BRPI0722411A2 - pirimidinonas bicìclicas e seus usos - Google Patents

Info

Publication number

BRPI0722411A2

BRPI0722411A2 BRPI0722411-7A BRPI0722411A BRPI0722411A2 BR PI0722411 A2 BRPI0722411 A2 BR PI0722411A2 BR PI0722411 A BRPI0722411 A BR PI0722411A BR PI0722411 A2 BRPI0722411 A2 BR PI0722411A2

Authority

BR

Brazil

Prior art keywords

formula

hydroxy

oxo

nmr

preparation

Prior art date

2006-12-22

Links

• Espacenet
• Global Dossier
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• -1 bicyclic pyrimidinones Chemical class 0.000 title claims description 99
• 238000000034 method Methods 0.000 claims abstract description 256
• 150000001875 compounds Chemical class 0.000 claims abstract description 186
• 150000003839 salts Chemical class 0.000 claims abstract description 23
• 239000000651 prodrug Substances 0.000 claims abstract description 21
• 229940002612 prodrug Drugs 0.000 claims abstract description 21
• 238000011282 treatment Methods 0.000 claims abstract description 15
• 208000036142 Viral infection Diseases 0.000 claims abstract description 14
• 230000009385 viral infection Effects 0.000 claims abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
• 239000003814 drug Substances 0.000 claims abstract description 11
• 238000011321 prophylaxis Methods 0.000 claims abstract description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 37
• 125000000217 alkyl group Chemical group 0.000 claims description 34
• 229910052717 sulfur Inorganic materials 0.000 claims description 23
• 125000001072 heteroaryl group Chemical group 0.000 claims description 21
• 125000003118 aryl group Chemical group 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 20
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 19
• 125000000623 heterocyclic group Chemical group 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
• 125000005842 heteroatom Chemical group 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
• 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 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 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 7
• 208000015181 infectious disease Diseases 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 230000001590 oxidative effect Effects 0.000 claims description 5
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 239000001257 hydrogen Substances 0.000 claims description 4
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 230000003647 oxidation Effects 0.000 claims description 3
• 238000007254 oxidation reaction Methods 0.000 claims description 3
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
• 125000002619 bicyclic group Chemical group 0.000 claims description 2
• 125000006286 dichlorobenzyl group Chemical group 0.000 claims description 2
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
• 150000003536 tetrazoles Chemical class 0.000 claims description 2
• VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
• 150000003852 triazoles Chemical class 0.000 claims description 2
• 125000006287 difluorobenzyl group Chemical group 0.000 claims 1
• 125000004175 fluorobenzyl group Chemical group 0.000 claims 1
• 238000002360 preparation method Methods 0.000 description 225
• 238000005160 1H NMR spectroscopy Methods 0.000 description 210
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 147
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
• 239000000047 product Substances 0.000 description 132
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 98
• 238000004128 high performance liquid chromatography Methods 0.000 description 98
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
• 239000000203 mixture Substances 0.000 description 71
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 67
• 239000000243 solution Substances 0.000 description 63
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• 238000006243 chemical reaction Methods 0.000 description 37
• 239000007787 solid Substances 0.000 description 36
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• 239000011734 sodium Substances 0.000 description 32
• 239000002253 acid Substances 0.000 description 30
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• 238000001914 filtration Methods 0.000 description 22
• IXHNFOOSLAWRBQ-UHFFFAOYSA-N (3,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(Cl)=C1 IXHNFOOSLAWRBQ-UHFFFAOYSA-N 0.000 description 21
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
• ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 18
• 238000004440 column chromatography Methods 0.000 description 17
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 17
• 239000002904 solvent Substances 0.000 description 17
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
• 239000012267 brine Substances 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
• IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• 150000002148 esters Chemical class 0.000 description 15
• 102100034343 Integrase Human genes 0.000 description 14
• 239000002244 precipitate Substances 0.000 description 14
• 239000011541 reaction mixture Substances 0.000 description 14
• 241000725303 Human immunodeficiency virus Species 0.000 description 12
• 108010061833 Integrases Proteins 0.000 description 12
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 239000000460 chlorine Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
• 238000012546 transfer Methods 0.000 description 12
• DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 230000000694 effects Effects 0.000 description 11
• 239000012044 organic layer Substances 0.000 description 11
• 239000012074 organic phase Substances 0.000 description 11
• 238000003556 assay Methods 0.000 description 10
• 229910052736 halogen Inorganic materials 0.000 description 10
• 150000002367 halogens Chemical class 0.000 description 10
• 239000000758 substrate Substances 0.000 description 10
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
• 230000003612 virological effect Effects 0.000 description 10
• 108020004414 DNA Proteins 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 238000003818 flash chromatography Methods 0.000 description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• 239000000872 buffer Substances 0.000 description 8
• 150000004702 methyl esters Chemical class 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• 239000007858 starting material Substances 0.000 description 8
• 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 8
• 239000000463 material Substances 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 238000001228 spectrum Methods 0.000 description 7
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
• 239000012043 crude product Substances 0.000 description 6
• 239000004615 ingredient Substances 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 239000000725 suspension Substances 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• 102000004190 Enzymes Human genes 0.000 description 5
• 108090000790 Enzymes Proteins 0.000 description 5
• 208000031886 HIV Infections Diseases 0.000 description 5
• 108010002459 HIV Integrase Proteins 0.000 description 5
• 229960000583 acetic acid Drugs 0.000 description 5
• 230000006978 adaptation Effects 0.000 description 5
• 125000000753 cycloalkyl group Chemical group 0.000 description 5
• NKGXGEHGPYWBDK-BQYQJAHWSA-N dimethyl (e)-2,3-diacetyloxybut-2-enedioate Chemical compound COC(=O)C(\OC(C)=O)=C(/OC(C)=O)C(=O)OC NKGXGEHGPYWBDK-BQYQJAHWSA-N 0.000 description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• 239000012046 mixed solvent Substances 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
• 238000012545 processing Methods 0.000 description 5
• 238000001953 recrystallisation Methods 0.000 description 5
• 230000002829 reductive effect Effects 0.000 description 5
• 229920006395 saturated elastomer Polymers 0.000 description 5
• 239000011780 sodium chloride Substances 0.000 description 5
• 238000003756 stirring Methods 0.000 description 5
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• 241000283690 Bos taurus Species 0.000 description 4
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
• 238000005481 NMR spectroscopy Methods 0.000 description 4
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
• 230000009471 action Effects 0.000 description 4
• 239000004480 active ingredient Substances 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• 230000015572 biosynthetic process Effects 0.000 description 4
• 125000004432 carbon atom Chemical group C* 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 4
• 201000010099 disease Diseases 0.000 description 4
• 229960003586 elvitegravir Drugs 0.000 description 4
• 239000012362 glacial acetic acid Substances 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• 229940124524 integrase inhibitor Drugs 0.000 description 4
• 239000002850 integrase inhibitor Substances 0.000 description 4
• 239000000543 intermediate Substances 0.000 description 4
• 239000002609 medium Substances 0.000 description 4
• URCPKQIWJAHFIE-UHFFFAOYSA-N methyl 3-acetyloxy-4-oxo-10-(2-piperazin-1-ylethyl)pyrimido[1,2-a]benzimidazole-2-carboxylate Chemical compound C12=CC=CC=C2N2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CCN1CCNCC1 URCPKQIWJAHFIE-UHFFFAOYSA-N 0.000 description 4
• QWVWABDDCKOKNU-UHFFFAOYSA-N methyl indazole-2-carboxylate Chemical compound C1=CC=CC2=NN(C(=O)OC)C=C21 QWVWABDDCKOKNU-UHFFFAOYSA-N 0.000 description 4
• 230000035772 mutation Effects 0.000 description 4
• MWRFJEFIIBXIGE-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]pyrimidine-5-carboxamide Chemical compound C1=CC(F)=CC=C1CNC(=O)C1=CN=CN=C1 MWRFJEFIIBXIGE-UHFFFAOYSA-N 0.000 description 4
• 239000012299 nitrogen atmosphere Substances 0.000 description 4
• 239000002245 particle Substances 0.000 description 4
• 230000001566 pro-viral effect Effects 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 229960004742 raltegravir Drugs 0.000 description 4
• 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 4
• 230000010076 replication Effects 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
• XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 3
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
• WXMLNSBINBLHPM-UHFFFAOYSA-N 4h-pyrido[1,2-a]pyrimidine-2-carboxylic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CCN21 WXMLNSBINBLHPM-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
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• 241000283086 Equidae Species 0.000 description 3
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
• 208000037357 HIV infectious disease Diseases 0.000 description 3
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
• 241000124008 Mammalia Species 0.000 description 3
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
• PEFSMUFITYGYHD-UHFFFAOYSA-N NCC(C=C1)=CC(Cl)=C1Cl.OC(C1=NC=CC=N1)=O Chemical compound NCC(C=C1)=CC(Cl)=C1Cl.OC(C1=NC=CC=N1)=O PEFSMUFITYGYHD-UHFFFAOYSA-N 0.000 description 3
• 229910004809 Na2 SO4 Inorganic materials 0.000 description 3
• 108091034117 Oligonucleotide Proteins 0.000 description 3
• 241001494479 Pecora Species 0.000 description 3
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
• 150000007513 acids Chemical class 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• 125000000539 amino acid group Chemical group 0.000 description 3
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical class NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 3
• 239000003153 chemical reaction reagent Substances 0.000 description 3
• 229910052801 chlorine Inorganic materials 0.000 description 3
• 239000003480 eluent Substances 0.000 description 3
• 238000007429 general method 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
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 3
• OZBWQGNTZCKOEG-UHFFFAOYSA-N indazole-2-carboxylic acid Chemical compound C1=CC=CC2=NN(C(=O)O)C=C21 OZBWQGNTZCKOEG-UHFFFAOYSA-N 0.000 description 3
• 239000007788 liquid Substances 0.000 description 3
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
• CMPZQBFZPXHDCN-UHFFFAOYSA-N methyl 7-bromo-3-hydroxy-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1=CC(Br)=CN2C(=O)C(O)=C(C(=O)OC)N=C21 CMPZQBFZPXHDCN-UHFFFAOYSA-N 0.000 description 3
• JOQJEWAXHQDQAG-UHFFFAOYSA-N methyl pyrimidine-2-carboxylate Chemical compound COC(=O)C1=NC=CC=N1 JOQJEWAXHQDQAG-UHFFFAOYSA-N 0.000 description 3
• 125000002950 monocyclic group Chemical group 0.000 description 3
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
• OUNUOYZSORPRSD-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-3-hydroxy-4-oxo-7-[(2,2,2-trifluoroacetyl)amino]pyrido[1,2-a]pyrimidine-2-carboxamide Chemical compound N1=C2C=CC(NC(=O)C(F)(F)F)=CN2C(=O)C(O)=C1C(=O)NCC1=CC=C(F)C=C1 OUNUOYZSORPRSD-UHFFFAOYSA-N 0.000 description 3
• 238000002953 preparative HPLC Methods 0.000 description 3
• 230000008569 process Effects 0.000 description 3
• 235000018102 proteins Nutrition 0.000 description 3
• 102000004169 proteins and genes Human genes 0.000 description 3
• 108090000623 proteins and genes Proteins 0.000 description 3
• 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
• 235000009518 sodium iodide Nutrition 0.000 description 3
• 159000000000 sodium salts Chemical class 0.000 description 3
• 241000894007 species Species 0.000 description 3
• 239000012258 stirred mixture Substances 0.000 description 3
• 238000007920 subcutaneous administration Methods 0.000 description 3
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• FQWVOKUTIJOGFM-UHFFFAOYSA-N methyl 1-[(4-fluorophenyl)methyl]-6-hydroxy-7-oxopyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound N12C(=O)C(O)=C(C(=O)OC)N=C2C=CN1CC1=CC=C(F)C=C1 FQWVOKUTIJOGFM-UHFFFAOYSA-N 0.000 description 1
• SPCWCZLEZPMZJL-UHFFFAOYSA-N methyl 3-[tert-butyl(dimethyl)silyl]oxy-7-[(3-chloro-2-fluorophenyl)methyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C=1N2C(=O)C(O[Si](C)(C)C(C)(C)C)=C(C(=O)OC)N=C2C=CC=1CC1=CC=CC(Cl)=C1F SPCWCZLEZPMZJL-UHFFFAOYSA-N 0.000 description 1
• AAGMZFHZMIWMAH-UHFFFAOYSA-N methyl 3-[tert-butyl(dimethyl)silyl]oxy-7-iodo-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1=CC(I)=CN2C(=O)C(O[Si](C)(C)C(C)(C)C)=C(C(=O)OC)N=C21 AAGMZFHZMIWMAH-UHFFFAOYSA-N 0.000 description 1
• LVTMXVWOKGODDA-UHFFFAOYSA-N methyl 3-hydroxy-10-morpholin-4-yl-4-oxopyrimido[1,2-b][1,2]benzoxazole-2-carboxylate Chemical compound C1=CC=C2ON3C(=O)C(O)=C(C(=O)OC)N=C3C2=C1N1CCOCC1 LVTMXVWOKGODDA-UHFFFAOYSA-N 0.000 description 1
• DKAVFQFNEGXHNC-UHFFFAOYSA-N methyl 3-hydroxy-4-oxo-7-piperidin-1-ylpyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C=1N2C(=O)C(O)=C(C(=O)OC)N=C2C=CC=1N1CCCCC1 DKAVFQFNEGXHNC-UHFFFAOYSA-N 0.000 description 1
• FDKCHZTZLLYDST-UHFFFAOYSA-N methyl 3-hydroxy-4-oxopyrimido[1,2-b][1,2]benzoxazole-2-carboxylate Chemical compound C12=CC=CC=C2ON2C1=NC(C(=O)OC)=C(O)C2=O FDKCHZTZLLYDST-UHFFFAOYSA-N 0.000 description 1
• XSYQEDMXXDLGDD-UHFFFAOYSA-N methyl 3-hydroxy-7-methyl-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C1=CC(C)=CN2C(=O)C(O)=C(C(=O)OC)N=C21 XSYQEDMXXDLGDD-UHFFFAOYSA-N 0.000 description 1
• CDQTVXGDNFZOIR-UHFFFAOYSA-N methyl 3-hydroxy-9-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidine-2-carboxylate Chemical compound C=1C=CN2C(=O)C(O)=C(C(=O)OC)N=C2C=1N1CCOCC1 CDQTVXGDNFZOIR-UHFFFAOYSA-N 0.000 description 1
• VTENWIPSWAMPKI-UHFFFAOYSA-N methyl 4-chloropyridine-2-carboxylate Chemical compound COC(=O)C1=CC(Cl)=CC=N1 VTENWIPSWAMPKI-UHFFFAOYSA-N 0.000 description 1
• MIRPRCLIIOLHOQ-UHFFFAOYSA-N methyl 4-oxo-3-phenylmethoxypyrimido[1,2-b][1,2]benzoxazole-2-carboxylate Chemical compound COC(=O)C=1N=C2C3=CC=CC=C3ON2C(=O)C=1OCC1=CC=CC=C1 MIRPRCLIIOLHOQ-UHFFFAOYSA-N 0.000 description 1
• CPXYMXNMRWTCPM-UHFFFAOYSA-N methyl 6-(2,2-dimethylpropanoyloxy)-5-oxo-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(OC(=O)C(C)(C)C)=C(C(=O)OC)N=C2SC=CN21 CPXYMXNMRWTCPM-UHFFFAOYSA-N 0.000 description 1
• XULOIGSJCBGTNM-UHFFFAOYSA-N methyl 6-acetyloxy-1-(2-morpholin-4-ylethyl)-5-oxoimidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound C1=CN2C(=O)C(OC(C)=O)=C(C(=O)OC)N=C2N1CCN1CCOCC1 XULOIGSJCBGTNM-UHFFFAOYSA-N 0.000 description 1
• SALJEWJQELMLJN-UHFFFAOYSA-N methyl 6-acetyloxy-5-oxo-1-(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=C2N1CCN1CCCCC1 SALJEWJQELMLJN-UHFFFAOYSA-N 0.000 description 1
• VHJVSXLPBZZEBM-UHFFFAOYSA-N methyl 6-acetyloxy-5-oxo-8h-imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(OC(C)=O)=C(C(=O)OC)N=C2NC=CN21 VHJVSXLPBZZEBM-UHFFFAOYSA-N 0.000 description 1
• CWOZUTLGBGKWPN-UHFFFAOYSA-N methyl 6-hydroxy-1-methyl-7-oxopyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2C=CN(C)N21 CWOZUTLGBGKWPN-UHFFFAOYSA-N 0.000 description 1
• LAGVEGLKCKGDSD-UHFFFAOYSA-N methyl 6-hydroxy-2-methyl-5-oxo-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2SC(C)=CN21 LAGVEGLKCKGDSD-UHFFFAOYSA-N 0.000 description 1
• IYZWUGVXHPNGRO-UHFFFAOYSA-N methyl 6-hydroxy-3-methyl-5-oxo-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2SC=C(C)N21 IYZWUGVXHPNGRO-UHFFFAOYSA-N 0.000 description 1
• KDNYXHQFSOCRDK-UHFFFAOYSA-N methyl 6-hydroxy-5-oxo-8h-imidazo[1,2-a]pyrimidine-7-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2NC=CN21 KDNYXHQFSOCRDK-UHFFFAOYSA-N 0.000 description 1
• PMJFXTZQFWUBJW-UHFFFAOYSA-N methyl 6-hydroxy-5-oxo-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxylate Chemical class O=C1C(O)=C(C(=O)OC)N=C2SC=CN21 PMJFXTZQFWUBJW-UHFFFAOYSA-N 0.000 description 1
• GXKXHKZYLLLQPM-UHFFFAOYSA-N methyl 6-hydroxy-7-oxo-1h-pyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound O=C1C(O)=C(C(=O)OC)N=C2C=CNN21 GXKXHKZYLLLQPM-UHFFFAOYSA-N 0.000 description 1
• QWWNGFFNGKPYPC-UHFFFAOYSA-N methyl 6-hydroxy-7-oxo-2-phenyl-1h-pyrazolo[1,5-a]pyrimidine-5-carboxylate Chemical compound N1N2C(=O)C(O)=C(C(=O)OC)N=C2C=C1C1=CC=CC=C1 QWWNGFFNGKPYPC-UHFFFAOYSA-N 0.000 description 1
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