TWI641615B - 經取代之核苷、核苷酸及其類似物 - Google Patents

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Publication number

TWI641615B

TWI641615B TW102147608A TW102147608A TWI641615B TW I641615 B TWI641615 B TW I641615B TW 102147608 A TW102147608 A TW 102147608A TW 102147608 A TW102147608 A TW 102147608A TW I641615 B TWI641615 B TW I641615B

Authority

TW

Taiwan

Prior art keywords

optionally substituted

alkyl

compound

hydrogen

group

Prior art date

2012-12-21

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• 125000003729 nucleotide group Chemical group 0.000 title abstract description 8
• 239000002777 nucleoside Substances 0.000 title description 18
• 239000002773 nucleotide Substances 0.000 title description 3
• 125000003835 nucleoside group Chemical group 0.000 title description 2
• 208000015181 infectious disease Diseases 0.000 claims abstract description 39
• 150000001875 compounds Chemical class 0.000 claims description 571
• 125000000217 alkyl group Chemical group 0.000 claims description 333
• 150000003839 salts Chemical class 0.000 claims description 261
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• 125000000623 heterocyclic group Chemical group 0.000 claims description 98
• 125000003107 substituted aryl group Chemical group 0.000 claims description 90
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• 125000001072 heteroaryl group Chemical group 0.000 claims description 77
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• 150000001413 amino acids Chemical class 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 39
• 239000003814 drug Substances 0.000 claims description 38
• 125000003342 alkenyl group Chemical group 0.000 claims description 35
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 32
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
• 230000000694 effects Effects 0.000 claims description 30
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 27
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 27
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• 229910052717 sulfur Inorganic materials 0.000 claims description 25
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• 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 23
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• 125000005843 halogen group Chemical group 0.000 claims description 17
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• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 14
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 13
• 102100031083 Uteroglobin Human genes 0.000 claims description 12
• 230000002401 inhibitory effect Effects 0.000 claims description 12
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• 125000003277 amino group Chemical group 0.000 claims description 11
• 150000002148 esters Chemical class 0.000 claims description 11
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• 241000700605 Viruses Species 0.000 claims description 10
• 235000004279 alanine Nutrition 0.000 claims description 10
• 125000001188 haloalkyl group Chemical group 0.000 claims description 10
• 239000003085 diluting agent Substances 0.000 claims description 9
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
• ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 8
• 239000011737 fluorine Substances 0.000 claims description 8
• 229910052731 fluorine Inorganic materials 0.000 claims description 8
• 229910052757 nitrogen Inorganic materials 0.000 claims description 8
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 7
• 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 7
• 101000777301 Homo sapiens Uteroglobin Proteins 0.000 claims description 6
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• 229910052805 deuterium Inorganic materials 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 6
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 5
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
• 125000005282 allenyl group Chemical group 0.000 claims description 3
• RFGUWOCFYCYEDM-ZOMNBDOOSA-N 8v42y78hru Chemical compound OP([C@@]12C[C@H]1CCCCCCC[C@@H](C(=O)N1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1N=C(NC(C)C)SC=1)Cl)OC)NC(=O)OC1CCCC1)(=O)CC1=C(F)C=CC=C1F RFGUWOCFYCYEDM-ZOMNBDOOSA-N 0.000 claims description 2
• OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 claims description 2
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• YEPBUHWNLNKZBW-UEMKMYPFSA-N O=C([C@]12NC(=O)[C@H]3N(C(N(C)CCCC\C=C/[C@@H]1C2)=O)CC[C@@H](C3)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(F)(F)F)C)OC)NS(=O)(=O)C1(C)CC1 Chemical compound O=C([C@]12NC(=O)[C@H]3N(C(N(C)CCCC\C=C/[C@@H]1C2)=O)CC[C@@H](C3)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(F)(F)F)C)OC)NS(=O)(=O)C1(C)CC1 YEPBUHWNLNKZBW-UEMKMYPFSA-N 0.000 claims description 2
• YAAQYJCOIFNMKX-RSTNYOGXSA-N [(2r,3r,4r,5r)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-4-methyl-2-[[[[(2s)-1-oxo-1-propan-2-yloxypropan-2-yl]amino]-phenoxyphosphoryl]oxymethyl]oxolan-3-yl] 2-methylpropanoate Chemical compound O([P@@](=O)(OC[C@@H]1[C@H]([C@@](C)(O)[C@](C#N)(C=2N3N=CN=C(N)C3=CC=2)O1)OC(=O)C(C)C)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 YAAQYJCOIFNMKX-RSTNYOGXSA-N 0.000 claims description 2
• XJBILYMRFVHPJB-XJQUKVTJSA-N [(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-2-azido-4-methyl-3-(2-methylpropanoyloxy)oxolan-2-yl]methyl 2-methylpropanoate Chemical compound C[C@H]1[C@H](OC(=O)C(C)C)[C@](COC(=O)C(C)C)(N=[N+]=[N-])O[C@H]1N1C(=O)N=C(N)C=C1 XJBILYMRFVHPJB-XJQUKVTJSA-N 0.000 claims description 2
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• NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 claims description 2
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• UDMJANYPQWEDFT-ZAWFUYGJSA-N deldeprevir Chemical compound C([C@@H]1C(=O)N2[C@H](C(N[C@@]3(C[C@H]3\C=C/CCCCC1)C(=O)NS(=O)(=O)C1CC1)=O)C[C@H](C2)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)C(=O)N1CCCC(F)(F)C1 UDMJANYPQWEDFT-ZAWFUYGJSA-N 0.000 claims description 2
• BMAIGAHXAJEULY-UKTHLTGXSA-N deleobuvir Chemical compound C12=CC=C(C(=O)NC3(CCC3)C=3N(C4=CC(\C=C\C(O)=O)=CC=C4N=3)C)C=C2N(C)C(C=2N=CC(Br)=CN=2)=C1C1CCCC1 BMAIGAHXAJEULY-UKTHLTGXSA-N 0.000 claims description 2
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• UAUIUKWPKRJZJV-MDJGTQRPSA-N paritaprevir Chemical compound C1=NC(C)=CN=C1C(=O)N[C@@H]1C(=O)N2C[C@H](OC=3C4=CC=CC=C4C4=CC=CC=C4N=3)C[C@H]2C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@@H]2\C=C/CCCCC1 UAUIUKWPKRJZJV-MDJGTQRPSA-N 0.000 claims description 2
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• 150000002431 hydrogen Chemical class 0.000 claims 42
• SRMCAKWGHOOMDV-ZETCQYMHSA-N (2s)-4-methylsulfanyl-2-(propan-2-ylamino)butanoic acid Chemical compound CSCC[C@@H](C(O)=O)NC(C)C SRMCAKWGHOOMDV-ZETCQYMHSA-N 0.000 claims 2
• LABFFVKLPSJCAN-UHFFFAOYSA-N 2-(propan-2-ylazaniumyl)propanoate Chemical compound CC(C)NC(C)C(O)=O LABFFVKLPSJCAN-UHFFFAOYSA-N 0.000 claims 2
• ICCBZGUDUOMNOF-UHFFFAOYSA-N azidoamine Chemical compound NN=[N+]=[N-] ICCBZGUDUOMNOF-UHFFFAOYSA-N 0.000 claims 2
• CJXAEXPPLWQRFR-UHFFFAOYSA-N clemizole Chemical compound C1=CC(Cl)=CC=C1CN1C2=CC=CC=C2N=C1CN1CCCC1 CJXAEXPPLWQRFR-UHFFFAOYSA-N 0.000 claims 2
• 229950002020 clemizole Drugs 0.000 claims 2
• OCAIYHCKLADPEG-UHFFFAOYSA-N propan-2-yl pentanoate Chemical compound CCCCC(=O)OC(C)C OCAIYHCKLADPEG-UHFFFAOYSA-N 0.000 claims 2
• AQHMBDAHQGYLIU-XNFHFXFQSA-N (3s,6s,9s,12r,15s,18s,21s,24s,27r,30s,33s)-27-[2-(dimethylamino)ethylsulfanyl]-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-24-(2-hydroxy-2-methylpropyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18-tris(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10, Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)(C)O)N(C)C(=O)[C@@H](SCCN(C)C)N(C)C1=O AQHMBDAHQGYLIU-XNFHFXFQSA-N 0.000 claims 1
• YQUCBFIQSJVCOR-JOCHJYFZSA-N (7r)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)amino}-7,8-dihydro-6h-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid Chemical compound C([C@@H](CN1C2=CC(=CC=C22)C(O)=O)N(C)CCN(C)C)OC3=CC=CC=C3C1=C2C1CCCCC1 YQUCBFIQSJVCOR-JOCHJYFZSA-N 0.000 claims 1
• 108010030583 (melle-4)cyclosporin Proteins 0.000 claims 1
• ISAQBYHVYXCWAV-UHFFFAOYSA-N 3-methyl-2-(propan-2-ylazaniumyl)butanoate Chemical compound CC(C)NC(C(C)C)C(O)=O ISAQBYHVYXCWAV-UHFFFAOYSA-N 0.000 claims 1
• MAQDQJWCSSCURR-UHFFFAOYSA-N 4-[5-(cyclopropanecarbonylamino)-2-(trifluoromethoxy)phenyl]-n-[4-[(4-propylsulfonylpiperazin-1-yl)methyl]phenyl]benzamide Chemical compound C1CN(S(=O)(=O)CCC)CCN1CC(C=C1)=CC=C1NC(=O)C1=CC=C(C=2C(=CC=C(NC(=O)C3CC3)C=2)OC(F)(F)F)C=C1 MAQDQJWCSSCURR-UHFFFAOYSA-N 0.000 claims 1
• VFOKSTCIRGDTBR-UHFFFAOYSA-N 4-amino-2-butoxy-8-[[3-(pyrrolidin-1-ylmethyl)phenyl]methyl]-5,7-dihydropteridin-6-one Chemical compound C12=NC(OCCCC)=NC(N)=C2NC(=O)CN1CC(C=1)=CC=CC=1CN1CCCC1 VFOKSTCIRGDTBR-UHFFFAOYSA-N 0.000 claims 1
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• MHFMTUBUVQZIRE-WINRQGAFSA-N Sovaprevir Chemical compound C([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C=C2N=C(C=1)C=1C=CC=CC=1)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(=O)NS(=O)(=O)C1CC1)C(C)(C)C)C(=O)N1CCCCC1 MHFMTUBUVQZIRE-WINRQGAFSA-N 0.000 claims 1
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• JYLMWUZJMRNMDA-SPRBZRACSA-N methyl n-[(2s)-1-[(2s)-2-[5-[6-[2-[(2s)-1-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-3h-benzimidazol-5-yl]naphthalen-2-yl]-1h-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate;dihydrochloride Chemical compound Cl.Cl.COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC=C(C=2C=C3C=CC(=CC3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)N1 JYLMWUZJMRNMDA-SPRBZRACSA-N 0.000 claims 1
• OSOOBMBDIGGTCP-UHFFFAOYSA-N miravirsen Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=S)OC2C3(COP(O)(=S)OC4C(OC(C4)N4C(N=C(N)C=C4)=O)COP(O)(=S)OC4C5(CO)COC4C(O5)N4C(N=C(N)C=C4)=O)COC2C(O3)N2C3=NC=NC(N)=C3N=C2)C(OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC23OC(C(OC2)C3OP(O)(=S)OCC23C(C(OC2)C(O3)N2C(N=C(N)C=C2)=O)O)N2C(N=C(N)C=C2)=O)N2C(N=C(N)C=C2)=O)N2C(N=C(N)C=C2)=O)N2C(NC(=O)C(C)=C2)=O)N2C3=C(C(NC(N)=N3)=O)N=C2)C1 OSOOBMBDIGGTCP-UHFFFAOYSA-N 0.000 claims 1
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• CEICQMBWAQAIQX-UHFFFAOYSA-N n-[3,5-dichloro-4-[2-(trifluoromethoxy)phenyl]phenyl]-2-(4-ethylsulfonylphenyl)acetamide Chemical compound C1=CC(S(=O)(=O)CC)=CC=C1CC(=O)NC1=CC(Cl)=C(C=2C(=CC=CC=2)OC(F)(F)F)C(Cl)=C1 CEICQMBWAQAIQX-UHFFFAOYSA-N 0.000 claims 1
• XMZSTQYSBYEENY-RMKNXTFCSA-N n-[4-[(e)-2-[3-tert-butyl-5-(2,4-dioxopyrimidin-1-yl)-2-methoxyphenyl]ethenyl]phenyl]methanesulfonamide Chemical compound C1=C(N2C(NC(=O)C=C2)=O)C=C(C(C)(C)C)C(OC)=C1\C=C\C1=CC=C(NS(C)(=O)=O)C=C1 XMZSTQYSBYEENY-RMKNXTFCSA-N 0.000 claims 1
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