-2-methylsulfanylphenyl)propanoate Chemical compound COC(=O)CCC1=CC=C(F)C=C1SC LUCZHWHTIYRJIT-UHFFFAOYSA-N 0.000 description 3
• 150000004702 methyl esters Chemical class 0.000 description 3
• 238000007144 microwave assisted synthesis reaction Methods 0.000 description 3
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
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• 238000002741 site-directed mutagenesis Methods 0.000 description 3
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
• 238000007920 subcutaneous administration Methods 0.000 description 3
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• 229940124597 therapeutic agent Drugs 0.000 description 3
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
• 210000002845 virion Anatomy 0.000 description 3
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• FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 1
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• PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 1
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• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
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• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
• CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
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• 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
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• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
• VSVFBZIHNSOQIJ-UHFFFAOYSA-N methyl 1-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-5-oxo-6-phenylmethoxyimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OCC=3C=CC=CC=3)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)OC(C)C1 VSVFBZIHNSOQIJ-UHFFFAOYSA-N 0.000 description 1
• HLBPOTUHZZFHRI-UHFFFAOYSA-N methyl 1-[2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl]-6-hydroxy-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(O)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)CC(C)C1 HLBPOTUHZZFHRI-UHFFFAOYSA-N 0.000 description 1
• BSAXACJKXSTMSC-UHFFFAOYSA-N methyl 1-[2-(4-methylpiperidin-1-yl)-2-oxoethyl]-5-oxo-6-phenylmethoxyimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OCC=3C=CC=CC=3)=C(C(=O)OC)N=C2N1CC(=O)N1CCC(C)CC1 BSAXACJKXSTMSC-UHFFFAOYSA-N 0.000 description 1
• YJWGTNTYXLSYLM-UHFFFAOYSA-N methyl 2-(2-bromo-3-oxopropyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1CC(Br)C=O YJWGTNTYXLSYLM-UHFFFAOYSA-N 0.000 description 1
• HLPUZROXLULFFL-UHFFFAOYSA-N methyl 2-[[2-[1-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-6-hydroxy-5-oxoimidazo[1,2-a]pyrimidin-7-yl]-1,3-thiazol-5-yl]methyl]-5-fluorobenzoate Chemical compound COC(=O)C1=CC(F)=CC=C1CC1=CN=C(C2=C(C(=O)N3C=CN(CC(=O)N4CC(C)OC(C)C4)C3=N2)O)S1 HLPUZROXLULFFL-UHFFFAOYSA-N 0.000 description 1
• KYMZTJZNCSYYRO-UHFFFAOYSA-N methyl 2-[[2-[5-oxo-1-(2-oxo-2-piperidin-1-ylethyl)-6-phenylmethoxyimidazo[1,2-a]pyrimidin-7-yl]-1,3-thiazol-5-yl]methyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1CC1=CN=C(C2=C(C(=O)N3C=CN(CC(=O)N4CCCCC4)C3=N2)OCC=2C=CC=CC=2)S1 KYMZTJZNCSYYRO-UHFFFAOYSA-N 0.000 description 1
• WVQWSUBGQYTHES-UHFFFAOYSA-N methyl 2-[[2-[6-hydroxy-5-oxo-1-(2-oxo-2-piperidin-1-ylethyl)imidazo[1,2-a]pyrimidin-7-yl]-1,3-thiazol-5-yl]methyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1CC1=CN=C(C2=C(C(=O)N3C=CN(CC(=O)N4CCCCC4)C3=N2)O)S1 WVQWSUBGQYTHES-UHFFFAOYSA-N 0.000 description 1
• BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical compound COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 description 1
• UTEMHQAGNZTRMZ-UHFFFAOYSA-N methyl 3-(4-fluoro-2-methylsulfonylphenyl)propanoate Chemical compound COC(=O)CCC1=CC=C(F)C=C1S(C)(=O)=O UTEMHQAGNZTRMZ-UHFFFAOYSA-N 0.000 description 1
• WUJSMHUCQVMXJF-UHFFFAOYSA-N methyl 3-(4-fluoro-2-morpholin-4-ylsulfonylphenyl)propanoate Chemical compound COC(=O)CCC1=CC=C(F)C=C1S(=O)(=O)N1CCOCC1 WUJSMHUCQVMXJF-UHFFFAOYSA-N 0.000 description 1
• OLPQEVGZOOVHBX-UHFFFAOYSA-N methyl 3-[2-(dimethylsulfamoyl)-4-fluorophenyl]prop-2-enoate Chemical compound COC(=O)C=CC1=CC=C(F)C=C1S(=O)(=O)N(C)C OLPQEVGZOOVHBX-UHFFFAOYSA-N 0.000 description 1
• KRWWZOLXINPOPI-UHFFFAOYSA-N methyl 3-bromo-1-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-5-oxo-6-phenylmethoxyimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=C(Br)N2C(=O)C(OCC=3C=CC=CC=3)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)OC(C)C1 KRWWZOLXINPOPI-UHFFFAOYSA-N 0.000 description 1
• DTIWOKISOJGBOZ-UHFFFAOYSA-N methyl 5-oxo-6-phenylmethoxy-1-(1,3-thiazol-2-ylmethyl)imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OCC=3C=CC=CC=3)=C(C(=O)OC)N=C2N1CC1=NC=CS1 DTIWOKISOJGBOZ-UHFFFAOYSA-N 0.000 description 1
• JXOGLNRSRKNWKN-UHFFFAOYSA-N methyl 6-acetyloxy-1-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)OC(C)C1 JXOGLNRSRKNWKN-UHFFFAOYSA-N 0.000 description 1
• YBVVHHULAHCSJO-UHFFFAOYSA-N methyl 6-acetyloxy-1-[2-(2-methylpiperidin-1-yl)-2-oxoethyl]-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC(=O)N1CCCCC1C YBVVHHULAHCSJO-UHFFFAOYSA-N 0.000 description 1
• FKFMMVNYDCXYEB-UHFFFAOYSA-N methyl 6-acetyloxy-1-[2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl]-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC(=O)N1CC(C)CC(C)C1 FKFMMVNYDCXYEB-UHFFFAOYSA-N 0.000 description 1
• DIEXDDRUGFMFBM-UHFFFAOYSA-N methyl 6-acetyloxy-1-[2-(4-methylpiperidin-1-yl)-2-oxoethyl]-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC(=O)N1CCC(C)CC1 DIEXDDRUGFMFBM-UHFFFAOYSA-N 0.000 description 1
• JQDHYFJZADDNEB-UHFFFAOYSA-N methyl 6-acetyloxy-3-bromo-5-oxo-8h-imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(OC(C)=O)=C(C(=O)OC)N=C2NC=C(Br)N21 JQDHYFJZADDNEB-UHFFFAOYSA-N 0.000 description 1
• SETKABOLLQPHLA-UHFFFAOYSA-N methyl 6-acetyloxy-5-oxo-1-(1,3-thiazol-2-ylmethyl)imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC1=NC=CS1 SETKABOLLQPHLA-UHFFFAOYSA-N 0.000 description 1
• DITFWHGWHLOLSL-UHFFFAOYSA-N methyl 6-acetyloxy-5-oxo-1-(2-oxo-2-piperidin-1-ylethyl)imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CC(=O)N1CCCCC1 DITFWHGWHLOLSL-UHFFFAOYSA-N 0.000 description 1
• JCMLTZGHOCEHTJ-UHFFFAOYSA-N methyl 6-hydroxy-1-methyl-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2N(C)C=CN21 JCMLTZGHOCEHTJ-UHFFFAOYSA-N 0.000 description 1
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