BR112021014079A2 - Ácidos carboxílicos policíclicos substituídos, análogos dos mesmos e métodos usando os mesmos - Google Patents

Info

Publication number

BR112021014079A2

BR112021014079A2 BR112021014079-4A BR112021014079A BR112021014079A2 BR 112021014079 A2 BR112021014079 A2 BR 112021014079A2 BR 112021014079 A BR112021014079 A BR 112021014079A BR 112021014079 A2 BR112021014079 A2 BR 112021014079A2

Authority

BR

Brazil

Prior art keywords

butyl

tert

oxo

difluoromethoxy

quinoline

Prior art date

2019-01-17

Links

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• 238000000034 method Methods 0.000 title claims abstract description 99
• 150000001735 carboxylic acids Chemical class 0.000 title abstract description 3
• 239000000203 mixture Substances 0.000 claims abstract description 278
• 150000001875 compounds Chemical class 0.000 claims abstract description 257
• 150000003839 salts Chemical class 0.000 claims abstract description 99
• 241000700721 Hepatitis B virus Species 0.000 claims abstract description 78
• 239000012453 solvate Substances 0.000 claims abstract description 74
• 208000037262 Hepatitis delta Diseases 0.000 claims abstract description 35
• 241000724709 Hepatitis delta virus Species 0.000 claims abstract description 34
• -1 2,5-dioxo-pyrrolidin-1-yl Chemical group 0.000 claims description 216
• 239000002253 acid Substances 0.000 claims description 112
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 104
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 83
• QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 claims description 74
• 239000008194 pharmaceutical composition Substances 0.000 claims description 60
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 45
• 229910052736 halogen Inorganic materials 0.000 claims description 36
• 239000003795 chemical substances by application Substances 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• 125000001424 substituent group Chemical group 0.000 claims description 33
• 125000000217 alkyl group Chemical group 0.000 claims description 32
• 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 31
• DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 claims description 30
• 230000015572 biosynthetic process Effects 0.000 claims description 27
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
• HJYYQFVLSQWEDJ-UHFFFAOYSA-N 1,7-naphthyridine-3-carboxylic acid Chemical compound C1=NC=CC2=CC(C(=O)O)=CN=C21 HJYYQFVLSQWEDJ-UHFFFAOYSA-N 0.000 claims description 24
• SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 24
• 125000003118 aryl group Chemical group 0.000 claims description 19
• 229910052757 nitrogen Inorganic materials 0.000 claims description 19
• 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 19
• 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
• 239000000427 antigen Substances 0.000 claims description 18
• 239000003937 drug carrier Substances 0.000 claims description 18
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
• 125000003729 nucleotide group Chemical group 0.000 claims description 18
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
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• 239000003112 inhibitor Substances 0.000 claims description 16
• 231100000283 hepatitis Toxicity 0.000 claims description 15
• 239000002773 nucleotide Substances 0.000 claims description 15
• 229940124765 capsid inhibitor Drugs 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 14
• 208000002672 hepatitis B Diseases 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• 241000700605 Viruses Species 0.000 claims description 13
• 102000036639 antigens Human genes 0.000 claims description 13
• 108091007433 antigens Proteins 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
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• 125000002252 acyl group Chemical group 0.000 claims description 11
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 10
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 230000009385 viral infection Effects 0.000 claims description 9
• JUXOCWXHUWKTTN-UHFFFAOYSA-N 12-tert-butyl-6-chloro-4-methyl-3-oxo-11,12-dihydrobenzo[c][1,10]phenanthroline-2-carboxylic acid Chemical compound CC(C)(C)C1CC2=C(C3=C1C=C(C(=O)N3C)C(=O)O)N=C(C4=CC=CC=C24)Cl JUXOCWXHUWKTTN-UHFFFAOYSA-N 0.000 claims description 8
• 125000006577 C1-C6 hydroxyalkyl group Chemical class 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 claims description 7
• 101710132601 Capsid protein Proteins 0.000 claims description 7
• 125000003566 oxetanyl group Chemical group 0.000 claims description 7
• 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims description 5
• GIHOOXYWJBWJEA-UHFFFAOYSA-N 12-tert-butyl-6-methoxy-3-oxo-11,12-dihydro-4H-benzo[c][1,10]phenanthroline-2-carboxylic acid Chemical compound CC(C)(C)C1CC2=C(C3=C1C=C(C(=O)N3)C(=O)O)N=C(C4=CC=CC=C24)OC GIHOOXYWJBWJEA-UHFFFAOYSA-N 0.000 claims description 5
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 229960001438 immunostimulant agent Drugs 0.000 claims description 5
• 239000003022 immunostimulating agent Substances 0.000 claims description 5
• 230000003308 immunostimulating effect Effects 0.000 claims description 5
• NGCGQBZIHUSODO-UHFFFAOYSA-N 12-tert-butyl-6-methoxy-4-methyl-3-oxo-11,12-dihydrobenzo[c][1,10]phenanthroline-2-carboxylic acid Chemical compound C(C)(C)(C)C1CC=2C3=C(C(=NC2C=2N(C(C(=CC12)C(=O)O)=O)C)OC)C=CC=C3 NGCGQBZIHUSODO-UHFFFAOYSA-N 0.000 claims description 4
• GBVWZIQPNYNQEC-UHFFFAOYSA-N 15-(difluoromethoxy)-4-oxo-9-propan-2-yl-3,11,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2(7),5,12,14,16-hexaene-5-carboxylic acid Chemical compound FC(OC1=CC=CN2C1=NC1=C2C(CC=2C=C(C(NC12)=O)C(=O)O)C(C)C)F GBVWZIQPNYNQEC-UHFFFAOYSA-N 0.000 claims description 4
• LOLMJVJLAJFTJI-UHFFFAOYSA-N 15-methoxy-4-oxo-8-propan-2-yl-3,11,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2(7),5,12,14,16-hexaene-5-carboxylic acid Chemical compound CC(C)C(CC1=C2N=C3N1C=CC=C3OC)C(C=C1C(O)=O)=C2NC1=O LOLMJVJLAJFTJI-UHFFFAOYSA-N 0.000 claims description 4
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
• 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 3
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 3
• 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 3
• 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 3
• JUADMHPZOMCVEA-UHFFFAOYSA-N 5-tert-butyl-11-(difluoromethoxy)-2-oxo-5,6-dihydro-1H-benzimidazolo[1,2-h][1,7]naphthyridine-3-carboxylic acid Chemical compound CC(C)(C)C1CN2C3=C(C(=CC=C3)OC(F)F)N=C2C4=C1C=C(C(=O)N4)C(=O)O JUADMHPZOMCVEA-UHFFFAOYSA-N 0.000 claims description 3
• 101100516572 Caenorhabditis elegans nhr-8 gene Proteins 0.000 claims description 3
• JVUFIFRNSGVHCD-UHFFFAOYSA-N 15-(difluoromethoxy)-4-oxo-8-propan-2-yl-3,11,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2(7),5,12,14,16-hexaene-5-carboxylic acid Chemical compound FC(OC1=CC=CN2C1=NC1=C2CC(C=2C=C(C(NC12)=O)C(=O)O)C(C)C)F JVUFIFRNSGVHCD-UHFFFAOYSA-N 0.000 claims description 2
• JHQLWRDSDLITKB-UHFFFAOYSA-N 5-tert-butyl-11-(difluoromethoxy)-4-hydroxy-2-oxo-5,6-dihydro-1H-benzimidazolo[1,2-h][1,7]naphthyridine-3-carboxylic acid Chemical compound CC(C)(C)C1CN2C3=C(C(=CC=C3)OC(F)F)N=C2C4=C1C(=C(C(=O)N4)C(=O)O)O JHQLWRDSDLITKB-UHFFFAOYSA-N 0.000 claims description 2
• NFTHVGYVBOMYFK-UHFFFAOYSA-N 5-tert-butyl-11-ethoxy-4-hydroxy-2-oxo-5,6-dihydro-1H-indolo[1,2-h][1,7]naphthyridine-3-carboxylic acid Chemical compound CCOC1=CC=CC2=C1C=C1N2CC(C(C)(C)C)C(C(O)=C2C(O)=O)=C1NC2=O NFTHVGYVBOMYFK-UHFFFAOYSA-N 0.000 claims description 2
• CLJIUKWQSWRJQN-UHFFFAOYSA-N 5-tert-butyl-4-hydroxy-11-(2-methoxyethoxy)-2-oxo-5,6-dihydro-1H-indolo[1,2-h][1,7]naphthyridine-3-carboxylic acid Chemical compound CC(C)(C)C1CN2C3=C(C=C2C4=C1C(=C(C(=O)N4)C(=O)O)O)C(=CC=C3)OCCOC CLJIUKWQSWRJQN-UHFFFAOYSA-N 0.000 claims description 2
• ZBFPSUKGYRIYPM-UHFFFAOYSA-N 5-tert-butyl-4-hydroxy-11-methoxy-2-oxo-5,6-dihydro-1H-indolo[1,2-h][1,7]naphthyridine-3-carboxylic acid Chemical compound CC(C)(C)C1CN2C3=C(C=C2C4=C1C(=C(C(=O)N4)C(=O)O)O)C(=CC=C3)OC ZBFPSUKGYRIYPM-UHFFFAOYSA-N 0.000 claims description 2
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