CA2607359C - Compounds and methods for the treatment or prevention of flavivirus infections - Google Patents

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Publication number

CA2607359C

CA2607359C CA2607359A CA2607359A CA2607359C CA 2607359 C CA2607359 C CA 2607359C CA 2607359 A CA2607359 A CA 2607359A CA 2607359 A CA2607359 A CA 2607359A CA 2607359 C CA2607359 C CA 2607359C

Authority

CA

Canada

Prior art keywords

alkyl

trans

methyl

optionally substituted

thiophene

Prior art date

2005-05-13

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.)

Expired - Fee Related

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 361
• 238000000034 method Methods 0.000 title description 54
• 206010054261 Flavivirus infection Diseases 0.000 title description 6
• 238000011282 treatment Methods 0.000 title description 6
• 230000002265 prevention Effects 0.000 title description 3
• 150000003839 salts Chemical class 0.000 claims abstract description 195
• 239000012453 solvate Substances 0.000 claims abstract description 182
• 241000711549 Hepacivirus C Species 0.000 claims abstract description 34
• 208000036142 Viral infection Diseases 0.000 claims abstract description 17
• 230000009385 viral infection Effects 0.000 claims abstract description 17
• 241000700605 Viruses Species 0.000 claims abstract description 6
• 241000710777 Classical swine fever virus Species 0.000 claims abstract description 4
• 208000001490 Dengue Diseases 0.000 claims abstract description 3
• 206010012310 Dengue fever Diseases 0.000 claims abstract description 3
• 241000710842 Japanese encephalitis virus Species 0.000 claims abstract description 3
• 241000710772 Yellow fever virus Species 0.000 claims abstract description 3
• 208000025729 dengue disease Diseases 0.000 claims abstract description 3
• 229940051021 yellow-fever virus Drugs 0.000 claims abstract description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 340
• -1 substituted Chemical class 0.000 claims description 300
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 220
• 125000000623 heterocyclic group Chemical group 0.000 claims description 149
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 131
• 125000001072 heteroaryl group Chemical group 0.000 claims description 129
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 123
• 229910052736 halogen Inorganic materials 0.000 claims description 113
• 150000002367 halogens Chemical class 0.000 claims description 109
• 125000003545 alkoxy group Chemical group 0.000 claims description 102
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 97
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 94
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 93
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 92
• 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 90
• 125000000304 alkynyl group Chemical group 0.000 claims description 85
• 125000003118 aryl group Chemical group 0.000 claims description 83
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 83
• 125000003342 alkenyl group Chemical group 0.000 claims description 82
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 81
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 76
• 229910052757 nitrogen Inorganic materials 0.000 claims description 74
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 73
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 70
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 57
• 125000004043 oxo group Chemical group O=* 0.000 claims description 53
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 49
• 230000003612 virological effect Effects 0.000 claims description 48
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 46
• 125000004104 aryloxy group Chemical group 0.000 claims description 43
• 229910006074 SO2NH2 Inorganic materials 0.000 claims description 41
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 40
• 239000003795 chemical substances by application Substances 0.000 claims description 39
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 37
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 37
• 239000003112 inhibitor Substances 0.000 claims description 31
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 27
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 23
• 102000014150 Interferons Human genes 0.000 claims description 22
• 108010050904 Interferons Proteins 0.000 claims description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
• 150000002923 oximes Chemical class 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 16
• 241000710781 Flaviviridae Species 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims description 12
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 229940079322 interferon Drugs 0.000 claims description 11
• 229920006395 saturated elastomer Polymers 0.000 claims description 10
• 239000003001 serine protease inhibitor Substances 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 9
• 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 claims description 9
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 125000005842 heteroatom Chemical group 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 239000011593 sulfur Chemical group 0.000 claims description 8
• 108060004795 Methyltransferase Proteins 0.000 claims description 7
• WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 claims description 7
• 125000005879 dioxolanyl group Chemical group 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• HQUCUQJOQOFEQW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(=O)CC1 HQUCUQJOQOFEQW-UHFFFAOYSA-N 0.000 claims description 6
• 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 6
• 108091005804 Peptidases Proteins 0.000 claims description 6
• 239000004365 Protease Substances 0.000 claims description 6
• 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 6
• 239000003242 anti bacterial agent Substances 0.000 claims description 6
• 230000000692 anti-sense effect Effects 0.000 claims description 6
• 239000003963 antioxidant agent Substances 0.000 claims description 6
• 230000000694 effects Effects 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 229960000329 ribavirin Drugs 0.000 claims description 6
• 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 6
• VSIYJQNFMOOGCU-UHFFFAOYSA-N 1-(cyclohexen-1-yl)cyclohexene Chemical group C1CCCC(C=2CCCCC=2)=C1 VSIYJQNFMOOGCU-UHFFFAOYSA-N 0.000 claims description 5
• MGIDOELNCIGRPO-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(O)CC1 MGIDOELNCIGRPO-UHFFFAOYSA-N 0.000 claims description 5
• NRWYAVDHRVTITK-UPRSBDKSSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCC=1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCC=1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 NRWYAVDHRVTITK-UPRSBDKSSA-N 0.000 claims description 5
• FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 claims description 5
• 125000004122 cyclic group Chemical group 0.000 claims description 5
• 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 5
• 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 5
• ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Chemical group C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 229940021747 therapeutic vaccine Drugs 0.000 claims description 5
• 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
• QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 4
• RNEQXUALSHFBCE-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-(4-oxocyclohexen-1-yl)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCC(=O)CC=1)C(O)=O)C1CCC(O)CC1 RNEQXUALSHFBCE-UHFFFAOYSA-N 0.000 claims description 4
• JVSQRBKXYYHNAL-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-(4-phenoxycyclohexen-1-yl)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCC(CC=1)OC=1C=CC=CC=1)C(O)=O)C1CCC(O)CC1 JVSQRBKXYYHNAL-UHFFFAOYSA-N 0.000 claims description 4
• AMOXNTAMLUCWJT-UHFFFAOYSA-N 5-(4,4-dimethylcyclohexyl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C1CCC(C)(C)CC1)C(O)=O)C(=O)C1CCC(C)CC1 AMOXNTAMLUCWJT-UHFFFAOYSA-N 0.000 claims description 4
• OFOMFFOXKMZUIW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-(n-(4-methylcyclohexanecarbonyl)anilino)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C=1C=CC=CC=1)C1=C(C(O)=O)SC(C=2CCCCC=2)=C1 OFOMFFOXKMZUIW-UHFFFAOYSA-N 0.000 claims description 4
• GJNZQSSHAVNWFW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(2,4-dichlorobenzoyl)-propan-2-ylamino]thiophene-2-carboxylic acid Chemical compound C1=C(C=2CCCCC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl GJNZQSSHAVNWFW-UHFFFAOYSA-N 0.000 claims description 4
• OSZNFYRPACBWAD-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-ethoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OCC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)C1CCC(C)CC1 OSZNFYRPACBWAD-UHFFFAOYSA-N 0.000 claims description 4
• SNHOCYVWFCETLM-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[[4-(methoxymethoxy)cyclohexyl]-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OCOC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)C1CCC(C)CC1 SNHOCYVWFCETLM-UHFFFAOYSA-N 0.000 claims description 4
• VCJJWZOMFHUKMX-UHFFFAOYSA-N 5-cyclohexyl-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C1CCCCC1)C(O)=O)C1CCC(O)CC1 VCJJWZOMFHUKMX-UHFFFAOYSA-N 0.000 claims description 4
• HZCUBYGLTQHCPR-JCNLHEQBSA-N C1=C(C=2CCCCC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)[C@H]1CC[C@H](C)CC1 Chemical compound C1=C(C=2CCCCC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)[C@H]1CC[C@H](C)CC1 HZCUBYGLTQHCPR-JCNLHEQBSA-N 0.000 claims description 4
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
• 229940123066 Polymerase inhibitor Drugs 0.000 claims description 4
• DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
• 229960003805 amantadine Drugs 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 229910052740 iodine Inorganic materials 0.000 claims description 4
• 229910052744 lithium Inorganic materials 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 239000011734 sodium Substances 0.000 claims description 4
• 229910052708 sodium Inorganic materials 0.000 claims description 4
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
• 150000003536 tetrazoles Chemical class 0.000 claims description 4
• 229920002554 vinyl polymer Chemical group 0.000 claims description 4
• OQJNOHVPDZQBCM-UHFFFAOYSA-N 5-(3-hydroxycyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[4-(oxan-2-yloxy)cyclohexyl]amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCC(O)C=1)C(O)=O)C1CCC(OC2OCCCC2)CC1 OQJNOHVPDZQBCM-UHFFFAOYSA-N 0.000 claims description 3
• KQXCUMQUYNMNKA-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(2,4-dimethylphenyl)sulfonylamino]thiophene-2-carboxylic acid Chemical compound CC1=CC(C)=CC=C1S(=O)(=O)NC1=C(C(O)=O)SC(C=2CCCCC=2)=C1 KQXCUMQUYNMNKA-UHFFFAOYSA-N 0.000 claims description 3
• VQNVTTOMIYUAAT-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-methylbenzoyl)-propan-2-ylamino]thiophene-2-carboxylic acid Chemical compound C1=C(C=2CCCCC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(C)C=C1 VQNVTTOMIYUAAT-UHFFFAOYSA-N 0.000 claims description 3
• NHRHXDMGFVGNRU-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[1,3-dioxan-5-yl-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1COCOC1 NHRHXDMGFVGNRU-UHFFFAOYSA-N 0.000 claims description 3
• NRWYAVDHRVTITK-UHFFFAOYSA-N 5-(cyclopenten-1-yl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCC=1)C(O)=O)C1CCC(O)CC1 NRWYAVDHRVTITK-UHFFFAOYSA-N 0.000 claims description 3
• YBQKQVZAEDDNAU-CTYIDZIISA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C)C1=C(C(O)=O)SC(C=2CCCCC=2)=C1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C)C1=C(C(O)=O)SC(C=2CCCCC=2)=C1 YBQKQVZAEDDNAU-CTYIDZIISA-N 0.000 claims description 3
• FPARYJXWWMDFFU-KQEUCTNFSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C1C=CCCC1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C1C=CCCC1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 FPARYJXWWMDFFU-KQEUCTNFSA-N 0.000 claims description 3
• YIBUSNKWAYXYIB-YSXIEMCBSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C1CCCCCC1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C1CCCCCC1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 YIBUSNKWAYXYIB-YSXIEMCBSA-N 0.000 claims description 3
• CMBPRRDJOSJOPZ-LBKZCYKOSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCC(CC=1)C(C)(C)C)C(O)=O)[C@@H]1CC[C@@H](O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCC(CC=1)C(C)(C)C)C(O)=O)[C@@H]1CC[C@@H](O)CC1 CMBPRRDJOSJOPZ-LBKZCYKOSA-N 0.000 claims description 3
• XMHTZCKCUJIEIC-PPFQCUIHSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CC(C)CCC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CC(C)CCC1 XMHTZCKCUJIEIC-PPFQCUIHSA-N 0.000 claims description 3
• DTJARGIYIUHGII-KOMQPUFPSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CC1 DTJARGIYIUHGII-KOMQPUFPSA-N 0.000 claims description 3
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• QJEOKVNLHVLDLL-SAABIXHNSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCOCC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCOCC1 QJEOKVNLHVLDLL-SAABIXHNSA-N 0.000 claims description 3
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• 125000003107 substituted aryl group Chemical group 0.000 claims 3
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• VRCATWVIEHHTHZ-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[cyclohexyl-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCCCC1 VRCATWVIEHHTHZ-UHFFFAOYSA-N 0.000 claims 2
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• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
• QMPSPZPLWQPLNV-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[[1-(2,2-difluoroethyl)piperidin-4-yl]-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCN(CC(F)F)CC1 QMPSPZPLWQPLNV-UHFFFAOYSA-N 0.000 claims 1
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• SNLFZVXDVWBLJR-FFPCIGOZSA-N [Cl-].C1(=CCCCC1)C1=CC(=C(S1)C(=O)OC)N(C1CC[NH+](CC1)C)C(=O)[C@@H]1CC[C@H](CC1)C Chemical compound [Cl-].C1(=CCCCC1)C1=CC(=C(S1)C(=O)OC)N(C1CC[NH+](CC1)C)C(=O)[C@@H]1CC[C@H](CC1)C SNLFZVXDVWBLJR-FFPCIGOZSA-N 0.000 claims 1
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• RGOXDVCFLLPALO-UHFFFAOYSA-N azanium;5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[1-(pyridin-3-ylmethyl)piperidin-4-yl]amino]thiophene-2-carboxylate Chemical compound [NH4+].C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C([O-])=O)C1CCN(CC=2C=NC=CC=2)CC1 RGOXDVCFLLPALO-UHFFFAOYSA-N 0.000 claims 1
• WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 claims 1
• 206010051511 Viral diarrhoea Diseases 0.000 abstract 1
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• GVIDKWMNFNCELI-UHFFFAOYSA-N methyl 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-tributylstannylthiophene-2-carboxylate Chemical compound S1C([Sn](CCCC)(CCCC)CCCC)=CC(N(C2CCC(O)CC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC GVIDKWMNFNCELI-UHFFFAOYSA-N 0.000 description 2
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• CXOZJRDPSBGTDT-UHFFFAOYSA-N methyl 5-(1-hydroxycyclohex-2-en-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[4-(oxan-2-yloxy)cyclohexyl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2(O)C=CCCC2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC1OC1CCCCO1 CXOZJRDPSBGTDT-UHFFFAOYSA-N 0.000 description 2
• DWPUQUYRFXVZMZ-UHFFFAOYSA-N methyl 5-(2,3-difluorocyclohexen-1-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C=1CCCC(F)C=1F)C(=O)OC)C(=O)C1CCC(C)CC1 DWPUQUYRFXVZMZ-UHFFFAOYSA-N 0.000 description 2
• LIXSQKKNCMTAOV-UHFFFAOYSA-N methyl 5-(2,6-difluorocyclohexen-1-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C=1C(CCCC=1F)F)C(=O)OC)C(=O)C1CCC(C)CC1 LIXSQKKNCMTAOV-UHFFFAOYSA-N 0.000 description 2
• TZWZECVZNWQKPF-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexen-1-yl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCC(C)(C)CC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1 TZWZECVZNWQKPF-UHFFFAOYSA-N 0.000 description 2
• IKOOQCARUDZMIN-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCC(C)(C)CC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1 IKOOQCARUDZMIN-UHFFFAOYSA-N 0.000 description 2
• SDBPCUBBQPSQIX-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[4-(1,2,4-triazol-1-yl)cyclohexyl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCC(C)(C)CC=2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC1N1C=NC=N1 SDBPCUBBQPSQIX-UHFFFAOYSA-N 0.000 description 2
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• WLZHXIQKYJUIQZ-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexyl)-3-[(4-methylcyclohexanecarbonyl)-(4-methylsulfonyloxycyclohexyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(OS(C)(=O)=O)CC1 WLZHXIQKYJUIQZ-UHFFFAOYSA-N 0.000 description 2
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• WWOYCMCZTZTIGU-UHFFFAOYSA-L magnesium;2-carboxybenzenecarboperoxoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].OOC(=O)C1=CC=CC=C1C([O-])=O.OOC(=O)C1=CC=CC=C1C([O-])=O WWOYCMCZTZTIGU-UHFFFAOYSA-L 0.000 description 1
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• OGJDZVITLCFAII-UHFFFAOYSA-N methyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate Chemical compound C1CC(=CC(=O)OC)CCC21OCCO2 OGJDZVITLCFAII-UHFFFAOYSA-N 0.000 description 1
• NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
• KMTPLRIOOJYJQD-UHFFFAOYSA-N methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)thiophene-2-carboxylate Chemical compound S1C=CC(NC2CCC3(CC2)OCCO3)=C1C(=O)OC KMTPLRIOOJYJQD-UHFFFAOYSA-N 0.000 description 1
• BQQHXIZCAPCAQE-UHFFFAOYSA-N methyl 3-amino-5-(4,4-dimethylcyclohexen-1-yl)thiophene-2-carboxylate Chemical compound NC1=C(C(=O)OC)SC(C=2CCC(C)(C)CC=2)=C1 BQQHXIZCAPCAQE-UHFFFAOYSA-N 0.000 description 1
• TWEQNZZOOFKOER-UHFFFAOYSA-N methyl 3-aminothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1N TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
• UEARGZRWCIVDOO-UHFFFAOYSA-N methyl 3-anilino-5-(cyclohexen-1-yl)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1NC1=CC=CC=C1 UEARGZRWCIVDOO-UHFFFAOYSA-N 0.000 description 1
• PEGSJNCGPSIJOX-UHFFFAOYSA-N methyl 3-bromothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1Br PEGSJNCGPSIJOX-UHFFFAOYSA-N 0.000 description 1
• XSKFBQUERIPAKH-UHFFFAOYSA-N methyl 5-(1,4-dioxaspiro[4.5]decan-8-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C1CCC2(CC1)OCCO2)C(=O)OC)C(=O)C1CCC(C)CC1 XSKFBQUERIPAKH-UHFFFAOYSA-N 0.000 description 1
• XHDJCEAGKSIJBB-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexen-1-yl)-3-[[4-(methoxymethoxy)cyclohexyl]-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OCOC)CCC1N(C1=C(SC(=C1)C=1CCC(C)(C)CC=1)C(=O)OC)C(=O)C1CCC(C)CC1 XHDJCEAGKSIJBB-UHFFFAOYSA-N 0.000 description 1
• IPICGJKKANUVMD-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1 IPICGJKKANUVMD-UHFFFAOYSA-N 0.000 description 1
• NBXAFBUAJVRUIU-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexyl)-3-[(4-methylcyclohexanecarbonyl)-[4-(1,2,4-triazol-1-yl)cyclohexyl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC1N1C=NC=N1 NBXAFBUAJVRUIU-UHFFFAOYSA-N 0.000 description 1
• ATEZBAUSRGJRTP-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-(n-(4-methylcyclohexanecarbonyl)anilino)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C=1C=CC=CC=1)C(=O)C1CCC(C)CC1 ATEZBAUSRGJRTP-UHFFFAOYSA-N 0.000 description 1
• UDFZVRTZRTUZLH-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(3-oxo-2-azaspiro[4.5]decan-8-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1NC(CC1)CCC21CNC(=O)C2 UDFZVRTZRTUZLH-UHFFFAOYSA-N 0.000 description 1
• HEZJUUMFRVLDCN-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(1-pyrimidin-5-ylpiperidin-4-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCN1C1=CN=CN=C1 HEZJUUMFRVLDCN-UHFFFAOYSA-N 0.000 description 1
• PYNHJVXZJFCQHI-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC21CN(C)C(=O)C2 PYNHJVXZJFCQHI-UHFFFAOYSA-N 0.000 description 1
• PFVAJVRMWSPGKC-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(3-oxo-2,5,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C1CC2N(C(CC2)=O)CC1)C(=O)C1CCC(C)CC1 PFVAJVRMWSPGKC-UHFFFAOYSA-N 0.000 description 1
• UJPXPQITBKABOQ-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[1-(2-methylpropanoyl)piperidin-4-yl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCN(C(=O)C(C)C)CC1 UJPXPQITBKABOQ-UHFFFAOYSA-N 0.000 description 1
• WUDQZNWCZNXVSM-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[1,3-dioxan-5-yl-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1COCOC1 WUDQZNWCZNXVSM-UHFFFAOYSA-N 0.000 description 1
• FRKRFOAZSVJFDM-UHFFFAOYSA-N methyl 5-bromo-3-[(1,3-dimethyl-2,4-dioxo-1,3-diazaspiro[4.5]decan-8-yl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C2CCC3(CC2)C(N(C)C(=O)N3C)=O)C(=O)C2CCC(C)CC2)=C1C(=O)OC FRKRFOAZSVJFDM-UHFFFAOYSA-N 0.000 description 1
• DNVFEPOGJHDYMJ-UHFFFAOYSA-N methyl 5-bromo-3-[(2,2-dimethyl-1,3-dioxan-5-yl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C2COC(C)(C)OC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC DNVFEPOGJHDYMJ-UHFFFAOYSA-N 0.000 description 1
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• YMZBNCXRVMHBHA-UHFFFAOYSA-N methyl 5-cyclohex-2-en-1-yl-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2C=CCCC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1 YMZBNCXRVMHBHA-UHFFFAOYSA-N 0.000 description 1
• UODPHKFUTYRNDZ-UHFFFAOYSA-N methyl 5-cyclohex-2-en-1-yl-3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2C=CCCC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1 UODPHKFUTYRNDZ-UHFFFAOYSA-N 0.000 description 1
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• WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
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