WO2021093860A1 - Composé bis-tricyclique substitué, composition pharmaceutique et utilisation de celui-ci - Google Patents
Composé bis-tricyclique substitué, composition pharmaceutique et utilisation de celui-ci Download PDFInfo
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- WO2021093860A1 WO2021093860A1 PCT/CN2020/128736 CN2020128736W WO2021093860A1 WO 2021093860 A1 WO2021093860 A1 WO 2021093860A1 CN 2020128736 W CN2020128736 W CN 2020128736W WO 2021093860 A1 WO2021093860 A1 WO 2021093860A1
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- NBYXJHXQLNHLFC-QQHUYRGFSA-N CC(C)(C)OC(N([C@H](COCC1)N1C1=O)N(C=C/C2=N\OCC=C)C1=C2OCOC(OC)=O)=O Chemical compound CC(C)(C)OC(N([C@H](COCC1)N1C1=O)N(C=C/C2=N\OCC=C)C1=C2OCOC(OC)=O)=O NBYXJHXQLNHLFC-QQHUYRGFSA-N 0.000 description 1
- FFAAVXLGIMZOND-HMHKGCENSA-N CC(C)(C)OC(N([C@H](COCC1)N1C1=O)N(C=C/C2=N\OS(C)(=O)=O)C1=C2OCOC(OC)=O)=O Chemical compound CC(C)(C)OC(N([C@H](COCC1)N1C1=O)N(C=C/C2=N\OS(C)(=O)=O)C1=C2OCOC(OC)=O)=O FFAAVXLGIMZOND-HMHKGCENSA-N 0.000 description 1
- BLLZWLNSPRFWKP-CCNSJBOCSA-N CCC(O/N=C(\C=C1)/C(OCOC(OC)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H](c1ccc2F)c3ccccc3SCc1c2F)=O Chemical compound CCC(O/N=C(\C=C1)/C(OCOC(OC)=O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H](c1ccc2F)c3ccccc3SCc1c2F)=O BLLZWLNSPRFWKP-CCNSJBOCSA-N 0.000 description 1
- KGRHJAOLNVEIOU-QZRMXMDGSA-N COC(OCOC(/C(/C=C1)=N/O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H](c1ccc2F)c3ccccc3SCc1c2F)=O Chemical compound COC(OCOC(/C(/C=C1)=N/O)=C(C(N2[C@H]3COCC2)=O)N1N3[C@@H](c1ccc2F)c3ccccc3SCc1c2F)=O KGRHJAOLNVEIOU-QZRMXMDGSA-N 0.000 description 1
- UWIUEKUNODEAEA-JSJZUPIVSA-N COC(OCOC(/C(/C=C1)=N/OS(C)(=O)=O)=C2N1N[C@H](COCC1)N1C2=O)=O Chemical compound COC(OCOC(/C(/C=C1)=N/OS(C)(=O)=O)=C2N1N[C@H](COCC1)N1C2=O)=O UWIUEKUNODEAEA-JSJZUPIVSA-N 0.000 description 1
- KWVQWRBATWAAJL-LURJTMIESA-N C[C@@H](C(OCCC=C)=O)N Chemical compound C[C@@H](C(OCCC=C)=O)N KWVQWRBATWAAJL-LURJTMIESA-N 0.000 description 1
- RDGSEFKMOREHNE-ZOZMEPSFSA-N C[C@@H](C(OCCC=C)=O)NP(Oc1ccccc1)(Cl)=O Chemical compound C[C@@H](C(OCCC=C)=O)NP(Oc1ccccc1)(Cl)=O RDGSEFKMOREHNE-ZOZMEPSFSA-N 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N O=P(Oc1ccccc1)(Cl)Cl Chemical compound O=P(Oc1ccccc1)(Cl)Cl TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to but not limited to the technical field of medicinal chemistry, in particular to a substituted bitricyclic compound and its pharmaceutical composition and use.
- Baloxavirmarboxil (Baloxavirmarboxil), trade name Xofluza TM , is the first single-dose oral antiviral drug developed by Shionoyi Pharmaceutical Co., Ltd. It was approved for marketing in Japan and the United States in 2018.
- the drug has an inhibitory effect on the viral cap-dependent endonuclease, and inhibits the synthesis of viral proteins by inhibiting the synthesis of influenza virus mRNA, and finally inhibits virus proliferation.
- the inventors have developed a bitricyclic compound with a novel structure, which can be used as a virus inhibitor and has anti-virus, especially anti-influenza virus effects.
- One aspect of the present invention provides a bitricyclic compound, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as shown in (I):
- R 1 and R 2 are each independently hydrogen, R 4 -C(O)-, R 4 -OC(O)- or R 4 -OC(O)-O-(CH 2 ) m -, wherein R 4 is hydrogen, aromatic hydrocarbon group, heteroaryl group, C 1 -C 18 alkyl group, or C substituted by one or more of hydroxyl, amino, carboxyl, halogen, aryl or aromatic hydrocarbon group 1- C 18 alkyl, or unsubstituted C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 18 alkyl, or by hydroxyl, amino, carboxy, halo, one or more of aryl or substituted C 3 -C 6 cycloalkyl group, or a hydroxyl group, an amino group, a carboxyl group, a halogen, or a plurality of aryl or substituted C 3 -C 6 Cycloalkyl substituted
- R 1 is a C 6 -C 20 aromatic hydrocarbon carbonyl group substituted with one or more groups A, or selected from the following groups optionally substituted or unsubstituted with one or more groups A: C 6- C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl group, C 2 -C 18 alkenyl group, C 2 -C 18 alkynyl group, C 1 -C 18 alkyl group, C 3 -C 8 cycloalkyl group , C 3 -C 8 heterocycloalkyl, carboxyl esterified or amidated amino acid residues; and,
- R 2 is hydrogen, R 4 -C(O)-, R 4 -OC(O)-, R 4 -O-(CH 2 ) m -or R 4 -OC(O)-O-(CH 2 ) m -, wherein R 4 is hydrogen, or is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl group, C 3 -C 8 cycloalkyl, C 1 -C 18 alkyl, or, R 4 is a C 3 -C 6 cycloalkyl substituted or unsubstituted C optionally substituted by one or more groups A 1- C 18 alkyl; m is 1, 2, 3 or 4; and it is specified that when R 1 is C 1 -C 18 alkoxycarbonyloxy C 1 -C 18 alkyl, R 2 is R 4 -O-(CH 2 )m-;
- R 1 and R 2 are directly connected to form a carbonyl group
- R 1 and R 2 is -(CH 2 ) k -P(O)(OR 5 )(YR 6 ), or -(CH 2 ) j -S(O) 2 -R 7 , where R 5 and R 6 are both hydrogen, R 5 is hydrogen and R 6 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 Heteroaryl, C 2 -C 18 alkenyl, C 2 -C 18 alkynyl, C 1 -C 18 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl , Carboxyl esterified or amidated amino acid residue; or both R 5 and R 6 are selected from the following groups optionally substituted or unsubstituted by one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl, C 2 -C 18
- R 1 and R 2 is hydrogen, R 4 -C(O)-, R 4 -OC(O)-, R 4 -O-(CH 2 ) m -or R 4 -OC(O)-O -(CH 2 ) m -, wherein R 4 is hydrogen, or is selected from the following groups optionally substituted or unsubstituted by one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 18 alkyl, or, R 4 is C 3 -C 6 optionally substituted or unsubstituted by one or more groups A Cycloalkyl substituted C 1 -C 18 alkyl; m is 1, 2, 3 or 4;
- R 1 and R 2 are directly connected to form P(O)-OR 8 ;
- R 8 is a C 6 -C 20 aromatic hydrocarbon group optionally substituted or unsubstituted by one or more groups A;
- the group A is: hydroxy, carboxy, amino, halogen, C 1 -C 18 alkoxycarbonyloxy, C 1 -C 18 alkoxy, C 3 -C 8 cycloalkoxy, C 3- C 8 heterocycloalkoxy, C 6 -C 12 aryloxy, C 5 -C 12 heteroaryloxy, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, C 5 -C 12 heteroaryl;
- R 3 is halogen, hydroxy, amino or carboxy
- n 0, 1, 2, 3, or 4.
- the present invention provides a bitricyclic compound, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as shown in (II):
- the present invention provides a bitricyclic compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in (III):
- R 3 is halogen; in some preferred embodiments, R 3 is fluorine or bromine; more preferably, it is fluorine.
- n is 1, 2, 3, or 4; in some embodiments, n is 1 or 2; preferably, n is 2.
- R 1 and R 2 are each independently hydrogen, R 4 -C(O)- or R 4 -OC(O)-O-(CH 2 ) m -, wherein , R 4 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, and the substituent is selected from one or more of the following: hydroxyl, amino, carboxyl, halogen, C 3 -C 6 cycloalkyl or C 6 -C 10 aryl; m is 1, 2 or 3.
- R 1 and R 2 are each independently hydrogen, R 4 -C(O)- or R 4 -OC(O)-O-(CH 2 ) m -, wherein R 4 is selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, and the substituent is selected from one or more of the following: hydroxy, amino, carboxy, halogen, phenyl, cyclohexyl; m is 1 or 2.
- R 1 is hydrogen
- R 1 and R 2 are both hydrogen.
- R 2 is R 4 -OC(O)-O-CH 2 -, wherein R 4 is a substituted or unsubstituted C 1 -C 6 alkyl group, preferably , R 4 is a substituted or unsubstituted C 1 -C 4 alkyl group; the substituent is selected from one or more of the following: hydroxy, amino, carboxy, halogen or phenyl.
- R 1 is H, R 4 -C(O)- or R 4 -OC(O)-O-CH 2 -, wherein R 4 is substituted or unsubstituted A C 1 -C 6 alkyl group, preferably, R 4 is a substituted or unsubstituted C 1 -C 4 alkyl group; the substituent is selected from one or more of the following: hydroxyl, amino, carboxyl, halogen, C 3- C 6 cycloalkyl or C 6 -C 10 aryl.
- R 1 is hydrogen, R 4 -C(O)-, R 4 -OC(O)-O-CH 2 -or R 4 -OC(O)-
- R 4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent is selected from one or more of the following: hydroxyl, amino, carboxyl, halogen, C 3 -C 6 cycloalkyl or C 6 -C 10 aryl
- R 2 is R 4 -OC(O)-O-CH 2 -, wherein R 4 is a substituted or unsubstituted C 1 -C 6 alkyl group, and the substituent is selected from one or more of the following One: hydroxyl, amino, carboxyl, halogen or phenyl;
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or a C 1 -C 18 alkyl group, and m is 1 or 2;
- R 1 is a C 6 -C 20 aromatic hydrocarbon carbonyl group substituted by one or more groups A, where the group A is: hydroxyl, carboxy, amino, halogen, C 1 -C 18 alkoxycarbonyl Oxy, C 1 -C 18 alkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 heterocyclic alkoxy, C 6 -C 12 aryloxy, C 5 -C 12 heteroaryloxy Group, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 5 -C 12 heteroaryl.
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or methyl, m is 1;
- R 1 is one or A phenylcarbonyl group substituted by a plurality of groups A, where the group A is: hydroxy, carboxy, amino, halogen, C 1 -C 18 alkoxycarbonyloxy, C 1 -C 18 alkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 heterocyclic alkoxy, C 6 -C 12 aryloxy, C 5 -C 12 heteroaryloxy, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 5 -C 12 heteroaryl, preferably, the group A is halogen.
- R 2 is R 4 -O-(CH 2 ) m -, R 4 is hydrogen, or is selected from optionally substituted or unsubstituted by one or more groups A The following groups of: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl group, C 3 -C 8 cycloalkyl group, C 1 -C 18 alkyl group; m is 1 or 2.
- R 2 is R 4 -O-(CH 2 ) m -, R 4 is a C 1 -C 18 alkyl group; m is 1 or 2.
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or a C 1 -C 18 alkyl group, and m is 1 or 2;
- R 1 is a C 1 -C 18 alkyl group substituted by one or more groups A, where the group A is: hydroxy, carboxy, amino, halogen, C 1 -C 18 alkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 heterocyclic alkoxy, C 6 -C 12 aryloxy, C 5 -C 12 heteroaryloxy, C 3 -C 8 cycloalkyl, C 3- C 8 heterocycloalkyl, C 6 -C 12 aryl, or C 5 -C 12 heteroaryl.
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or methyl, m is 1 or 2;
- R 1 is A C 1 -C 18 alkyl group substituted by one or more groups A, where the group A is: hydroxyl, carboxyl, amino, halogen, C 1 -C 18 alkoxy, C 3 -C 8 ring Alkoxy, C 3 -C 8 heterocyclic alkoxy, C 6 -C 12 aryloxy, C 5 -C 12 heteroaryloxy, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclic Alkyl, C 6 -C 12 aryl, or C 5 -C 12 heteroaryl.
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or a C 1 -C 18 alkyl group, and m is 1 or 2;
- R 1 is -P(O)(OR 5 )(YR 6 ), or -S(O) 2 -R 7 , where R 5 and R 6 are both hydrogen, R 5 is hydrogen and R 6 or R Both 5 and R 6 are selected from the following groups optionally substituted or unsubstituted by one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl group, C 2 -C 18 Alkenyl, C 2 -C 18 alkynyl, C 1 -C 18 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, carboxyl esterified or amidated amino acid residue Group;
- Y is nitrogen or oxygen atom;
- R 7 is hydroxyl, amino,
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is hydrogen or methyl, m is 1;
- R 1 is -P( O)(OR 5 )(YR 6 ), or -S(O) 2 -R 7 , where R 5 is hydrogen and R 6 is selected from the following optionally substituted or unsubstituted by one or more groups A Group: phenyl, C 5 -C 20 heteroaryl, C 2 -C 18 alkenyl, C 2 -C 18 alkynyl, C 1 -C 18 alkyl, C 3 -C 8 cycloalkane Group, C 3 -C 8 heterocycloalkyl, carboxyl esterified or amidated amino acid residue; or R 5 and R 6 are selected from the following groups optionally substituted or unsubstituted by one or more groups A Group: phenyl, C 5 -C 20 heteroaryl, C 2 -C 18 alken
- R 1 is R 4 -C(O)-, and R 4 is selected from the following groups optionally substituted or unsubstituted with one or more groups A: C 6 -C 20 aromatic hydrocarbon group, C 5 -C 20 heteroaryl group, C 3 -C 8 cycloalkyl group, C 1 -C 18 alkyl group;
- R 2 is -P(O)(OR 5 )(YR 6 ),
- R 5 is hydrogen and R 6 is selected from the following groups optionally substituted or unsubstituted by one or more groups A: phenyl, C 5 -C 20 heteroaryl, C 2 -C 18 alkene Group, C 2 -C 18 alkynyl, C 1 -C 18 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, carboxyl esterified or amidated amino acid residue ;
- R 5 and R 6 are selected from the following groups optionally substituted or
- R 2 is R 4 -OC(O)-O-(CH 2 ) m -, R 4 is methyl, m is 1;
- R 1 is -S(O) 2 -R 7 , where R 7 is hydroxyl, amino, or selected from the following groups substituted or unsubstituted by group A: C1-C8 alkyl, C1-C8 alkoxy, mono C1-C8 alkylamine Group, double C1-C8 alkylamino group, C 6 -C 20 aromatic hydrocarbon group.
- R 2 is -P(O)(OR 5 )(YR 6 ), wherein R 5 is hydrogen and R 6 is selected from the group optionally consisting of one or more groups The following groups substituted or unsubstituted by A: C 6 -C 20 aryl, C 5 -C 20 heteroaryl, C 1 -C 18 alkyl; preferably, R 5 is hydrogen and R 6 is C 6- C 10 aryl group, more preferably a phenyl group.
- R 2 is, R 4 is hydrogen or a C 1 -C 18 alkyl group, preferably, R 4 is hydrogen or a C 1 -C 6 alkyl group; further preferred , R 4 is hydrogen or C 1 -C 3 alkyl; in some specific embodiments, R 4 is hydrogen or methyl; m is 1 or 2, preferably, m is 1;
- R 2 is R 4 -O-(CH 2 ) m -
- R 4 is hydrogen, or is selected from optionally substituted or unsubstituted by one or more groups
- A The following groups: C 6 -C 20 aryl, C 5 -C 20 heteroaryl, C 3 -C 8 cycloalkyl, C 1 -C 18 alkyl; preferably, R 4 is C 1 -C 18 is an alkyl group; more preferably, R 4 is hydrogen or a C 1 -C 3 alkyl group; in some specific embodiments, R 4 is hydrogen or methyl; m is 1 or 2, preferably, m is 1.
- R 1 is R 4 -C(O)-, (CH 2 ) k -P(O)(OR 5 )(YR 6 ), -(CH 2 ) j- S(O) 2 -R 7 or R 9 -(CH 2 ) P ;
- R 4 is selected from a substituted or unsubstituted C 6 -C 20 aryl group, a C 1 -C 18 alkyl group; preferably, a substituted or unsubstituted C 6 -C 10 aryl group, a C 1 -C 6 alkyl group More preferably, it is a substituted or unsubstituted phenyl group, a C 1 -C 3 alkyl group; the substituent is a halogen or a C 1 -C 3 chloroalkyl group, preferably, Br, F Or trifluoromethane;
- R 5 is selected from hydrogen, C 6 -C 15 aryl, C 1 -C 6 alkyl;
- R 6 is selected from hydrogen, C 1 -C 6 alkyl; preferably hydrogen or C 1 -C 3 alkyl; or R 6 is selected from Wherein, R 11 is selected from C 2 -C 10 alkenyl, C 1 -C 10 alkyl; preferably selected from C 2 -C 6 alkenyl, C 1 -C 6 alkyl; R 12 is selected from C 1 -C 10 alkyl group, preferably selected from C 1 -C 6 alkyl group;
- R 7 is selected from the group consisting of hydroxyl, amino, C 1 -C 6 alkyl, and C 1 -C 6 alkylhydroxy;
- R 9 is selected from hydrogen, carboxyl, cyano, hydroxyl, amino, C 6 -C 15 aryl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycle Alkyl, C 2 -C 10 alkenyl or -OR 10 ; preferably, R 9 is selected from hydrogen, carboxyl, cyano, hydroxyl, amino, C 6 -C 10 aryl, C 1 -C 3 alkyl , C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 2 -C 6 alkenyl or -OR 10 ; wherein R 10 is selected from C 6 -C 10 aryl, C 1 -C 3 alkyl, C 1 -C 3 alkyl carboxy;
- k is selected from 0, 1 or 2; preferably 0;
- j is selected from 0, 1 or 2; preferably 0;
- p is selected from 0, 1 or 2;
- Y is N or O.
- R 1 and R 2 are combined and connected to NO and O to form a ring; R 1 and R 2 are combined to form
- R 8 is a C 6 -C 10 aryl group.
- the above-mentioned bitricyclic compounds provided by the present invention are selected from the following compounds:
- the present invention provides pharmaceutical compositions comprising the above-mentioned bitricyclic compounds, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof.
- the present invention discloses a pharmaceutical composition, which uses the compound, isomer or pharmaceutically acceptable salt thereof as the active ingredient or main active ingredient, supplemented by a pharmaceutically acceptable carrier.
- the present invention also provides a preparation route of the bitricyclic compound represented by formula (I), which route includes the following steps:
- formula (I) is formula (V), and further includes:
- Pr 2 is an amino protecting group
- L 1 is a leaving group
- substituents in other formulas are as defined for the corresponding groups in formula (I).
- the present invention provides the use of the above-mentioned bitricyclic compounds, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof as antiviral cap drugs, which can be used for anti-influenza viruses and for treatment And/or prevent diseases caused by influenza viruses.
- the bitricyclic compound of the present invention can be formulated as a pharmaceutical composition and administered to a patient in a variety of appropriately selected modes of administration, including systemic such as oral or parenteral, intravenous, intramuscular, transdermal or subcutaneous Wait.
- Part of the present invention is a pharmaceutically acceptable solvate, which can be crystal hydrate or crystallized with other solvents, such as ethanol.
- Forming part of the present invention are pharmaceutically acceptable salts:
- a suitable "pharmaceutically acceptable salt” includes the conventional non-toxic salt of the compound of the present invention formed by the reaction of the compound of the present invention with an inorganic acid or an organic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
- organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane Salts of disulfonic acid, oxalic acid, ise
- a suitable "pharmaceutically acceptable salt” refers to a salt prepared by the compound of the present invention with pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like.
- aromatic hydrocarbon group means a hydrocarbon group substituted with an aryl group.
- heteroaryl means a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, and the remaining ring atoms are C, in addition has a fully conjugated ⁇ electron system.
- unsubstituted heteroaromatic groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.
- alkyl means a saturated aliphatic hydrocarbon group of 1-20 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as “1-18", refers to this group, In this case, it is an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 18 carbon atoms).
- Alkyl groups can be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably 1 to 3, and most preferably 1 or 2 substituents.
- hydroxyl means -OH group.
- amino refers to the -NH 2 group.
- halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
- cycloalkyl means a monocyclic or fused ring of all carbons ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group, where One or more rings do not have a fully connected ⁇ -electron system.
- Examples (not limited to) cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, and cyclohexane Ene, cycloheptane and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted.
- aryl means an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms, with a fully conjugated ⁇ -electron system.
- Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl.
- Aryl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two.
- the bitricyclic compound of the present invention has an inhibitory effect on viruses and inhibits virus proliferation.
- the bitricyclic compound of the present invention can be used as an antiviral drug with a novel structure.
- influenza virus of the present invention is influenza A virus .
- step 1
- step 1
- step 1
- step 1
- step 1
- step 1
- step 1
- the following example compounds were synthesized by using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.
- the compounds prepared in the examples of the present invention have an inhibitory effect on viruses.
- control S-033188 which is baloxavir dipivoxil, has the following structural formula and is commercially available:
- mice (BALB/C, male, weighing about 20 grams)
- Influenza A virus also known as influenza A virus, H1N1
- mice The male mice were divided into groups, 10 mice in each group. A phosphate buffer containing 500 pfu of influenza A virus was prepared, and the selected mice were infected by intranasal drip, except for the blank control group. After 24 hours, each group except the control group was given the above-mentioned compounds. Each compound was orally administered at a dose of 10 ⁇ mol/kg, 20 ⁇ mol/kg, and 30 ⁇ mol/kg, twice a day for 5 consecutive days. Observe the survival of the mice within 14 days.
- mice treated with oxime-based compounds DSC611 to DSC620 showed a survival rate of 40% to 60%; in the 20 ⁇ mol/kg dose group, mice treated with baloxavir dipivoxil had a survival rate of about 40%, while The mice treated with the oxime-based compounds DSC611 to DSC620 showed a survival rate of 50% to 70%; in the 30 ⁇ mol/kg dose group, the mice treated with baloxavir dipivoxil had a survival rate of about 60%, while the mice treated with oxime The mice treated with the oxime-based compounds DSC611 to DSC620 showed a survival rate of 70% to 90%; this indicates that the oxime-based compounds DSC611 to DSC620 showed highly effective therapeutic effects.
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Abstract
L'invention concerne un composé bis-tricyclique substitué, et une composition pharmaceutique et une utilisation de celui-ci. Le composé bis-tricyclique substitué est tel que représenté dans la formule (I) ; et le composé a un effet inhibiteur sur les virus et peut être utilisé contre le virus de la grippe.
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